U.S. flag

An official website of the United States government

Format

Send to:

Choose Destination

Motor delay

MedGen UID:
381392
Concept ID:
C1854301
Finding
Synonym: Motor retardation
 
HPO: HP:0001270

Definition

A type of Developmental delay characterized by a delay in acquiring motor skills. [from HPO]

Conditions with this feature

Achondroplasia
MedGen UID:
1289
Concept ID:
C0001080
Congenital Abnormality
Achondroplasia is the most common cause of disproportionate short stature. Affected individuals have rhizomelic shortening of the limbs, macrocephaly, and characteristic facial features with frontal bossing and midface retrusion. In infancy, hypotonia is typical, and acquisition of developmental motor milestones is often both aberrant in pattern and delayed. Intelligence and life span are usually near normal, although craniocervical junction compression increases the risk of death in infancy. Additional complications include obstructive sleep apnea, middle ear dysfunction, kyphosis, and spinal stenosis.
Gorlin syndrome
MedGen UID:
2554
Concept ID:
C0004779
Neoplastic Process
Nevoid basal cell carcinoma syndrome (NBCCS) is characterized by the development of multiple jaw keratocysts, frequently beginning in the second decade of life, and/or basal cell carcinomas (BCCs) usually from the third decade onward. Approximately 60% of individuals have a recognizable appearance with macrocephaly, frontal bossing, coarse facial features, and facial milia. Most individuals have skeletal anomalies (e.g., bifid ribs, wedge-shaped vertebrae). Ectopic calcification, particularly in the falx, is present in more than 90% of affected individuals by age 20 years. Cardiac and ovarian fibromas occur in approximately 2% and 20% of individuals respectively. Approximately 5% of all children with NBCCS develop medulloblastoma (primitive neuroectodermal tumor), generally the desmoplastic subtype. The risk of developing medulloblastoma is substantially higher in individuals with an SUFU pathogenic variant (33%) than in those with a PTCH1 pathogenic variant (<2%). Peak incidence is at age one to two years. Life expectancy in NBCCS is not significantly different from average.
Dejerine-Sottas disease
MedGen UID:
3710
Concept ID:
C0011195
Disease or Syndrome
Dejerine-Sottas neuropathy is a demyelinating peripheral neuropathy with onset in infancy. It can show autosomal dominant or recessive inheritance. Affected individuals have delayed motor development due to severe distal motor and sensory impairment, resulting in difficulties in gait. Some patients have generalized hypotonia in infancy. Other features may include pes cavus, scoliosis, and sensory ataxia. Nerve conduction velocities are severely decreased (sometimes less than 10 m/s), and sural nerve biopsy shows severe loss of myelinated fibers (summary by Baets et al., 2011).
Langer-Giedion syndrome
MedGen UID:
6009
Concept ID:
C0023003
Disease or Syndrome
Trichorhinophalangeal syndrome (TRPS) comprises TRPS I (caused by a heterozygous pathogenic variant in TRPS1) and TRPS II (caused by contiguous gene deletion of TRPS1, RAD21, and EXT1). Both types of TRPS are characterized by distinctive facial features; ectodermal features (fine, sparse, depigmented, and slow growing hair; dystrophic nails; and small breasts); and skeletal findings (short stature; short feet; brachydactyly with ulnar or radial deviation of the fingers; and early, marked hip dysplasia). TRPS II is characterized by multiple osteochondromas (typically first observed clinically on the scapulae and around the elbows and knees between ages 1 month and 6 years) and an increased risk of mild-to-moderate intellectual disability.
Lesch-Nyhan syndrome
MedGen UID:
9721
Concept ID:
C0023374
Disease or Syndrome
HPRT1 disorders, caused by deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt), are typically associated with clinical evidence for overproduction of uric acid (hyperuricemia, nephrolithiasis, and/or gouty arthritis) and varying degrees of neurologic and/or behavioral problems. Historically, three phenotypes were identified in the spectrum of HPRT1 disorders: Lesch-Nyhan disease (LND) at the most severe end with motor dysfunction resembling severe cerebral palsy, intellectual disability, and self-injurious behavior; HPRT1-related neurologic dysfunction (HND) in the intermediate range with similar but fewer severe neurologic findings than LND and no self-injurious behavior; and HPRT1-related hyperuricemia (HRH) at the mild end without overt neurologic deficits. It is now recognized that these neurobehavioral phenotypes cluster along a continuum from severe to mild.
Short-rib thoracic dysplasia 6 with or without polydactyly
MedGen UID:
44252
Concept ID:
C0024507
Disease or Syndrome
Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013). There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330). For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500).
Melnick-Needles syndrome
MedGen UID:
6292
Concept ID:
C0025237
Disease or Syndrome
The X-linked otopalatodigital (X-OPD) spectrum disorders, characterized primarily by skeletal dysplasia, include the following: Otopalatodigital syndrome type 1 (OPD1). Otopalatodigital syndrome type 2 (OPD2). Frontometaphyseal dysplasia type 1 (FMD1). Melnick-Needles syndrome (MNS). Terminal osseous dysplasia with pigmentary skin defects (TODPD). In OPD1, most manifestations are present at birth; females can present with severity similar to affected males, although some have only mild manifestations. In OPD2, females are less severely affected than related affected males. Most males with OPD2 die during the first year of life, usually from thoracic hypoplasia resulting in pulmonary insufficiency. Males who live beyond the first year of life are usually developmentally delayed and require respiratory support and assistance with feeding. In FMD1, females are less severely affected than related affected males. Males do not experience a progressive skeletal dysplasia but may have joint contractures and hand and foot malformations. Progressive scoliosis is observed in both affected males and females. In MNS, wide phenotypic variability is observed; some individuals are diagnosed in adulthood, while others require respiratory support and have reduced longevity. MNS in males results in perinatal lethality in all recorded cases. TODPD, seen only in females, is characterized by a skeletal dysplasia that is most prominent in the digits, pigmentary defects of the skin, and recurrent digital fibromata.
Prader-Willi syndrome
MedGen UID:
46057
Concept ID:
C0032897
Disease or Syndrome
Prader-Willi syndrome (PWS) is characterized by severe hypotonia and feeding difficulties in early infancy, followed in later infancy or early childhood by excessive eating and gradual development of morbid obesity (unless eating is externally controlled). Motor milestones and language development are delayed. All individuals have some degree of cognitive impairment. A distinctive behavioral phenotype (with temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsive characteristics) is common. Hypogonadism is present in both males and females and manifests as genital hypoplasia, incomplete pubertal development, and, in most, infertility. Short stature is common (if not treated with growth hormone); characteristic facial features, strabismus, and scoliosis are often present.
Mucopolysaccharidosis, MPS-III-C
MedGen UID:
39477
Concept ID:
C0086649
Disease or Syndrome
Mucopolysaccharidosis type III (MPS III) is a multisystem lysosomal storage disease characterized by progressive central nervous system degeneration manifest as severe intellectual disability (ID), developmental regression, and other neurologic manifestations including autism spectrum disorder (ASD), behavioral problems, and sleep disturbances. Disease onset is typically before age ten years. Disease course may be rapidly or slowly progressive; some individuals with an extremely attenuated disease course present in mid-to-late adulthood with early-onset dementia with or without a history of ID. Systemic manifestations can include musculoskeletal problems (joint stiffness, contractures, scoliosis, and hip dysplasia), hearing loss, respiratory tract and sinopulmonary infections, and cardiac disease (valvular thickening, defects in the cardiac conduction system). Neurologic decline is seen in all affected individuals; however, clinical severity varies within and among the four MPS III subtypes (defined by the enzyme involved) and even among members of the same family. Death usually occurs in the second or third decade of life secondary to neurologic regression or respiratory tract infections.
Mucopolysaccharidosis, MPS-IV-A
MedGen UID:
43375
Concept ID:
C0086651
Disease or Syndrome
The phenotypic spectrum of mucopolysaccharidosis IVA (MPS IVA) is a continuum that ranges from a severe and rapidly progressive early-onset form to a slowly progressive later-onset form. Children with MPS IVA typically have no distinctive clinical findings at birth. The severe form is usually apparent between ages one and three years, often first manifesting as kyphoscoliosis, genu valgum (knock-knee), and pectus carinatum; the slowly progressive form may not become evident until late childhood or adolescence, often first manifesting as hip problems (pain, stiffness, and Legg Perthes disease). Progressive bone and joint involvement leads to short stature, and eventually to disabling pain and arthritis. Involvement of other organ systems can lead to significant morbidity, including respiratory compromise, obstructive sleep apnea, valvular heart disease, hearing impairment, visual impairment from corneal clouding, dental abnormalities, and hepatomegaly. Compression of the spinal cord is a common complication that results in neurologic impairment. Children with MPS IVA have normal intellectual abilities at the outset of the disease.
Cyclical vomiting syndrome
MedGen UID:
57509
Concept ID:
C0152164
Disease or Syndrome
A condition characterized by recurrent, self-limiting episodes of vomiting associated with intense nausea, pallor, and lethargy. It is commonly a migraine precursor.
Angelman syndrome
MedGen UID:
58144
Concept ID:
C0162635
Disease or Syndrome
Angelman syndrome (AS) is characterized by severe developmental delay or intellectual disability, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and unique behavior with an apparent happy demeanor that includes frequent laughing, smiling, and excitability. Microcephaly and seizures are also common. Developmental delays are first noted at around age six months; however, the unique clinical features of AS do not become manifest until after age one year.
Radial aplasia-thrombocytopenia syndrome
MedGen UID:
61235
Concept ID:
C0175703
Disease or Syndrome
Thrombocytopenia absent radius (TAR) syndrome is characterized by bilateral absence of the radii with the presence of both thumbs, and thrombocytopenia that is generally transient. Thrombocytopenia may be congenital or may develop within the first few weeks to months of life; in general, thrombocytopenic episodes decrease with age. Cow's milk allergy is common and can be associated with exacerbation of thrombocytopenia. Other anomalies of the skeleton (upper and lower limbs, ribs, and vertebrae), heart, and genitourinary system (renal anomalies and agenesis of uterus, cervix, and upper part of the vagina) can occur.
Roussy-Lévy syndrome
MedGen UID:
64430
Concept ID:
C0205713
Disease or Syndrome
Roussy-Levy syndrome is an autosomal dominant disorder characterized by early onset of prominent ataxia followed by late onset of mild motor involvement. Symptoms progress very slowly, and affected individuals may remain ambulatory throughout life (Auer-Grumbach et al., 1998; Plante-Bordeneuve et al., 1999).
Congenital contractural arachnodactyly
MedGen UID:
67391
Concept ID:
C0220668
Congenital Abnormality
Congenital contractural arachnodactyly (CCA) appears to comprise a broad phenotypic spectrum. Classic CCA is characterized by arachnodactyly; flexion contractures of multiple joints including elbows, knees, hips, ankles, and/or fingers; kyphoscoliosis (usually progressive); a marfanoid habitus (a long and slender build, dolichostenomelia, pectus deformity, muscular hypoplasia, highly arched palate); and abnormal "crumpled" ears. At the mildest end, parents who are diagnosed retrospectively upon evaluation of their more severely affected child may show a lean body build, mild arachnodactyly, mild contractures without impairment, and minor ear abnormalities. At the most severe end is "severe CCA with cardiovascular and/or gastrointestinal anomalies," a rare phenotype in infants with pronounced features of CCA (severe crumpling of the ears, arachnodactyly, contractures, congenital scoliosis, and/or hypotonia) and severe cardiovascular and/or gastrointestinal anomalies. Phenotypic expression can vary within and between families.
FG syndrome 1
MedGen UID:
113106
Concept ID:
C0220769
Disease or Syndrome
MED12-related disorders include the phenotypes of FG syndrome type 1 (FGS1), Lujan syndrome (LS), X-linked Ohdo syndrome (XLOS), Hardikar syndrome (HS), and nonspecific intellectual disability (NSID). FGS1 and LS share the clinical findings of cognitive impairment, hypotonia, and abnormalities of the corpus callosum. FGS1 is further characterized by absolute or relative macrocephaly, tall forehead, downslanted palpebral fissures, small and simple ears, constipation and/or anal anomalies, broad thumbs and halluces, and characteristic behavior. LS is further characterized by large head, tall thin body habitus, long thin face, prominent nasal bridge, high narrow palate, and short philtrum. Carrier females in families with FGS1 and LS are typically unaffected. XLOS is characterized by intellectual disability, blepharophimosis, and facial coarsening. HS has been described in females with cleft lip and/or cleft palate, biliary and liver anomalies, intestinal malrotation, pigmentary retinopathy, and coarctation of the aorta. Developmental and cognitive concerns have not been reported in females with HS. Pathogenic variants in MED12 have been reported in an increasing number of males and females with NSID, with affected individuals often having clinical features identified in other MED12-related disorders.
Oromandibular-limb hypogenesis spectrum
MedGen UID:
66357
Concept ID:
C0221060
Disease or Syndrome
The most basic description of Moebius syndrome is a congenital facial palsy with impairment of ocular abduction. The facial nerve (cranial nerve VII) and abducens nerve (CN VI) are most frequently involved, but other cranial nerves may be involved as well. Other variable features include orofacial dysmorphism and limb malformations. Mental retardation has been reported in a subset of patients. Most cases of Moebius syndrome are sporadic, but familial occurrence has been reported (Verzijl et al., 2003). The definition of and diagnostic criteria for Moebius syndrome have been controversial and problematic. The syndrome has most frequently been confused with hereditary congenital facial paresis (HCFP; see 601471), which is restricted to involvement of the facial nerve and no other abnormalities. Verzijl et al. (2003) and Verzijl et al. (2005) concluded that HCFP and Moebius syndrome are distinct disorders, and that Moebius syndrome is a complex developmental disorder of the brainstem. Moebius syndrome was defined at the Moebius Syndrome Foundation Research Conference in 2007 as congenital, nonprogressive facial weakness with limited abduction of one or both eyes. Additional features can include hearing loss and other cranial nerve dysfunction, as well as motor, orofacial, musculoskeletal, neurodevelopmental, and social problems (summary by Webb et al., 2012). Kumar (1990) provided a review of Moebius syndrome, which was critiqued by Lipson et al. (1990). Briegel (2006) provided a review of Moebius sequence with special emphasis on neuropsychiatric findings.
Abortive cerebellar ataxia
MedGen UID:
66358
Concept ID:
C0221061
Disease or Syndrome
'Behr syndrome' is a clinical term that refers to the constellation of early-onset optic atrophy accompanied by neurologic features, including ataxia, pyramidal signs, spasticity, and mental retardation (Behr, 1909; Thomas et al., 1984). Patients with mutations in genes other than OPA1 can present with clinical features reminiscent of Behr syndrome. Mutations in one of these genes, OPA3 (606580), result in type III 3-methylglutaconic aciduria (MGCA3; 258501). Lerman-Sagie (1995) noted that the abnormal urinary pattern in MGCA3 may not be picked up by routine organic acid analysis, suggesting that early reports of Behr syndrome with normal metabolic features may actually have been 3-methylglutaconic aciduria type III.
Marshall-Smith syndrome
MedGen UID:
75551
Concept ID:
C0265211
Disease or Syndrome
The Marshall-Smith syndrome (MRSHSS) is a malformation syndrome characterized by accelerated skeletal maturation, relative failure to thrive, respiratory difficulties, mental retardation, and unusual facies, including prominent forehead, shallow orbits, blue sclerae, depressed nasal bridge, and micrognathia (Adam et al., 2005).
Miller Dieker syndrome
MedGen UID:
78538
Concept ID:
C0265219
Disease or Syndrome
PAFAH1B1-related lissencephaly/subcortical band heterotopia (SBH) comprises a spectrum of severity. Affected newborns typically have mild-to-moderate hypotonia, feeding difficulties, and poor head control. During the first years, neurologic examination typically demonstrates poor visual tracking and response to sounds, axial hypotonia, and mild distal spasticity that can transition over time to more severe spasticity. Seizures occur in more than 90% of individuals with lissencephaly and often include infantile spasms. Seizures are often drug resistant, but even with good seizure control, the best developmental level achieved (excluding the few individuals with partial lissencephaly) is the equivalent of about age three to five months. In individuals with PAFAH1B1-related lissencephaly/SBH, developmental delay ranges from mild to severe. Other findings in PAFAH1B1-related lissencephaly/SBH include feeding issues and aspiration (which may result in need for gastrostomy tube placement), progressive microcephaly, and occasional developmental regression.
Cohen syndrome
MedGen UID:
78539
Concept ID:
C0265223
Congenital Abnormality
Cohen syndrome is characterized by failure to thrive in infancy and childhood; truncal obesity in the teen years; early-onset hypotonia and developmental delays; microcephaly developing during the first year of life; moderate to profound psychomotor retardation; progressive retinochoroidal dystrophy and high myopia; neutropenia in many with recurrent infections and aphthous ulcers in some; a cheerful disposition; joint hypermobility; and characteristic facial features.
Freeman-Sheldon syndrome
MedGen UID:
120516
Concept ID:
C0265224
Disease or Syndrome
Freeman-Sheldon syndrome (FSS), or DA2A, is phenotypically similar to DA1. In addition to contractures of the hands and feet, FSS is characterized by oropharyngeal abnormalities, scoliosis, and a distinctive face that includes a very small oral orifice (often only a few millimeters in diameter at birth), puckered lips, and an H-shaped dimple of the chin; hence, FSS has been called 'whistling face syndrome.' The limb phenotypes of DA1 and FSS may be so similar that they can only be distinguished by the differences in facial morphology (summary by Bamshad et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Kniest dysplasia
MedGen UID:
75559
Concept ID:
C0265279
Disease or Syndrome
Kniest dysplasia is characterized by skeletal and craniofacial anomalies. Skeletal anomalies include disproportionate dwarfism, a short trunk and small pelvis, kyphoscoliosis, short limbs, and prominent joints and premature osteoarthritis that restrict movement. Craniofacial manifestations include midface hypoplasia, cleft palate, early-onset myopia, retinal detachment, and hearing loss. The phenotype is severe in some patients and mild in others. There are distinct radiographic changes including coronal clefts of vertebrae and dumbbell-shaped femora. The chondrooseous morphology is pathognomonic with perilacunar 'foaminess' and sparse, aggregated collagen fibrils resulting in an interterritorial matrix with a 'Swiss-cheese' appearance (summary by Wilkin et al., 1999).
CHARGE association
MedGen UID:
75567
Concept ID:
C0265354
Disease or Syndrome
CHD7 disorder encompasses the entire phenotypic spectrum of heterozygous CHD7 pathogenic variants that includes CHARGE syndrome as well as subsets of features that comprise the CHARGE syndrome phenotype. The mnemonic CHARGE syndrome, introduced in the premolecular era, stands for coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies (including deafness). Following the identification of the genetic cause of CHD7 disorder, the phenotypic spectrum expanded to include cranial nerve anomalies, vestibular defects, cleft lip and/or palate, hypothyroidism, tracheoesophageal anomalies, brain anomalies, seizures, and renal anomalies. Life expectancy highly depends on the severity of manifestations; mortality can be high in the first few years when severe birth defects (particularly complex heart defects) are present and often complicated by airway and feeding issues. In childhood, adolescence, and adulthood, decreased life expectancy is likely related to a combination of residual heart defects, infections, aspiration or choking, respiratory issues including obstructive and central apnea, and possibly seizures. Despite these complications, the life expectancy for many individuals can be normal.
Purine-nucleoside phosphorylase deficiency
MedGen UID:
75653
Concept ID:
C0268125
Disease or Syndrome
Purine nucleoside phosphorylase deficiency is a rare autosomal recessive immunodeficiency disorder characterized mainly by decreased T-cell function. Some patients also have neurologic impairment (review by Aust et al., 1992).
Gaucher disease type III
MedGen UID:
78653
Concept ID:
C0268251
Disease or Syndrome
Gaucher disease (GD) encompasses a continuum of clinical findings from a perinatal lethal disorder to an asymptomatic type. The identification of three major clinical types (1, 2, and 3) and two other subtypes (perinatal-lethal and cardiovascular) is useful in determining prognosis and management. GD type 1 is characterized by the presence of clinical or radiographic evidence of bone disease (osteopenia, focal lytic or sclerotic lesions, and osteonecrosis), hepatosplenomegaly, anemia and thrombocytopenia, lung disease, and the absence of primary central nervous system disease. GD types 2 and 3 are characterized by the presence of primary neurologic disease; in the past, they were distinguished by age of onset and rate of disease progression, but these distinctions are not absolute. Disease with onset before age two years, limited psychomotor development, and a rapidly progressive course with death by age two to four years is classified as GD type 2. Individuals with GD type 3 may have onset before age two years, but often have a more slowly progressive course, with survival into the third or fourth decade. The perinatal-lethal form is associated with ichthyosiform or collodion skin abnormalities or with nonimmune hydrops fetalis. The cardiovascular form is characterized by calcification of the aortic and mitral valves, mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia. Cardiopulmonary complications have been described with all the clinical subtypes, although varying in frequency and severity.
Farber lipogranulomatosis
MedGen UID:
78654
Concept ID:
C0268255
Disease or Syndrome
The spectrum of ASAH1-related disorders ranges from Farber disease (FD) to spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Classic FD is characterized by onset in the first weeks of life of painful, progressive deformity of the major joints; palpable subcutaneous nodules of joints and mechanical pressure points; and a hoarse cry resulting from granulomas of the larynx and epiglottis. Life expectancy is usually less than two years. In the other less common types of FD, onset, severity, and primary manifestations vary. SMA-PME is characterized by early-childhood-onset progressive lower motor neuron disease manifest typically between ages three and seven years as proximal lower-extremity weakness, followed by progressive myoclonic and atonic seizures, tremulousness/tremor, and sensorineural hearing loss. Myoclonic epilepsy typically begins in late childhood after the onset of weakness and can include jerking of the upper limbs, action myoclonus, myoclonic status, and eyelid myoclonus. Other findings include generalized tremor, and cognitive decline. The time from disease onset to death from respiratory complications is usually five to 15 years.
Cutis laxa with osteodystrophy
MedGen UID:
82795
Concept ID:
C0268355
Disease or Syndrome
ATP6V0A2-related cutis laxa is characterized by generalized cutis laxa, findings associated with generalized connective tissue disorder, developmental delays, and a variety of neurologic findings including abnormality on brain MRI. At birth, hypotonia, overfolded skin, and distinctive facial features are present and enlarged fontanelles are often observed. During childhood, the characteristic facial features and thick or coarse hair may become quite pronounced. The skin findings decrease with age, although easy bruising and Ehlers-Danlos-like scars have been described in some. In most (not all) affected individuals, cortical and cerebellar malformations are observed on brain MRI. Nearly all affected individuals have developmental delays, seizures, and neurologic regression.
Hyperphosphatasemia with bone disease
MedGen UID:
75678
Concept ID:
C0268414
Disease or Syndrome
Paget disease of bone-5 is an autosomal recessive, juvenile-onset form of Paget disease, a disorder of the skeleton resulting from abnormal bone resorption and formation. Clinical manifestations include short stature, progressive long bone deformities, fractures, vertebral collapse, skull enlargement, and hyperostosis with progressive deafness. There is phenotypic variability, with some patients presenting in infancy, while others present later in childhood (summary by Naot et al., 2014). For discussion of genetic heterogeneity of Paget disease of bone, see 167250.
Succinate-semialdehyde dehydrogenase deficiency
MedGen UID:
124340
Concept ID:
C0268631
Disease or Syndrome
Succinic semialdehyde dehydrogenase (SSADH) deficiency is characterized by infantile-onset hypotonia, developmental delay, cognitive impairment, expressive language deficit, and mild ataxia. Epilepsy is present in about half of affected individuals and is more common in adults. Hyperkinetic behavior, aggression, self-injurious behaviors, hallucinations, and sleep disturbances have been reported in nearly half of all affected individuals, more commonly in those who are older. Basal ganglia signs including choreoathetosis, dystonia, and myoclonus have been reported in a few individuals with earlier-onset, more severe disease. Involvement beyond the central nervous system has not been described. Individuals with SSADH deficiency typically have 4-hydroxybutyric aciduria present on urine organic acid analysis. Head MRI reveals T2 hyperintensities in multiple regions, involving the globus pallidi, cerebellar dentate nuclei, subthalamic nuclei, subcortical white matter, and brain stem, as well as cerebral and sometimes cerebellar atrophy. EEG findings include background slowing and spike discharges that are usually generalized.
Vitamin D-dependent rickets, type 1
MedGen UID:
124344
Concept ID:
C0268689
Disease or Syndrome
Vitamin D-dependent rickets is a disorder of bone development that leads to softening and weakening of the bones (rickets). There are several forms of the condition that are distinguished primarily by their genetic causes: type 1A (VDDR1A), type 1B (VDDR1B), and type 2A (VDDR2A). There is also evidence of a very rare form of the condition, called type 2B (VDDR2B), although not much is known about this form.\n\nThe signs and symptoms of vitamin D-dependent rickets begin within months after birth, and most are the same for all types of the condition. The weak bones often cause bone pain and delayed growth and have a tendency to fracture. When affected children begin to walk, they may develop abnormally curved (bowed) legs because the bones are too weak to bear weight. Impaired bone development also results in widening of the areas near the ends of bones where new bone forms (metaphyses), especially in the knees, wrists, and ribs. Some people with vitamin D-dependent rickets have dental abnormalities such as thin tooth enamel and frequent cavities. Poor muscle tone (hypotonia) and muscle weakness are also common in this condition, and some affected individuals develop seizures.\n\nHair loss (alopecia) can occur in VDDR2A, although not everyone with this form of the condition has alopecia. Affected individuals can have sparse or patchy hair or no hair at all on their heads. Some affected individuals are missing body hair as well.\n\nIn vitamin D-dependent rickets, there is an imbalance of certain substances in the blood. An early sign in all types of the condition is low levels of the mineral calcium (hypocalcemia), which is essential for the normal formation of bones and teeth. Affected individuals also develop high levels of a hormone involved in regulating calcium levels called parathyroid hormone (PTH), which leads to a condition called secondary hyperparathyroidism. Low levels of a mineral called phosphate (hypophosphatemia) also occur in affected individuals. Vitamin D-dependent rickets types 1 and 2 can be grouped by blood levels of a hormone called calcitriol, which is the active form of vitamin D; individuals with VDDR1A and VDDR1B have abnormally low levels of calcitriol and individuals with VDDR2A and VDDR2B have abnormally high levels.
Vitamin D-dependent rickets type II with alopecia
MedGen UID:
90989
Concept ID:
C0342646
Disease or Syndrome
Vitamin D-dependent rickets type 2A (VDDR2A) is caused by a defect in the vitamin D receptor gene. This defect leads to an increase in the circulating ligand, 1,25-dihydroxyvitamin D3. Most patients have total alopecia in addition to rickets. VDDR2B (600785) is a form of vitamin D-dependent rickets with a phenotype similar to VDDR2A but a normal vitamin D receptor, in which end-organ resistance to vitamin D has been shown to be caused by a nuclear ribonucleoprotein that interferes with the vitamin D receptor-DNA interaction. For a general phenotypic description and discussion of genetic heterogeneity of rickets due to disorders in vitamin D metabolism or action, see vitamin D-dependent rickets type 1A (VDDR1A; 264700).
3-methylglutaconic aciduria type 1
MedGen UID:
90994
Concept ID:
C0342727
Disease or Syndrome
3-methylglutaconyl-CoA hydratase deficiency is an inherited condition that causes neurological problems. Beginning in infancy to early childhood, children with this condition often have delayed development of mental and motor skills (psychomotor delay), speech delay, involuntary muscle cramping (dystonia), and spasms and weakness of the arms and legs (spastic quadriparesis). Affected individuals can also have optic atrophy, which is the breakdown (atrophy) of nerve cells that carry visual information from the eyes to the brain.\n\nIn some cases, signs and symptoms of 3-methylglutaconyl-CoA hydratase deficiency begin in adulthood, often in a person's twenties or thirties. These individuals have damage to a type of brain tissue called white matter (leukoencephalopathy). This damage likely contributes to progressive problems with speech (dysarthria), difficulty coordinating movements (ataxia), stiffness (spasticity), optic atrophy, and a decline in intellectual function (dementia).\n\nAffected individuals who show symptoms of 3-methylglutaconyl-CoA hydratase deficiency in childhood often go on to develop leukoencephalopathy and other neurological problems in adulthood.\n\nAll people with 3-methylglutaconyl-CoA hydratase deficiency accumulate large amounts of a substance called 3-methylglutaconic acid in their body fluids. As a result, they have elevated levels of acid in their blood (metabolic acidosis) and excrete large amounts of acid in their urine (aciduria). 3-methylglutaconyl-CoA hydratase deficiency is one of a group of metabolic disorders that can be diagnosed by the presence of increased levels 3-methylglutaconic acid in urine (3-methylglutaconic aciduria). People with 3-methylglutaconyl-CoA hydratase deficiency also have high urine levels of another acid called 3-methylglutaric acid.
Troyer syndrome
MedGen UID:
97950
Concept ID:
C0393559
Disease or Syndrome
Troyer syndrome is characterized by progressive spastic paraparesis, dysarthria, pseudobulbar palsy, distal amyotrophy, short stature, and subtle skeletal abnormalities. Most affected children exhibit delays in walking and speech and difficulty in managing oral secretions, followed by increased lower-limb spasticity and slow deterioration in both gait and speech. Mild cerebellar signs are common. The most severely affected individuals have choreoathetosis. Emotional lability / difficulty in controlling emotions and affective disorders, such as inappropriate euphoria and/or crying, are frequently described. Life expectancy is normal.
Benign hereditary chorea
MedGen UID:
98278
Concept ID:
C0393584
Disease or Syndrome
NKX2-1-related disorders range from benign hereditary chorea (BHC) to choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress (also known as brain-lung-thyroid syndrome). Childhood-onset chorea, the hallmark of NKX2-1-related disorders, may or may not be associated with respiratory distress syndrome or congenital hypothyroidism. Chorea generally begins in early infancy or about age one year (most commonly) or in late childhood or adolescence, and progresses into the second decade after which it remains static or (rarely) remits. Pulmonary disease, the second most common manifestation, can include respiratory distress syndrome in neonates, interstitial lung disease in young children, and pulmonary fibrosis in older persons. The risk for pulmonary carcinoma is increased in young adults with an NKX2-1-related disorder. Thyroid dysfunction, the result of dysembryogenesis, can present as congenital hypothyroidism or compensated hypothyroidism. The risk for thyroid cancer is unknown and may not be increased. In one review, 50% of affected individuals had the full brain-lung-thyroid syndrome, 30% had involvement of brain and thyroid only, and 13% had isolated chorea only.
Charcot-Marie-Tooth disease X-linked dominant 1
MedGen UID:
98290
Concept ID:
C0393808
Disease or Syndrome
GJB1 disorders are typically characterized by peripheral motor and sensory neuropathy with or without fixed CNS abnormalities and/or acute, self-limited episodes of transient neurologic dysfunction (especially weakness and dysarthria). Peripheral neuropathy typically manifests in affected males between ages five and 25 years. Although both men and women are affected, manifestations tend to be less severe in women, some of whom may remain asymptomatic. Less commonly, initial manifestations in some affected individuals are stroke-like episodes (acute fulminant episodes of reversible CNS dysfunction).
Ataxic cerebral palsy
MedGen UID:
95998
Concept ID:
C0394005
Disease or Syndrome
Cerebral palsy (CP) is defined as a nonprogressive but not unchanging disorder of posture or movement, caused by an abnormality of the brain and first evident at the stage of rapid brain development (Hughes and Newton, 1992). It is a common disorder of childhood, with an incidence of 1 in 250 to 1,000 births (Pharoah et al., 1987; Bundey and Alam, 1993). Ataxic cerebral palsy accounts for 5 to 10% of all forms of CP, and approximately 50% of ataxic CP is thought to be inherited as an autosomal recessive trait (McHale et al., 2000). Also see spastic cerebral palsy (603513).
Gapo syndrome
MedGen UID:
98034
Concept ID:
C0406723
Disease or Syndrome
GAPO syndrome is the acronymic designation for a complex of growth retardation, alopecia, pseudoanodontia (failure of tooth eruption), and progressive optic atrophy (Tipton and Gorlin, 1984). Ilker et al. (1999) and Bayram et al. (2014) noted that optic atrophy is not a consistent feature of the disorder.
Ullrich congenital muscular dystrophy 1
MedGen UID:
98046
Concept ID:
C0410179
Disease or Syndrome
Collagen VI-related dystrophies (COL6-RDs) represent a continuum of overlapping clinical phenotypes with Bethlem muscular dystrophy at the milder end, Ullrich congenital muscular dystrophy (UCMD) at the more severe end, and a phenotype in between UCMD and Bethlem muscular dystrophy, referred to as intermediate COL6-RD. Bethlem muscular dystrophy is characterized by a combination of proximal muscle weakness and joint contractures. Hypotonia and delayed motor milestones occur in early childhood; mild hypotonia and weakness may be present congenitally. By adulthood, there is evidence of proximal weakness and contractures of the elbows, Achilles tendons, and long finger flexors. The progression of weakness is slow, and more than two thirds of affected individuals older than age 50 years remain independently ambulatory indoors, while relying on supportive means for mobility outdoors. Respiratory involvement is not a consistent feature. UCMD is characterized by congenital weakness, hypotonia, proximal joint contractures, and striking hyperlaxity of distal joints. Decreased fetal movements are frequently reported. Some affected children acquire the ability to walk independently; however, progression of the disease results in a loss of ambulation by age ten to eleven years. Early and severe respiratory insufficiency occurs in all individuals, resulting in the need for nocturnal noninvasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) by age 11 years. Intermediate COL6-RD is characterized by independent ambulation past age 11 years and respiratory insufficiency that is later in onset than in UCMD and results in the need for NIV in the form of BiPAP by the late teens to early 20s. In contrast to individuals with Bethlem muscular dystrophy, those with intermediate COL6-RD typically do not achieve the ability to run, jump, or climb stairs without use of a railing.
Eichsfeld type congenital muscular dystrophy
MedGen UID:
98047
Concept ID:
C0410180
Disease or Syndrome
Desmin-related myopathies (DRM) are a clinically and genetically heterogeneous group of muscular disorders defined morphologically by intrasarcoplasmic aggregates of desmin (DES; 125660), usually accompanied by other protein aggregates. Approximately one-third of DRM are caused by mutations in the desmin gene (Ferreiro et al., 2004). For other forms of DRM, see primary desminopathy (601419).
Severe X-linked myotubular myopathy
MedGen UID:
98374
Concept ID:
C0410203
Congenital Abnormality
X-linked myotubular myopathy (X-MTM), also known as myotubular myopathy (MTM), is characterized by muscle weakness that ranges from severe to mild. Approximately 80% of affected males present with severe (classic) X-MTM characterized by polyhydramnios, decreased fetal movement, and neonatal weakness, hypotonia, and respiratory failure. Motor milestones are significantly delayed and most individuals fail to achieve independent ambulation. Weakness is profound and often involves facial and extraocular muscles. Respiratory failure is nearly uniform, with most individuals requiring 24-hour ventilatory assistance. It is estimated that at least 25% of boys with severe X-MTM die in the first year of life, and those who survive rarely live into adulthood. Males with mild or moderate X-MTM (~20%) achieve motor milestones more quickly than males with the severe form; many ambulate independently, and may live into adulthood. Most require gastrostomy tubes and/or ventilator support. In all subtypes of X-MTM, the muscle disease is not obviously progressive. Female carriers of X-MTM are generally asymptomatic, although manifesting heterozygotes are increasingly being identified. In affected females, symptoms range from severe, generalized weakness presenting in childhood, with infantile onset similar to affected male patients, to mild (often asymmetric) weakness manifesting in adulthood. Affected adult females may experience progressive respiratory decline and ultimately require ventilatory support.
Myopathy, centronuclear, 2
MedGen UID:
98049
Concept ID:
C0410204
Disease or Syndrome
Centronuclear myopathy is a condition characterized by muscle weakness (myopathy) and wasting (atrophy) in the skeletal muscles, which are the muscles used for movement. The severity of centronuclear myopathy varies among affected individuals, even among members of the same family.\n\nPeople with centronuclear myopathy begin experiencing muscle weakness at any time from birth to early adulthood. The muscle weakness slowly worsens over time and can lead to delayed development of motor skills, such as crawling or walking; muscle pain during exercise; and difficulty walking. Some affected individuals may need wheelchair assistance as the muscles atrophy and weakness becomes more severe. In rare instances, the muscle weakness improves over time.\n\nSome people with centronuclear myopathy experience mild to severe breathing problems related to the weakness of muscles needed for breathing. People with centronuclear myopathy may have droopy eyelids (ptosis) and weakness in other facial muscles, including the muscles that control eye movement. People with this condition may also have foot abnormalities, a high arch in the roof of the mouth (high-arched palate), and abnormal side-to-side curvature of the spine (scoliosis). Rarely, individuals with centronuclear myopathy have a weakened heart muscle (cardiomyopathy), disturbances in nerve function (neuropathy), or intellectual disability.\n\nA key feature of centronuclear myopathy is the displacement of the nucleus in muscle cells, which can be viewed under a microscope. Normally the nucleus is found at the edges of the rod-shaped muscle cells, but in people with centronuclear myopathy the nucleus is located in the center of these cells. How the change in location of the nucleus affects muscle cell function is unknown.
Gillespie syndrome
MedGen UID:
96563
Concept ID:
C0431401
Disease or Syndrome
Gillespie syndrome (GLSP) is usually diagnosed in the first year of life by the presence of fixed dilated pupils in a hypotonic infant. Affected individuals have a characteristic form of iris hypoplasia in which the pupillary border of the iris exhibits a scalloped or 'festooned' edge, with iris strands extending onto the anterior lens surface at regular intervals. The key extraocular features of Gillespie syndrome are congenital hypotonia, progressive cerebellar hypoplasia, and ataxia, as well as variable cognitive impairment that is usually mild (summary by Gerber et al., 2016 and McEntagart et al., 2016).
Opsismodysplasia
MedGen UID:
140927
Concept ID:
C0432219
Disease or Syndrome
Opsismodysplasia (OPSMD) is a rare skeletal dysplasia involving delayed bone maturation. Clinical signs observed at birth include short limbs, small hands and feet, relative macrocephaly with a large anterior fontanel, and characteristic craniofacial abnormalities including a prominent brow, depressed nasal bridge, a small anteverted nose, and a relatively long philtrum. Death in utero or secondary to respiratory failure during the first few years of life has been reported, but there can be long-term survival. Typical radiographic findings include shortened long bones with delayed epiphyseal ossification, severe platyspondyly, metaphyseal cupping, and characteristic abnormalities of the metacarpals and phalanges (summary by Below et al., 2013 and Fradet and Fitzgerald, 2017).
Metaphyseal chondrodysplasia, Spahr type
MedGen UID:
140928
Concept ID:
C0432225
Disease or Syndrome
A rare, genetic, primary bone dysplasia disease characterized by usually moderate, postnatal short stature, progressive genu vara deformity, a waddling gait, and radiological signs of metaphyseal dysplasia (i.e. irregular, sclerotic and widened metaphyses), in the absence of biochemical abnormalities suggestive of rickets disease. Intermittent knee pain, lordosis, and delayed motor development may also occasionally be associated.
Deletion of long arm of chromosome 18
MedGen UID:
96605
Concept ID:
C0432443
Disease or Syndrome
Monosomy 18q is a partial deletion of the long arm of chromosome 18 characterized by highly variable phenotype, most commonly including hypotonia, developmental delay, short stature, growth hormone deficiency, hearing loss and external ear anomalies, intellectual disability, palatal defects, dysmorphic facial features, skeletal anomalies (foot deformities, tapering fingers, scoliosis) and mood disorders.
3-Methylglutaconic aciduria type 2
MedGen UID:
107893
Concept ID:
C0574083
Disease or Syndrome
Barth syndrome is characterized in affected males by cardiomyopathy, neutropenia, skeletal myopathy, prepubertal growth delay, and distinctive facial gestalt (most evident in infancy); not all features may be present in a given affected male. Cardiomyopathy, which is almost always present before age five years, is typically dilated cardiomyopathy with or without endocardial fibroelastosis or left ventricular noncompaction; hypertrophic cardiomyopathy can also occur. Heart failure is a significant cause of morbidity and mortality; risk of arrhythmia and sudden death is increased. Neutropenia is most often associated with mouth ulcers, pneumonia, and sepsis. The nonprogressive myopathy predominantly affects the proximal muscles, and results in early motor delays. Prepubertal growth delay is followed by a postpubertal growth spurt with remarkable "catch-up" growth. Heterozygous females who have a normal karyotype are asymptomatic and have normal biochemical studies.
Severe myoclonic epilepsy in infancy
MedGen UID:
148243
Concept ID:
C0751122
Disease or Syndrome
SCN1A seizure disorders encompass a spectrum that ranges from simple febrile seizures and generalized epilepsy with febrile seizures plus (GEFS+) at the mild end to Dravet syndrome and intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC) at the severe end. Phenotypes with intractable seizures including Dravet syndrome are often associated with cognitive decline. Less commonly observed phenotypes include myoclonic astatic epilepsy (MAE), Lennox-Gastaut syndrome, infantile spasms, epilepsy with focal seizures, and vaccine-related encephalopathy and seizures. The phenotype of SCN1A seizure disorders can vary even within the same family.
Scapuloperoneal spinal muscular atrophy
MedGen UID:
148283
Concept ID:
C0751335
Disease or Syndrome
The autosomal dominant TRPV4 disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within each group is considerable. Affected individuals typically have either neuromuscular or skeletal manifestations alone, and in only rare instances an overlap syndrome has been reported. The three autosomal dominant neuromuscular disorders (mildest to most severe) are: Charcot-Marie-Tooth disease type 2C. Scapuloperoneal spinal muscular atrophy. Congenital distal spinal muscular atrophy. The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six autosomal dominant skeletal dysplasias (mildest to most severe) are: Familial digital arthropathy-brachydactyly. Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the autosomal dominant TRPV4 disorders life span is normal; in the most severe it is shortened. Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias.
Central core myopathy
MedGen UID:
199773
Concept ID:
C0751951
Disease or Syndrome
Typical central core disease is a relatively mild congenital myopathy, usually characterized by motor developmental delay and signs of mild proximal weakness most pronounced in the hip girdle musculature. Orthopedic complications, particularly congenital dislocation of the hips and scoliosis, are common, and CCD patients are at risk of having malignant hyperthermia (MHS1; 145600). Onset of CCD is usually in childhood, although adult onset has also been reported, illustrating phenotypic variability (Jungbluth et al., 2009). Some patients can present in utero or at birth with severe congenital myopathy (Bharucha-Goebel et al., 2013).
Edinburgh malformation syndrome
MedGen UID:
167084
Concept ID:
C0795933
Disease or Syndrome
A rare genetic lethal multiple congenital anomalies/dysmorphic syndrome characterized by consistently abnormal facial appearance, true or apparent hydrocephalus, motor and cognitive developmental delay, failure to thrive (feeding difficulties, vomiting, chest infections) and death within a few months of birth. Carp mouth, hairiness of the forehead, neonatal hyperbilirubinemia and advanced bone age may also be associated. There have been no further descriptions in the literature since 1991.
Agenesis of the corpus callosum with peripheral neuropathy
MedGen UID:
162893
Concept ID:
C0795950
Disease or Syndrome
Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), a neurodevelopmental and neurodegenerative disorder, is characterized by severe progressive sensorimotor neuropathy with resulting hypotonia, areflexia, and amyotrophy, and by variable degrees of dysgenesis of the corpus callosum. Mild-to-severe intellectual disability and "psychotic episodes" during adolescence are observed. Sensory modalities are moderately to severely affected beginning in infancy. The average age of onset of walking is 3.8 years; the average age of loss of walking is 13.8 years; the average age of death is 33 years.
Microphthalmia, syndromic 1
MedGen UID:
162898
Concept ID:
C0796016
Congenital Abnormality
Microphthalmia-ankyloblepharon-intellectual disability syndrome is characterized by microphthalmia, ankyloblepharon and intellectual deficit. It has been described in seven male patients from two generations of a Northern Ireland family. The causative gene is localized to the Xq27-q28 region. The syndrome is transmitted as an X-linked recessive trait.
Simpson-Golabi-Behmel syndrome type 1
MedGen UID:
162917
Concept ID:
C0796154
Disease or Syndrome
Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is characterized by pre- and postnatal macrosomia; distinctive craniofacial features (including macrocephaly, coarse facial features, macrostomia, macroglossia, and palatal abnormalities); and commonly, mild-to-severe intellectual disability with or without structural brain anomalies. Other variable findings include supernumerary nipples, diastasis recti / umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and gastrointestinal anomalies. Skeletal anomalies can include vertebral fusion, scoliosis, rib anomalies, and congenital hip dislocation. Hand anomalies can include large hands and postaxial polydactyly. Affected individuals are at increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma, and medulloblastoma.
X-linked progressive cerebellar ataxia
MedGen UID:
163229
Concept ID:
C0796205
Disease or Syndrome
SCAX1 is an X-linked recessive neurologic disorder characterized by hypotonia at birth, delayed motor development, gait ataxia, difficulty standing, dysarthria, and slow eye movements. Brain MRI shows cerebellar ataxia (summary by Bertini et al., 2000). Genetic Heterogeneity of X-linked Spinocerebellar Ataxia X-linked recessive spinocerebellar ataxia (SCAX) is a clinically and genetically heterogeneous disorder. See also SCAX2 (302600), SCAX3 (301790), SCAX4 (301840), and SCAX5 (300703).
Intellectual disability, X-linked 19
MedGen UID:
208676
Concept ID:
C0796225
Disease or Syndrome
X-linked intellectual development disorder-19 (XLID19) is characterized by mildly to moderately impaired intellectual development. Carrier females may be mildly affected. Mutation in the RPS6KA3 gene also causes Coffin-Lowry syndrome (CLS; 303600), a syndrome with impaired intellectual deveopment, dysmorphic facial features, and skeletal anomalies. Some patients with RPS6KA3 mutations have an intermediate phenotype with impaired intellectual development and only mild anomalies reminiscent of CLS. These individuals have mutations resulting in some residual protein function, which likely explains the milder phenotype (summary by Field et al., 2006).
Brunner syndrome
MedGen UID:
208683
Concept ID:
C0796275
Disease or Syndrome
Brunner syndrome is a recessive X-linked disorder characterized by impulsive aggressiveness and mild mental retardation associated with MAOA deficiency (Brunner et al., 1993).
Schimke immuno-osseous dysplasia
MedGen UID:
164078
Concept ID:
C0877024
Congenital Abnormality
Schimke immunoosseous dysplasia (SIOD) is characterized by spondyloepiphyseal dysplasia (SED) resulting in short stature, nephropathy, and T-cell deficiency. Radiographic manifestations of SED include ovoid and mildly flattened vertebral bodies, small ilia with shallow dysplastic acetabular fossae, and small deformed capital femoral epiphyses. Nearly all affected individuals have progressive steroid-resistant nephropathy, usually developing within five years of the diagnosis of growth failure and terminating with end-stage renal disease. The majority of tested individuals have T-cell deficiency and an associated risk for opportunistic infection, a common cause of death. SIOD involves a spectrum that ranges from an infantile or severe early-onset form with a greater risk of death during childhood to a juvenile or milder later-onset form with likely survival into adulthood if renal disease is appropriately treated.
Merosin deficient congenital muscular dystrophy
MedGen UID:
224728
Concept ID:
C1263858
Disease or Syndrome
Merosin-deficient congenital muscular dystrophy is an autosomal recessive form of muscular dystrophy characterized by muscle weakness apparent at birth or in the first 6 months of life. Patients show hypotonia, poor suck and cry, and delayed motor development; most never achieve independent ambulation. Most patients also have periventricular white matter abnormalities on brain imaging, but mental retardation and/or seizures occur only rarely (summary by Xiong et al., 2015).
Deficiency of beta-ureidopropionase
MedGen UID:
226944
Concept ID:
C1291512
Disease or Syndrome
Beta-ureidopropionase deficiency is a rare autosomal recessive inborn error of metabolism due to a defect in pyrimidine degradation. Less than 10 patients have been reported, and the phenotype can range from severe neurologic involvement with mental retardation and seizures to normal neurologic development (Yaplito-Lee et al., 2008).
Microcephalic osteodysplastic dysplasia, Saul-Wilson type
MedGen UID:
722057
Concept ID:
C1300285
Disease or Syndrome
Saul-Wilson syndrome (SWS) is a skeletal dysplasia characterized by profound short stature, distinctive craniofacial features, short distal phalanges of fingers and toes, and often clubfoot. Early development (primarily speech and motor) is delayed; cognition is normal. Other findings can include hearing loss (conductive, sensorineural, and mixed), lamellar cataracts, and/or rod-cone retinal dystrophy. To date, 16 affected individuals have been reported.
Hyperparathyroidism, transient neonatal
MedGen UID:
722059
Concept ID:
C1300287
Disease or Syndrome
Transient neonatal hyperparathyroidism is characterized by interference with placental maternal-fetal calcium transport, causing fetal calcium deficiency resulting in hyperparathyroidism and metabolic bone disease. Because 80% of calcium is transferred during the third trimester, abnormalities may not be detected on second-trimester ultrasounds. Affected infants present at birth with prenatal fractures, shortened ribs, and bowing of long bones, as well as respiratory and feeding difficulties. Postnatal recovery or improvement is observed once calcium is provided orally, with most patients showing complete resolution of skeletal abnormalities by 2 years of age (Suzuki et al., 2018).
Usher syndrome type 1
MedGen UID:
292820
Concept ID:
C1568247
Disease or Syndrome
Usher syndrome type I (USH1) is characterized by congenital, bilateral, profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP). Unless fitted with a cochlear implant, individuals do not typically develop speech. RP, a progressive, bilateral, symmetric degeneration of rod and cone functions of the retina, develops in adolescence, resulting in progressively constricted visual fields and impaired visual acuity.
Charcot-Marie-Tooth disease type 4B1
MedGen UID:
321947
Concept ID:
C1832399
Disease or Syndrome
Charcot-Marie-Tooth disease, type 4B1 (CMT4B1) is a severe early-onset demyelinating CMT peripheral sensorimotor polyneuropathy. It was initially described in an Italian family and around 10 additional families have been described so far. Onset occurs during early childhood with distal and proximal muscular weakness starting in the lower extremities, sensory loss and cranial nerve involvement. Foot deformities are frequent and diaphragmatic and facial involvement has been reported. CMT4B1 is caused by mutations in the gene encoding myotubularin-related protein 2 (MTMR2; 11q22), involved in polyphosphoinositide signaling. Transmitted in an autosomal recessive manner.
Brody myopathy
MedGen UID:
371441
Concept ID:
C1832918
Disease or Syndrome
Brody disease (BROD) is an autosomal recessive skeletal muscle disorder characterized by exercise-induced muscle stiffness and cramps primarily affecting the arms, legs, and eyelids, although more generalized muscle involvement may also occur. Symptom onset is most often in the first decade, but many patients present and are diagnosed later in life. Skeletal muscle biopsy typically shows variation in fiber size, increased internal nuclei, and atrophy of type II muscle fibers. Rare patients have been reported to develop malignant hyperthermia after administration of anesthesia, suggesting that patients with the disorder should be tested. The disorder results from defective relaxation of fast-twitch (type II) skeletal muscle fibers due to defects in calcium homeostasis and reuptake in the muscle fiber (summary by Odermatt et al., 2000 and Molenaar et al., 2020).
Bethlem myopathy
MedGen UID:
331805
Concept ID:
C1834674
Disease or Syndrome
Individuals with collagen VI-related dystrophy often have signs and symptoms of multiple forms of this condition, so it can be difficult to assign a specific diagnosis. The overlap in disease features, in addition to their common cause, is why these once separate conditions are now considered part of the same disease spectrum.\n\nPeople with Ullrich congenital muscular dystrophy have severe muscle weakness beginning soon after birth. Some affected individuals are never able to walk and others can walk only with support. Those who can walk often lose the ability, usually in early adolescence. Individuals with Ullrich congenital muscular dystrophy develop contractures in their shoulders, elbows, hips, and knees, which further impair movement. Many individuals with this form of the condition have loose joints (joint laxity) in the fingers, wrists, toes, ankles, and other joints. Affected individuals need continuous mechanical ventilation to help them breathe while sleeping, and some may need it in the daytime. As in Bethlem muscular dystrophy, some people with Ullrich congenital muscular dystrophy have follicular hyperkeratosis; soft, velvety skin on the palms and soles; and abnormal wound healing.\n\nThe intermediate form of collagen VI-related dystrophy is characterized by muscle weakness that begins in infancy. Affected children are able to walk, although walking becomes increasingly difficult starting in early adulthood. They develop contractures in their fingers, elbows, shoulders, and ankles in childhood. In some affected people, the respiratory muscles are weakened, requiring people to use a machine to help them breathe (mechanical ventilation), particularly during sleep.\n\nPeople with Bethlem muscular dystrophy usually have low muscle tone (hypotonia) in infancy. Muscle weakness can begin at any age but often appears in childhood to early adulthood. The muscle weakness is slowly progressive, with about two-thirds of affected individuals over age 50 needing walking assistance, particularly when outdoors. Affected individuals usually develop contractures by adulthood, typically in their fingers, elbows, shoulders, and ankles. Older individuals may develop weakness in respiratory muscles, which can cause breathing problems. Some people with this mild form of collagen VI-related dystrophy have skin abnormalities, including small bumps called follicular hyperkeratosis on the arms and legs; soft, velvety skin on the palms of the hands and soles of the feet; and abnormal wound healing that creates shallow scars.\n\nCollagen VI-related dystrophy is a group of disorders that affect skeletal muscles (which are the muscles used for movement) and connective tissue (which provides strength and flexibility to the skin, joints, and other structures throughout the body). Most affected individuals have muscle weakness and joint deformities called contractures that restrict movement of the affected joints and worsen over time. Researchers have described several forms of collagen VI-related dystrophy, which range in severity: Bethlem muscular dystrophy is the mildest, an intermediate form is moderate in severity, and Ullrich congenital muscular dystrophy is the most severe.
SPOAN syndrome
MedGen UID:
324411
Concept ID:
C1836010
Disease or Syndrome
Spastic paraplegia, optic atrophy, and neuropathy (SPOAN) is an autosomal recessive neurodegenerative disorder characterized by early-onset progressive spastic paraplegia resulting in loss of independent ambulation in the teenage years. Additional features include optic atrophy, later onset of sensorimotor peripheral neuropathy, and progressive joint contractures; cognition remains intact (summary by Melo et al., 2015).
Charcot-Marie-Tooth disease type 4H
MedGen UID:
324487
Concept ID:
C1836336
Disease or Syndrome
Charcot-Marie-Tooth disease, type 4H (CMT4H) is a demyelinating CMT peripheral sensorimotor polyneuropathy. It has been described in 10 individuals from two large consanguineous families from Lebanon and Algeria. Onset occurs within the first two years of life with slowly progressive muscle weakness in the distal extremities. Other common features include delayed walking, an abnormal gait, scoliosis and pes equines with toe retraction. CMT4H is caused by mutations in the FGD4 gene (12p11.1). Transmitted in an autosomal recessive manner.
Autosomal recessive limb-girdle muscular dystrophy type 2K
MedGen UID:
332193
Concept ID:
C1836373
Disease or Syndrome
Limb-girdle muscular dystrophies resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239) represent the mildest end of the phenotypic spectrum of muscular dystrophies collectively known as dystroglycanopathies. The limb-girdle phenotype is characterized by onset of muscular weakness apparent after ambulation is achieved; mental retardation and mild brain anomalies are variable (Balci et al., 2005; review by Godfrey et al., 2007). The most severe end of the phenotypic spectrum of dystroglycanopathies is represented by congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A; see MDDGA1, 236670), previously designated Walker-Warburg syndrome (WWS) or muscle-eye-brain disease (MEB), and the intermediate range of the spectrum is represented by congenital muscular dystrophy-dystroglycanopathy with or without mental retardation (type B; see MDDGB1, 613155). Genetic Heterogeneity of Limb-Girdle Muscular Dystrophy-Dystroglycanopathy (Type C) Limb-girdle muscular dystrophy due to defective glycosylation of DAG1 is genetically heterogeneous. See also MDDGC2 (613158), caused by mutation in the POMT2 gene (607439); MDDGC3 (613157), caused by mutation in the POMGNT1 gene (606822); MDDGC4 (611588), caused by mutation in the FKTN gene (607440); MDDGC5 (607155), caused by mutation in the FKRP gene (606596); MDDGC7 (616052), caused by mutation in the ISPD gene (CRPPA; 614631); MDDGC8 (618135), caused by mutation in the POMGNT2 gene (614828); MDDGC9 (613818) caused by mutation in the DAG1 gene (128239); MDDGC12 (616094), caused by mutation in the POMK gene (615247); MDDGC14 (615352) caused by mutation in the GMPPB gene (615320); and MDDGC15 (612937), caused by mutation in the DPM3 gene (605951).
Nemaline myopathy 4
MedGen UID:
324513
Concept ID:
C1836447
Disease or Syndrome
Nemaline myopathy is divided into six types. In order of decreasing severity, the types are: severe congenital, Amish, intermediate congenital, typical congenital, childhood-onset, and adult-onset. The types are distinguished by the age when symptoms first appear and the severity of symptoms; however, there is overlap among the various types. The severe congenital type is the most life-threatening. Most individuals with this type do not survive past early childhood due to respiratory failure. The Amish type solely affects the Old Order Amish population of Pennsylvania and is typically fatal in early childhood. The most common type of nemaline myopathy is the typical congenital type, which is characterized by muscle weakness and feeding problems beginning in infancy. Most of these individuals do not have severe breathing problems and can walk unassisted. People with the childhood-onset type usually develop muscle weakness in adolescence. The adult-onset type is the mildest of all the various types. People with this type usually develop muscle weakness between ages 20 and 50.\n\nNemaline myopathy is a disorder that primarily affects skeletal muscles, which are muscles that the body uses for movement. People with nemaline myopathy have muscle weakness (myopathy) throughout the body, but it is typically most severe in the muscles of the face; neck; trunk; and other muscles close to the center of the body (proximal muscles), such as those of the upper arms and legs. This weakness can worsen over time. Affected individuals may have feeding and swallowing difficulties, foot deformities, abnormal curvature of the spine (scoliosis), and joint deformities (contractures). Most people with nemaline myopathy are able to walk, although some affected children may begin walking later than usual. As the condition progresses, some people may require wheelchair assistance. In severe cases, the muscles used for breathing are affected and life-threatening breathing difficulties can occur.
Nemaline myopathy 1
MedGen UID:
373089
Concept ID:
C1836448
Disease or Syndrome
Nemaline myopathy-1 is a disorder characterized by muscle weakness, usually beginning in early childhood. The severity and pattern of muscle weakness varies, but most affected individuals show mildly delayed motor development, hypotonia, generalized muscle weakness, and weakness of the proximal limb muscles and neck muscles, resulting in difficulty running and easy fatigability. Most patients have respiratory insufficiency due to muscle weakness. Other common features include myopathic facies, high-arched palate, and scoliosis. Histologic findings on skeletal muscle biopsy are variable, even in patients with the same mutation. Muscle fibers can contain nemaline rod inclusions, or so-called subsarcolemmal 'cap' structures, as well as show overall fiber-type disproportion. It has been suggested that unknown modifying factors confer a tendency to one or another pattern of inclusions on skeletal muscle biopsy in those with TPM3 mutations (summary by Waddell et al., 2010 and Malfatti et al., 2013). For a discussion of genetic heterogeneity of nemaline myopathy, see 161800.
Familial hyperthyroidism due to mutations in TSH receptor
MedGen UID:
373154
Concept ID:
C1836706
Disease or Syndrome
A rare hyperthyroidism characterized by mild to severe hyperthyroidism, presence of goiter, absence of features of autoimmunity, frequent relapses while on treatment and a positive family history.
Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1
MedGen UID:
322999
Concept ID:
C1836797
Disease or Syndrome
Combined oxidative phosphorylation deficiency is an autosomal recessive multisystem disorder with variable manifestations resulting from a defect in the mitochondrial oxidative phosphorylation (OXPHOS) system. Onset occurs at or soon after birth, and features can include growth retardation, microcephaly, hypertonicity, axial hypotonia, encephalopathy, cardiomyopathy, and liver dysfunction. Death usually occurs in the first weeks or years of life (summary by Smits et al., 2011). Genetic Heterogeneity of Combined Oxidative Phosphorylation Deficiency See also COXPD2 (610498), caused by mutation in the MRPS16 gene (609204) on 10q22; COXPD3 (610505), caused by mutation in the TSFM gene (604723) on 12q14; COXPD4 (610678), caused by mutation in the TUFM gene (602389) on 16p11; COXPD5 (611719), caused by mutation in the MRPS22 gene (605810) on 3q23; COXPD6 (300816), caused by mutation in the AIFM1 gene (300169) on Xq26; COXPD7 (613559), caused by mutation in the MTRFR gene (613541) on 12q24; COXPD8 (614096), caused by mutation in the AARS2 gene (612035) on 6p21; COXPD9 (614582), caused by mutation in the MRPL3 gene (607118) on 3q22; COXPD10 (614702), caused by mutation in the MTO1 gene (614667) on 6q13; COXPD11 (614922), caused by mutation in the RMND1 gene (614917) on 6q25; COXPD12 (614924), caused by mutation in the EARS2 gene (612799) on 16p13; COXPD13 (614932), caused by mutation in the PNPT1 gene (610316) on 2p16; COXPD14 (614946), caused by mutation in the FARS2 gene (611592) on 6p25; COXPD15 (614947), caused by mutation in the MTFMT gene (611766) on 15q; COXPD16 (615395), caused by mutation in the MRPL44 gene (611849) on 2q36; COXPD17 (615440), caused by mutation in the ELAC2 gene (605367) on 17p11; COXPD18 (615578), caused by mutation in the SFXN4 gene (615564) on 10q26; COXPD19 (615595), caused by mutation in the LYRM4 gene (613311) on 6p25; COXPD20 (615917), caused by mutation in the VARS2 gene (612802) on 6p21; COXPD21 (615918), caused by mutation in the TARS2 gene (612805) on 1q21; COXPD22 (616045), caused by mutation in the ATP5A1 gene (164360) on 18q12; COXPD23 (616198), caused by mutation in the GTPBP3 (608536) gene on 19p13; COXPD24 (616239), caused by mutation in the NARS2 gene (612803) on 11q14; COXPD25 (616430), caused by mutation in the MARS2 gene (609728) on 2q33; COXPD26 (616539), caused by mutation in the TRMT5 gene (611023) on 14q23; COXPD27 (616672), caused by mutation in the CARS2 gene (612800) on 13q34; COXPD28 (616794), caused by mutation in the SLC25A26 gene (611037) on 3p14; COXPD29 (616811), caused by mutation in the TXN2 gene (609063) on 22q12; COXPD30 (616974), caused by mutation in the TRMT10C gene (615423) on 3q12; and COXPD31 (617228), caused by mutation in the MIPEP gene (602241) on 13q12; COXPD32 (617664), caused by mutation in the MRPS34 gene (611994) on 16q13; COXPD33 (617713), caused by mutation in the C1QBP gene (601269) on 17p13; and COXPD34 (617872), caused by mutation in the MRPS7 gene (611974) on 17q25; COXPD35 (617873), caused by mutation in the TRIT1 gene (617840) on 1p34; COXPD36 (617950), caused by mutation in the MRPS2 gene (611971) on 9q34; COXPD37 (618329), caused by mutation in the MICOS13 gene (616658) on 19p13; COXPD38 (618378), caused by mutation in the MRPS14 gene (611978) on 1q23; COXPD39 (618397), caused by mutation in the GFM2 gene (606544) on 5q13; COXPD40 (618835), caused by mutation in the QRSL1 gene (617209) on 6q21; COXPD41 (618838), caused by mutation in the GATB gene (603645) on 4q31; COXPD42 (618839), caused by mutation in the GATC gene (617210) on 12q24; COXPD43 (618851), caused by mutation in the TIMM22 gene (607251) on 17p13; COXPD44 (618855), caused by mutation in the FASTKD2 gene (612322) on 2q33; COXPD45 (618951), caused by mutation in the MRPL12 gene (602375) on 17q25; COXPD46 (618952), caused by mutation in the MRPS23 gene (611985) on 17q22; COXPD47 (618958), caused by mutation in the MRPS28 gene (611990) on 8q21; COXPD48 (619012), caused by mutation in the NSUN3 gene (617491) on 3q11; COXPD49 (619024), caused by mutation in the MIEF2 gene (615498) on 17p11; COXPD50 (619025), caused by mutation in the MRPS25 gene (611987) on 3p25; COXPD51 (619057), caused by mutation in the PTCD3 gene (614918) on 2p11; COXPD52 (619386), caused by mutation in the NFS1 gene (603485) on 20q11; COXPD53 (619423), caused by mutation in the C2ORF69 gene (619219) on 2q33; and COXPD54 (619737), caused by mutation in the PRORP gene (609947) on 14q13.; COXPD55 (619743), caused by mutation in the POLRMT gene (601778) on 19p13; COXPD56 (620139), caused by mutation in the TAMM41 gene (614948) on 3p25; and COXPD57 (620167), caused by mutation in the CRLS1 gene (608188) on 20p12.
Pierson syndrome
MedGen UID:
373199
Concept ID:
C1836876
Disease or Syndrome
Pierson syndrome (PIERS) is an autosomal recessive disorder comprising congenital nephrotic syndrome with diffuse mesangial sclerosis and distinct ocular abnormalities, including microcoria and hypoplasia of the ciliary and pupillary muscles, as well as other anomalies. Many patients die early, and those who survive tend to show neurodevelopmental delay and visual loss (summary by Zenker et al., 2004). Mutations in the LAMB2 gene also cause nephrotic syndrome type 5 with or without mild ocular anomalies (NPHS5; 614199).
Congenital myasthenic syndrome 4C
MedGen UID:
373251
Concept ID:
C1837091
Disease or Syndrome
Congenital myasthenic syndrome associated with AChR deficiency is a disorder of the postsynaptic neuromuscular junction (NMJ) clinically characterized by early-onset muscle weakness with variable severity. Electrophysiologic studies show low amplitude of the miniature endplate potential (MEPP) and current (MEPC) resulting from deficiency of AChR at the endplate. Patients with mutations in the CHRNE gene may have compensatory increased expression of the fetal subunit CHRNG (100730) and may respond to treatment with cholinergic agents, pyridostigmine, or amifampridine (summary by Engel et al., 2015). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Muscular dystrophy-dystroglycanopathy type B6
MedGen UID:
373284
Concept ID:
C1837229
Disease or Syndrome
MDDGB6 is an autosomal recessive congenital muscular dystrophy with impaired intellectual development and structural brain abnormalities (Longman et al., 2003). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Mercuri et al., 2009). For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (613155).
Hypomyelinating leukodystrophy 2
MedGen UID:
325157
Concept ID:
C1837355
Disease or Syndrome
Pelizaeus-Merzbacher-like disease 1 (PMLD1) is a slowly progressive leukodystrophy that typically presents during the neonatal or early-infantile period with nystagmus, commonly associated with hypotonia, delayed acquisition of motor milestones, speech delay, and dysarthria. Over time the hypotonia typically evolves into spasticity that affects the ability to walk and communicate. Cerebellar signs (gait ataxia, dysmetria, intention tremor, head titubation, and dysdiadochokinesia) frequently manifest during childhood. Some individuals develop extrapyramidal movement abnormalities (choreoathetosis and dystonia). Hearing loss and optic atrophy are observed in rare cases. Motor impairments can lead to swallowing difficulty and orthopedic complications, including hip dislocation and scoliosis. Most individuals have normal cognitive skills or mild intellectual disability – which, however, can be difficult to evaluate in the context of profound motor impairment.
Growth delay due to insulin-like growth factor type 1 deficiency
MedGen UID:
373337
Concept ID:
C1837475
Disease or Syndrome
Syndrome with the association of intrauterine and postnatal growth retardation, sensorineural deafness and intellectual deficit. The syndrome is extremely rare and only four cases have been reported in the literature so far. Additional clinical features include microcephaly, adiposity, and insulin resistance. Partial gonadal dysfunction and osteoporosis may also be present. Caused by homozygous mutations in the insulin-like growth factor 1 gene (12q22-q24.1). Transmitted as an autosomal recessive trait.
Microcephaly 5, primary, autosomal recessive
MedGen UID:
373344
Concept ID:
C1837501
Disease or Syndrome
ASPM primary microcephaly (ASPM-MCPH) is characterized by: (1) significant microcephaly (below -3 SD for age) usually present at birth and always present before age one year and (2) the absence of other congenital anomalies. While developmental milestones are usually normal in young children, older children have variable levels of intellectual disability. Neurologic examination is usually normal except for mild spasticity. Seizures are not common.
Joubert syndrome 3
MedGen UID:
332931
Concept ID:
C1837713
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
CODAS syndrome
MedGen UID:
333031
Concept ID:
C1838180
Disease or Syndrome
CODAS is an acronym for cerebral, ocular, dental, auricular, and skeletal anomalies. CODAS syndrome is a rare disorder characterized by a distinctive constellation of features that includes developmental delay, craniofacial anomalies, cataracts, ptosis, median nasal groove, delayed tooth eruption, hearing loss, short stature, delayed epiphyseal ossification, metaphyseal hip dysplasia, and vertebral coronal clefts (summary by Strauss et al., 2015).
Eiken syndrome
MedGen UID:
325097
Concept ID:
C1838779
Congenital Abnormality
Eiken syndrome (EKNS) is an autosomal recessive skeletal dysplasia characterized by delayed ossification of bones, epiphyseal dysplasia, and bone remodeling abnormalities. Type A1 brachydactyly (see 112500), supernumerary epiphyses of proximal phalanges and metacarpals, and failure of eruption of primary teeth have also been described. Defining radiologic features include delayed ossification of epiphyses and primary ossification centers of short tubular bones, modeling abnormalities of tubular bones, and angel-shaped phalanges (Jacob et al., 2019). See 603740 for a disorder with similar radiologic features.
Myopathy and diabetes mellitus
MedGen UID:
333236
Concept ID:
C1839028
Disease or Syndrome
A rare, genetic, mitochondrial DNA-related mitochondrial myopathy disorder characterized by slowly progressive muscular weakness (proximal greater than distal), predominantly involving the facial muscles and scapular girdle, associated with insulin-dependent diabetes mellitus. Neurological involvement and congenital myopathy may be variably observed.
Charcot-Marie-Tooth disease X-linked recessive 5
MedGen UID:
374254
Concept ID:
C1839566
Disease or Syndrome
X-linked Charcot-Marie-Tooth neuropathy type 5 (CMTX5), part of the spectrum of PRPS1-related disorders, is characterized by peripheral neuropathy, early-onset (prelingual) bilateral profound sensorineural hearing loss, and optic neuropathy. The onset of peripheral neuropathy is between ages five and 12 years. The lower extremities are affected earlier and more severely than upper extremities. Initial manifestations often include foot drop or gait disturbance. Onset of visual impairment is between ages seven and 20 years. Intellect and life span are normal. Carrier females do not have findings of CMTX5.
X-linked myopathy with excessive autophagy
MedGen UID:
374264
Concept ID:
C1839615
Disease or Syndrome
X-linked myopathy with excessive autophagy (XMEA) is an X-linked recessive skeletal muscle disorder characterized by childhood onset of progressive muscle weakness and atrophy primarily affecting the proximal muscles. While onset is usually in childhood, it can range from infancy to adulthood. Many patients lose ambulation and become wheelchair-bound. Other organ systems, including the heart, are clinically unaffected. Muscle biopsy shows intracytoplasmic autophagic vacuoles with sarcolemmal features and a multilayered basal membrane (summary by Ramachandran et al., 2013; Kurashige et al., 2013, and Ruggieri et al., 2015). Danon disease (300257), caused by mutation in the LAMP2 gene (309060) on chromosome Xq24, is a distinct disorder with similar pathologic features.
King Denborough syndrome
MedGen UID:
327082
Concept ID:
C1840365
Disease or Syndrome
King-Denborough syndrome (KDS) is an autosomal dominant disorder characterized by the triad of congenital myopathy, dysmorphic features, and susceptibility to malignant hyperthermia (summary by Dowling et al., 2011).
Growth failure, microcephaly, intellectual disability, cataracts, large joint contractures, osteoporosis, cortical dysplasia, and cerebellar atrophy
MedGen UID:
330820
Concept ID:
C1842321
Disease or Syndrome
Hermansky-Pudlak syndrome 2
MedGen UID:
374912
Concept ID:
C1842362
Disease or Syndrome
Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. Ocular findings include reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1.
Infantile-onset autosomal recessive nonprogressive cerebellar ataxia
MedGen UID:
334220
Concept ID:
C1842676
Disease or Syndrome
A rare genetic autosomal recessive cerebellar ataxia disease with characteristics of nonprogressive cerebellar ataxia, with onset in infancy, manifesting with delayed motor and speech development, gait ataxia, dysmetria, hypotonia, increased deep tendon reflexes and dysarthria. Additional variable manifestations include moderate nystagmus on lateral gaze, mild spasticity, intention tremor, short stature and pes planus. Brain imaging reveals cerebellar vermis atrophy.
ALG2-congenital disorder of glycosylation
MedGen UID:
334618
Concept ID:
C1842836
Disease or Syndrome
Congenital disorder of glycosylation type Ii (CDG1I) is a rare autosomal recessive disorder characterized by neurologic involvement, including a convulsive syndrome of unknown origin, axial hypotonia, and mental and motor regression (summary by Papazoglu et al., 2021). For a general discussion of CDGs, see CDG1A (212065).
Charcot-Marie-Tooth disease type 1F
MedGen UID:
334337
Concept ID:
C1843164
Disease or Syndrome
A form of Charcot-Marie-Tooth disease type 1, with a variable clinical presentation that can range from severe impairment with onset in childhood to mild impairment appearing during adulthood. The disease has characteristics of progressive peripheral motor and sensory neuropathy with distal paresis in the lower limbs that varies from mild weakness to complete paralysis of the distal muscle groups, absent tendon reflexes and reduced nerve conduction. Caused by mutations in the NEFL gene (8p21.2).
Charcot-Marie-Tooth disease type 2E
MedGen UID:
375127
Concept ID:
C1843225
Disease or Syndrome
A form of axonal Charcot-Marie-Tooth disease a peripheral sensorimotor neuropathy. Onset is in the first to sixth decade with a gait anomaly and a leg weakness that reaches the arms secondarily. Tendon reflexes are reduced or absent and after years all patients have a pes cavus. Other signs may be present including hearing loss and postural tremor.
Pontocerebellar hypoplasia type 1A
MedGen UID:
335969
Concept ID:
C1843504
Disease or Syndrome
Pontocerebellar hypoplasia (PCH) refers to a group of severe neurodegenerative disorders affecting growth and function of the brainstem and cerebellum, resulting in little or no development. Different types were classified based on the clinical picture and the spectrum of pathologic changes. PCH type 1 is characterized by central and peripheral motor dysfunction associated with anterior horn cell degeneration resembling infantile spinal muscular atrophy (SMA; see SMA1, 253300); death usually occurs early. Genetic Heterogeneity of Pontocerebellar Hypoplasia Also see PCH1B (614678), caused by mutation in the EXOSC3 gene (606489); PCH1C (616081), caused by mutation in the EXOSC8 gene (606019); PCH1D (618065), caused by mutation in the EXOSC9 gene (606180); PCH1E (619303), caused by mutation in the SLC25A46 gene (610826); PCH1F (619304), caused by mutation in the EXOSC1 gene (606493); PCH2A (277470), caused by mutation in the TSEN54 gene (608755); PCH2B (612389), caused by mutation in the TSEN2 gene (608753); PCH2C (612390), caused by mutation in the TSEN34 gene (608754); PCH2D (613811), caused by mutation in the SEPSECS gene (613009); PCH3 (608027), caused by mutation in the PCLO gene (604918); PCH4 (225753), caused by mutation in the TSEN54 gene; PCH5 (610204), caused by mutation in the TSEN54 gene; PCH6 (611523), caused by mutation in the RARS2 gene (611524); PCH7 (614969), caused by mutation in the TOE1 gene (613931); PCH8 (614961), caused by mutation in the CHMP1A gene (164010); PCH9 (615809), caused by mutation in the AMPD2 gene (102771); PCH10 (615803), caused by mutation in the CLP1 gene (608757); PCH11 (617695), caused by mutation in the TBC1D23 gene (617687); PCH12 (618266), caused by mutation in the COASY gene (609855); PCH13 (618606), caused by mutation in the VPS51 gene (615738); PCH14 (619301), caused by mutation in the PPIL1 gene (601301); PCH15 (619302), caused by mutation in the CDC40 gene (605585); PCH16 (619527), caused by mutation in the MINPP1 gene (605391); and PCH17 (619909), caused by mutation in the PRDM13 gene (616741) on chromosome 6q16.
Syndromic X-linked intellectual disability Claes-Jensen type
MedGen UID:
335139
Concept ID:
C1845243
Disease or Syndrome
Claes-Jensen type of X-linked syndromic intellectual developmental disorder (MRXSCJ) is characterized by impaired intellectual development with substantial clinical heterogeneity in affected males. However, males are usually reported to have short stature, microcephaly, hyperreflexia, and aggressive behavior. In rare cases, female carriers exhibit mildly impaired intellectual development or learning difficulties (summary by Guerra et al., 2020).
Syndromic X-linked intellectual disability Hedera type
MedGen UID:
337257
Concept ID:
C1845543
Disease or Syndrome
The Hedera type of X-linked syndromic intellectual developmental disorder (MRXSH) is characterized by global developmental delay apparent from infancy and progressive neurologic decline with abnormal movements, spasticity, and seizures. Brain imaging shows volume loss of cortical white and gray matter, thin corpus callosum, and myelination defects, consistent with a neurodegenerative process. Only males are affected (summary by Hirose et al., 2019).
X-linked intellectual disability Cabezas type
MedGen UID:
337334
Concept ID:
C1845861
Disease or Syndrome
The Cabezas type of X-linked syndromic intellectual developmental disorder is characterized primarily by short stature, hypogonadism, and abnormal gait, with other more variable features such as speech delay, prominent lower lip, and tremor (Cabezas et al., 2000).
Creatine transporter deficiency
MedGen UID:
337451
Concept ID:
C1845862
Disease or Syndrome
The creatine deficiency disorders (CDDs), inborn errors of creatine metabolism and transport, comprise three disorders: the creatine biosynthesis disorders guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency; and creatine transporter (CRTR) deficiency. Developmental delay and cognitive dysfunction or intellectual disability and speech-language disorder are common to all three CDDs. Onset of clinical manifestations of GAMT deficiency (reported in ~130 individuals) is between ages three months and two years; in addition to developmental delays, the majority of individuals have epilepsy and develop a behavior disorder (e.g., hyperactivity, autism, or self-injurious behavior), and about 30% have movement disorder. AGAT deficiency has been reported in 16 individuals; none have had epilepsy or movement disorders. Clinical findings of CRTR deficiency in affected males (reported in ~130 individuals) in addition to developmental delays include epilepsy (variable seizure types and may be intractable) and behavior disorders (e.g., attention deficit and/or hyperactivity, autistic features, impulsivity, social anxiety), hypotonia, and (less commonly) a movement disorder. Poor weight gain with constipation and prolonged QTc on EKG have been reported. While mild-to-moderate intellectual disability is commonly observed up to age four years, the majority of adult males with CRTR deficiency have been reported to have severe intellectual disability. Females heterozygous for CRTR deficiency are typically either asymptomatic or have mild intellectual disability, although a more severe phenotype resembling the male phenotype has been reported.
Oculofaciocardiodental syndrome
MedGen UID:
337547
Concept ID:
C1846265
Disease or Syndrome
Oculofaciocardiodental (OFCD) syndrome is a condition that affects the development of the eyes (oculo-), facial features (facio-), heart (cardio-) and teeth (dental). This condition occurs only in females.\n\nThe eye abnormalities associated with OFCD syndrome can affect one or both eyes. Many people with this condition are born with eyeballs that are abnormally small (microphthalmia). Other eye problems can include clouding of the lens (cataract) and a higher risk of glaucoma, an eye disease that increases the pressure in the eye. These abnormalities can lead to vision loss or blindness.\n\nPeople with OFCD syndrome often have a long, narrow face with distinctive facial features, including deep-set eyes and a broad nasal tip that is divided by a cleft. Some affected people have an opening in the roof of the mouth called a cleft palate.\n\nHeart defects are another common feature of OFCD syndrome. Babies with this condition may be born with a hole between two chambers of the heart (an atrial or ventricular septal defect) or a leak in one of the valves that controls blood flow through the heart (mitral valve prolapse).\n\nTeeth with very large roots (radiculomegaly) are characteristic of OFCD syndrome. Additional dental abnormalities can include delayed loss of primary (baby) teeth, missing or abnormally small teeth, misaligned teeth, and defective tooth enamel.
Developmental malformations-deafness-dystonia syndrome
MedGen UID:
339494
Concept ID:
C1846331
Disease or Syndrome
Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome is a multiple congenital anomaly syndrome characterized by typical craniofacial features and intellectual disability. Many (but not all) affected individuals have pachygyria that is predominantly frontal, wasting of the shoulder girdle muscles, and sensory impairment due to iris or retinal coloboma and/or sensorineural deafness. Intellectual disability, which is common but variable, is related to the severity of the brain malformations. Seizures, congenital heart defects, renal malformations, and gastrointestinal dysfunction are also common.
Autosomal recessive cerebellar ataxia-saccadic intrusion syndrome
MedGen UID:
335442
Concept ID:
C1846492
Disease or Syndrome
VPS13D movement disorder is a hyperkinetic movement disorder (dystonia, chorea, and/or ataxia) of variable age of onset that can be associated with developmental delay. Onset ranges from birth to adulthood. Individuals can present in childhood with motor delays and gait instability. Cognitive impairment ranging from mild intellectual disability to developmental delay has been reported, and several individuals have normal cognitive function. Individuals have also presented as young adults with gait difficulties caused by spastic ataxia or ataxia. In addition to gait ataxia, affected individuals had limb ataxia, dysarthria, and eye movement abnormalities (macro-saccadic oscillations, nystagmus, and saccadic pursuit). Additional features reported in some individuals include peripheral neuropathy and/or seizures. The disorder progresses to spastic ataxia or generalized dystonia, which can lead to loss of independent ambulation.
Multiple epiphyseal dysplasia, Al-Gazali type
MedGen UID:
335505
Concept ID:
C1846722
Disease or Syndrome
Al-Gazali-Bakalinova syndrome (AGBK) is characterized by multiple epiphyseal dysplasia, macrocephaly, and distinctive facial features including frontal bossing, hypertelorism, flat malar regions, low-set ears, and short neck. Other features include pectus excavatum, spindle-shaped fingers, clinodactyly, prominent joints, and genu valgum (summary by Ali et al., 2012).
Growth delay due to insulin-like growth factor I resistance
MedGen UID:
338622
Concept ID:
C1849157
Disease or Syndrome
Patients with mutations in the receptor for insulin-like growth factor I show intrauterine growth retardation and postnatal growth failure, resulting in short stature and microcephaly. Other features may include delayed bone age, developmental delay, and dysmorphic features.
Pterin-4 alpha-carbinolamine dehydratase 1 deficiency
MedGen UID:
337890
Concept ID:
C1849700
Disease or Syndrome
Tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) D is an autosomal recessive disorder characterized by mild transient hyperphenylalaninemia often detected by newborn screening. Patients also show increased excretion of 7-biopterin. Affected individuals are asymptomatic and show normal psychomotor development, although transient neurologic deficits in infancy have been reported (Thony et al., 1998). Patients may also develop hypomagnesemia and nonautoimmune diabetes mellitus during puberty (summary by Ferre et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of BH4-deficient hyperphenylalaninemia, see HPABH4A (261640).
Pleoconial myopathy with salt craving
MedGen UID:
337911
Concept ID:
C1849773
Disease or Syndrome
Palant cleft palate syndrome
MedGen UID:
337971
Concept ID:
C1850102
Disease or Syndrome
Otoonychoperoneal syndrome
MedGen UID:
376704
Concept ID:
C1850105
Disease or Syndrome
A rare multiple congenital anomalies/dysmorphic syndrome characterized by the association of dysplastic external ears, nail hypoplasia, and variable skeletal malformations, such as hypoplastic or absent fibulae, abnormalities of the scapula, clavicle, and acromioclavicular joint, and talipes equinovarus, among others. Joint contractures and mild facial dysmorphism have also been reported.
Giant axonal neuropathy 1
MedGen UID:
376775
Concept ID:
C1850386
Disease or Syndrome
GAN-related neurodegeneration comprises a phenotypic continuum ranging from severe (sometimes called classic giant axonal neuropathy) to milder pure early-onset peripheral motor and sensory neuropathies. The classic giant axonal neuropathy phenotype typically manifests as an infantile-onset neurodegenerative disorder, starting as a severe peripheral motor and sensory neuropathy and evolving into central nervous system impairment (intellectual disability, seizures, cerebellar signs, and pyramidal tract signs). Most affected individuals become wheelchair dependent in the second decade of life and eventually bedridden with severe polyneuropathy, ataxia, and dementia. Death usually occurs in the third decade. At the milder end of the spectrum are predominantly motor and sensory neuropathies (with little to no CNS involvement) that overlap with the axonal form of Charcot-Marie-Tooth neuropathies.
Navajo neurohepatopathy
MedGen UID:
338045
Concept ID:
C1850406
Disease or Syndrome
MPV17-related mitochondrial DNA (mtDNA) maintenance defect presents in the vast majority of affected individuals as an early-onset encephalohepatopathic (hepatocerebral) disease that is typically associated with mtDNA depletion, particularly in the liver. A later-onset neuromyopathic disease characterized by myopathy and neuropathy, and associated with multiple mtDNA deletions in muscle, has also rarely been described. MPV17-related mtDNA maintenance defect, encephalohepatopathic form is characterized by: Hepatic manifestations (liver dysfunction that typically progresses to liver failure, cholestasis, hepatomegaly, and steatosis); Neurologic involvement (developmental delay, hypotonia, microcephaly, and motor and sensory peripheral neuropathy); Gastrointestinal manifestations (gastrointestinal dysmotility, feeding difficulties, and failure to thrive); and Metabolic derangements (lactic acidosis and hypoglycemia). Less frequent manifestations include renal tubulopathy, nephrocalcinosis, and hypoparathyroidism. Progressive liver disease often leads to death in infancy or early childhood. Hepatocellular carcinoma has been reported.
Nemaline myopathy 2
MedGen UID:
342534
Concept ID:
C1850569
Disease or Syndrome
Nemaline myopathy-2 (NEM2) is an autosomal recessive skeletal muscle disorder with a wide range of severity. The most common clinical presentation is early-onset (in infancy or childhood) muscle weakness predominantly affecting proximal limb muscles. Muscle biopsy shows accumulation of Z-disc and thin filament proteins into aggregates named 'nemaline bodies' or 'nemaline rods,' usually accompanied by disorganization of the muscle Z discs. The clinical and histologic spectrum of entities caused by variants in the NEB gene is a continuum, ranging in severity. The distribution of weakness can vary from generalized muscle weakness, more pronounced in proximal limb muscles, to distal-only involvement, although neck flexor weakness appears to be rather consistent. Histologic patterns range from a severe usually nondystrophic disturbance of the myofibrillar pattern to an almost normal pattern, with or without nemaline bodies, sometimes combined with cores (summary by Lehtokari et al., 2014). For a discussion of genetic heterogeneity of nemaline myopathy, see NEM3 (161800). Mutations in the NEB gene are the most common cause of nemaline myopathy (Lehtokari et al., 2006).
Bailey-Bloch congenital myopathy
MedGen UID:
340586
Concept ID:
C1850625
Disease or Syndrome
STAC3 disorder is characterized by congenital myopathy, musculoskeletal involvement of the trunk and extremities, feeding difficulties, and delayed motor milestones. Most affected individuals have weakness with myopathic facies, scoliosis, kyphosis or kyphoscoliosis, and contractures. Other common findings are ptosis, abnormalities of the palate (including cleft palate), and short stature. Risk for malignant hyperthermia susceptibility and restrictive lung disease are increased. Intellect is typically normal. Originally described in individuals from the Lumbee Native American tribe (an admixture of Cheraw Indian, English, and African American ancestry) in the state of North Carolina and reported as Native American myopathy, STAC3 disorder has now been identified in numerous other populations worldwide.
Congenital multicore myopathy with external ophthalmoplegia
MedGen UID:
340597
Concept ID:
C1850674
Disease or Syndrome
Multiminicore disease (MMD) is an inherited neuromuscular disorder defined pathologically by the presence of multiple areas of reduced mitochondrial oxidative activity running along a limited extent of the longitudinal axis of the muscle fiber, so-called 'minicores.' These regions show sarcomere disorganization and mitochondria depletion. Typically, no dystrophic signs, such as muscle fiber necrosis or regeneration or significant endomysial fibrosis, are present. MMD is a pathologic diagnosis and shows clinical and genetic heterogeneity. Affected individuals have clinical features of a congenital myopathy, including neonatal hypotonia, delayed motor development, and generalized muscle weakness and amyotrophy, which may progress slowly or remain stable (Ferreiro and Fardeau, 2002). Patients with recessive mutations in the RYR1 gene typically show severe congenital muscular dystrophy with ophthalmoplegia, although there is phenotypic variability. Some patients may present in utero with fetal akinesia, arthrogryposis, and lung hypoplasia resulting in fetal or perinatal death (McKie et al., 2014). Skeletal muscle biopsy of patients with recessive RYR1 mutations show variable features, including central cores (Jungbluth et al., 2007), congenital fiber-type disproportion (CFTD) (Monnier et al., 2009), and centronuclear myopathy (Wilmshurst et al., 2010).
Lateral meningocele syndrome
MedGen UID:
342070
Concept ID:
C1851710
Disease or Syndrome
NOTCH3-related lateral meningocele syndrome (LMS) is characterized by multiple lateral spinal meningoceles (protrusions of the arachnoid and dura through spinal foramina), distinctive facial features, joint hyperextensibility, hypotonia, and skeletal, cardiac, and urogenital anomalies. Neurologic sequelæ of the meningoceles depend on size and location and can include neurogenic bladder, paresthesia, back pain, and/or paraparesis. Other neurologic findings can include Chiari I malformation, syringomyelia, and rarely, hydrocephalus. Additional findings of LMS include developmental delay, mixed or conductive hearing loss, and cleft palate. Skeletal abnormalities may include scoliosis, vertebral fusion, scalloping of vertebrae, and wormian bones. Infants may demonstrate feeding difficulties with poor weight gain.
Early-onset generalized limb-onset dystonia
MedGen UID:
338823
Concept ID:
C1851945
Disease or Syndrome
DYT1 early-onset isolated dystonia typically presents in childhood or adolescence and only on occasion in adulthood. Dystonic muscle contractions causing posturing or irregular tremor of a leg or arm are the most common presenting findings. Dystonia is usually first apparent with specific actions such as writing or walking. Over time, the contractions frequently (but not invariably) become evident with less specific actions and spread to other body regions. No other neurologic abnormalities are present. Disease severity varies considerably even within the same family. Isolated writer's cramp may be the only sign.
Calvarial doughnut lesions-bone fragility syndrome
MedGen UID:
377572
Concept ID:
C1852022
Disease or Syndrome
Calvarial doughnut lesions with bone fragility (CDL) is characterized by low bone mineral density, multiple spinal and peripheral fractures beginning in childhood, and sclerotic doughnut-shaped lesions in the cranial bones. Some more severely affected individuals exhibit neonatal onset of fractures, severe short stature, marked cranial sclerosis, and spondylometaphyseal dysplasia (CDLSMD) (Pekkinen et al., 2019).
Phelan-McDermid syndrome
MedGen UID:
339994
Concept ID:
C1853490
Disease or Syndrome
Phelan-McDermid syndrome is characterized by neonatal hypotonia, absent to severely delayed speech, developmental delay, and minor dysmorphic facial features. Most affected individuals have moderate to profound intellectual disability. Other features include large fleshy hands, dysplastic toenails, and decreased perspiration that results in a tendency to overheat. Normal stature and normal head size distinguishes Phelan-McDermid syndrome from other autosomal chromosome disorders. Behavior characteristics include mouthing or chewing non-food items, decreased perception of pain, and autism spectrum disorder or autistic-like affect and behavior.
Spinocerebellar ataxia type 13
MedGen UID:
344297
Concept ID:
C1854488
Disease or Syndrome
Spinocerebellar ataxia type 13 (SCA13) is a phenotypic spectrum that includes both non-progressive infantile-onset ataxia and progressive childhood-onset and adult-onset cerebellar ataxia. Three phenotypes are seen: Cerebellar hypoplasia with non-progressive infantile-onset limb, truncal, and gait ataxia with mild-to-moderate intellectual disability and occasionally seizures and/or psychiatric manifestations. Cognition and motor skills improve over time. Childhood-onset slowly progressive cerebellar atrophy with slowly progressive cerebellar ataxia and dysarthria, delayed motor milestones, and mild-to-moderate intellectual disability. Adult-onset progressive cerebellar atrophy with progressive ataxia and spasticity.
Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency
MedGen UID:
344419
Concept ID:
C1855100
Disease or Syndrome
For this GeneReview, the term "isolated methylmalonic acidemia" refers to a group of inborn errors of metabolism associated with elevated methylmalonic acid (MMA) concentration in the blood and urine that result from the failure to isomerize (convert) methylmalonyl-coenzyme A (CoA) into succinyl-CoA during propionyl-CoA metabolism in the mitochondrial matrix, without hyperhomocysteinemia or homocystinuria, hypomethioninemia, or variations in other metabolites, such as malonic acid. Isolated MMA is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut– enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, 5-deoxy-adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Prior to the advent of newborn screening, common phenotypes included: Infantile/non-B12-responsive form (mut0 enzymatic subtype, cblB), the most common phenotype, associated with infantile-onset lethargy, tachypnea, hypothermia, vomiting, and dehydration on initiation of protein-containing feeds. Without appropriate treatment, the infantile/non-B12-responsive phenotype could rapidly progress to coma due to hyperammonemic encephalopathy. Partially deficient or B12-responsive phenotypes (mut– enzymatic subtype, cblA, cblB [rare], cblD-MMA), in which symptoms occur in the first few months or years of life and are characterized by feeding problems, failure to thrive, hypotonia, and developmental delay marked by episodes of metabolic decompensation. Methylmalonyl-CoA epimerase deficiency, in which findings range from complete absence of symptoms to severe metabolic acidosis. Affected individuals can also develop ataxia, dysarthria, hypotonia, mild spastic paraparesis, and seizures. In those individuals diagnosed by newborn screening and treated from an early age, there appears to be decreased early mortality, less severe symptoms at diagnosis, favorable short-term neurodevelopmental outcome, and lower incidence of movement disorders and irreversible cerebral damage. However, secondary complications may still occur and can include intellectual disability, tubulointerstitial nephritis with progressive impairment of renal function, "metabolic stroke" (bilateral lacunar infarction of the basal ganglia during acute metabolic decompensation), pancreatitis, growth failure, functional immune impairment, bone marrow failure, optic nerve atrophy, arrhythmias and/or cardiomyopathy (dilated or hypertrophic), liver steatosis/fibrosis/cancer, and renal cancer.
Metaphyseal chondrodysplasia, Kaitila type
MedGen UID:
344446
Concept ID:
C1855217
Disease or Syndrome
A rare multiple metaphyseal dysplasia disease with characteristics of disproportionate short stature, short limbs and digits, tracheobronchial malacia and progressive thoracolumbar scoliosis. Radiographic imaging shows progression from marked metaphyseal dysplasia of tubular bones in childhood to short and broad bones with mild dysplasia of the joints in adulthood. There have been no further descriptions in the literature since 1982.
Frank-Ter Haar syndrome
MedGen UID:
383652
Concept ID:
C1855305
Disease or Syndrome
The primary characteristics of the Frank-ter Haar syndrome are brachycephaly, wide fontanels, prominent forehead, hypertelorism, prominent eyes, macrocornea with or without glaucoma, full cheeks, small chin, bowing of the long bones, and flexion deformity of the fingers. Protruding, simple ears and prominent coccyx are also regarded as important diagnostic signs (summary by Maas et al., 2004). Borrone syndrome was described as a severe progressive multisystem disorder with features overlapping those of FTHS, including thick skin, acne conglobata, osteolysis, gingival hypertrophy, brachydactyly, camptodactyly, and mitral valve prolapse. Although it was initially thought to be a distinct phenotype, mutations in the FTHS-associated gene SH3PXD2B have been identified in patients diagnosed with Borrone syndrome. The earlier differential description was attributed to phenotypic variability as well as to differences in the ages at which patients were examined (Wilson et al., 2014).
Mast syndrome
MedGen UID:
343325
Concept ID:
C1855346
Disease or Syndrome
Mast syndrome is an autosomal recessive complicated form of hereditary spastic paraplegia in which progressive spastic paraparesis is associated in more advanced cases with cognitive decline, dementia, and other neurologic abnormalities. Symptom onset usually occurs in adulthood, and the disorder is progressive with variable severity. Brain imaging shows thinning of the corpus callosum. The disorder occurs with high frequency in the Old Order Amish (summary by Simpson et al., 2003). For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).
Pyruvate dehydrogenase E2 deficiency
MedGen UID:
343386
Concept ID:
C1855565
Disease or Syndrome
Pyruvate dehydrogenase deficiency is characterized by the buildup of a chemical called lactic acid in the body and a variety of neurological problems. Signs and symptoms of this condition usually first appear shortly after birth, and they can vary widely among affected individuals. The most common feature is a potentially life-threatening buildup of lactic acid (lactic acidosis), which can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. People with pyruvate dehydrogenase deficiency usually have neurological problems as well. Most have delayed development of mental abilities and motor skills such as sitting and walking. Other neurological problems can include intellectual disability, seizures, weak muscle tone (hypotonia), poor coordination, and difficulty walking. Some affected individuals have abnormal brain structures, such as underdevelopment of the tissue connecting the left and right halves of the brain (corpus callosum), wasting away (atrophy) of the exterior part of the brain known as the cerebral cortex, or patches of damaged tissue (lesions) on some parts of the brain. Because of the severe health effects, many individuals with pyruvate dehydrogenase deficiency do not survive past childhood, although some may live into adolescence or adulthood.
Oculocerebrofacial syndrome, Kaufman type
MedGen UID:
343403
Concept ID:
C1855663
Disease or Syndrome
Kaufman oculocerebrofacial syndrome (KOS) is characterized by developmental delay, severe intellectual disability, and distinctive craniofacial features. Most affected children have prenatal-onset microcephaly, hypotonia, and growth deficiency. Feeding issues, ocular abnormalities, hearing impairment, and respiratory tract abnormalities are common. Ocular abnormalities can include structural abnormalities (microcornea or microphthalmia, coloboma, optic nerve hypoplasia), refractive errors (myopia ± astigmatism, hyperopia), strabismus, and entropion. Both conductive and sensorineural hearing loss have been reported as well as mixed conductive-sensorineural hearing loss of variable severity. Breathing problems can lead to prolonged hospitalization after birth in more than half of individuals. Less common findings include ectodermal abnormalities, cardiac manifestations, urogenital abnormalities, seizures, and skeletal abnormalities.
Vici syndrome
MedGen UID:
340962
Concept ID:
C1855772
Disease or Syndrome
With the current widespread use of multigene panels and comprehensive genomic testing, it has become apparent that the phenotypic spectrum of EPG5-related disorder represents a continuum. At the most severe end of the spectrum is classic Vici syndrome (defined as a neurodevelopmental disorder with multisystem involvement characterized by the combination of agenesis of the corpus callosum, cataracts, hypopigmentation, cardiomyopathy, combined immunodeficiency, microcephaly, and failure to thrive); at the milder end of the spectrum are attenuated neurodevelopmental phenotypes with variable multisystem involvement. Median survival in classic Vici syndrome appears to be 24 months, with only 10% of children surviving longer than age five years; the most common causes of death are respiratory infections as a result of primary immunodeficiency and/or cardiac insufficiency resulting from progressive cardiac failure. No data are available on life span in individuals at the milder end of the spectrum.
Mowat-Wilson syndrome
MedGen UID:
341067
Concept ID:
C1856113
Disease or Syndrome
Mowat-Wilson syndrome (MWS) is characterized by distinctive facial features (widely spaced eyes, broad eyebrows with a medial flare, low-hanging columella, prominent or pointed chin, open-mouth expression, and uplifted earlobes with a central depression), congenital heart defects with predilection for abnormalities of the pulmonary arteries and/or valves, Hirschsprung disease or chronic constipation, genitourinary anomalies (particularly hypospadias in males), and hypogenesis or agenesis of the corpus callosum. Most affected individuals have moderate-to-severe intellectual disability. Speech is typically limited to a few words or is absent, with relative preservation of receptive language skills. Growth restriction with microcephaly and seizure disorder are also common. Most affected people have a happy demeanor and a wide-based gait that can sometimes be confused with Angelman syndrome.
Congenital muscular dystrophy 1B
MedGen UID:
346746
Concept ID:
C1858118
Disease or Syndrome
A rare genetic neuromuscular disorder characterized by proximal and symmetrical muscle weakness (particularly of neck, sternomastoid, facial and diaphragm muscles), spinal rigidity, joint contractures (Achilles tendon, elbows, hands), generalized muscle hypertrophy and early respiratory failure (usually in the first decade of life). Patients typically present delayed motor milestones and grossly elevated serum creatine kinase levels, and with disease progression, forced expiratory abdominal squeeze and nocturnal hypoventilation.
Microcephaly 2, primary, autosomal recessive, with or without cortical malformations
MedGen UID:
346929
Concept ID:
C1858535
Disease or Syndrome
In WDR62 primary microcephaly (WDR62-MCPH), microcephaly (occipitofrontal circumference [OFC] = -2 SD) is usually present at birth, but in some instances becomes evident later in the first year of life. Growth is otherwise normal. Except for brain malformations in most affected individuals, no other congenital malformations are observed. Central nervous system involvement can include delayed motor development, mild-to-severe intellectual disability (ID), behavior problems, epilepsy, spasticity, and ataxia.
Chudley-McCullough syndrome
MedGen UID:
347699
Concept ID:
C1858695
Disease or Syndrome
Chudley-McCullough syndrome is an autosomal recessive neurologic disorder characterized by early-onset sensorineural deafness and specific brain anomalies on MRI, including hypoplasia of the corpus callosum, enlarged cysterna magna with mild focal cerebellar dysplasia, and nodular heterotopia. Some patients have hydrocephalus. Psychomotor development is normal (summary by Alrashdi et al., 2011).
Congenital cataracts-facial dysmorphism-neuropathy syndrome
MedGen UID:
346973
Concept ID:
C1858726
Congenital Abnormality
CTDP1-related congenital cataracts, facial dysmorphism, and neuropathy (CTDP1-CCFDN) is characterized by abnormalities of the eye (bilateral congenital cataracts, microcornea, microphthalmia, micropupils), mildly dysmorphic facial features apparent in late childhood, and a hypo-/demyelinating, symmetric, distal peripheral neuropathy. The neuropathy is predominantly motor at the onset and results in delays in early motor development, progressing to severe disability by the third decade of life. Secondary foot deformities and scoliosis are common. Sensory neuropathy develops after age ten years. Most affected individuals have a mild nonprogressive intellectual deficit and cerebellar involvement including ataxia, nystagmus, intention tremor, and dysmetria. All have short stature and most have subnormal weight. Adults have hypogonadotropic hypogonadism. Parainfectious rhabdomyolysis (profound muscle weakness, myoglobinuria, and excessively elevated serum concentration of creatine kinase usually following a viral infection) is a potentially life-threatening complication. To date all affected individuals and carriers identified have been from the Romani population.
Megalencephalic leukoencephalopathy with subcortical cysts
MedGen UID:
347006
Concept ID:
C1858854
Congenital Abnormality
The classic phenotype of megalencephalic leukoencephalopathy with subcortical cysts (MLC) is characterized by early-onset macrocephaly, often in combination with mild gross motor developmental delay and seizures; gradual onset of ataxia, spasticity, and sometimes extrapyramidal findings; and usually late onset of mild mental deterioration. Macrocephaly, observed in virtually all individuals, may be present at birth but more frequently develops during the first year of life. The degree of macrocephaly is variable and can be as great as 4 to 6 SD above the mean in some individuals. After the first year of life, head growth rate normalizes and growth follows a line parallel to and usually several centimeters above the 98th centile. Initial mental and motor development is normal in most individuals. Walking is often unstable, followed by ataxia of the trunk and extremities, then minor signs of pyramidal dysfunction and brisk deep-tendon stretch reflexes. Almost all individuals have epilepsy from an early age. The epilepsy is typically well controlled with anti-seizure medication, but status epilepticus occurs relatively frequently. Mental deterioration is late and mild. Disease severity ranges from independent walking for a few years only to independent walking in the fifth decade. Some individuals have died in their teens or twenties; others are alive in their fifties. An improving phenotype has a similar initial presentation with delayed mental or motor development, followed by an improving clinical course: macrocephaly usually persists, but some children become normocephalic; motor function improves or normalizes; hypotonia and clumsiness may persist in some or neurologic examination may become normal. Some have intellectual disability that is stable, with or without autism. Epilepsy and status epilepticus may occur.
Charcot-Marie-Tooth disease type 4A
MedGen UID:
347821
Concept ID:
C1859198
Disease or Syndrome
GDAP1-related hereditary motor and sensory neuropathy (GDAP1-HMSN) is a peripheral neuropathy (also known as a subtype of Charcot-Marie-Tooth disease) that typically affects the lower extremities earlier and more severely than the upper extremities. As the neuropathy progresses, the distal upper extremities also become severely affected. Proximal muscles can also become weak. Age at onset ranges from infancy to early childhood. In most cases, disease progression causes disabilities within the first or second decade of life. At the end of the second decade, most individuals are wheelchair bound. Disease progression varies considerably even within the same family. The neuropathy can be either of the demyelinating type with reduced nerve conduction velocities or the axonal type with normal nerve conduction velocities. Vocal cord paresis is common. Intelligence is normal. Life expectancy is usually normal, but on occasion may be reduced because of secondary complications.
Sengers syndrome
MedGen UID:
395228
Concept ID:
C1859317
Disease or Syndrome
Sengers syndrome is an autosomal recessive mitochondrial disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Mental development is normal, but affected individuals may die early from cardiomyopathy (summary by Mayr et al., 2012). Skeletal muscle biopsies of 2 affected individuals showed severe mtDNA depletion (Calvo et al., 2012).
Spinocerebellar ataxia type 29
MedGen UID:
350085
Concept ID:
C1861732
Disease or Syndrome
Spinocerebellar ataxia-29 (SCA29) is an autosomal dominant neurologic disorder characterized by onset in infancy of delayed motor development and mild cognitive delay. Affected individuals develop a very slowly progressive or nonprogressive gait and limb ataxia associated with cerebellar atrophy on brain imaging. Additional variable features include nystagmus, dysarthria, and tremor (summary by Huang et al., 2012). For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency
MedGen UID:
354935
Concept ID:
C1863236
Disease or Syndrome
Adenosine deaminase (ADA) deficiency is a systemic purine metabolic disorder that primarily affects lymphocyte development, viability, and function. The clinical phenotypic spectrum includes: Severe combined immunodeficiency disease (SCID), often diagnosed by age six months and usually by age 12 months; Less severe "delayed" onset combined immune deficiency (CID), usually diagnosed between age one and ten years; "Late/adult onset" CID, diagnosed in the second to fourth decades; Benign "partial ADA deficiency" (very low or absent ADA activity in erythrocytes but greater ADA activity in nucleated cells), which is compatible with normal immune function. Infants with typical early-onset ADA-deficient SCID have failure to thrive and opportunistic infections associated with marked depletion of T, B, and NK lymphocytes, and an absence of both humoral and cellular immune function. If immune function is not restored, children with ADA-deficient SCID rarely survive beyond age one to two years. Infections in delayed- and late-onset types (commonly, recurrent otitis, sinusitis, and upper respiratory) may initially be less severe than those in individuals with ADA-deficient SCID; however, by the time of diagnosis these individuals often have chronic pulmonary insufficiency and may have autoimmune phenomena (cytopenias, anti-thyroid antibodies), allergies, and elevated serum concentration of IgE. The longer the disorder goes unrecognized, the more immune function deteriorates and the more likely are chronic sequelae of recurrent infection.
Blepharophimosis - intellectual disability syndrome, SBBYS type
MedGen UID:
350209
Concept ID:
C1863557
Disease or Syndrome
KAT6B disorders include genitopatellar syndrome (GPS) and Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome (SBBYSS) which are part of a broad phenotypic spectrum with variable expressivity; individuals presenting with a phenotype intermediate between GPS and SBBYSS have been reported. Both phenotypes are characterized by some degree of global developmental delay / intellectual disability; hypotonia; genital abnormalities; and skeletal abnormalities including patellar hypoplasia/agenesis, flexion contractures of the knees and/or hips, and anomalies of the digits, spine, and/or ribs. Congenital heart defects, small bowel malrotation, feeding difficulties, slow growth, cleft palate, hearing loss, and dental anomalies have been observed in individuals with either phenotype.
Hypomyelination and Congenital Cataract
MedGen UID:
501134
Concept ID:
C1864663
Congenital Abnormality
Hypomyelination and congenital cataract (HCC) is usually characterized by bilateral congenital cataracts and normal psychomotor or only mildly delayed development in the first year of life, followed by slowly progressive neurologic impairment manifest as ataxia, spasticity (brisk tendon reflexes and bilateral extensor plantar responses), and mild-to-moderate cognitive impairment. Dysarthria and truncal hypotonia are observed. Cerebellar signs (truncal titubation and intention tremor) and peripheral neuropathy (muscle weakness and wasting of the legs) are present in the majority of affected individuals. Seizures can occur. Cataracts may be absent in some individuals.
Deficiency of 2-methylbutyryl-CoA dehydrogenase
MedGen UID:
355324
Concept ID:
C1864912
Disease or Syndrome
2-Methylbutyryl-CoA dehydrogenase deficiency is an autosomal recessive metabolic disorder of impaired isoleucine degradation. It is most often ascertained via newborn screening and is usually clinically asymptomatic, although some patients have been reported to have delayed development and neurologic signs. Therefore, the clinical relevance of the deficiency is unclear (Sass et al., 2008).
Megaconial type congenital muscular dystrophy
MedGen UID:
355943
Concept ID:
C1865233
Disease or Syndrome
Megaconial-type congenital muscular dystrophy is an autosomal recessive disorder characterized by early-onset muscle wasting and mental retardation. Some patients develop fatal cardiomyopathy. Muscle biopsy shows peculiar enlarged mitochondria that are prevalent toward the periphery of the fibers but are sparse in the center (summary by Mitsuhashi et al., 2011).
Bartter disease type 4a
MedGen UID:
355430
Concept ID:
C1865270
Disease or Syndrome
Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997). Patients with antenatal (or neonatal) forms of Bartter syndrome typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome (see BARTS3, 607364) present later in life and may be sporadically asymptomatic or mildly symptomatic (summary by Simon et al., 1996 and Fremont and Chan, 2012). For a discussion of genetic heterogeneity of Bartter syndrome, see 607364.
Usher syndrome type 1F
MedGen UID:
356393
Concept ID:
C1865885
Disease or Syndrome
Usher syndrome type I (USH1) is characterized by congenital, bilateral, profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP). Unless fitted with a cochlear implant, individuals do not typically develop speech. RP, a progressive, bilateral, symmetric degeneration of rod and cone functions of the retina, develops in adolescence, resulting in progressively constricted visual fields and impaired visual acuity.
Ehlers-Danlos syndrome, musculocontractural type
MedGen UID:
356497
Concept ID:
C1866294
Disease or Syndrome
The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility (Beighton et al., 1998). The major characteristics of the musculocontractural form of EDS include distinctive craniofacial dysmorphism, congenital contractures of thumbs and fingers, clubfeet, severe kyphoscoliosis, muscular hypotonia, hyperextensible thin skin with easy bruisability and atrophic scarring, wrinkled palms, joint hypermobility, and ocular involvement (summary by Malfait et al., 2010). Janecke et al. (2015) reviewed the clinical findings in 34 reported EDSMC patients, 31 with CHST14 mutations and 3 with DSE (605942) mutations (see 615539), and stated that the disorder can be recognized based on the presence of distal arthrogryposis, including adducted thumbs or clenched fists and talipes equinovarus, as well as hands with atypically shallow palmar creases and tapering fingers, and neonatal muscular hypotonia. Characteristic craniofacial features include brachycephaly, large fontanel, hypertelorism, downslanting palpebral fissures, microcorneae, strabismus, prominent nasolabial folds, short philtrum, thin upper lip, small mouth, high palate, microretrognathia, and prominent and often low-set and posteriorly rotated ears. In addition, EDSMC patients show muscular hypoplasia and weakness, which has been confirmed by ultrasound and electromyography, and intellectual development appears to be normal. Genetic Heterogeneity of Musculocontractural Ehlers-Danlos Syndrome Ehlers-Danlos syndrome musculocontractural type 2 (EDSMC2; 615539) is caused by mutation in the DSE gene (605942) on chromosome 6q22.
Charcot-Marie-Tooth disease type 4C
MedGen UID:
356581
Concept ID:
C1866636
Disease or Syndrome
SH3TC2-related hereditary motor and sensory neuropathy (SH3TC2-HMSN) is a demyelinating neuropathy characterized by severe spine deformities (scoliosis or kyphoscoliosis) and foot deformities (pes cavus, pes planus, or pes valgus) that typically present in the first decade of life or early adolescence. Other findings can include cranial nerve involvement (most commonly tongue involvement, facial weakness/paralysis, hearing impairment, dysarthria) and respiratory problems.
Benign paroxysmal tonic upgaze of childhood with ataxia
MedGen UID:
401473
Concept ID:
C1868576
Disease or Syndrome
A rare paroxysmal movement disorder with episodes of sustained, conjugate, upward deviation of the eyes and down beating saccades in attempted downgaze (with preserved horizontal eye movements). This is accompanied by ataxic symptoms (unsteady gait, lack of balance and movement coordination disturbances) in an otherwise healthy individual. Bilateral vertical nystagmus is associated. Symptoms generally disappear spontaneously within 1-2 years after onset.
Dihydropyrimidine dehydrogenase deficiency
MedGen UID:
409522
Concept ID:
C1959620
Disease or Syndrome
Dihyropyrimidine dehydrogenase deficiency shows large phenotypic variability, ranging from no symptoms to a convulsive disorder with motor and mental retardation in homozygous patients. In addition, homozygous and heterozygous mutation carriers can develop severe toxicity after the administration of the antineoplastic drug 5-fluorouracil (5FU), which is also catabolized by the DPYD enzyme. This is an example of a pharmacogenetic disorder (Van Kuilenburg et al., 1999). Since there is no correlation between genotype and phenotype in DPD deficiency, it appears that the deficiency is a necessary, but not sufficient, prerequisite for the development of clinical abnormalities (Van Kuilenburg et al., 1999; Enns et al., 2004).
Lissencephaly due to TUBA1A mutation
MedGen UID:
369910
Concept ID:
C1969029
Disease or Syndrome
Lissencephaly (LIS) due to TUBA1A mutation is a congenital cortical development anomaly due to abnormal neuronal migration involving neocortical and hippocampal lamination, corpus callosum, cerebellum and brainstem. A large clinical spectrum can be observed, from children with severe epilepsy and intellectual and motor deficit to cases with severe cerebral dysgenesis in the antenatal period leading to pregnancy termination due to the severity of the prognosis.
Autosomal recessive limb-girdle muscular dystrophy type 2M
MedGen UID:
370585
Concept ID:
C1969040
Disease or Syndrome
MDDGC4 is an autosomal recessive muscular dystrophy with onset in infancy or early childhood. Cognition and brain structure are usually normal (Godfrey et al., 2006). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Mercuri et al., 2009).
Intellectual disability, autosomal dominant 1
MedGen UID:
409857
Concept ID:
C1969562
Mental or Behavioral Dysfunction
MBD5 haploinsufficiency is a neurodevelopmental disorder characterized by developmental delay, intellectual disability, severe speech impairment, seizures, sleep disturbances, and abnormal behaviors. Most children lack speech entirely or have single words, short phrases, or short sentences. Seizures are present in more than 80% of children; onset is usually around age two years. Sleep disturbances, present in about 90%, can result in excessive daytime drowsiness. Abnormal behaviors can include autistic-like behaviors (80%) and self-injury and aggression (>60%).
Charcot-Marie-Tooth disease type 4J
MedGen UID:
370808
Concept ID:
C1970011
Disease or Syndrome
Charcot-Marie-Tooth disease type 4J is an autosomal recessive progressive neurologic disorder with a highly variable phenotype and onset ranging from early childhood to adulthood. Most patients have both proximal and distal asymmetric muscle weakness of the upper and lower limbs. There is significant motor dysfunction, followed by variably progressive sensory loss, which may be mild. Nerve conduction studies and nerve biopsies indicate demyelination as well as axonal loss (summary by Nicholson et al., 2011). For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating Charcot-Marie-Tooth disease, see CMT4A (214400).
Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome
MedGen UID:
370845
Concept ID:
C1970180
Disease or Syndrome
Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is characterized by slowly progressive cerebellar ataxia and spasticity with dorsal column dysfunction (decreased position and vibration sense) in most individuals. The neurologic dysfunction involves the legs more than the arms. The tendon reflexes are retained. Deterioration of motor skills usually starts in childhood or adolescence, but occasionally not until adulthood. Dysarthria develops over time. Occasional findings include epilepsy; learning problems; cognitive decline; and reduced consciousness, neurologic deterioration, and fever following minor head trauma. Individuals with neonatal or early-infantile onset have a severe disease course often associated with early death. Those with childhood onset have slow progression with wheelchair dependence in the teens or twenties. Adult onset is associated with slow progression and mild impairment.
Intellectual disability, autosomal recessive 10
MedGen UID:
410010
Concept ID:
C1970194
Mental or Behavioral Dysfunction
Intellectual disability, autosomal recessive 9
MedGen UID:
369678
Concept ID:
C1970195
Mental or Behavioral Dysfunction
Brain-lung-thyroid syndrome
MedGen UID:
369694
Concept ID:
C1970269
Disease or Syndrome
NKX2-1-related disorders range from benign hereditary chorea (BHC) to choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress (also known as brain-lung-thyroid syndrome). Childhood-onset chorea, the hallmark of NKX2-1-related disorders, may or may not be associated with respiratory distress syndrome or congenital hypothyroidism. Chorea generally begins in early infancy or about age one year (most commonly) or in late childhood or adolescence, and progresses into the second decade after which it remains static or (rarely) remits. Pulmonary disease, the second most common manifestation, can include respiratory distress syndrome in neonates, interstitial lung disease in young children, and pulmonary fibrosis in older persons. The risk for pulmonary carcinoma is increased in young adults with an NKX2-1-related disorder. Thyroid dysfunction, the result of dysembryogenesis, can present as congenital hypothyroidism or compensated hypothyroidism. The risk for thyroid cancer is unknown and may not be increased. In one review, 50% of affected individuals had the full brain-lung-thyroid syndrome, 30% had involvement of brain and thyroid only, and 13% had isolated chorea only.
Pitt-Hopkins syndrome
MedGen UID:
370910
Concept ID:
C1970431
Disease or Syndrome
Pitt-Hopkins syndrome (PTHS) is characterized by significant developmental delays with moderate-to-severe intellectual disability and behavioral differences, characteristic facial features, and episodic hyperventilation and/or breath-holding while awake. Speech is significantly delayed and most individuals are nonverbal with receptive language often stronger than expressive language. Other common findings are autism spectrum disorder symptoms, sleep disturbance, stereotypic hand movements, seizures, constipation, and severe myopia.
Phosphoribosylpyrophosphate synthetase superactivity
MedGen UID:
370358
Concept ID:
C1970827
Disease or Syndrome
Phosphoribosylpyrophosphate synthetase (PRS) superactivity comprises two phenotypes, both characterized by hyperuricemia and hyperuricosuria. The mild phenotype (~75% of affected males) with onset in the second or third decade of life is typically limited to these biochemical findings, whereas the severe phenotype (~25% of affected males) with onset in the first decade of life has in addition to these biochemical findings variable combinations of developmental delay (DD) / intellectual disability (ID), sensorineural hearing loss, hypotonia, and ataxia. In the mild phenotype, uric acid crystalluria or a urinary stone is commonly the first clinical finding, followed later by gouty arthritis if serum urate concentration is not controlled.
Autosomal recessive DOPA responsive dystonia
MedGen UID:
382128
Concept ID:
C2673535
Disease or Syndrome
Tyrosine hydroxylase (TH) deficiency is associated with a broad phenotypic spectrum. Based on severity of symptoms/signs as well as responsiveness to levodopa therapy, clinical phenotypes caused by pathogenic variants in TH are divided into (1) TH-deficient dopa-responsive dystonia (the mild form of TH deficiency), (2) TH-deficient infantile parkinsonism with motor delay (the severe form), and (3) TH-deficient progressive infantile encephalopathy (the very severe form). In individuals with TH-deficient dopa-responsive dystonia (DYT5b, DYT-TH), onset is between age 12 months and 12 years; initial symptoms are typically lower-limb dystonia and/or difficulty in walking. Diurnal fluctuation of symptoms (worsening of the symptoms toward the evening and their alleviation in the morning after sleep) may be present. In most individuals with TH-deficient infantile parkinsonism with motor delay, onset is between age three and 12 months. In contrast to TH-deficient DRD, motor milestones are overtly delayed in this severe form. Affected infants demonstrate truncal hypotonia and parkinsonian symptoms and signs (hypokinesia, rigidity of extremities, and/or tremor). In individuals with TH-deficient progressive infantile encephalopathy, onset is before age three to six months. Fetal distress is reported in most. Affected individuals have marked delay in motor development, truncal hypotonia, severe hypokinesia, limb hypertonia (rigidity and/or spasticity), hyperreflexia, oculogyric crises, ptosis, intellectual disability, and paroxysmal periods of lethargy (with increased sweating and drooling) alternating with irritability.
Early-onset myopathy with fatal cardiomyopathy
MedGen UID:
435983
Concept ID:
C2673677
Disease or Syndrome
Salih myopathy is characterized by muscle weakness (manifest during the neonatal period or in early infancy) and delayed motor development; children acquire independent walking between ages 20 months and four years. In the first decade of life, global motor performance is stable or tends to improve. Moderate joint and neck contractures and spinal rigidity may manifest in the first decade but become more obvious in the second decade. Scoliosis develops after age 11 years. Cardiac dysfunction manifests between ages five and 16 years, progresses rapidly, and leads to death between ages eight and 20 years, usually from heart rhythm disturbances.
Kahrizi syndrome
MedGen UID:
382543
Concept ID:
C2675185
Disease or Syndrome
Kahrizi syndrome is an autosomal recessive neurodevelopmental disorder characterized by mental retardation, cataracts, coloboma, kyphosis, and coarse facial features (summary by Kahrizi et al., 2009). See also congenital disorder of glycosylation type Iq (CDG1Q; 612379), an allelic disorder with overlapping features.
Episodic ataxia type 6
MedGen UID:
390739
Concept ID:
C2675211
Disease or Syndrome
An exceedingly rare form of hereditary episodic ataxia with varying degrees of ataxia and associated findings including slurred speech, headache, confusion and hemiplegia.
Intellectual disability, autosomal dominant 5
MedGen UID:
382611
Concept ID:
C2675473
Mental or Behavioral Dysfunction
SYNGAP1-related intellectual disability (SYNGAP1-ID) is characterized by developmental delay (DD) or intellectual disability (ID) (100% of affected individuals), generalized epilepsy (~84%), and autism spectrum disorder (ASD) and other behavioral abnormalities (=50%). To date more than 50 individuals with SYNGAP1-ID have been reported. In the majority DD/ID was moderate to severe; in some it was mild. The epilepsy is generalized; a subset of individuals with epilepsy have myoclonic astatic epilepsy (Doose syndrome) or epilepsy with myoclonic absences. Behavioral abnormalities can include stereotypic behaviors (e.g., hand flapping, obsessions with certain objects) as well as poor social development. Feeding difficulties can be significant in some.
Chromosome 6pter-p24 deletion syndrome
MedGen UID:
393396
Concept ID:
C2675486
Disease or Syndrome
Distal monosomy 6p is responsible for a distinct chromosome deletion syndrome with a recognizable clinical picture including intellectual deficit, ocular abnormalities, hearing loss, and facial dysmorphism.
Hypomyelinating leukodystrophy 6
MedGen UID:
436642
Concept ID:
C2676244
Disease or Syndrome
TUBB4A-related leukodystrophy comprises a phenotypic spectrum in which the MRI findings range from hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) at the severe end to isolated hypomyelination at the mild end. Progressive neurologic findings reflect involvement of the pyramidal tracts (spasticity, brisk deep tendon reflexes, and Babinski sign), extrapyramidal system (rigidity, dystonia, choreoathetosis, oculogyric crisis, and perioral dyskinesia), cerebellum (ataxia, intention tremor, dysmetria), and bulbar function (dysarthria, dysphonia, and swallowing). Cognition is variably affected, usually less severely than motor function. Typically, those with H-ABC present in early childhood (ages 1-3 years) and those with isolated hypomyelination in later childhood or adulthood. The rate of progression varies with disease severity.
Ehlers-Danlos syndrome, spondylocheirodysplastic type
MedGen UID:
393515
Concept ID:
C2676510
Disease or Syndrome
Ehlers-Danlos syndrome spondylodysplastic type 3 is characterized by short stature, hyperelastic skin and hypermobile joints, protuberant eyes with bluish sclerae, finely wrinkled palms, and characteristic radiologic features (Giunta et al., 2008). For a discussion of genetic heterogeneity of the spondylodysplastic type of Ehlers-Danlos syndrome, see 130070.
Autosomal recessive osteopetrosis 7
MedGen UID:
436770
Concept ID:
C2676766
Disease or Syndrome
Osteopetrosis is a bone disease that makes bones abnormally dense and prone to breakage (fracture). Researchers have described several major types of osteopetrosis, which are usually distinguished by their pattern of inheritance: autosomal dominant, autosomal recessive, or X-linked. The different types of the disorder can also be distinguished by the severity of their signs and symptoms.\n\nAutosomal dominant osteopetrosis (ADO), which is also called Albers-Schönberg disease, is typically the mildest type of the disorder. Some affected individuals have no symptoms. In these people, the unusually dense bones may be discovered by accident when an x-ray is done for another reason. In affected individuals who develop signs and symptoms, the major features of the condition include multiple bone fractures, abnormal side-to-side curvature of the spine (scoliosis) or other spinal abnormalities, arthritis in the hips, and a bone infection called osteomyelitis. These problems usually become apparent in late childhood or adolescence.\n\nAutosomal recessive osteopetrosis (ARO) is a more severe form of the disorder that becomes apparent in early infancy. Affected individuals have a high risk of bone fracture resulting from seemingly minor bumps and falls. Their abnormally dense skull bones pinch nerves in the head and face (cranial nerves), often resulting in vision loss, hearing loss, and paralysis of facial muscles. Dense bones can also impair the function of bone marrow, preventing it from producing new blood cells and immune system cells. As a result, people with severe osteopetrosis are at risk of abnormal bleeding, a shortage of red blood cells (anemia), and recurrent infections. In the most severe cases, these bone marrow abnormalities can be life-threatening in infancy or early childhood.\n\nOther features of autosomal recessive osteopetrosis can include slow growth and short stature, dental abnormalities, and an enlarged liver and spleen (hepatosplenomegaly). Depending on the genetic changes involved, people with severe osteopetrosis can also have brain abnormalities, intellectual disability, or recurrent seizures (epilepsy).\n\nA few individuals have been diagnosed with intermediate autosomal osteopetrosis (IAO), a form of the disorder that can have either an autosomal dominant or an autosomal recessive pattern of inheritance. The signs and symptoms of this condition become noticeable in childhood and include an increased risk of bone fracture and anemia. People with this form of the disorder typically do not have life-threatening bone marrow abnormalities. However, some affected individuals have had abnormal calcium deposits (calcifications) in the brain, intellectual disability, and a form of kidney disease called renal tubular acidosis.\n\nRarely, osteopetrosis can have an X-linked pattern of inheritance. In addition to abnormally dense bones, the X-linked form of the disorder is characterized by abnormal swelling caused by a buildup of fluid (lymphedema) and a condition called anhydrotic ectodermal dysplasia that affects the skin, hair, teeth, and sweat glands. Affected individuals also have a malfunctioning immune system (immunodeficiency), which allows severe, recurrent infections to develop. Researchers often refer to this condition as OL-EDA-ID, an acronym derived from each of the major features of the disorder.
Dystonia 16
MedGen UID:
436979
Concept ID:
C2677567
Disease or Syndrome
Dystonia 16 is one of many forms of dystonia, which is a group of conditions characterized by involuntary movements, twisting (torsion) and tensing of various muscles, and unusual positioning of affected body parts. Dystonia 16 can appear at any age from infancy through adulthood, although it most often begins in childhood.\n\nThe signs and symptoms of dystonia 16 vary among people with the condition. In many affected individuals, the disorder first affects muscles in one or both arms or legs. Tensing (contraction) of the muscles often sets the affected limb in an abnormal position, which may be painful and can lead to difficulty performing tasks, such as walking. In others, muscles in the neck are affected first, causing the head to be pulled backward and positioned with the chin in the air (retrocollis).\n\nIn dystonia 16, muscles of the jaw, lips, and tongue are also commonly affected (oromandibular dystonia), causing difficulty opening and closing the mouth and problems with swallowing and speech. Speech can also be affected by involuntary tensing of the muscles that control the vocal cords (laryngeal dystonia), resulting in a quiet, breathy voice or an inability to speak clearly. Dystonia 16 gradually gets worse, eventually involving muscles in most parts of the body.\n\nSome people with dystonia 16 develop a pattern of movement abnormalities known as parkinsonism. These abnormalities include unusually slow movement (bradykinesia), muscle rigidity, tremors, and an inability to hold the body upright and balanced (postural instability). In dystonia 16, parkinsonism is relatively mild if it develops at all.\n\nThe signs and symptoms of dystonia 16 usually do not get better when treated with drugs that are typically used for movement disorders.
Intellectual disability, X-linked syndromic, Turner type
MedGen UID:
394425
Concept ID:
C2678046
Disease or Syndrome
Turner-type X-linked syndromic intellectual developmental disorder (MRXST) is a neurodevelopmental disorder with a highly variable phenotype. Some affected families show X-linked recessive inheritance, with only males being affected and carrier females having no abnormal findings. In other affected families, males are severely affected, and female mutation carriers show milder cognitive abnormalities or dysmorphic features. In addition, there are female patients with de novo mutations who show the full phenotype, despite skewed X-chromosome inactivation. Affected individuals show global developmental delay from infancy, with variably impaired intellectual development and poor or absent speech, often with delayed walking. Dysmorphic features are common and can include macrocephaly, microcephaly, deep-set eyes, hypotelorism, small palpebral fissures, dysplastic, large, or low-set ears, long face, bitemporal narrowing, high-arched palate, thin upper lip, and scoliosis or mild distal skeletal anomalies, such as brachydactyly or tapered fingers. Males tend to have cryptorchidism. Other features, such as hypotonia, seizures, and delayed bone age, are more variable (summary by Moortgat et al., 2018).
X-linked non progressive cerebellar ataxia
MedGen UID:
394718
Concept ID:
C2678048
Disease or Syndrome
X-linked non progressive cerebellar ataxia is a rare hereditary ataxia characterized by delayed early motor development, severe neonatal hypotonia, non-progressive ataxia and slow eye movements, presenting normal cognitive abilities and absence of pyramidal signs. Frequently patients also manifest intention tremor, mild dysphagia, and dysarthria. Brain MRI reveals global cerebellar atrophy with absence of other malformations or degenerations of the central and peripheral nervous systems.
Ehlers-Danlos syndrome, dermatosparaxis type
MedGen UID:
397792
Concept ID:
C2700425
Disease or Syndrome
Dermatosparaxis (meaning 'tearing of skin') is an autosomal recessive disorder of connective tissue resulting from deficiency of procollagen peptidase, an enzyme that aids in the processing of type I procollagen. The disorder and the responsible biochemical defect was first observed in cattle (Lapiere et al., 1971). Lapiere and Nusgens (1993) reviewed the discovery of dermatosparaxis in cattle, the elucidation of the disorder, its occurrence in other animals, and the delayed recognition of the disorder in the human.
Sterile multifocal osteomyelitis with periostitis and pustulosis
MedGen UID:
411230
Concept ID:
C2748507
Disease or Syndrome
A rare severe genetic autoinflammatory syndrome characterized by usually neonatal onset of generalized neutrophilic cutaneous pustulosis and severe recurrent multifocal aseptic osteomyelitis with marked periostitis, typically affecting distal ribs, long bones and vertebral bodies. High levels of acute-phase reactants (with no fever associated) and onychosis are frequently observed additional features. Caused by homozygous mutation in the IL1RN gene on chromosome 2q14.
Intellectual disability, X-linked 97
MedGen UID:
440689
Concept ID:
C2749020
Mental or Behavioral Dysfunction
Any non-syndromic X-linked intellectual disability in which the cause of the disease is a mutation in the ZNF711 gene.
Spondylo-megaepiphyseal-metaphyseal dysplasia
MedGen UID:
412869
Concept ID:
C2750066
Disease or Syndrome
Spondylo-megaepiphyseal-metaphyseal dysplasia is a rare autosomal recessive skeletal dysplasia characterized by disproportionate short stature with a short and stiff neck and trunk; relatively long limbs that may show flexion contractures of the distal joints; delayed and impaired ossification of the vertebral bodies and the presence of large epiphyseal ossification centers and wide growth plates in the long tubular bones; and numerous pseudoepiphyses of the short tubular bones in hands and feet (summary by Hellemans et al., 2009).
Noonan syndrome 6
MedGen UID:
413028
Concept ID:
C2750732
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Congenital muscular dystrophy due to LMNA mutation
MedGen UID:
413043
Concept ID:
C2750785
Disease or Syndrome
LMNA-related congenital muscular dystrophy (L-CMD) is a condition that primarily affects muscles used for movement (skeletal muscles). It is part of a group of genetic conditions called congenital muscular dystrophies, which cause weak muscle tone (hypotonia) and muscle wasting (atrophy) beginning very early in life.\n\nIn people with L-CMD, muscle weakness becomes apparent in infancy or early childhood and can worsen quickly. The most severely affected infants develop few motor skills, and they are never able to hold up their heads, roll over, or sit. Less severely affected children may learn to sit, stand, and walk before muscle weakness becomes apparent. First the neck muscles weaken, causing the head to fall forward (dropped-head syndrome). As other skeletal muscles become weaker, these children may ultimately lose the ability to sit, stand, and walk unassisted.\n\nOther features of L-CMD often include spinal rigidity and abnormal curvature of the spine (scoliosis and lordosis); joint deformities (contractures) that restrict movement, particularly in the hips and legs; and an inward-turning foot. People with L-CMD also have an increased risk of heart rhythm abnormalities (arrhythmias).\n\nOver time, muscle weakness causes most infants and children with L-CMD to have trouble eating and breathing. The breathing problems result from restrictive respiratory insufficiency, which occurs when muscles in the chest are weakened and the ribcage becomes increasingly rigid. This problem can be life-threatening, and many affected children require support with a machine to help them breathe (mechanical ventilation).
Congenital muscular dystrophy due to integrin alpha-7 deficiency
MedGen UID:
413044
Concept ID:
C2750786
Disease or Syndrome
A rare genetic congenital muscular dystrophy due to extracellular matrix protein anomaly. The disease has characteristics of early motor development delay and muscle weakness with mild elevation of serum creatine kinase that may be followed by progressive disease course with predominantly proximal muscle weakness and atrophy, motor development regress, scoliosis and respiratory insufficiency. There is evidence this disease is caused by compound heterozygous mutation in the ITGA7 gene on chromosome 12q13.
Muscular dystrophy-dystroglycanopathy (congenital without intellectual disability), type B4
MedGen UID:
413465
Concept ID:
C2751052
Disease or Syndrome
MDDGB4 is a rare autosomal recessive congenital muscular dystrophy that is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies.' In contrast to most dystroglycanopathies, impaired intellectual development is not a feature of MDDGB4 (Godfrey et al., 2007). For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (613155).
Glycogen storage disease IXc
MedGen UID:
442778
Concept ID:
C2751643
Disease or Syndrome
Phosphorylase kinase (PhK) deficiency causing glycogen storage disease type IX (GSD IX) results from deficiency of the enzyme phosphorylase b kinase, which has a major regulatory role in the breakdown of glycogen. The two types of PhK deficiency are liver PhK deficiency (characterized by early childhood onset of hepatomegaly and growth restriction, and often, but not always, fasting ketosis and hypoglycemia) and muscle PhK deficiency, which is considerably rarer (characterized by any of the following: exercise intolerance, myalgia, muscle cramps, myoglobinuria, and progressive muscle weakness). While symptoms and biochemical abnormalities of liver PhK deficiency were thought to improve with age, it is becoming evident that affected individuals need to be monitored for long-term complications such as liver fibrosis and cirrhosis.
PGM1-congenital disorder of glycosylation
MedGen UID:
414536
Concept ID:
C2752015
Disease or Syndrome
Congenital disorder of glycosylation type It (CDG1T) is an autosomal recessive disorder characterized by a wide range of clinical manifestations and severity. The most common features include cleft lip and bifid uvula, apparent at birth, followed by hepatopathy, intermittent hypoglycemia, short stature, and exercise intolerance, often accompanied by increased serum creatine kinase. Less common features include rhabdomyolysis, dilated cardiomyopathy, and hypogonadotropic hypogonadism (summary by Tegtmeyer et al., 2014). For a discussion of the classification of CDGs, see CDG1A (212065).
Oxoglutaricaciduria
MedGen UID:
414553
Concept ID:
C2752074
Disease or Syndrome
Oxoglutarate dehydrogenase deficiency (OGDHD) is an autosomal recessive disorder associated with features of infantile- and pediatric-onset basal ganglia-associated movement disorders, hypotonia, developmental delays, ataxia, and seizures (summary by Yap et al., 2021).
Clark-Baraitser syndrome
MedGen UID:
443983
Concept ID:
C2931130
Disease or Syndrome
Hereditary spastic paraplegia 3A
MedGen UID:
419393
Concept ID:
C2931355
Disease or Syndrome
Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) is characterized by progressive bilateral and mostly symmetric spasticity and weakness of the legs. Compared to other forms of autosomal dominant hereditary spastic paraplegia (HSP), in which diminished vibration sense (caused by degeneration of the corticospinal tracts and dorsal columns) and urinary bladder hyperactivity are present in all affected individuals, these findings occur in a minority of individuals with SPG3A. The average age of onset is four years. More than 80% of reported individuals manifest spastic gait before the end of the first decade of life. Most persons with early-onset ATL1-HSP have a "pure" ("uncomplicated") HSP; however, complicated HSP with axonal motor neuropathy and/or distal amyotrophy with lower motor neuron involvement (Silver syndrome phenotype) has been observed. The rate of progression in ATL1-HSP is slow, and wheelchair dependency or need for a walking aid (cane, walker, or wheelchair) is relatively rare.
Infantile-onset ascending hereditary spastic paralysis
MedGen UID:
419413
Concept ID:
C2931441
Disease or Syndrome
ALS2-related disorder involves retrograde degeneration of the upper motor neurons of the pyramidal tracts and comprises a clinical continuum of the following three phenotypes: Infantile ascending hereditary spastic paraplegia (IAHSP), characterized by onset of spasticity with increased reflexes and sustained clonus of the lower limbs within the first two years of life, progressive weakness and spasticity of the upper limbs by age seven to eight years, and wheelchair dependence in the second decade with progression toward severe spastic tetraparesis and a pseudobulbar syndrome caused by progressive cranial nerve involvement. Juvenile primary lateral sclerosis (JPLS), characterized by upper motor neuron findings of pseudobulbar palsy and spastic quadriplegia without dementia or cerebellar, extrapyramidal, or sensory signs. Juvenile amyotrophic lateral sclerosis (JALS or ALS2), characterized by onset between ages three and 20 years. All affected individuals show a spastic pseudobulbar syndrome (spasticity of speech and swallowing) together with spastic paraplegia. Some individuals are bedridden by age 12 to 50 years.
Seizures, benign familial neonatal, 1
MedGen UID:
460425
Concept ID:
C3149074
Disease or Syndrome
KCNQ2-related disorders represent a continuum of overlapping neonatal epileptic phenotypes ranging from self-limited familial neonatal epilepsy (SLFNE) at the mild end to neonatal-onset developmental and epileptic encephalopathy (NEO-DEE) at the severe end. Additional, less common phenotypes consisting of neonatal encephalopathy with non-epileptic myoclonus, infantile or childhood-onset developmental and epileptic encephalopathy (DEE), and isolated intellectual disability (ID) without epilepsy have also been described. KCNQ2-SLFNE is characterized by seizures that start in otherwise healthy infants between two and eight days after term birth and spontaneously disappear between the first and the sixth to 12th month of life. There is always a seizure-free interval between birth and the onset of seizures. Seizures are characterized by sudden onset with prominent motor involvement, often accompanied by apnea and cyanosis; video EEG identifies seizures as focal onset with tonic stiffening of limb(s) and some migration during each seizure's evolution. About 30% of individuals with KCNQ2-SLFNE develop epileptic seizures later in life. KCNQ2-NEO-DEE is characterized by multiple daily seizures beginning in the first week of life that are mostly tonic, with associated focal motor and autonomic features. Seizures generally cease between ages nine months and four years. At onset, EEG shows a burst-suppression pattern or multifocal epileptiform activity; early brain MRI can show basal ganglia hyperdensities and later MRIs may show white matter or general volume loss. Moderate-to-profound developmental impairment is present.
Proximal 16p11.2 microdeletion syndrome
MedGen UID:
461504
Concept ID:
C3150154
Disease or Syndrome
The 16p11.2 recurrent deletion phenotype is characterized by motor speech disorder, language disorder, motor coordination difficulties, psychiatric conditions, and autistic features. While most, if not all, individuals with the 16p11.2 recurrent deletion experience some degree of developmental delay, the severity varies significantly. Most affected individuals do not have intellectual disability (defined as an IQ of <70), but many have below average cognition and learning disabilities in both verbal and nonverbal domains. Obesity is a feature of this disorder and generally emerges in childhood; BMI in individuals with the 16p11.2 recurrent deletion is significantly higher than in the general population by age five years. Seizures are observed in approximately 25% of individuals with the recurrent deletion. Vertebral anomalies, hearing impairment, macrocephaly, and cardiovascular malformation have each been observed in some individuals. Clinical follow-up data from adults suggests that the greatest medical challenges are obesity and related comorbidities that can be exacerbated by medications used to treat behavioral and psychiatric problems.
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3
MedGen UID:
461762
Concept ID:
C3150412
Disease or Syndrome
MDDGB3 is an autosomal recessive congenital muscular dystrophy with impaired intellectual development and mild brain abnormalities (Clement et al., 2008). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Mercuri et al., 2009). For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (613155).
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5
MedGen UID:
461763
Concept ID:
C3150413
Disease or Syndrome
Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and death usually in the first years of life. It represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of DAG1 (128239), collectively known as 'dystroglycanopathies' (Beltran-Valero de Bernabe et al., 2004). For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (236670).
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2
MedGen UID:
461766
Concept ID:
C3150416
Disease or Syndrome
MDDGB2 is an autosomal recessive congenital muscular dystrophy associated with impaired intellectual development and mild structural brain abnormalities (Yanagisawa et al., 2007). It is part of a group of similar disorders, collectively known as 'dystroglycanopathies,' resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239) (Godfrey et al., 2007). For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (613155).
Autosomal recessive limb-girdle muscular dystrophy type 2O
MedGen UID:
461767
Concept ID:
C3150417
Disease or Syndrome
MDDGC3 is a rare form of autosomal recessive limb-girdle muscular dystrophy with normal cognition (Clement et al., 2008). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Godfrey et al., 2007). For a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type C, see MDDGC1 (609308).
Autosomal recessive limb-girdle muscular dystrophy type 2N
MedGen UID:
461768
Concept ID:
C3150418
Disease or Syndrome
MDDGC2 is an autosomal recessive muscular dystrophy with onset after ambulation is achieved. Cognition is normal (Biancheri et al., 2007). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Godfrey et al., 2007). For a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type C, see MDDGC1 (609308).
Syndromic multisystem autoimmune disease due to ITCH deficiency
MedGen UID:
461999
Concept ID:
C3150649
Disease or Syndrome
Syndromic multisystem autoimmune disease due to Itch deficiency is a rare, genetic, systemic autoimmune disease characterized by failure to thrive, global developmental delay, distinctive craniofacial dysmorphism (relative macrocephaly, dolichocephaly, frontal bossing, orbital proptosis, flattened midface with a prominent occiput, low, posteriorly rotated ears, micrognatia), hepato- and/or splenomegaly, and multisystemic autoimmune disease involving the lungs, liver, gut and/or thyroid gland.
Autosomal recessive nonsyndromic hearing loss 84A
MedGen UID:
462004
Concept ID:
C3150654
Disease or Syndrome
Any autosomal recessive nonsyndromic deafness in which the cause of the disease is a mutation in the PTPRQ gene.
Microcephaly, seizures, and developmental delay
MedGen UID:
462017
Concept ID:
C3150667
Disease or Syndrome
Microcephaly, seizures, and developmental delay (MCSZ) is an autosomal recessive neurodevelopmental disorder with onset in infancy. There is a range of phenotypic severity: some patients develop refractory seizures in infancy, consistent with a developmental and epileptic encephalopathy (DEE), whereas others have more well-controlled seizures and a more protracted course associated with cerebellar atrophy and peripheral neuropathy (Shen et al., 2010 and Poulton et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Intellectual disability, autosomal dominant 20
MedGen UID:
462050
Concept ID:
C3150700
Disease or Syndrome
Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL) is characterized by global developmental delay with hypotonia, poor motor development with limited walking, impaired intellectual development with poor or absent speech, and behavioral abnormalities. Almost all affected individuals demonstrate repetitive stereotypic hand movements that can be categorized as hyperkinetic and resembling those of Rett syndrome (RTT; 312750). About 80% of patients develop various types of seizures that may be refractory to treatment. Additional features may include dysmorphic facial features, particularly dysplastic ears, poor eye contact, episodic hyperventilation, tendency to infection, and abnormalities on brain imaging, such as enlarged ventricles, thin corpus callosum, and delayed myelination (summary by Vrecar et al., 2017, Paciorkowski et al., 2013).
Rett syndrome, congenital variant
MedGen UID:
462055
Concept ID:
C3150705
Disease or Syndrome
The congenital variant of Rett syndrome is a severe neurodevelopmental disorder with features of classic Rett syndrome (RTT; 312750), but earlier onset in the first months of life. Classic Rett syndrome shows later onset and is caused by mutation in the MECP2 gene (300005).
COG5-congenital disorder of glycosylation
MedGen UID:
462226
Concept ID:
C3150876
Disease or Syndrome
COG5-congenital disorder of glycosylation (COG5-CDG, formerly known as congenital disorder of glycosylation type IIi) is an inherited condition that causes neurological problems and other abnormalities. The pattern and severity of this disorder's signs and symptoms vary among affected individuals.\n\nIndividuals with COG5-CDG typically develop signs and symptoms of the condition during infancy. These individuals often have weak muscle tone (hypotonia) and delayed development. Other neurological features include moderate to severe intellectual disability, poor coordination, and difficulty walking. Some affected individuals never learn to speak. Other features of COG5-CDG include short stature, an unusually small head size (microcephaly), and distinctive facial features, which can include ears that are set low and rotated backward, a short neck with a low hairline in the back, and a prominent nose. Less commonly, affected individuals can have hearing loss caused by changes in the inner ear (sensorineural hearing loss), vision impairment, damage to the nerves that control bladder function (a condition called neurogenic bladder), liver disease, and joint deformities (contractures).
Treacher Collins syndrome 2
MedGen UID:
462333
Concept ID:
C3150983
Disease or Syndrome
Treacher Collins syndrome (TCS) is characterized by bilateral and symmetric downslanting palpebral fissures, malar hypoplasia, micrognathia, and external ear abnormalities. Hypoplasia of the zygomatic bones and mandible can cause significant feeding and respiratory difficulties. About 40%-50% of individuals have conductive hearing loss attributed most commonly to malformation of the ossicles and hypoplasia of the middle ear cavities. Inner ear structures tend to be normal. Other, less common abnormalities include cleft palate and unilateral or bilateral choanal stenosis or atresia. Typically intellect is normal.
Autosomal recessive limb-girdle muscular dystrophy type 2Q
MedGen UID:
462339
Concept ID:
C3150989
Disease or Syndrome
Autosomal recessive limb-girdle muscular dystrophy-17 (LGMDR17) is characterized by early childhood onset of proximal muscle weakness and atrophy without skin involvement. One family has shown rapid progression of the disorder in adolescence (summary by Gundesli et al., 2010). For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600).
Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase
MedGen UID:
462408
Concept ID:
C3151058
Disease or Syndrome
Hypermethioninemia is an excess of a particular protein building block (amino acid), called methionine, in the blood. This condition can occur when methionine is not broken down (metabolized) properly in the body.\n\nPeople with hypermethioninemia often do not show any symptoms. Some individuals with hypermethioninemia exhibit intellectual disability and other neurological problems; delays in motor skills such as standing or walking; sluggishness; muscle weakness; liver problems; unusual facial features; and their breath, sweat, or urine may have a smell resembling boiled cabbage.\n\nHypermethioninemia can occur with other metabolic disorders, such as homocystinuria, tyrosinemia, and galactosemia, which also involve the faulty breakdown of particular molecules. It can also result from liver disease or excessive dietary intake of methionine from consuming large amounts of protein or a methionine-enriched infant formula. The condition is called primary hypermethioninemia when it is not associated with other metabolic disorders or excess methionine in the diet.
Meier-Gorlin syndrome 3
MedGen UID:
462463
Concept ID:
C3151113
Disease or Syndrome
Abnormalities in sexual development may also occur in Meier-Gorlin syndrome. In some males with this condition, the testes are small or undescended (cryptorchidism). Affected females may have unusually small external genital folds (hypoplasia of the labia majora) and small breasts. Both males and females with this condition can have sparse or absent underarm (axillary) hair.\n\nAdditional features of Meier-Gorlin syndrome can include difficulty feeding and a lung condition known as pulmonary emphysema or other breathing problems.\n\nMeier-Gorlin syndrome is a condition primarily characterized by short stature. It is considered a form of primordial dwarfism because the growth problems begin before birth (intrauterine growth retardation). After birth, affected individuals continue to grow at a slow rate. Other characteristic features of this condition are underdeveloped or missing kneecaps (patellae), small ears, and, often, an abnormally small head (microcephaly). Despite a small head size, most people with Meier-Gorlin syndrome have normal intellect.\n\nSome people with Meier-Gorlin syndrome have other skeletal abnormalities, such as unusually narrow long bones in the arms and legs, a deformity of the knee joint that allows the knee to bend backwards (genu recurvatum), and slowed mineralization of bones (delayed bone age).\n\nMost people with Meier-Gorlin syndrome have distinctive facial features. In addition to being abnormally small, the ears may be low-set or rotated backward. Additional features can include a small mouth (microstomia), an underdeveloped lower jaw (micrognathia), full lips, and a narrow nose with a high nasal bridge.
Megalencephalic leukoencephalopathy with subcortical cysts 2A
MedGen UID:
462705
Concept ID:
C3151355
Disease or Syndrome
The classic phenotype of megalencephalic leukoencephalopathy with subcortical cysts (MLC) is characterized by early-onset macrocephaly, often in combination with mild gross motor developmental delay and seizures; gradual onset of ataxia, spasticity, and sometimes extrapyramidal findings; and usually late onset of mild mental deterioration. Macrocephaly, observed in virtually all individuals, may be present at birth but more frequently develops during the first year of life. The degree of macrocephaly is variable and can be as great as 4 to 6 SD above the mean in some individuals. After the first year of life, head growth rate normalizes and growth follows a line parallel to and usually several centimeters above the 98th centile. Initial mental and motor development is normal in most individuals. Walking is often unstable, followed by ataxia of the trunk and extremities, then minor signs of pyramidal dysfunction and brisk deep-tendon stretch reflexes. Almost all individuals have epilepsy from an early age. The epilepsy is typically well controlled with anti-seizure medication, but status epilepticus occurs relatively frequently. Mental deterioration is late and mild. Disease severity ranges from independent walking for a few years only to independent walking in the fifth decade. Some individuals have died in their teens or twenties; others are alive in their fifties. An improving phenotype has a similar initial presentation with delayed mental or motor development, followed by an improving clinical course: macrocephaly usually persists, but some children become normocephalic; motor function improves or normalizes; hypotonia and clumsiness may persist in some or neurologic examination may become normal. Some have intellectual disability that is stable, with or without autism. Epilepsy and status epilepticus may occur.
Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability
MedGen UID:
462706
Concept ID:
C3151356
Disease or Syndrome
The classic phenotype of megalencephalic leukoencephalopathy with subcortical cysts (MLC) is characterized by early-onset macrocephaly, often in combination with mild gross motor developmental delay and seizures; gradual onset of ataxia, spasticity, and sometimes extrapyramidal findings; and usually late onset of mild mental deterioration. Macrocephaly, observed in virtually all individuals, may be present at birth but more frequently develops during the first year of life. The degree of macrocephaly is variable and can be as great as 4 to 6 SD above the mean in some individuals. After the first year of life, head growth rate normalizes and growth follows a line parallel to and usually several centimeters above the 98th centile. Initial mental and motor development is normal in most individuals. Walking is often unstable, followed by ataxia of the trunk and extremities, then minor signs of pyramidal dysfunction and brisk deep-tendon stretch reflexes. Almost all individuals have epilepsy from an early age. The epilepsy is typically well controlled with anti-seizure medication, but status epilepticus occurs relatively frequently. Mental deterioration is late and mild. Disease severity ranges from independent walking for a few years only to independent walking in the fifth decade. Some individuals have died in their teens or twenties; others are alive in their fifties. An improving phenotype has a similar initial presentation with delayed mental or motor development, followed by an improving clinical course: macrocephaly usually persists, but some children become normocephalic; motor function improves or normalizes; hypotonia and clumsiness may persist in some or neurologic examination may become normal. Some have intellectual disability that is stable, with or without autism. Epilepsy and status epilepticus may occur.
Osteogenesis imperfecta type 12
MedGen UID:
462783
Concept ID:
C3151433
Disease or Syndrome
Osteogenesis imperfecta (OI) comprises a group of connective tissue disorders characterized by bone fragility and low bone mass. The disorder is clinically and genetically heterogeneous. OI type XII is an autosomal recessive form characterized by recurrent fractures, mild bone deformations, generalized osteoporosis, delayed teeth eruption, progressive hearing loss, no dentinogenesis imperfecta, and white sclerae (summary by Lapunzina et al., 2010).
Mitochondrial DNA depletion syndrome 9
MedGen UID:
462826
Concept ID:
C3151476
Disease or Syndrome
SUCLG1-related mitochondrial DNA (mtDNA) depletion syndrome, encephalomyopathic form with methylmalonic aciduria is characterized in the majority of affected newborns by hypotonia, muscle atrophy, feeding difficulties, and lactic acidosis. Affected infants commonly manifest developmental delay / cognitive impairment, growth retardation / failure to thrive, hepatopathy, sensorineural hearing impairment, dystonia, and hypertonia. Notable findings in some affected individuals include hypertrophic cardiomyopathy, epilepsy, myoclonus, microcephaly, sleep disturbance, rhabdomyolysis, contractures, hypothermia, and/or hypoglycemia. Life span is shortened, with median survival of 20 months.
Chromosome 15q11.2 deletion syndrome
MedGen UID:
467404
Concept ID:
C3180937
Disease or Syndrome
A heterozygous deletion of chromosome 15q11.2 may increase the susceptibility to neuropsychiatric or neurodevelopmental problems, including delayed psychomotor development, speech delay, autism spectrum disorder, attention deficit-hyperactivity disorder, obsessive-compulsive disorder, and possibly seizures (summary by Doornbos et al., 2009 and Burnside et al., 2011). See also chromosome 15q11.2 duplication syndrome (608636).
Intellectual disability, X-linked 90
MedGen UID:
477074
Concept ID:
C3275443
Mental or Behavioral Dysfunction
Any non-syndromic X-linked intellectual disability in which the cause of the disease is a mutation in the DLG3 gene.
Syndromic X-linked intellectual disability 17
MedGen UID:
477091
Concept ID:
C3275460
Mental or Behavioral Dysfunction
Intellectual disability-alacrima-achalasia syndrome is a rare, genetic intellectual disability syndrome characterized by delayed motor and cognitive development, absence or severe delay in speech development, intellectual disability, and alacrima. Achalasia/dysphagia and mild autonomic dysfunction (i.e. anisocoria) have also been reported in some patients. The phenotype is similar to the one observed in autosomal recessive Triple A syndrome, but differs by the presence of intellectual disability in all affected individuals.
Larsen-like syndrome, B3GAT3 type
MedGen UID:
480034
Concept ID:
C3278404
Disease or Syndrome
CHST3-related skeletal dysplasia is characterized by short stature of prenatal onset, joint dislocations (knees, hips, radial heads), clubfeet, and limitation of range of motion that can involve all large joints. Kyphosis and occasionally scoliosis with slight shortening of the trunk develop in childhood. Minor heart valve dysplasia has been described in several persons. Intellect and vision are normal.
Immunodeficiency-centromeric instability-facial anomalies syndrome 2
MedGen UID:
481378
Concept ID:
C3279748
Disease or Syndrome
Immunodeficiency, centromeric instability, and facial dysmorphism (ICF) syndrome is a rare autosomal recessive disorder characterized by facial dysmorphism, immunoglobulin deficiency resulting in recurrent infections, and mental retardation. Laboratory studies of patient cells show hypomethylation of satellite regions of chromosomes 1, 9, and 16, as well as pericentromeric chromosomal instability in response to phytohemagglutinin stimulation (summary by de Greef et al., 2011). For a discussion of genetic heterogeneity of immunodeficiency-centromeric instability-facial anomalies syndrome, see ICF1 (242860).
Congenital myasthenic syndrome 16
MedGen UID:
481742
Concept ID:
C3280112
Disease or Syndrome
Congenital myasthenic syndrome is a disorder characterized by variable degrees of muscle fatigability caused by impaired transmission of electrical signals at the neuromuscular junction (NMJ) (summary by Arnold et al., 2015). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Rafiq syndrome
MedGen UID:
481757
Concept ID:
C3280127
Disease or Syndrome
Rafiq syndrome (RAFQS) is an autosomal recessive disorder characterized by variably impaired intellectual and motor development, a characteristic facial dysmorphism, truncal obesity, and hypotonia. The facial dysmorphism comprises prominent eyebrows with lateral thinning, downward-slanting palpebral fissures, bulbous tip of the nose, large ears, and a thin upper lip. Behavioral problems, including overeating, verbal and physical aggression, have been reported in some cases. Serum transferrin isoelectric focusing shows a type 2 pattern (summary by Balasubramanian et al., 2019).
Charcot-Marie-Tooth disease axonal type 2O
MedGen UID:
481850
Concept ID:
C3280220
Disease or Syndrome
A rare genetic subtype of autosomal dominant Charcot-Marie-Tooth disease type 2 with characteristics of early childhood-onset of slowly progressive, predominantly distal, lower limb muscle weakness and atrophy, delayed motor development, variable sensory loss and pes cavus in the presence of normal or near-normal nerve conduction velocities. Additional variable features may include proximal muscle weakness, abnormal gait, arthrogryposis, scoliosis, cognitive impairment, and spasticity. Caused by heterozygous mutation in the DYNC1H1 gene on chromosome 14q32.
Intellectual disability, autosomal recessive 29
MedGen UID:
482155
Concept ID:
C3280525
Mental or Behavioral Dysfunction
Intellectual disability, autosomal recessive 19
MedGen UID:
482171
Concept ID:
C3280541
Mental or Behavioral Dysfunction
Intellectual disability, autosomal recessive 23
MedGen UID:
482172
Concept ID:
C3280542
Mental or Behavioral Dysfunction
Intellectual disability, autosomal recessive 24
MedGen UID:
482173
Concept ID:
C3280543
Mental or Behavioral Dysfunction
Intellectual disability, autosomal recessive 25
MedGen UID:
482174
Concept ID:
C3280544
Mental or Behavioral Dysfunction
Intellectual disability, autosomal recessive 28
MedGen UID:
482175
Concept ID:
C3280545
Mental or Behavioral Dysfunction
Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1
MedGen UID:
482290
Concept ID:
C3280660
Disease or Syndrome
Encephalopathy due to defective mitochondrial and peroxisomal fission-1 (EMPF1) is characterized by delayed psychomotor development and hypotonia that may lead to death in childhood. Many patients develop refractory seizures, consistent with an epileptic encephalopathy, and thereafter show neurologic decline. The age at onset, features, and severity are variable, and some patients may not have clinical evidence of mitochondrial or peroxisomal dysfunction (summary by Sheffer et al., 2016; Fahrner et al., 2016). Genetic Heterogeneity of Encephalopathy Due to Defective Mitochondrial And Peroxisomal Fission See also EMPF2 (617086), caused by mutation in the MFF gene (614785) on chromosome 2q36.
MEGF10-Related Myopathy
MedGen UID:
482309
Concept ID:
C3280679
Disease or Syndrome
EMARDD is a congenital myopathy characterized by proximal and generalized muscle weakness, respiratory difficulties, joint contractures, and scoliosis. More variable features include cleft palate and feeding difficulties. There is variable severity: some patients become ventilator-dependent, never achieve walking, and die in childhood, whereas others have a longer and more favorable course (summary by Logan et al., 2011 and Boyden et al., 2012).
Lipoic acid synthetase deficiency
MedGen UID:
482517
Concept ID:
C3280887
Disease or Syndrome
Hyperglycinemia, lactic acidosis, and seizures is a severe autosomal recessive disorder characterized by onset of hypotonia and seizures associated with increased serum glycine and lactate in the first days of life. Affected individuals develop an encephalopathy or severely delayed psychomotor development, which may result in death in childhood. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; 605899), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including HGCLAS, appear to result from defects of mitochondrial lipoate biosynthesis (summary by Baker et al., 2014).
Ehlers-Danlos syndrome, kyphoscoliotic and deafness type
MedGen UID:
482790
Concept ID:
C3281160
Disease or Syndrome
FKBP14 kyphoscoliotic Ehlers-Danlos syndrome (FKBP14-kEDS) is characterized by congenital muscle hypotonia and weakness (typically improving during childhood), progressive scoliosis, joint hypermobility, hyperelastic skin, gross motor developmental delay, myopathy, and hearing impairment. Most affected children achieve independent walking between ages two and four years. A decline of motor function in adulthood may be seen, but affected individuals are likely to be able to participate in activities of daily living in adulthood and maintain independent walking. Occasional features underlying systemic connective tissue involvement include aortic rupture and arterial dissection, subdural hygroma, insufficiency of cardiac valves, bluish sclerae, bladder diverticula, inguinal or umbilical herniae, and premature rupture of membranes during pregnancy. Rarer findings may include bifid uvula with submucous or frank cleft palate, speech/language delay without true cognitive impairment, and rectal prolapse.
Developmental and epileptic encephalopathy, 13
MedGen UID:
482821
Concept ID:
C3281191
Disease or Syndrome
SCN8A-related epilepsy with encephalopathy is characterized by developmental delay, seizure onset in the first 18 months of life (mean 4 months), and intractable epilepsy characterized by multiple seizure types (generalized tonic-clonic seizures, infantile spasms, and absence and focal seizures). Epilepsy syndromes can include Lennox-Gastaut syndrome, West syndrome, and epileptic encephalopathies (e.g., Dravet syndrome). Hypotonia and movement disorders including dystonia, ataxia, and choreoathetosis are common. Psychomotor development varies from normal prior to seizure onset (with subsequent slowing or regression after seizure onset) to abnormal from birth. Intellectual disability, present in all, ranges from mild to severe (in ~50% of affected individuals). Autistic features are noted in some. Sudden unexpected death in epilepsy (SUDEP) of unknown cause has been reported in approximately 10% of published cases. To date SCN8A-related epilepsy with encephalopathy has been reported in the literature in about 50 individuals.
Usher syndrome type 1K
MedGen UID:
761332
Concept ID:
C3539124
Disease or Syndrome
Usher syndrome type I (USH1) is characterized by congenital, bilateral, profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP). Unless fitted with a cochlear implant, individuals do not typically develop speech. RP, a progressive, bilateral, symmetric degeneration of rod and cone functions of the retina, develops in adolescence, resulting in progressively constricted visual fields and impaired visual acuity.
Hereditary spastic paraplegia 56
MedGen UID:
761343
Concept ID:
C3539507
Disease or Syndrome
Spastic paraplegia-56 with or without pseudoxanthoma elasticum (SPG56) is an autosomal recessive neurodegenerative disorder characterized by early-onset progressive lower-limb spasticity resulting in walking difficulties. Upper limbs are often also affected, and some patients may have a subclinical axonal neuropathy (summary by Tesson et al., 2012). Some patients also have pseudoxanthoma elasticum (Legrand et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see 270800.
Charcot-Marie-Tooth disease type 4F
MedGen UID:
761704
Concept ID:
C3540453
Disease or Syndrome
Charcot-Marie-Tooth disease type 4F is an autosomal recessive demyelinating neuropathy characterized by distal sensory impairment and distal muscle weakness and atrophy affecting the lower more than the upper limbs. Nerve conduction velocities are decreased and sural nerve biopsy shows loss of myelinated fibers. The age at onset is variable and can range from childhood to adult years. When the onset is in infancy, the phenotype is characterized as Dejerine-Sottas syndrome (DSS; 145900). For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating Charcot-Marie-Tooth disease, see CMT4A (214400).
Coenzyme Q10 deficiency, primary, 1
MedGen UID:
764868
Concept ID:
C3551954
Disease or Syndrome
Primary coenzyme Q10 (CoQ10) deficiency is usually associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypotonia; a late-onset slowly progressive multiple-system atrophy-like phenotype (neurodegeneration with autonomic failure and various combinations of parkinsonism and cerebellar ataxia, and pyramidal dysfunction); and dystonia, spasticity, seizures, and intellectual disability. Steroid-resistant nephrotic syndrome (SRNS), the hallmark renal manifestation, is often the initial manifestation either as isolated renal involvement that progresses to end-stage renal disease (ESRD), or associated with encephalopathy (seizures, stroke-like episodes, severe neurologic impairment) resulting in early death. Hypertrophic cardiomyopathy (HCM), retinopathy or optic atrophy, and sensorineural hearing loss can also be seen.
Complex cortical dysplasia with other brain malformations 7
MedGen UID:
765150
Concept ID:
C3552236
Disease or Syndrome
Complex cortical dysplasia with other brain malformations-7 is an autosomal dominant, clinically heterogeneous disorder showing a wide spectrum of abnormalities of cortical brain development. The most severely affected patients are fetuses with microlissencephaly, absence of the cortical plate, agenesis of the corpus callosum, and severely hypoplastic brainstem and cerebellum. Other patients have lissencephaly, polymicrogyria, cortical dysplasia, or neuronal heterotopia. Those with less severe malformations can survive, but usually have some degree of neurologic impairment, such as mental retardation, seizures, and movement abnormalities (summary by Chang et al., 2006; Fallet-Bianco et al., 2014). For a discussion of genetic heterogeneity of CDCBM, see CDCBM1 (614039).
Congenital myasthenic syndrome 12
MedGen UID:
765249
Concept ID:
C3552335
Disease or Syndrome
Congenital myasthenic syndrome-12 is an autosomal recessive neuromuscular disorder characterized by onset of proximal muscle weakness in the first decade. EMG classically shows a decremental response to repeated nerve stimulation. Affected individuals show a favorable response to acetylcholinesterase (AChE) inhibitors (summary by Senderek et al., 2011). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Hyperekplexia 2
MedGen UID:
766205
Concept ID:
C3553291
Disease or Syndrome
Hereditary hyperekplexia is a condition in which affected infants have increased muscle tone (hypertonia) and an exaggerated startle reaction to unexpected stimuli, especially loud noises. Following the startle reaction, infants experience a brief period in which they are very rigid and unable to move. During these rigid periods, some infants stop breathing, which, if prolonged, can be fatal. Infants with hereditary hyperekplexia have hypertonia at all times, except when they are sleeping.\n\nOther signs and symptoms of hereditary hyperekplexia can include muscle twitches when falling asleep (hypnagogic myoclonus) and movements of the arms or legs while asleep. Some infants, when tapped on the nose, extend their head forward and have spasms of the limb and neck muscles. Rarely, infants with hereditary hyperekplexia experience recurrent seizures (epilepsy).\n\nHereditary hyperekplexia may explain some cases of sudden infant death syndrome (SIDS), which is a major cause of unexplained death in babies younger than 1 year.\n\nThe signs and symptoms of hereditary hyperekplexia typically fade by age 1. However, older individuals with hereditary hyperekplexia may still startle easily and have periods of rigidity, which can cause them to fall down. They may also continue to have hypnagogic myoclonus or movements during sleep. As they get older, individuals with this condition may have a low tolerance for crowded places and loud noises. People with hereditary hyperekplexia who have epilepsy have the seizure disorder throughout their lives.
Congenital myasthenic syndrome 13
MedGen UID:
766559
Concept ID:
C3553645
Disease or Syndrome
Congenital myasthenic syndrome-13 is an autosomal recessive neuromuscular disorder characterized by onset of proximal muscle weakness in the first decade. EMG classically shows a decremental response to repeated nerve stimulation. Affected individuals show a favorable response to acetylcholinesterase (AChE) inhibitors (summary by Belaya et al., 2012). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Malan overgrowth syndrome
MedGen UID:
766574
Concept ID:
C3553660
Disease or Syndrome
Malan syndrome (MALNS) is clinically characterized by overgrowth, advanced bone age, macrocephaly, and dysmorphic facial features. Patients develop marfanoid habitus, with long and slender body, very low body mass, long narrow face, and arachnodactyly, with age. Impaired intellectual development and behavior anomalies are present (summary by Martinez et al., 2015).
Usher syndrome type 1J
MedGen UID:
766858
Concept ID:
C3553944
Disease or Syndrome
Usher syndrome type I (USH1) is characterized by congenital, bilateral, profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP). Unless fitted with a cochlear implant, individuals do not typically develop speech. RP, a progressive, bilateral, symmetric degeneration of rod and cone functions of the retina, develops in adolescence, resulting in progressively constricted visual fields and impaired visual acuity.
Autism, susceptibility to, 18
MedGen UID:
767287
Concept ID:
C3554373
Disease or Syndrome
CHD8-related neurodevelopmental disorder with overgrowth (CHD8-NDD) is characterized by generalized overgrowth, developmental delay / intellectual disability (DD/ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, sleep disturbance, and gastrointestinal issues The most common findings are the development of macrocephaly (most often during infancy) and tall stature (most typically during puberty), which is often accompanied by ASD and/or DD/ID. Most, if not all, affected individuals have some degree of DD, most commonly speech and motor delays. When present, ID is most often in the mild-to-moderate range. Sleep disturbance is characterized by difficulty with both initiation (delayed sleep onset) and maintenance (frequent night awakenings) of sleep. The most common gastrointestinal issue is constipation with or without periods of diarrhea. Less common features are hypotonia (about 30% of affected individuals), seizures (10%-15%), dystonia (rare), and Chiari I malformation (rare).
Osteogenesis imperfecta type 14
MedGen UID:
767342
Concept ID:
C3554428
Disease or Syndrome
Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclerae (259420); and OI type IV, with normal sclerae (166220). Most cases of OI are autosomal dominant with mutations in 1 of the 2 genes that code for type I collagen alpha chains, COL1A1 (120150) and COL1A2 (120160). Shaheen et al. (2012) described osteogenesis imperfecta type XIV (OI14), an autosomal recessive form of the disorder characterized by variable degrees of severity of multiple fractures and osteopenia, with normal teeth, sclerae, and hearing. Fractures first occur prenatally or by age 6 years.
Cobblestone lissencephaly without muscular or ocular involvement
MedGen UID:
767571
Concept ID:
C3554657
Disease or Syndrome
Lissencephaly-5 (LIS5) is an autosomal recessive brain malformation characterized by cobblestone changes in the cortex, more severe in the posterior region, and subcortical band heterotopia. Affected individuals have hydrocephalus, seizures, and severely delayed psychomotor development (Radmanesh et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (607432).
Hydrocephalus, nonsyndromic, autosomal recessive 2
MedGen UID:
767605
Concept ID:
C3554691
Disease or Syndrome
Congenital hydrocephalus-2 is a congenital disorder with onset in utero. Affected individuals have hydrocephalus with variably dilated ventricles and variable neurologic sequelae. Some individuals have other brain abnormalities, including lissencephaly, thinning of the corpus callosum, and neuronal heterotopia. Most patients have delayed motor development and some have delayed intellectual development and/or seizures. Additional congenital features, including cardiac septal defects, iris coloboma, and nonspecific dysmorphic features, may be observed. Some patients die in utero, in infancy, or in early childhood, whereas others have long-term survival (summary by Shaheen et al., 2017). For a discussion of genetic heterogeneity of congenital hydrocephalus, see 233600.
Glycogen storage disease IXa1
MedGen UID:
854172
Concept ID:
C3694531
Disease or Syndrome
Phosphorylase kinase (PhK) deficiency causing glycogen storage disease type IX (GSD IX) results from deficiency of the enzyme phosphorylase b kinase, which has a major regulatory role in the breakdown of glycogen. The two types of PhK deficiency are liver PhK deficiency (characterized by early childhood onset of hepatomegaly and growth restriction, and often, but not always, fasting ketosis and hypoglycemia) and muscle PhK deficiency, which is considerably rarer (characterized by any of the following: exercise intolerance, myalgia, muscle cramps, myoglobinuria, and progressive muscle weakness). While symptoms and biochemical abnormalities of liver PhK deficiency were thought to improve with age, it is becoming evident that affected individuals need to be monitored for long-term complications such as liver fibrosis and cirrhosis.
Actin accumulation myopathy
MedGen UID:
777997
Concept ID:
C3711389
Disease or Syndrome
Nemaline myopathy is a form of congenital myopathy characterized by abnormal thread- or rod-like structures in muscle fibers on histologic examination ('nema' is Greek for 'thread'). The clinical phenotype is highly variable, with differing age at onset and severity. Muscle weakness typically involves proximal muscles, with involvement of the facial, bulbar, and respiratory muscles (Ilkovski et al., 2001). Attempts at classification of nemaline myopathies into clinical subtypes have been complicated by the overlap of clinical features and a continuous phenotypic spectrum of disease (North et al., 1997; Wallgren-Pettersson et al., 1999; Ryan et al., 2001; Sanoudou and Beggs, 2001). In general, 2 clinical groups can be readily distinguished: 'typical' and 'severe.' Typical nemaline myopathy is the most common form, presenting as infantile hypotonia and muscle weakness. It is slowly progressive or nonprogressive, and most adults achieve ambulation. The severe form of the disorder is characterized by absence of spontaneous movement or respiration at birth, arthrogryposis, and death in the first months of life. Much less commonly, late-childhood or even adult-onset can occur. However, adult-onset nemaline myopathy is usually not familial and may represent a different disease (Wallgren-Pettersson et al., 1999; Sanoudou and Beggs, 2001). Myopathy caused by mutations in the ACTA1 gene can show a range of clinical and pathologic phenotypes. Some patients have classic rods, whereas others may also show intranuclear rods, clumped filaments, cores, or fiber-type disproportion (see 255310), all of which are nonspecific pathologic findings and not pathognomonic of a specific congenital myopathy. The spectrum of clinical phenotypes caused by mutations in ACTA1 may result from different mutations, modifying factors affecting the severity of the disorder, variability in clinical care, or a combination of these factors (Nowak et al., 1999; Kaindl et al., 2004). Genetic Heterogeneity of Nemaline Myopathy See also NEM1 (609284), caused by mutation in the tropomyosin-3 gene (TPM3; 191030) on chromosome 1q22; NEM2 (256030), caused by mutation in the nebulin gene (NEB; 161650) on chromosome 2q23; NEM4 (609285), caused by mutation in the beta-tropomyosin gene (TPM2; 190990) on chromosome 9p13; NEM5 (605355), also known as Amish nemaline myopathy, caused by mutation in the troponin T1 gene (TNNT1; 191041) on chromosome 19q13; NEM6 (609273), caused by mutation in the KBTBD13 gene (613727) on chromosome 15q22; NEM7 (610687), caused by mutation in the cofilin-2 gene (CFL2; 601443) on chromosome 14q13; NEM8 (615348), caused by mutation in the KLHL40 gene (615340), on chromosome 3p22; NEM9 (615731), caused by mutation in the KLHL41 gene (607701) on chromosome 2q31; NEM10 (616165), caused by mutation in the LMOD3 gene (616112) on chromosome 3p14; and NEM11 (617336), caused by mutation in the MYPN gene (608517) on chromosome 10q21. Several of the genes encode components of skeletal muscle sarcomeric thin filaments (Sanoudou and Beggs, 2001). Mutations in the NEB gene are the most common cause of nemaline myopathy (Lehtokari et al., 2006).
Perrault syndrome 4
MedGen UID:
815435
Concept ID:
C3809105
Disease or Syndrome
Perrault syndrome is characterized by sensorineural hearing loss (SNHL) in males and females and ovarian dysfunction in females. SNHL is bilateral and ranges from profound with prelingual (congenital) onset to moderate with early-childhood onset. When onset is in early childhood, hearing loss can be progressive. Ovarian dysfunction ranges from gonadal dysgenesis (absent or streak gonads) manifesting as primary amenorrhea to primary ovarian insufficiency (POI) defined as cessation of menses before age 40 years. Fertility in affected males is reported as normal (although the number of reported males is limited). Neurologic features described in some individuals with Perrault syndrome include learning difficulties and developmental delay, cerebellar ataxia, and motor and sensory peripheral neuropathy.
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14
MedGen UID:
815551
Concept ID:
C3809221
Disease or Syndrome
MDDGB14 is an autosomal recessive congenital muscular dystrophy characterized by severe muscle weakness apparent in infancy and impaired intellectual development. Some patients may have additional features, such as microcephaly, cardiac dysfunction, seizures, or cerebellar hypoplasia. It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (summary by Carss et al., 2013). For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (613155).
Hereditary sensory and autonomic neuropathy type 7
MedGen UID:
816212
Concept ID:
C3809882
Disease or Syndrome
Hereditary sensory and autonomic neuropathy type VII (HSAN7) is characterized by congenital absence of pain sensation resulting in recurrent injuries and self-inflicted wounds. Severe pruritis, intestinal dysmotility, and hyperhydrosis may be present (Woods et al., 2015; Salvatierra et al., 2018). For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1 (162400).
Macrocephaly-developmental delay syndrome
MedGen UID:
816555
Concept ID:
C3810225
Mental or Behavioral Dysfunction
Macrocephaly-developmental delay syndrome is a rare, intellectual disability syndrome characterized by macrocephaly, mild dysmorphic features (frontal bossing, long face, hooded eye lids with small, downslanting palpebral fissures, broad nasal bridge, and prominent chin), global neurodevelopmental delay, behavioral abnormalities (e.g. anxiety, stereotyped movements) and absence or generalized tonic-clonic seizures. Additional features reported in some patients include craniosynostosis, fifth finger clinodactyly, recurrent pneumonia, and hepatosplenomegaly.
Proximal myopathy with extrapyramidal signs
MedGen UID:
816615
Concept ID:
C3810285
Disease or Syndrome
Myopathy with extrapyramidal signs is an autosomal recessive disorder characterized by early childhood onset of proximal muscle weakness and learning disabilities. While the muscle weakness is static, most patients develop progressive extrapyramidal signs that may become disabling (summary by Logan et al., 2014). Brain MRI in 1 patient showed congenital malformations, including polymicrogyria and cerebellar dysplasia (Wilton et al., 2020).
Autosomal recessive spinocerebellar ataxia 15
MedGen UID:
816656
Concept ID:
C3810326
Disease or Syndrome
Autosomal recessive spinocerebellar ataxia-15 (SCAR15) is characterized by early-onset ataxia, cognitive impairment, dysarthria, and developmental delay. Variable features include seizures, nystagmus, and abnormal reflexes (Seidahmed et al., 2020).
Nemaline myopathy 9
MedGen UID:
816714
Concept ID:
C3810384
Disease or Syndrome
Nemaline myopathy-9 is an autosomal recessive muscle disorder characterized by onset of muscle weakness in early infancy. The phenotype is highly variable, ranging from death in infancy due to lack of antigravity movements, to slowly progressive distal muscle weakness with preserved ambulation later in childhood. Muscle biopsy shows typical rod-like structure in myofibers (summary by Gupta et al., 2013). For a discussion of genetic heterogeneity of nemaline myopathy, see 161800.
Hereditary spastic paraplegia 45
MedGen UID:
854816
Concept ID:
C3888209
Disease or Syndrome
A rare pure or complex form of hereditary spastic paraplegia with characteristics of onset in infancy of progressive lower limb spasticity, abnormal gait, increased deep tendon reflexes and extensor plantar responses that may be associated with intellectual disability. Additional signs such as contractures in the lower limbs, amyotrophy, clubfoot and optic atrophy, have also been reported. Caused by homozygous mutation in the NT5C2 gene on chromosome 10q24.
Desbuquois dysplasia 1
MedGen UID:
860583
Concept ID:
C4012146
Disease or Syndrome
Desbuquois dysplasia (DBQD) is an autosomal recessive chondrodysplasia belonging to the multiple dislocation group and characterized by severe prenatal and postnatal growth retardation (stature less than -5 SD), joint laxity, short extremities, and progressive scoliosis. The main radiologic features are short long bones with metaphyseal splay, a 'Swedish key' appearance of the proximal femur (exaggerated trochanter), and advanced carpal and tarsal bone age with a delta phalanx (summary by Huber et al., 2009). Desbuquois dysplasia is clinically and radiographically heterogeneous, and had been classified into 2 types based on the presence (type 1) or absence (type 2) of characteristic hand anomalies, including an extra ossification center distal to the second metacarpal, delta phalanx, bifid distal thumb phalanx, and dislocation of the interphalangeal joints (Faivre et al., 2004). However, patients with and without these additional hand anomalies have been reported to have mutations in the same gene (see, e.g., CANT1); thus, these features are not distinctive criteria to predict the molecular basis of DBQD (Furuichi et al., 2011). In addition, Kim et al. (2010) described another milder variant of DBQD with almost normal outwardly appearing hands, but significant radiographic changes, including short metacarpals, elongated phalanges, and remarkably advanced carpal bone age. However, there is no accessory ossification center distal to the second metacarpal, and patients do not have thumb anomalies. Similar changes occur in the feet. These patients also tend to develop precocious osteoarthritis of the hand and spine with age. This phenotype is sometimes referred to as the 'Kim variant' of DBQD (Furuichi et al., 2011). Genetic Heterogeneity of Desbuquois Dysplasia DBQD2 (615777) is caused by mutation in the XYLT1 gene (608124) on chromosome 16p12. Two unrelated patients with immunodeficiency-23 (IMD23; 615816), due to mutation in the PGM3 gene (172100), were reported to have skeletal features reminiscent of DBQD.
Intellectual disability-severe speech delay-mild dysmorphism syndrome
MedGen UID:
862201
Concept ID:
C4013764
Mental or Behavioral Dysfunction
Intellectual developmental disorder with language impairment and with or without autistic features is a neurodevelopmental disorder characterized by global developmental delay with moderate to severe speech delay that particularly affects expressive speech. Most patients have articulation defects, but frank verbal dyspraxia is not observed. Common dysmorphic features include broad forehead, downslanting palpebral fissures, short nose with broad tip, relative macrocephaly, frontal hair upsweep, and prominent digit pads. Gross motor skills are also delayed. Some patients have autistic features and/or behavioral problems. All reported cases have occurred de novo (review by Le Fevre et al., 2013).
Intellectual disability, autosomal recessive 42
MedGen UID:
862780
Concept ID:
C4014343
Disease or Syndrome
Neurodevelopmental disorder with dysmorphic features, spasticity, and brain abnormalities (NEDDSBA) is an autosomal recessive neurodevelopmental disorder characterized by severely delayed global development, with hypotonia, impaired intellectual development, and poor or absent speech. Most patients have spasticity with limb hypertonia and brisk tendon reflexes. Additional features include nonspecific dysmorphic facial features, structural brain abnormalities, and cortical visual impairment (summary by Bosch et al., 2015). Novarino et al. (2014) labeled the disorder 'spastic paraplegia-67' (SPG67). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Myopathy, centronuclear, 5
MedGen UID:
863251
Concept ID:
C4014814
Disease or Syndrome
Centronuclear myopathy-5 (CNM5) is an autosomal recessive congenital myopathy characterized by severe neonatal hypotonia with respiratory insufficiency and difficulty feeding. Some patients die in infancy, and some develop dilated cardiomyopathy. Children show severely delayed motor development (summary by Agrawal et al., 2014). For a discussion of genetic heterogeneity of centronuclear myopathy, see CNM1 (160150).
Ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome
MedGen UID:
863258
Concept ID:
C4014821
Disease or Syndrome
Poretti-Boltshauser syndrome is an autosomal recessive disorder characterized by cerebellar dysplasia, cerebellar vermis hypoplasia, cerebellar cysts in most patients, high myopia, variable retinal dystrophy, and eye movement abnormalities. Affected individuals have delayed motor development and often have speech delay. Cognitive function can range from normal to intellectually disabled (summary by Aldinger et al., 2014).
Cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome
MedGen UID:
863379
Concept ID:
C4014942
Disease or Syndrome
CAGSSS, which comprises cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, is an autosomal recessive multisystemic disorder with a highly variable phenotypic spectrum. Not all of these features are always present, and almost all the features may present at different times and/or become more apparent with age. The skeletal features are consistent with spondyloepimetaphyseal dysplasia (SEMD) (summary by Vona et al., 2018). One family had a distinctive presentation with infantile-onset intractable seizures and cortical abnormalities reminiscent of Leigh syndrome (see 256000). The correlation between genotype and phenotype remains unclear, but since the IARS2 gene is involved in mitochondrial function, heterogeneous manifestations can be expected (Takezawa et al., 2018).
Microcephaly, short stature, and impaired glucose metabolism 1
MedGen UID:
863434
Concept ID:
C4014997
Disease or Syndrome
Congenital myasthenic syndrome 7
MedGen UID:
863475
Concept ID:
C4015038
Disease or Syndrome
Presynaptic congenital myasthenic syndrome-7A with distal motor neuropathy (CMS7A) is an autosomal dominant neuromuscular disorder characterized by onset of foot deformities, delayed motor development, and slowly progressive distal muscle weakness resulting in gait difficulties in early childhood. Other features may include hyporeflexia, muscle atrophy, and upper limb involvement. Electrophysiologic studies show low compound muscle action potentials (CMAPs), consistent with a distal hereditary motor neuropathy (dHMN), as well as a decremental response to repetitive stimulation, indicating presynaptic defects at the neuromuscular junction (NMJ), consistent with myasthenic syndrome (summary by Fionda et al., 2021). The complex phenotype of patients with dominant SYT2 mutations likely results from impairment of 2 fundamental functions of SYT2: (1) disturbance of calcium-dependent synchronous presynaptic neurotransmitter release, resulting in a myasthenic disorder, and (2) disruption of exocytosis and endocytosis, causing a degenerative process affecting peripheral motor nerve terminals and resulting in a motor neuropathy (Maselli et al., 2021). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462). For a discussion of genetic heterogeneity of dHMN, see 182960.
Intellectual disability, autosomal dominant 29
MedGen UID:
863578
Concept ID:
C4015141
Mental or Behavioral Dysfunction
SETBP1 haploinsufficiency disorder (SETBP1-HD) is characterized by hypotonia and mild motor developmental delay; intellectual abilities ranging from normal to severe disability; speech and language disorder; behavioral problems (most commonly attention/concentration deficits and hyperactivity, impulsivity), and refractive errors and strabismus. Typically children with SETBP1-HD whose intellect is in the normal or borderline range (IQ 80-90) were diagnosed following genetic testing for behavioral problems and/or severe speech and language disorders (respectively: the inability to produce sounds in words correctly, and deficits in the understanding and/or expression of words and sentences). To date, 47 individuals with SETBP1-HD have been reported.
Intellectual disability, autosomal dominant 30
MedGen UID:
863604
Concept ID:
C4015167
Mental or Behavioral Dysfunction
Autosomal dominant intellectual developmental disorder-30 with speech delay and behavioral abnormalities (MRD30) is characterized by developmental delay apparent from early infancy. Cognitive impairment is variable; many patients are able to attend special schools. Behavioral abnormalities, including ADHD, autistic features, and aggression are commonly observed. Additional features may include various types of seizures, hypotonia, mild skeletal defects, feeding difficulties, and dysmorphic features (Yates et al., 2020; Oates et al., 2021).
Limb-girdle muscular dystrophy due to POMK deficiency
MedGen UID:
863621
Concept ID:
C4015184
Disease or Syndrome
Limb-girdle muscular dystrophy due to POMK deficiency is a form of limb-girdle muscular dystrophy presenting in infancy with muscle weakness and delayed motor development (eventually learning to walk at 18 months of age) followed by progressive proximal weakness, pseudohypertrophy of calf muscles, mild facial weakness, and borderline intelligence.
Polyendocrine-polyneuropathy syndrome
MedGen UID:
863698
Concept ID:
C4015261
Disease or Syndrome
A rare genetic disease characterized by childhood onset of multiple endocrine manifestations in combination with central and peripheral nervous system abnormalities. Reported signs and symptoms include postnatal growth retardation, moderate intellectual disability, hypogonadotropic hypogonadism, insulin-dependent diabetes mellitus, central hypothyroidism, demyelinating sensorimotor polyneuropathy, and cerebellar and pyramidal signs. Progressive hearing loss and a hypoplastic pituitary gland have also been described. Brain imaging shows moderate white matter abnormalities.
Lissencephaly 6 with microcephaly
MedGen UID:
863962
Concept ID:
C4015525
Congenital Abnormality
Lissencephaly-6 (LIS6) is an autosomal recessive neurodevelopmental disorder characterized by severe microcephaly and developmental delay. Brain imaging shows variable malformations of cortical development, including lissencephaly, pachygyria, and hypoplasia of the corpus callosum (summary by Mishra-Gorur et al., 2014). For a general description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (607432).
Motor developmental delay due to 14q32.2 paternally expressed gene defect
MedGen UID:
863995
Concept ID:
C4015558
Disease or Syndrome
Temple syndrome is a short stature disorder of imprinting. The cardinal features are low birth weight, hypotonia and motor delay, feeding problems early in life, early puberty, and significantly reduced final height. Facial features include a broad forehead and short nose with a wide nasal tip, and the majority of patients have small hands and feet. However, many of the clinical features are nonspecific, making diagnosis difficult. In addition, isodisomy may uncover recessive disorders, which may influence the phenotype in maternal uniparental disomy of chromosome 14 (UPD14mat) cases (summary by Ioannides et al., 2014).
Congenital myasthenic syndrome 14
MedGen UID:
864034
Concept ID:
C4015597
Disease or Syndrome
Congenital myasthenic syndrome-14 is an autosomal recessive neuromuscular disorder characterized by onset of limb-girdle muscle weakness in early childhood. The disorder is slowly progressive, and some patients may become wheelchair-bound. There is no respiratory or cardiac involvement. Treatment with anticholinesterase medication may be beneficial (summary by Cossins et al., 2013). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Meier-Gorlin syndrome 6
MedGen UID:
905079
Concept ID:
C4225188
Disease or Syndrome
Any Meier-Gorlin syndrome in which the cause of the disease is a mutation in the GMNN gene.
Cardiac anomalies - developmental delay - facial dysmorphism syndrome
MedGen UID:
900924
Concept ID:
C4225208
Disease or Syndrome
Impaired intellectual development and distinctive facial features with or without cardiac defects (MRFACD) is an autosomal dominant, complex syndromic neurodevelopmental disorder characterized by delayed psychomotor development, poor speech acquisition, distinctive dysmorphic facial features, including frontal bossing, upslanting palpebral fissures, depressed nasal bridge with bulbous tip, and macrostomia. There is variable penetrance of cardiac malformations, ranging from no malformations to patent foramen ovale to septal defects and/or transposition of the great arteries (summary by Adegbola et al., 2015).
Intellectual disability, autosomal recessive 51
MedGen UID:
903243
Concept ID:
C4225220
Disease or Syndrome
Any autosomal recessive non-syndromic intellectual disability in which the cause of the disease is a mutation in the HNMT gene.
Skin creases, congenital symmetric circumferential, 2
MedGen UID:
902880
Concept ID:
C4225225
Congenital Abnormality
Congenital symmetric circumferential skin creases is characterized by the folding of excess skin, which leads to ringed creases, primarily of the limbs. Affected individuals also exhibit intellectual disability, cleft palate, and dysmorphic features (summary by Isrie et al., 2015). For a discussion of genetic heterogeneity of congenital symmetric circumferential skin creases, see CSCSC1 (156610).
Primary coenzyme Q10 deficiency 8
MedGen UID:
908648
Concept ID:
C4225226
Disease or Syndrome
Primary coenzyme Q10 (CoQ10) deficiency is usually associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypotonia; a late-onset slowly progressive multiple-system atrophy-like phenotype (neurodegeneration with autonomic failure and various combinations of parkinsonism and cerebellar ataxia, and pyramidal dysfunction); and dystonia, spasticity, seizures, and intellectual disability. Steroid-resistant nephrotic syndrome (SRNS), the hallmark renal manifestation, is often the initial manifestation either as isolated renal involvement that progresses to end-stage renal disease (ESRD), or associated with encephalopathy (seizures, stroke-like episodes, severe neurologic impairment) resulting in early death. Hypertrophic cardiomyopathy (HCM), retinopathy or optic atrophy, and sensorineural hearing loss can also be seen.
Palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome
MedGen UID:
895943
Concept ID:
C4225229
Disease or Syndrome
Palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome is a rare, genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, axial hypotonia, palate abnormalities (including cleft palate and/or high and narrow palate), dysmorphic facial features (including prominent forehead, hypertelorism, downslanting palpebral fissures, wide nasal bridge, thin lips and widely spaced teeth), and short stature. Additional manifestations may include digital anomalies (such as brachydactyly, clinodactyly, and hypoplastic toenails), a single palmar crease, lower limb hypertonia, joint hypermobility, as well as ocular and urogenital anomalies.
Congenital myasthenic syndrome 19
MedGen UID:
897962
Concept ID:
C4225235
Disease or Syndrome
Congenital myasthenic syndrome-19 (CMS19) is an autosomal recessive disorder resulting from a defect in the neuromuscular junction, causing generalized muscle weakness, exercise intolerance, and respiratory insufficiency. Patients present with hypotonia, feeding difficulties, and respiratory problems soon after birth, but the severity of the weakness and disease course is variable (summary by Logan et al., 2015). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Seizures-scoliosis-macrocephaly syndrome
MedGen UID:
909039
Concept ID:
C4225248
Disease or Syndrome
Seizures, scoliosis, and macrocephaly/microcephaly syndrome (SSMS) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay apparent from early infancy, impaired intellectual development, behavioral problems, poor or absent speech, seizures, dysmorphic facial features with macro- or microcephaly, and skeletal abnormalities, including scoliosis and delayed bone age. Other features may include hypotonia, gastrointestinal problems, and exostoses (summary by Gentile et al., 2019).
Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome
MedGen UID:
894399
Concept ID:
C4225285
Disease or Syndrome
Klippel-Feil syndrome-4 with nemaline myopathy and facial dysmorphism (KFS4) is an autosomal recessive disorder characterized mainly by severe hypotonia apparent from infancy. Klippel-Feil anomaly is primarily defined by fusion of the cervical spine, with associated low posterior hairline and limited neck mobility being observed in about half of patients (summary by Alazami et al., 2015). For a general description and a discussion of genetic heterogeneity of Klippel-Feil syndrome, see KFS1 (118100).
Osteogenesis imperfecta type 17
MedGen UID:
903845
Concept ID:
C4225301
Disease or Syndrome
Osteogenesis imperfecta (OI) is a group of genetic disorders that mainly affect the bones. The term "osteogenesis imperfecta" means imperfect bone formation. People with this condition have bones that break (fracture) easily, often from mild trauma or with no apparent cause. Multiple fractures are common, and in severe cases, can occur even before birth. Milder cases may involve only a few fractures over a person's lifetime.\n\nThere are at least 19 recognized forms of osteogenesis imperfecta, designated type I through type XIX. Several types are distinguished by their signs and symptoms, although their characteristic features overlap. Increasingly, genetic causes are used to define rarer forms of osteogenesis imperfecta. Type I (also known as classic non-deforming osteogenesis imperfecta with blue sclerae) is the mildest form of osteogenesis imperfecta. Type II (also known as perinatally lethal osteogenesis imperfecta) is the most severe. Other types of this condition, including types III (progressively deforming osteogenesis imperfecta) and IV (common variable osteogenesis imperfecta with normal sclerae), have signs and symptoms that fall somewhere between these two extremes.\n\nThe milder forms of osteogenesis imperfecta, including type I, are characterized by bone fractures during childhood and adolescence that often result from minor trauma, such as falling while learning to walk. Fractures occur less frequently in adulthood. People with mild forms of the condition typically have a blue or grey tint to the part of the eye that is usually white (the sclera), and about half develop hearing loss in adulthood. Unlike more severely affected individuals, people with type I are usually of normal or near normal height.\n\nOther types of osteogenesis imperfecta are more severe, causing frequent bone fractures that are present at birth and result from little or no trauma. Additional features of these types can include blue sclerae of the eyes, short stature, curvature of the spine (scoliosis), joint deformities (contractures), hearing loss, respiratory problems, and a disorder of tooth development called dentinogenesis imperfecta. Mobility can be reduced in affected individuals, and some may use a walker or wheelchair. The most severe forms of osteogenesis imperfecta, particularly type II, can include an abnormally small, fragile rib cage and underdeveloped lungs. Infants with these abnormalities may have life-threatening problems with breathing and can die shortly after birth.
Silver-Russell syndrome 3
MedGen UID:
894912
Concept ID:
C4225307
Disease or Syndrome
Silver-Russell syndrome-3 (SRS3) is characterized by intrauterine growth retardation with relative macrocephaly, followed by feeding difficulties and postnatal growth restriction. Dysmorphic facial features include triangular face, prominent forehead, and low-set ears. Other variable features include limb defects, genitourinary and cardiovascular anomalies, hearing impairment, and developmental delay (Begemann et al., 2015; Yamoto et al., 2017). For a discussion of genetic heterogeneity of Silver-Russell syndrome, see SRS1 (180860).
Bethlem myopathy 2
MedGen UID:
907426
Concept ID:
C4225313
Disease or Syndrome
A rare systemic disease characterized by congenital muscle hypotonia and/or muscle atrophy that improves with age, proximal joint contractures (knee, hip, elbow), and hypermobility of distal joints. Additional features include soft, doughy skin, atrophic scarring, delayed motor development, and myopathic findings in muscle biopsy. Abnormal craniofacial features have been reported in some patients. Molecular testing is obligatory to confirm the diagnosis.
Ullrich congenital muscular dystrophy 2
MedGen UID:
899150
Concept ID:
C4225314
Disease or Syndrome
Any Ullrich congenital muscular dystrophy in which the cause of the disease is a mutation in the COL12A1 gene.
Intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome
MedGen UID:
897984
Concept ID:
C4225351
Disease or Syndrome
White-Sutton syndrome is a neurodevelopmental disorder characterized by a wide spectrum of cognitive dysfunction, developmental delays (particularly in speech and language acquisition), hypotonia, autism spectrum disorder, and other behavioral problems. Additional features commonly reported include seizures, refractive errors and strabismus, hearing loss, sleep disturbance (particularly sleep apnea), feeding and gastrointestinal problems, mild genital abnormalities in males, and urinary tract involvement in both males and females.
Congenital myasthenic syndrome 3C
MedGen UID:
903088
Concept ID:
C4225370
Disease or Syndrome
Congenital myasthenic syndrome associated with AChR deficiency is a disorder of the postsynaptic neuromuscular junction (NMJ) clinically characterized by early-onset muscle weakness with variable severity. Electrophysiologic studies show low amplitude of the miniature endplate potential (MEPP) and current (MEPC) resulting from deficiency of AChR at the endplate. Treatment with acetylcholinesterase inhibitors or amifampridine may be helpful (summary by Engel et al., 2015). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Lichtenstein-Knorr syndrome
MedGen UID:
898996
Concept ID:
C4225383
Disease or Syndrome
Lichtenstein-Knorr syndrome is an autosomal recessive neurologic disorder characterized by postnatal onset of severe progressive sensorineural hearing loss and progressive cerebellar ataxia. Features usually develop in childhood or young adulthood (summary by Guissart et al., 2015). Some patients with SLC9A1 mutations may not have deafness (Iwama et al., 2018)
Congenital contractures of the limbs and face, hypotonia, and developmental delay
MedGen UID:
907234
Concept ID:
C4225398
Disease or Syndrome
CLIFAHDD is a congenital disorder characterized by congenital contractures of the limbs and face, resulting in characteristic facial features, hypotonia, and variable degrees of developmental delay. All reported cases have occurred de novo (summary by Chong et al., 2015).
Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency
MedGen UID:
895551
Concept ID:
C4225400
Disease or Syndrome
Interstitial lung and liver disease is an autosomal recessive disorder characterized by onset of respiratory insufficiency and progressive liver disease in infancy or early childhood. Pathologic examination of lung lavage is consistent with pulmonary alveolar proteinosis (summary by Hadchouel et al., 2015).
Myasthenic syndrome, congenital, 1B, fast-channel
MedGen UID:
909200
Concept ID:
C4225405
Disease or Syndrome
Fast-channel congenital myasthenic syndrome (FCCMS) is a disorder of the postsynaptic neuromuscular junction (NMJ) characterized by early-onset progressive muscle weakness. The disorder results from kinetic abnormalities of the acetylcholine receptor (AChR) channel, specifically from abnormally brief opening and activity of the channel, with a rapid decay in endplate current and a failure to reach the threshold for depolarization. Treatment with pyridostigmine or amifampridine may be helpful; quinine, quinidine, and fluoxetine should be avoided (summary by Sine et al., 2003 and Engel et al., 2015). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Syndromic X-linked intellectual disability 34
MedGen UID:
902184
Concept ID:
C4225417
Mental or Behavioral Dysfunction
X-linked syndromic intellectual developmental disorder-34 (MRXS34) is an X-linked recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability with poor speech, dysmorphic facial features, and mild structural brain abnormalities, including thickening of the corpus callosum (summary by Mircsof et al., 2015).
Maternal uniparental disomy of chromosome 20
MedGen UID:
909388
Concept ID:
C4275029
Congenital Abnormality
The Mulchandani-Bhoj-Conlin syndrome (MBCS) is characterized by prenatal growth restriction, severe short stature with proportional head circumference, and profound feeding difficulty (Mulchandani et al., 2016).
MIRAGE syndrome
MedGen UID:
924576
Concept ID:
C4284088
Disease or Syndrome
MIRAGE syndrome is an acronym for the major findings of myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. Cytopenias are typically seen soon after birth; thrombocytopenia is the most common followed by anemia and pancytopenia. Recurrent infections from early infancy include pneumonia, urinary tract infection, gastroenteritis, meningitis, otitis media, dermatitis, subcutaneous abscess, and sepsis. Reported genital phenotypes in those with 46,XY karyotype included hypospadias, microphallus, bifid shawl scrotum, ambiguous genitalia, or complete female genitalia. Hypoplastic or dysgenetic ovaries have been reported in females. Gastrointestinal complications include chronic diarrhea and esophageal dysfunction. Moderate-to-severe developmental delay is reported in most affected individuals. Autonomic dysfunction and renal dysfunction are also reported.
Hypotonia, ataxia, and delayed development syndrome
MedGen UID:
934585
Concept ID:
C4310618
Disease or Syndrome
EBF3 neurodevelopmental disorder (EBF3-NDD) is associated with developmental delay (DD) / intellectual disability (ID), speech delay, gait or truncal ataxia, hypotonia, behavioral problems, and facial dysmorphism. Variability between individuals with EBF3-NDD is significant. Although all affected children have DD noted in early infancy, intellect generally ranges from mild to severe ID, with two individuals functioning in the low normal range. Less common issues can include genitourinary abnormalities and gastrointestinal and/or musculoskeletal involvement. To date, 42 symptomatic individuals from 39 families have been reported.
Mucopolysaccharidosis-like syndrome with congenital heart defects and hematopoietic disorders
MedGen UID:
934594
Concept ID:
C4310627
Disease or Syndrome
MPSPS is an autosomal recessive inborn error of metabolism resulting in a multisystem disorder with features of the mucopolysaccharidosis lysosomal storage diseases (see, e.g., 607016). Patients present in infancy or early childhood with respiratory difficulties, cardiac problems, anemia, dysostosis multiplex, renal involvement, coarse facies, and delayed psychomotor development. Most patients die of cardiorespiratory failure in the first years of life (summary by Kondo et al., 2017).
Epilepsy, early-onset, vitamin B6-dependent
MedGen UID:
934599
Concept ID:
C4310632
Disease or Syndrome
Early-onset vitamin B6-dependent epilepsy is an autosomal recessive neurologic disorder characterized by onset of seizures in the neonatal period or first months of life. The seizures show favorable response to treatment with activated vitamin B6 (pyridoxal 5-prime-phosphate; PLP) and/or pyridoxine. However, most patients show delayed psychomotor development (summary by Darin et al., 2016).
Dystonia 28, childhood-onset
MedGen UID:
934600
Concept ID:
C4310633
Disease or Syndrome
KMT2B-related dystonia (DYT-KMT2B) is a complex childhood-onset (mean age 7 years) movement disorder described to date in 39 individuals. It is characterized by a progressive disease course evolving commonly from lower-limb focal dystonia into generalized dystonia with prominent cervical, cranial, and laryngeal involvement. Communication difficulties, secondary to articulation difficulties and low speech volume, are common. Bulbar dysfunction leads to impaired swallowing. Intellectual disability (ID) / developmental delay (DD) are commonly reported. Additional findings can include eye movement abnormalities, skin changes, psychiatric comorbidities (attention-deficit/hyperactivity disorder, anxiety, depression, and obsessive-compulsive disorder), myoclonus, seizures, spasticity, and sensorineural hearing loss. Many affected individuals follow a similar disease course, though milder and atypical findings have been described.
Language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmia
MedGen UID:
934645
Concept ID:
C4310678
Disease or Syndrome
GNB5-related neurodevelopmental disorder (GNB5-NDD) is characterized by a spectrum of neurodevelopmental phenotypes that range from severe-to-profound intellectual disability (ID; 31/41 reported individuals), to mild-to-moderate ID (5/41), to normal intellect with severe language disorder (5/41, one extended family). A unique and specific feature of GNB5-NDD – regardless of neurodevelopmental phenotype – is nearly universal bradycardia caused by sinoatrial node dysfunction (sick sinus syndrome). Most individuals with severe and profound ID have a developmental and epileptic encephalopathy with focal seizures or epileptic spasms, as well as visual impairment (central or retinal) with nystagmus, difficulty feeding, and gastroesophageal reflux disease. The risk of early mortality is increased.
Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay
MedGen UID:
934653
Concept ID:
C4310686
Disease or Syndrome
The core features of short stature-micrognathia syndrome (SSMG) are intrauterine growth restriction (IUGR), postnatal short stature that is often rhizomelic, and micrognathia. Other common features include preterm birth, microcephaly, developmental delay, and genitourinary malformations in males. Transient liver dysfunction and glycosylation abnormalities during illness, giant cell hepatitis, hepatoblastoma, and cataracts have also been observed. Inter- and intrafamilial phenotypic severity varies greatly, from a relatively mild disorder to intrauterine death or stillbirth (Ritter et al., 2022).
Arthrogryposis, distal, with impaired proprioception and touch
MedGen UID:
934659
Concept ID:
C4310692
Disease or Syndrome
Distal arthrogryposis with impaired proprioception and touch is an autosomal recessive neurologic disorder characterized by loss of certain mechanosensation modalities resulting in ataxia, difficulty walking, dysmetria, muscle weakness and atrophy, and progressive skeletal contractures. Patients have onset of symptoms in early childhood (summary by Chesler et al., 2016 and Delle Vedove et al., 2016).
Congenital myasthenic syndrome 20
MedGen UID:
934661
Concept ID:
C4310694
Disease or Syndrome
Congenital myasthenic syndrome-20 is an autosomal recessive neuromuscular disorder characterized by severe hypotonia associated with episodic apnea soon after birth. Patients have muscle weakness resulting in delayed walking, ptosis, poor sucking and swallowing, and generalized limb fatigability and weakness. EMG studies usually show a decremental response to repetitive nerve stimulation, and some patients may show a good response to AChE inhibitors (summary by Bauche et al., 2016). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Short-rib thoracic dysplasia 16 with or without polydactyly
MedGen UID:
934685
Concept ID:
C4310718
Disease or Syndrome
Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013). There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330). For a discussion of genetic heterogeneity of short-rib thoracic dysplasia with or without polydactyly, see SRTD1 (208500).
Encephalopathy due to defective mitochondrial and peroxisomal fission 2
MedGen UID:
934693
Concept ID:
C4310726
Disease or Syndrome
Encephalopathy due to defective mitochondrial and peroxisomal fission-2 (EMPF2) is an autosomal recessive disorder characterized by delayed psychomotor development, severe hypotonia with inability to walk, microcephaly, and abnormal signals in the basal ganglia. More variable features include early-onset seizures, optic atrophy, and peripheral neuropathy (summary by Koch et al., 2016). For a discussion of genetic heterogeneity of EMPF, see EMPF1 (614388).
Congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity syndrome
MedGen UID:
934703
Concept ID:
C4310736
Disease or Syndrome
A rare congenital muscular dystrophy characterised by neonatal hypotonia, life-threatening respiratory failure and feeding difficulties, furthermore by delayed motor development, severe muscle weakness predominantly affecting axial muscles (leading to poor head control, rigid cervical spine, and severe scoliosis), generalised joint laxity with no or mild contractures, as well as dry skin with follicular hyperkeratosis. Serum creatine kinase is normal or slightly elevated. Muscle biopsy shows fibre size variability, rounded fibres with mild increase of endomysial connective tissue and adipose replacement, abundant minicore lesions, increase of centrally located nuclei, angular fibres and cap lesions.
Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome
MedGen UID:
934707
Concept ID:
C4310740
Disease or Syndrome
TRIO-related intellectual disability (ID) is characterized by delay in acquisition of motor and language skills, mild to borderline intellectual disability, and neurobehavioral problems (including autistic traits or autism spectrum disorder, attention-deficit/hyperactivity disorder, and/or aggression). Neonatal or infantile feeding difficulties including poor suck, impaired bottle feeding, and failure to thrive are common and are often the presenting finding. Other findings can include microcephaly, variable hand and dental abnormalities, and suggestive facial features. Only ten of the 20 individuals with a TRIO pathogenic variant reported to date had sufficient information to make preliminary generalizations about clinical manifestations; it is anticipated that the phenotype of this newly described disorder will continue to evolve.
Trichothiodystrophy 6, nonphotosensitive
MedGen UID:
934752
Concept ID:
C4310785
Disease or Syndrome
Any nonphotosensitive trichothiodystrophy in which the cause of the disease is a mutation in the GTF2E2 gene.
Progeroid and marfanoid aspect-lipodystrophy syndrome
MedGen UID:
934763
Concept ID:
C4310796
Disease or Syndrome
The marfanoid-progeroid-lipodystrophy syndrome (MFLS) is characterized by congenital lipodystrophy, premature birth with an accelerated linear growth disproportionate to weight gain, and progeroid appearance with distinct facial features, including proptosis, downslanting palpebral fissures, and retrognathia. Other characteristic features include arachnodactyly, digital hyperextensibility, myopia, dural ectasia, and normal psychomotor development (Takenouchi et al., 2013). Takenouchi et al. (2013) noted phenotypic overlap with Marfan syndrome (154700) and Shprintzen-Goldberg craniosynostosis syndrome (182212).
Immunodeficiency-centromeric instability-facial anomalies syndrome 4
MedGen UID:
934765
Concept ID:
C4310798
Disease or Syndrome
Immunodeficiency-centromeric instability-facial anomalies syndrome-4 is an autosomal recessive disorder characterized by recurrent infections in childhood and variable dysmorphic facial features. Laboratory studies show hypomethylation of certain chromosomal regions. Additional features, including delayed development, are variable (summary by Thijssen et al., 2015). For a discussion of genetic heterogeneity of immunodeficiency-centromeric instability-facial anomalies syndrome, see ICF1 (242860).
SIN3A-related intellectual disability syndrome due to a point mutation
MedGen UID:
934771
Concept ID:
C4310804
Disease or Syndrome
Witteveen-Kolk syndrome (WITKOS) is an autosomal dominant disorder with characteristic distinctive facial features, microcephaly, short stature, and mildly impaired intellectual development with delayed cognitive and motor development and subtle anomalies on MRI-brain imaging (summary by Balasubramanian et al., 2021).
Bartter disease type 4B
MedGen UID:
934772
Concept ID:
C4310805
Disease or Syndrome
Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997). Patients with antenatal (or neonatal) forms of Bartter syndrome (e.g., BARTS1, 601678) typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome present later in life and may be sporadically asymptomatic or mildly symptomatic (summary by Simon et al., 1996 and Fremont and Chan, 2012). For a discussion of genetic heterogeneity of Bartter syndrome, see 607364.
SRD5A3-congenital disorder of glycosylation
MedGen UID:
1392124
Concept ID:
C4317224
Disease or Syndrome
SRD5A3-congenital disorder of glycosylation (SRD5A3-CDG, formerly known as congenital disorder of glycosylation type Iq) is an inherited condition that causes neurological and vision problems and other signs and symptoms. The pattern and severity of this condition's features vary widely among affected individuals.\n\nIndividuals with SRD5A3-CDG typically develop signs and symptoms of the condition during infancy or early childhood. Most individuals with SRD5A3-CDG have intellectual disability, vision problems, unusual facial features,low muscle tone (hypotonia), and problems with coordination and balance (ataxia). \n\nVision problems in SRD5A3-CDG often include  involuntary side-side movements of the eyes (nystagmus), a gap or hole in one of the structures of the eye (coloboma), underdevelopment of the nerves that carry signals between the eyes and the brain(optic nerve hypoplasia), or vision loss early in life (early-onset severe retinal dystrophy). Over time, affected individuals may develop clouding of the lenses of the eyes (cataracts) or increased pressure in the eyes (glaucoma).\n\nOther features of SRD5A3-CDG can include skin rash, unusually small red blood cells (microcytic anemia),and liver problems.
Myasthenic syndrome, congenital, 22
MedGen UID:
1393545
Concept ID:
C4479088
Disease or Syndrome
Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder
MedGen UID:
1385307
Concept ID:
C4479246
Disease or Syndrome
CDK13-related disorder, reported in 43 individuals to date, is characterized in all individuals by developmental delay / intellectual disability (DD/ID); nearly all individuals older than age one year display impaired verbal language skills (either absent or restricted speech). Other common findings are recognizable facial features in some individuals, behavioral problems (autism spectrum disorder or autistic traits/stereotypies, attention-deficit/hyperactivity disorder), feeding difficulties in infancy, structural cardiac defects, and seizures.
Autosomal recessive cutis laxa type 2D
MedGen UID:
1376619
Concept ID:
C4479409
Disease or Syndrome
Autosomal recessive cutis laxa type IID (ARCL2D) is characterized by generalized skin wrinkling with sparse subcutaneous fat and dysmorphic progeroid facial features. Most patients also exhibit severe hypotonia as well as cardiovascular and neurologic involvement (summary by Van Damme et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (219100).
Congenital muscular dystrophy with cataracts and intellectual disability
MedGen UID:
1382291
Concept ID:
C4479410
Disease or Syndrome
MDCCAID is an autosomal recessive form of muscular dystrophy with onset of progressive muscle weakness in early childhood. Almost all patients also have early-onset cataracts, most have intellectual disability of varying severity, and some have seizures (summary by Wiessner et al., 2017 and Osborn et al., 2017).
Brachycephaly, trichomegaly, and developmental delay
MedGen UID:
1374289
Concept ID:
C4479431
Disease or Syndrome
BTDD is an autosomal dominant disorder characterized by brachycephaly, trichomegaly, and developmental delay. Although it is caused by dysfunction of the ribosome, patients do not have anemia (summary by Paolini et al., 2017).
Immunoskeletal dysplasia with neurodevelopmental abnormalities
MedGen UID:
1381460
Concept ID:
C4479452
Disease or Syndrome
Stankiewicz-Isidor syndrome
MedGen UID:
1375936
Concept ID:
C4479599
Disease or Syndrome
Stankiewicz-Isidor syndrome (STISS) is a neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, behavioral disorders, mild craniofacial anomalies, and variable congenital defects of the cardiac and/or urogenital systems (summary by Kury et al., 2017).
Neurodevelopmental disorder with midbrain and hindbrain malformations
MedGen UID:
1385580
Concept ID:
C4479613
Disease or Syndrome
Gabriele de Vries syndrome
MedGen UID:
1375401
Concept ID:
C4479652
Disease or Syndrome
Gabriele-de Vries syndrome is characterized by mild-to-profound developmental delay / intellectual disability (DD/ID) in all affected individuals and a wide spectrum of functional and morphologic abnormalities. Intrauterine growth restriction or low birth weight and feeding difficulties are common. Congenital brain, eye, heart, kidney, genital, and/or skeletal system anomalies have also been reported. About half of affected individuals have neurologic manifestations, including hypotonia and gait abnormalities. Behavioral issues can include attention-deficit/hyperactivity disorder, anxiety, autism or autistic behavior, and schizoaffective disorder.
Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy
MedGen UID:
1382553
Concept ID:
C4479653
Disease or Syndrome
NKX6-2-related disorder is characterized by a spectrum of progressive neurologic manifestations resulting from diffuse central nervous system hypomyelination. At the severe end of the spectrum is neonatal-onset nystagmus, severe spastic tetraplegia with joint contractures and scoliosis, and visual and hearing impairment, all of which rapidly progress resulting in death in early childhood. At the milder end of the spectrum is normal achievement of early motor milestones in the first year of life followed by slowly progressive complex spastic ataxia with pyramidal findings (spasticity with increased muscle tone and difficulty with gait and fine motor coordination) and cerebellar findings (nystagmus, extraocular movement disorder, dysarthria, titubation, and ataxia) with loss of developmental milestones. To date NKX6-2-related disorder has been reported in 25 individuals from 13 families.
Autosomal recessive limb-girdle muscular dystrophy type 2T
MedGen UID:
1377325
Concept ID:
C4518000
Disease or Syndrome
MDDGC14 is an autosomal recessive form of muscular dystrophy characterized by onset in early childhood of mild proximal muscle weakness. Some patients may have additional features, such as mild intellectual disability or seizures. It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (summary by Carss et al., 2013). Some patients with GMPPB mutations may show features consistent with a congenital myasthenic syndrome (see, e.g., CMS1A; 601462), such as fatigability and decremental compound muscle action potential response to repetitive nerve stimulation; these patients may show a positive therapeutic response to treatment with pyridostigmine (Belaya et al., 2015). For a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type C, see MDDGC1 (609308).
Combined oxidative phosphorylation defect type 8
MedGen UID:
1377817
Concept ID:
C4518839
Disease or Syndrome
COXPD8 is an autosomal recessive disorder due to dysfunction of the mitochondrial respiratory chain. The main clinical manifestation is a lethal infantile hypertrophic cardiomyopathy, but there may also be subtle skeletal muscle and brain involvement. Biochemical studies show combined respiratory chain complex deficiencies in complexes I, III, and IV in cardiac muscle, skeletal muscle, and brain. The liver is not affected (summary by Gotz et al., 2011). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Spinocerebellar ataxia 44
MedGen UID:
1611168
Concept ID:
C4521563
Disease or Syndrome
Orofaciodigital syndrome 16
MedGen UID:
1620071
Concept ID:
C4539729
Disease or Syndrome
Intellectual disability, autosomal dominant 45
MedGen UID:
1616472
Concept ID:
C4539848
Mental or Behavioral Dysfunction
Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay
MedGen UID:
1612119
Concept ID:
C4539968
Disease or Syndrome
CAKUTHED is an autosomal dominant highly pleiotropic developmental disorder characterized mainly by variable congenital anomalies of the kidney and urinary tract, sometimes resulting in renal dysfunction or failure, dysmorphic facial features, and abnormalities of the outer ear, often with hearing loss. Most patients have global developmental delay (summary by Heidet et al., 2017 and Slavotinek et al., 2017).
Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome
MedGen UID:
1620960
Concept ID:
C4540096
Disease or Syndrome
Mitochondrial myopathy and ataxia (MMYAT) is an autosomal recessive mtDNA depletion disorder characterized by cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic, and pigmentary retinopathy (summary by Donkervoort et al., 2019).
Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies
MedGen UID:
1627464
Concept ID:
C4540327
Disease or Syndrome
NEDDFL is a neurodevelopmental disorder characterized by delayed psychomotor development and intellectual disability, poor growth with small head size, dysmorphic facial features, and mild abnormalities of the hands and feet (summary by Stankiewicz et al., 2017).
Myopathy, centronuclear, 6, with fiber-type disproportion
MedGen UID:
1627492
Concept ID:
C4540345
Disease or Syndrome
Centronuclear myopathy-6 with fiber-type disproportion (CNM6) is an autosomal recessive, slowly progressive congenital myopathy with onset in infancy or early childhood. Patients may be hypotonic at birth, but all show delayed motor development and walking difficulties due to muscle weakness mainly affecting the proximal lower and upper limbs. Other features include scapular winging, scoliosis, and mildly decreased respiratory vital capacity. The phenotype and muscle biopsy abnormalities are variable, although centralized nuclei and fiber-type disproportion appear to be a common finding on muscle biopsy (summary by Vasli et al., 2017). For a discussion of genetic heterogeneity of centronuclear myopathy, see CNM1 (160150).
Retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome
MedGen UID:
1615526
Concept ID:
C4540367
Disease or Syndrome
SHRF is an autosomal recessive disorder characterized by short stature, brachydactyly, dysmorphic facial features, hearing loss, and visual impairment. Onset of the hearing and visual abnormalities, including retinitis pigmentosa, varies from birth to the second decade. Patients have mild intellectual disability and mild cerebellar atrophy with myelination defects on brain imaging (summary by Di Donato et al., 2016).
Intellectual disability, autosomal recessive 61
MedGen UID:
1622296
Concept ID:
C4540424
Mental or Behavioral Dysfunction
MRT61 is an autosomal recessive neurodevelopmental disorder characterized by delayed psychomotor development, moderate to severe intellectual disability, and variable dysmorphic facial features. More severely affected patients may develop refractory seizures and have brain abnormalities, including hypoplasia of the corpus callosum (summary by Alwadei et al., 2016).
Intellectual disability, autosomal dominant 50
MedGen UID:
1616989
Concept ID:
C4540470
Mental or Behavioral Dysfunction
Autosomal dominant intellectual developmental disorder-50 with behavioral abnormalities (MRD50) is characterized by variable levels of impaired intellectual development, delayed speech and motor milestones, and behavioral abnormalities, most commonly autism spectrum disorder (ASD). Some patients may also have mild craniofacial dysmorphism, congenital cardiac anomalies, or seizures (summary by Cheng et al., 2019).
Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy
MedGen UID:
1615361
Concept ID:
C4540493
Disease or Syndrome
Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (NDMSCA) is an autosomal recessive disorder characterized by severe global developmental delay with poor motor and intellectual function apparent soon after birth, as well as postnatal progressive microcephaly. Most patients develop early-onset, frequent, and often intractable seizures, compatible with an epileptic encephalopathy. Other features include poor feeding, poor overall growth, absent speech, poor or absent eye contact, inability to achieve walking, hypotonia, and peripheral spasticity. Brain imaging usually shows progressive cerebral atrophy, thin corpus callosum, and abnormalities in myelination. Death in childhood may occur (summary by Siekierska et al., 2019).
Coffin-Siris syndrome 6
MedGen UID:
1615540
Concept ID:
C4540499
Disease or Syndrome
Coffin-Siris syndrome (CSS) is classically characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, distinctive facial features, hypotonia, hirsutism/hypertrichosis, and sparse scalp hair. Congenital anomalies can include malformations of the cardiac, gastrointestinal, genitourinary, and/or central nervous systems. Other findings commonly include feeding difficulties, slow growth, ophthalmologic abnormalities, and hearing impairment.
Sotos syndrome 1
MedGen UID:
1634368
Concept ID:
C4551477
Disease or Syndrome
Sotos syndrome is characterized by a distinctive facial appearance (broad and prominent forehead with a dolichocephalic head shape, sparse frontotemporal hair, downslanting palpebral fissures, malar flushing, long and narrow face, long chin); learning disability (early developmental delay, mild-to-severe intellectual impairment); and overgrowth (height and/or head circumference =2 SD above the mean). These three clinical features are considered the cardinal features of Sotos syndrome. Major features of Sotos syndrome include behavioral problems (most notably autistic spectrum disorder), advanced bone age, cardiac anomalies, cranial MRI/CT abnormalities, joint hyperlaxity with or without pes planus, maternal preeclampsia, neonatal complications, renal anomalies, scoliosis, and seizures.
Multiple benign circumferential skin creases on limbs 1
MedGen UID:
1631916
Concept ID:
C4551592
Disease or Syndrome
Congenital symmetric circumferential skin creases is characterized by the folding of excess skin, which leads to ringed creases, primarily of the limbs. Affected individuals also exhibit intellectual disability, cleft palate, and dysmorphic features (summary by Isrie et al., 2015). Genetic Heterogeneity of Congenital Symmetric Circumferential Skin Creases CSCSC2 (616734) is caused by mutation in the MAPRE2 gene (605789) on chromosome 18q12.
Perrault syndrome 1
MedGen UID:
1640257
Concept ID:
C4551721
Disease or Syndrome
Perrault syndrome is characterized by sensorineural hearing loss (SNHL) in males and females and ovarian dysfunction in females. SNHL is bilateral and ranges from profound with prelingual (congenital) onset to moderate with early-childhood onset. When onset is in early childhood, hearing loss can be progressive. Ovarian dysfunction ranges from gonadal dysgenesis (absent or streak gonads) manifesting as primary amenorrhea to primary ovarian insufficiency (POI) defined as cessation of menses before age 40 years. Fertility in affected males is reported as normal (although the number of reported males is limited). Neurologic features described in some individuals with Perrault syndrome include learning difficulties and developmental delay, cerebellar ataxia, and motor and sensory peripheral neuropathy.
Autosomal dominant centronuclear myopathy
MedGen UID:
1645741
Concept ID:
C4551952
Disease or Syndrome
Centronuclear myopathy-1 (CNM1) is an autosomal dominant congenital myopathy characterized by slowly progressive muscular weakness and wasting. The disorder involves mainly limb girdle, trunk, and neck muscles but may also affect distal muscles. Weakness may be present during childhood or adolescence or may not become evident until the third decade of life, and some affected individuals become wheelchair-bound in their fifties. Ptosis and limitation of eye movements occur frequently. The most prominent histopathologic features include high frequency of centrally located nuclei in a large number of extrafusal muscle fibers (which is the basis of the name of the disorder), radial arrangement of sarcoplasmic strands around the central nuclei, and predominance and hypotrophy of type 1 fibers (summary by Bitoun et al., 2005). Genetic Heterogeneity of Centronuclear Myopathy Centronuclear myopathy is a genetically heterogeneous disorder. See also X-linked CNM (CNMX; 310400), caused by mutation in the MTM1 gene (300415) on chromosome Xq28; CNM2 (255200), caused by mutation in the BIN1 gene (601248) on chromosome 2q14; CNM4 (614807), caused by mutation in the CCDC78 gene (614666) on chromosome 16p13; CNM5 (615959), caused by mutation in the SPEG gene (615950) on chromosome 2q35; and CNM6 (617760), caused by mutation in the ZAK gene (609479) on chromosome 2q31. The mutation in the MYF6 gene that was reported to cause a form of CNM, formerly designated CNM3, has been reclassified as a variant of unknown significance; see 159991.0001. Some patients with mutation in the RYR1 gene (180901) have findings of centronuclear myopathy on skeletal muscle biopsy (see 255320).
Lissencephaly type 1 due to doublecortin gene mutation
MedGen UID:
1644310
Concept ID:
C4551968
Disease or Syndrome
DCX-related disorders include the neuronal migration disorders: Classic thick lissencephaly (more severe anteriorly), usually in males. Subcortical band heterotopia (SBH), primarily in females. Males with classic DCX-related lissencephaly typically have early and profound cognitive and language impairment, cerebral palsy, and epileptic seizures. The clinical phenotype in females with SBH varies widely with cognitive abilities that range from average or mild cognitive impairment to severe intellectual disability and language impairment. Seizures, which frequently are refractory to anti-seizure medication, may be either focal or generalized and behavioral problems may also be observed. In DCX-related lissencephaly and SBH the severity of the clinical manifestation correlates roughly with the degree of the underlying brain malformation as observed in cerebral imaging.
Ehlers-Danlos syndrome, spondylodysplastic type, 1
MedGen UID:
1646889
Concept ID:
C4552003
Disease or Syndrome
Other types of Ehlers-Danlos syndrome have additional signs and symptoms. The cardiac-valvular type causes severe problems with the valves that control the movement of blood through the heart. People with the kyphoscoliotic type experience severe curvature of the spine that worsens over time and can interfere with breathing by restricting lung expansion. A type of Ehlers-Danlos syndrome called brittle cornea syndrome is characterized by thinness of the clear covering of the eye (the cornea) and other eye abnormalities. The spondylodysplastic type features short stature and skeletal abnormalities such as abnormally curved (bowed) limbs. Abnormalities of muscles, including hypotonia and permanently bent joints (contractures), are among the characteristic signs of the musculocontractural and myopathic forms of Ehlers-Danlos syndrome. The periodontal type causes abnormalities of the teeth and gums.\n\nAn unusually large range of joint movement (hypermobility) occurs in most forms of Ehlers-Danlos syndrome, and it is a hallmark feature of the hypermobile type. Infants and children with hypermobility often have weak muscle tone (hypotonia), which can delay the development of motor skills such as sitting, standing, and walking. The loose joints are unstable and prone to dislocation and chronic pain. In the arthrochalasia type of Ehlers-Danlos syndrome, infants have hypermobility and dislocations of both hips at birth.\n\nBleeding problems are common in the vascular type of Ehlers-Danlos syndrome and are caused by unpredictable tearing (rupture) of blood vessels and organs. These complications can lead to easy bruising, internal bleeding, a hole in the wall of the intestine (intestinal perforation), or stroke. During pregnancy, women with vascular Ehlers-Danlos syndrome may experience rupture of the uterus. Additional forms of Ehlers-Danlos syndrome that involve rupture of the blood vessels include the kyphoscoliotic, classical, and classical-like types.\n\nMany people with the Ehlers-Danlos syndromes have soft, velvety skin that is highly stretchy (elastic) and fragile. Affected individuals tend to bruise easily, and some types of the condition also cause abnormal scarring. People with the classical form of Ehlers-Danlos syndrome experience wounds that split open with little bleeding and leave scars that widen over time to create characteristic "cigarette paper" scars. The dermatosparaxis type of the disorder is characterized by loose skin that sags and wrinkles, and extra (redundant) folds of skin may be present.\n\nThe various forms of Ehlers-Danlos syndrome have been classified in several different ways. Originally, 11 forms of Ehlers-Danlos syndrome were named using Roman numerals to indicate the types (type I, type II, and so on). In 1997, researchers proposed a simpler classification (the Villefranche nomenclature) that reduced the number of types to six and gave them descriptive names based on their major features. In 2017, the classification was updated to include rare forms of Ehlers-Danlos syndrome that were identified more recently. The 2017 classification describes 13 types of Ehlers-Danlos syndrome.\n\nEhlers-Danlos syndrome is a group of disorders that affect connective tissues supporting the skin, bones, blood vessels, and many other organs and tissues. Defects in connective tissues cause the signs and symptoms of these conditions, which range from mildly loose joints to life-threatening complications.
Intellectual disability, autosomal dominant 55, with seizures
MedGen UID:
1635938
Concept ID:
C4693371
Disease or Syndrome
Charcot-Marie-Tooth disease, dominant intermediate G
MedGen UID:
1642893
Concept ID:
C4693509
Disease or Syndrome
CMTDIG is an autosomal dominant neurologic disorder with a highly variable phenotype. Most affected individuals have onset in the first or second decades of slowly progressive distal motor weakness and atrophy, resulting in gait instability and distal upper limb impairment, as well as distal sensory impairment. More severely affected individuals may have pes cavus and claw hands and become wheelchair-bound, whereas other affected individuals have later onset with a milder disease course. Electrophysiologic studies tend to show median motor nerve conduction velocities (NCV) in the 'intermediate' range, between 25 and 45 m/s (summary by Berciano et al., 2017). In a review of intermediate CMT, Berciano et al. (2017) noted that advanced axonal degeneration may induce secondary demyelinating changes resulting in decreased NCV and attenuated compound muscle action potential (CMAP) in median nerve conduction studies. They thus suggested that testing the upper arm, axilla to elbow, may provide more accurate assessment of NCV and CMAP and reveal an intermediate phenotype (review by Berciano et al., 2017). For a discussion of genetic heterogeneity of CMTDI, see 606482.
Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome
MedGen UID:
1647427
Concept ID:
C4693578
Disease or Syndrome
Neurodegeneration with brain iron accumulation 8
MedGen UID:
1645224
Concept ID:
C4693587
Disease or Syndrome
Neurodegeneration with brain iron accumulation-8 (NBIA8) is characterized by iron accumulation in the basal ganglia and manifests as a progressive extrapyramidal syndrome with dystonia, rigidity, and choreoathetosis (Drecourt et al., 2018).
Spinocerebellar ataxia 47
MedGen UID:
1636349
Concept ID:
C4693672
Disease or Syndrome
Leukodystrophy, hypomyelinating, 15
MedGen UID:
1633653
Concept ID:
C4693733
Disease or Syndrome
Hypomyelinating leukodystrophy-15 is an autosomal recessive neurodegenerative disorder characterized by onset of motor and cognitive impairment in the first or second decade of life. Features include dystonia, ataxia, spasticity, and dysphagia. Most patients develop severe optic atrophy, and some have hearing loss. Brain imaging shows hypomyelinating leukodystrophy with thin corpus callosum. The severity of the disorder is variable (summary by Mendes et al., 2018) For a discussion of genetic heterogeneity of HLD, see 312080.
Osteogenesis imperfecta, type 18
MedGen UID:
1635201
Concept ID:
C4693736
Disease or Syndrome
Osteogenesis imperfecta type XVIII (OI18) is characterized by congenital bowing of the long bones, wormian bones, blue sclerae, vertebral collapse, and multiple fractures in the first years of life (Doyard et al., 2018).
Ververi-Brady syndrome
MedGen UID:
1647785
Concept ID:
C4693824
Disease or Syndrome
Ververi-Brady syndrome (VEBRAS) is characterized by mild developmental delay, mildly impaired intellectual development and speech delay, and mild dysmorphic facial features. Affected individuals can usually attend mainstream schools with support, and may also show autistic features (summary by Ververi et al., 2018).
Jaberi-Elahi syndrome
MedGen UID:
1647359
Concept ID:
C4693848
Disease or Syndrome
JABELS is an autosomal recessive neurodevelopmental disorder characterized by developmental delay and intellectual disability with additional variable features. Patients have onset of symptoms in infancy, but the severity is highly variable. Some patients have social interaction and learn to walk but have an ataxic gait and abnormal movements, such as tremor or dystonia, whereas others do not achieve any motor control and are unable to speak. Additional features may include retinal anomalies, visual impairment, microcephaly, abnormal foot or hand posturing, and kyphoscoliosis; some patients have dysmorphic facial features or seizures. Brain imaging typically shows cerebellar atrophy and hypoplasia of the corpus callosum (summary by et al., 2016 and Bertoli-Avella et al., 2018).
Congenital myopathy with internal nuclei and atypical cores
MedGen UID:
1642424
Concept ID:
C4707232
Disease or Syndrome
A rare genetic skeletal muscle disease with characteristics of neonatal hypotonia, distal more than proximal muscle weakness, progressive exercise intolerance with prominent myalgias, and mild-to-moderate overall motor impairment with preserved ambulation. Face, extraocular, cardiac, and respiratory muscles are unaffected. Mild cognitive impairment is also noted in most patients.
Charcot-Marie-Tooth disease type 4E
MedGen UID:
1648303
Concept ID:
C4721436
Disease or Syndrome
Congenital hypomyelinating neuropathy (CHN) is characterized clinically by onset of hypotonia at birth, areflexia, distal muscle weakness, and very slow nerve conduction velocities (often less than 10 m/s). Warner et al. (1997, 1998) noted that pathologic findings on sural nerve biopsies show hypomyelination of most or all fibers. Based on these findings, CHN is considered to be a result of congenital impairment in myelin formation. There has been some controversy and difficulty in differentiating congenital hypomyelination from Dejerine-Sottas syndrome (DSS; 145900) because there is considerable overlap in clinical presentation. Based on pathologic findings of sural nerve biopsies (the absence of active myelin breakdown and the paucity of the onion bulbs in CHN and the presence of demyelination/remyelination and an abundance of well-organized onion bulbs in DSS; see Balestrini et al., 1991), CHN is considered to result from a congenital impairment in myelin formation, whereas DSS is thought to be due to aberrant demyelination and subsequent remyelination of the peripheral nerve. There is also variation in the prognosis of patients diagnosed with CHN. In patients with CHN, Harati and Butler (1985) showed correlation of morbidity and mortality with the presence/absence of onion bulbs: patients with few onion bulbs died in early infancy, usually because of difficulty in swallowing and respiration after birth. Patients with atypical onion bulbs survived but were affected with severe motor and sensory impairment. These differences in outcome may represent genetic heterogeneity such that mutations in essential early myelin gene(s) cause a severe phenotype, whereas mutations in other, possibly later acting gene(s), such as MPZ, lead to a less severe outcome. Genetic Heterogeneity of Congenital Hypomyelinating Neuropathy See also CHN2 (618184), caused by mutation in the MPZ gene (159440) on chromosome 1q23; and CHN3 (618186), caused by mutation in the CNTNAP1 gene (602346) on chromosome 17q21.
Neuropathy, congenital hypomyelinating, 2
MedGen UID:
1648446
Concept ID:
C4722277
Disease or Syndrome
Congenital hypomyelinating neuropathy-2 is an autosomal dominant neurologic disorder characterized by early-onset hypotonia, severely delayed motor development, muscle weakness with areflexia, and severely decreased nerve conduction velocities (NCV) resulting from improper myelination of axons. The severity is variable: some patients may present at birth with contractures and respiratory insufficiency, whereas others may achieve walking (summary by Warner et al., 1996). CHN shows significant phenotypic overlap with Dejerine-Sottas syndrome (DSS; 145900), which is also a neuropathy with early onset. Some classify the disorders differently, noting that CHN is characterized by hypo- or amyelination resulting from a congenital defect in myelin formation, whereas DSS has features of continuous myelin breakdown, with demyelination and remyelination (summary by Smit et al., 2008). For a discussion of genetic heterogeneity of CHN, see CHN1 (605253).
Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures
MedGen UID:
1669929
Concept ID:
C4747715
Disease or Syndrome
SMALED2A is an autosomal dominant form of spinal muscular atrophy characterized by early childhood onset of muscle weakness and atrophy predominantly affecting the proximal and distal muscles of the lower extremity, although some patients may show upper extremity involvement. The disorder results in delayed walking, waddling gait, difficulty walking, and loss of distal reflexes. Some patients may have foot deformities or hyperlordosis, and some show mild upper motor signs, such as spasticity. Sensation, bulbar function, and cognitive function are preserved. The disorder shows very slow progression throughout life (summary by Oates et al., 2013). For discussion of genetic heterogeneity of lower extremity-predominant spinal muscular atrophy, see SMALED1 (158600).
Coffin-Siris syndrome 7
MedGen UID:
1648281
Concept ID:
C4747954
Disease or Syndrome
Coffin-Siris syndrome (CSS) is classically characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, distinctive facial features, hypotonia, hirsutism/hypertrichosis, and sparse scalp hair. Congenital anomalies can include malformations of the cardiac, gastrointestinal, genitourinary, and/or central nervous systems. Other findings commonly include feeding difficulties, slow growth, ophthalmologic abnormalities, and hearing impairment.
Intellectual disability, autosomal dominant 57
MedGen UID:
1648280
Concept ID:
C4748003
Mental or Behavioral Dysfunction
MRD57 is an autosomal dominant neurodevelopmental disorder with a highly variable phenotype. Most affected individuals have delayed psychomotor development apparent in infancy or early childhood, language delay, and behavioral abnormalities. Additional features may include hypotonia, feeding problems, gastrointestinal issues, and dysmorphic facial features (summary by Reijnders et al., 2018).
Intellectual developmental disorder with or without epilepsy or cerebellar ataxia
MedGen UID:
1648354
Concept ID:
C4748041
Disease or Syndrome
Intellectual disability, autosomal recessive 64
MedGen UID:
1648279
Concept ID:
C4748192
Mental or Behavioral Dysfunction
Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development
MedGen UID:
1648480
Concept ID:
C4748283
Disease or Syndrome
Autosomal recessive peripheral neuropathy with or without impaired intellectual development is an early childhood-onset neurologic disorder characterized by slowly progressive distal motor impairment resulting in gait difficulties, often with loss of ambulation, and difficulties using the hands in most patients. Most affected individuals also have impaired intellectual development, although some have normal cognition. Electrophysiologic testing and sural nerve biopsy are most compatible with an axonal motor neuropathy; some patients may show signs of demyelination. Additional features may include eye movement abnormalities, claw hands, foot deformities, and scoliosis (summary by Ylikallio et al., 2017).
Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 8
MedGen UID:
1648468
Concept ID:
C4748320
Disease or Syndrome
MDDGC8 is an autosomal recessive muscular dystrophy with onset in childhood. The phenotype is highly variable: some patients may have gait difficulties and impaired intellectual development, whereas others may be clinically asymptomatic. Common features include calf hypertrophy and increased serum creatine kinase, and muscle biopsy often shows dystrophic features (summary by Endo et al., 2015). The disorder is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Godfrey et al., 2007). For a discussion of genetic heterogeneity of muscular dystrophy- dystroglycanopathy type C, see MDDGC1 (609308).
Muscular dystrophy, limb-girdle, autosomal recessive 23
MedGen UID:
1648462
Concept ID:
C4748327
Disease or Syndrome
The clinical manifestations of LAMA2 muscular dystrophy (LAMA2-MD) comprise a continuous spectrum ranging from severe congenital muscular dystrophy type 1A (MDC1A) to milder late-onset LAMA2-MD. MDC1A is typically characterized by neonatal profound hypotonia, poor spontaneous movements, and respiratory failure. Failure to thrive, gastroesophageal reflux, aspiration, and recurrent chest infections necessitating frequent hospitalizations are common. As disease progresses, facial muscle weakness, temporomandibular joint contractures, and macroglossia may further impair feeding and can affect speech. In late-onset LAMA2-MD onset of manifestations range from early childhood to adulthood. Affected individuals may show muscle hypertrophy and develop a rigid spine syndrome with joint contractures, usually most prominent in the elbows. Progressive respiratory insufficiency, scoliosis, and cardiomyopathy can occur.
Intellectual developmental disorder with macrocephaly, seizures, and speech delay
MedGen UID:
1648339
Concept ID:
C4748428
Disease or Syndrome
IDDMSSD is a neurodevelopmental disorder characterized by impaired intellectual development, poor speech, postnatal macrocephaly, and seizures (Harms et al., 2018).
Myasthenic syndrome, congenital, 23, presynaptic
MedGen UID:
1648392
Concept ID:
C4748678
Disease or Syndrome
Myasthenic syndrome, congenital, 24, presynaptic
MedGen UID:
1648337
Concept ID:
C4748684
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 23
MedGen UID:
1648408
Concept ID:
C4748799
Disease or Syndrome
Mitochondrial complex I deficiency nuclear type 23 (MC1DN23) is an autosomal recessive nuclear-encoded mitochondrial disease with clinical presentations ranging from movement disorder phenotypes (dystonia and/or spasticity) to isolated optic atrophy. MRI findings may include basal ganglia abnormalities or optic atrophy (summary by Magrinelli et al., 2022).
Neurodegeneration, childhood-onset, with cerebellar atrophy
MedGen UID:
1648286
Concept ID:
C4748934
Disease or Syndrome
Childhood-onset neurodegeneration with cerebellar atrophy (CONDCA) is a severe autosomal recessive neurodevelopmental disorder affecting the central and peripheral nervous system. Patients present in the first year of life with global developmental delay, impaired intellectual development, poor or absent speech, and motor abnormalities. Brain imaging shows cerebellar atrophy. The severity is variable, but death in childhood may occur (Shashi et al., 2018).
Fibrosis, neurodegeneration, and cerebral angiomatosis
MedGen UID:
1648312
Concept ID:
C4748939
Disease or Syndrome
Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) is characterized by severe progressive cerebropulmonary symptoms, resulting in death in infancy from respiratory failure. Features include malabsorption, progressive growth failure, recurrent infections, chronic hemolytic anemia, and transient liver dysfunction. Neuropathology shows increased angiomatosis-like leptomeningeal, cortical, and superficial white matter vascularization and congestion, vacuolar degeneration and myelin loss in white matter, as well as neuronal degeneration. Interstitial fibrosis and granuloma-like lesions are seen in the lungs, and there is hepatomegaly with steatosis and collagen accumulation (Uusimaa et al., 2018).
Cardiac-urogenital syndrome
MedGen UID:
1648333
Concept ID:
C4748946
Disease or Syndrome
Cardiac-urogenital syndrome is characterized by partial anomalous pulmonary venous return in association with tracheal anomalies, pulmonary hypoplasia, congenital diaphragmatic hernia, thyroid fibrosis, thymic involution, cleft spleen, penoscrotal hypospadias, and cryptorchidism (Pinz et al., 2018).
Microcephaly, cataracts, impaired intellectual development, and dystonia with abnormal striatum
MedGen UID:
1648355
Concept ID:
C4748984
Disease or Syndrome
The MCIDDS syndrome is characterized by microcephaly and growth retardation, congenital cataracts, impaired intellectual development with attention deficit-hyperactivity disorder, and dystonia, with striatal thinning seen on MRI (Al-Owain et al., 2013).
Spinal muscular atrophy, lower extremity-predominant, 2b, prenatal onset, autosomal dominant
MedGen UID:
1648362
Concept ID:
C4749003
Disease or Syndrome
SMALED2B is a severe neuromuscular disorder with onset in utero. Affected individuals show decreased fetal movements and are usually born with congenital contractures consistent with arthrogryposis multiplex congenita (AMC). After birth, they have severe hypotonia and muscle atrophy as well as respiratory insufficiency due to muscle weakness. Some patients may have dysmorphic facial features and/or abnormalities on brain imaging. Many patients die in early childhood (summary by Storbeck et al., 2017) For discussion of genetic heterogeneity of lower extremity-predominant spinal muscular atrophy, see SMALED1 (158600).
Intellectual developmental disorder, autosomal recessive 68
MedGen UID:
1648490
Concept ID:
C4749033
Disease or Syndrome
Hypomyelination with brain stem and spinal cord involvement and leg spasticity
MedGen UID:
1667792
Concept ID:
C4755254
Disease or Syndrome
Hypomyelination with brainstem and spinal cord involvement and leg spasticity is an autosomal recessive leukoencephalopathy characterized by onset in the first year of life of severe spasticity, mainly affecting the lower limbs and resulting in an inability to achieve independent ambulation. Affected individuals show delayed motor development and nystagmus; some may have mild mental retardation. Brain MRI shows hypomyelination and white matter lesions in the cerebrum, brainstem, cerebellum, and spinal cord (summary by Taft et al., 2013).
MITOCHONDRIAL MYOPATHY, EPISODIC, WITH OR WITHOUT OPTIC ATROPHY AND REVERSIBLE LEUKOENCEPHALOPATHY
MedGen UID:
1677461
Concept ID:
C5193007
Disease or Syndrome
Lethal arthrogryposis-anterior horn cell disease syndrome
MedGen UID:
1677784
Concept ID:
C5193016
Disease or Syndrome
Congenital arthrogryposis with anterior horn cell disease (CAAHD) is an autosomal recessive neuromuscular disorder with highly variable severity. Affected individuals are usually noted to have contractures in utero on prenatal ultrasound studies, and present at birth with generalized contractures manifest as arthrogryposis multiplex congenita (AMC). Patients have severe hypotonia with respiratory insufficiency, often resulting in death in infancy or early childhood. Some patients may survive into later childhood with supportive care, but may be unable to walk or sit independently due to a combination of muscle weakness and contractures. Cognition may be normal. The disorder also includes multiple congenital anomalies associated with AMC and hypotonia, including high-arched palate, myopathic facies, and bulbar weakness. Neuropathologic studies demonstrate severe loss of anterior horn cells in the spinal cord, as well as diffuse motor neuron axonopathy (summary by Smith et al., 2017 and Tan et al., 2017). Distinction from Lethal Congenital Contracture Syndrome 1 Biallelic mutation in the GLE1 gene can also cause LCCS1, which is lethal in utero. However, distinguishing between LCCS1 and CAAHD is controversial. Smith et al. (2017) suggested that differentiating between the 2 disorders has limited utility, and that they may represent a genotype/phenotype correlation rather than 2 different disease entities. In contrast, Said et al. (2017) concluded that LCCS1 represents a distinct clinical entity in which all affected individuals die prenatally and exhibit no fetal movements. Vuopala et al. (1995) differentiated CAAHD from LCCS1, noting that both are prevalent in Finland. LCCS1 is always fatal during the fetal period, presenting with severe hydrops and intrauterine growth retardation. In LCCS1, the spinal cord is macroscopically thinned because of an early reduction of the anterior horn and a paucity of anterior horn cells. The skeletal muscles are extremely hypoplastic, even difficult to locate. Infants with CAAHD survive longer than those with LCCS1, and when present, hydrops and intrauterine growth retardation are mild. The macroscopic findings of the central nervous system and skeletal muscles are closer to normal, although microscopic analysis also shows degeneration of anterior horn cells. In addition, birthplaces of ancestors of affected individuals do not show clustering in the northeast part of Finland, as is the case with LCCS1.
Intellectual developmental disorder with cardiac defects and dysmorphic facies
MedGen UID:
1675627
Concept ID:
C5193024
Disease or Syndrome
IDDCDF is an autosomal recessive syndromic neurodevelopmental disorder characterized by globally impaired development with intellectual disability and speech delay, congenital cardiac malformations, and dysmorphic facial features. Additional features, such as distal skeletal anomalies, may also be observed (Stephen et al., 2018).
Myasthenic syndrome, congenital, 25, presynaptic
MedGen UID:
1683288
Concept ID:
C5193027
Disease or Syndrome
Congenital myasthenic syndrome-25 (CMS25) is an autosomal recessive neuromuscular disorder characterized by hypotonia and generalized muscle weakness apparent from birth. Affected individuals have feeding difficulties and delayed motor development, usually never achieving independent ambulation. Additional variable features include eye movement abnormalities, joint contractures, and rigid spine. Pyridostigmine treatment may be partially effective (summary by Shen et al., 2017). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Intellectual developmental disorder with abnormal behavior, microcephaly, and short stature
MedGen UID:
1675423
Concept ID:
C5193039
Disease or Syndrome
Polymicrogyria with or without vascular-type ehlers-danlos syndrome
MedGen UID:
1675672
Concept ID:
C5193040
Disease or Syndrome
Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome is an autosomal recessive disorder with a highly variable phenotype. Although all patients have polymicrogyria and other variable structural brain anomalies on imaging, only some show developmental delay and/or seizures. Similarly, only some patients have connective tissue defects that particularly affect the vascular system and can result in early death (summary by Vandervore et al., 2017).
Galloway-Mowat syndrome 6
MedGen UID:
1674560
Concept ID:
C5193043
Disease or Syndrome
Galloway-Mowat syndrome is a phenotypically heterogeneous disorder characterized by neurodevelopmental defects combined with renal-glomerular disease manifest as nephrotic syndrome and proteinuria. Most patients with GAMOS6 also have growth deficiency with variable microcephaly, and the renal disease may be age-dependent. Additional variable endocrine abnormalities have also been reported (summary by Braun et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of GAMOS, see GAMOS1 (251300).
Intellectual developmental disorder, autosomal recessive 70
MedGen UID:
1679317
Concept ID:
C5193077
Disease or Syndrome
MRT70 is characterized primarily by impaired intellectual development. Mild facial dysmorphism, febrile seizures, and behavioral abnormalities have been reported in some patients (Maddirevula et al., 2018; Perez et al., 2018).
Congenital myopathy with reduced type 2 muscle fibers
MedGen UID:
1672638
Concept ID:
C5193081
Disease or Syndrome
Congenital myopathy with fast-twitch (type II) fiber atrophy (MYOFTA) is an autosomal recessive skeletal muscle disorder characterized by onset of severe muscle weakness apparent at birth and sometimes in utero. Affected infants have difficulty breathing independently and usually require mechanical ventilation for variable lengths of time. Other features include delayed motor development with delayed walking, hypo- or areflexia, and high-arched palate. Skeletal muscle biopsy shows variation in fiber size with specific atrophy of the fast-twitch type II fibers. Cardiac muscle is not affected (summary by Ravenscroft et al., 2018).
Developmental delay with variable intellectual impairment and behavioral abnormalities
MedGen UID:
1676192
Concept ID:
C5193092
Disease or Syndrome
Developmental delay with variable intellectual impairment and behavioral abnormalities (DDVIBA) is an autosomal dominant neurodevelopmental disorder. Most patients have impaired intellectual development with speech difficulties, and many have behavioral abnormalities, most commonly autism spectrum disorder (ASD), defects in attention, and/or hyperactivity. Many patients have dysmorphic features, although there is not a consistent gestalt. Additional more variable features may include hypotonia, somatic overgrowth with macrocephaly, mild distal skeletal anomalies, sleep disturbances, movement disorders, and gastrointestinal issues, such as constipation. The phenotype is highly variable (summary by Vetrini et al., 2019 and Torti et al., 2019).
Neurodevelopmental disorder with microcephaly and structural brain anomalies
MedGen UID:
1677276
Concept ID:
C5193123
Disease or Syndrome
Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facial features
MedGen UID:
1682428
Concept ID:
C5193147
Disease or Syndrome
Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic features (IKSHD) is characterized by epidermal hyperproliferation and increased keratinization, resulting in ichthyosis; hypomyelination of central white matter, causing spastic paraplegia and central nystagmus; and optic atrophy, resulting in reduction of peripheral vision and visual acuity (Mueller et al., 2019). In addition, patients exhibit mild facial dysmorphism (Kutkowska-Kazmierczak et al., 2018).
Developmental and epileptic encephalopathy, 79
MedGen UID:
1684738
Concept ID:
C5231410
Disease or Syndrome
Developmental and epileptic encephalopathy-79 (DEE79) is a severe neurologic disorder characterized by onset of refractory seizures in the first months of life. Affected individuals have severely impaired psychomotor development and may show hypotonia or spasticity. Brain imaging may show hypomyelination, cerebral atrophy, and thinning of the corpus callosum (summary by Butler et al., 2018 and Hernandez et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly
MedGen UID:
1684871
Concept ID:
C5231413
Disease or Syndrome
Myopathy, congenital, progressive, with scoliosis
MedGen UID:
1684769
Concept ID:
C5231417
Disease or Syndrome
Progressive congenital myopathy with scoliosis (MYOSCO) is an autosomal recessive skeletal muscle disorder characterized by infantile-onset of progressive muscle weakness and atrophy associated with scoliosis, variably impaired walking, and dysmorphic facial features (Feichtinger et al., 2019).
Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies
MedGen UID:
1684881
Concept ID:
C5231426
Disease or Syndrome
Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies (IDNADFS) is characterized by mildly impaired global development, speech delay with nasal speech, and dysmorphic facial features, including high forehead, midface hypoplasia, micrognathia or high-arched palate, hypo/hypertelorism, upslanting palpebral fissures, and thin upper lip. Some patients may have skeletal anomalies, such as brachydactyly, 2-3 toe syndactyly, and flat feet (summary by Alesi et al., 2019 and Uehara et al., 2019).
Noonan syndrome 12
MedGen UID:
1684730
Concept ID:
C5231432
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Siddiqi syndrome
MedGen UID:
1684813
Concept ID:
C5231435
Disease or Syndrome
Siddiqi syndrome (SIDDIS) is an autosomal recessive disorder characterized by global developmental delay, early-onset progressive sensorineural hearing impairment, regression of motor skills, dystonia, poor overall growth, and low body mass index (BMI). More variable features may include ichthyosis-like skin abnormalities or sensory neuropathy (summary by Zazo Seco et al., 2017).
Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies
MedGen UID:
1684792
Concept ID:
C5231448
Disease or Syndrome
Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA) is a global neurodevelopmental disorder with highly variable features. Patients often show poor feeding, poor overall growth, and hypotonia from early infancy, followed by mildly delayed motor development, poor language acquisition, and behavioral abnormalities. Intellectual development varies from severe with absent speech to mild with the ability to attend special schools. Common features include dysmorphic facial features with notable eye anomalies, joint hypermobility, and mild skeletal anomalies of the hands and feet (summary by Carapito et al., 2019).
Intellectual developmental disorder with short stature and behavioral abnormalities
MedGen UID:
1684812
Concept ID:
C5231462
Disease or Syndrome
Neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia
MedGen UID:
1684663
Concept ID:
C5231471
Disease or Syndrome
Neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia (NEDBASH) is an autosomal recessive disorder characterized by severely impaired intellectual and motor development, axial and peripheral hypotonia usually with inability to walk, and significant behavioral abnormalities consistent with autism spectrum disorder and reminiscent of Rett syndrome (RTT; 312750), such as poor communication, stereotypic or repetitive behaviors, hand-wringing, bruxism, and sleep disturbances. Other features include poor overall growth, and joint hypermobility. Rare features include seizures, dystonia, spasticity, and nonspecific brain abnormalities (summary by Abu-Libdeh et al., 2019 and Dias et al., 2019).
Intellectual developmental disorder with hypotonia and behavioral abnormalities
MedGen UID:
1684709
Concept ID:
C5231489
Disease or Syndrome
Intellectual developmental disorder with hypotonia and behavioral abnormalities (IDDHBA) is a neurodevelopmental disorder characterized by onset of hypotonia and variably impaired global developmental delay in infancy. Affected individuals tend to have learning disability, usually requiring special schooling, as well as behavioral abnormalities, such as autistic features and attention deficit-hyperactivity disorder (ADHD). Additional more variable features may include nonspecific dysmorphic facial features, congenital heart defects, visual or ocular movement anomalies, and poor feeding and/or gastroesophageal reflux (summary by Calpena et al., 2019).
Spastic paraplegia 81, autosomal recessive
MedGen UID:
1711668
Concept ID:
C5394033
Disease or Syndrome
Spastic paraplegia-81 (SPG81) is an autosomal recessive neurologic disorder with onset in infancy. Affected individuals have delayed motor development, progressive spasticity, and other neurologic impairment, including impaired intellectual development and speech delay. Some patients may have additional features, including bifid uvula, microcephaly, seizures, and variable ocular anomalies. One severely affected patient was reported to have cortical visual loss, sensorineural deafness, and achievement of almost no developmental milestones. Brain imaging shows white matter abnormalities, hypomyelination with progressive white matter loss, and sometimes cerebral atrophy. These significant additional abnormalities enable classification of this disorder as a complicated form of SPG (summary by Ahmed et al., 2017 and Horibata et al., 2018). For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).
CEBALID syndrome
MedGen UID:
1710973
Concept ID:
C5394044
Disease or Syndrome
Individuals with MN1 C-terminal truncation (MCTT) syndrome have mild-to-moderate intellectual disability, severe expressive language delay, dysmorphic facial features (midface hypoplasia, downslanting palpebral fissures, hypertelorism, exophthalmia, short upturned nose, and small low-set ears), and distinctive findings on brain imaging (including perisylvian polymicrogyria and atypical rhombencephalosynapsis). Mild-to-moderate prelingual hearing loss (usually bilateral, conductive, and/or sensorineural) is common. Generalized seizures (observed in the minority of individuals) are responsive to anti-seizure medication. There is an increased risk for craniosynostosis and, thus, increased intracranial pressure. To date, 25 individuals with MCTT syndrome have been identified.
Mitochondrial complex 3 deficiency, nuclear type 10
MedGen UID:
1719382
Concept ID:
C5394051
Disease or Syndrome
Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation
MedGen UID:
1716098
Concept ID:
C5394091
Disease or Syndrome
Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation (NEDHRIT) is a severe autosomal recessive disorder characterized by neonatal respiratory distress, poor feeding, and impaired global development. Affected individuals are unable to walk or speak and have poor or absent eye contact. Some patients may develop seizures (summary by Wagner et al., 2020).
Spinocerebellar ataxia, autosomal recessive 28
MedGen UID:
1712568
Concept ID:
C5394101
Disease or Syndrome
Autosomal recessive spinocerebellar ataxia-28 (SCAR28) is a neurologic disorder characterized by onset in early childhood of mildly delayed motor development, gait ataxia, incoordination of fine motor movements, and dysarthria. Affected individuals may have features of spasticity and may show mildly impaired cognitive function. Brain imaging shows cerebellar vermis hypoplasia (summary by Walker et al., 2019).
Triokinase and FMN cyclase deficiency syndrome
MedGen UID:
1710207
Concept ID:
C5394125
Disease or Syndrome
Triokinase and FMN cyclase deficiency syndrome (TKFCD) is a multisystem disease with marked clinical variability, even intrafamilially. In addition to cataract and developmental delay of variable severity, other features may include liver dysfunction, microcytic anemia, and cerebellar hypoplasia. Fatal cardiomyopathy with lactic acidosis has been observed (Wortmann et al., 2020).
Myopathy, congenital, with respiratory insufficiency and bone fractures
MedGen UID:
1718097
Concept ID:
C5394189
Disease or Syndrome
Congenital myopathy with respiratory insufficiency and bone fractures (MYORIBF) is an autosomal recessive early-onset severe muscular disorder resulting in early death. Affected individuals present at birth with neonatal hypotonia, poor feeding, fractures of the long bones, and respiratory insufficiency. Laboratory investigations are consistent with a defect in early muscle development (summary by Estan et al., 2019).
Myopathy, congenital proximal, with minicore lesions
MedGen UID:
1717569
Concept ID:
C5394193
Disease or Syndrome
Congenital proximal myopathy with minicore lesions (MYOPMIL) is an autosomal recessive early-onset muscular disorder affecting mainly the proximal muscles. Affected individuals have neonatal hypotonia followed by mildly delayed walking in childhood. They show slowly progressive, primarily proximal muscle weakness with Gowers sign and difficulty running or climbing, but they remain ambulatory. Cardiac function is unaffected, but most patients have obstructive sleep apnea. Muscle biopsy shows type 1 fiber predominance with disorganized Z-lines and multiminicore myopathy with areas devoid of NADH enzymatic activity and mitochondria, suggestive of abnormal early muscle development (summary by Estan et al., 2019).
Neurodevelopmental disorder with microcephaly and dysmorphic facies
MedGen UID:
1719418
Concept ID:
C5394218
Disease or Syndrome
Nabais Sa-de Vries syndrome type 1 (NSDVS1) is characterized by global developmental delay apparent from infancy, variable behavioral abnormalities, microcephaly, and dysmorphic facial features, including round face, small palpebral fissures, highly arched eyebrows, and short nose. The severity is variable (summary by Nabais Sa et al., 2020).
Neurodevelopmental disorder with relative macrocephaly and with or without cardiac or endocrine anomalies
MedGen UID:
1714169
Concept ID:
C5394221
Disease or Syndrome
Nabais Sa-de Vries syndrome type 2 (NSDVS2) is characterized by global developmental delay apparent from birth and distinctive dysmorphic facial features. Most patients have additional anomalies, including congenital heart defects, sleep disturbances, hypotonia, and variable endocrine abnormalities, such as hypothyroidism (summary by Nabais Sa et al., 2020).
Diets-Jongmans syndrome
MedGen UID:
1714920
Concept ID:
C5394263
Disease or Syndrome
Diets-Jongmans syndrome (DIJOS) is an autosomal dominant disorder characterized by mild to moderately impaired intellectual development with a recognizable facial gestalt (summary by Diets et al., 2019).
Anauxetic dysplasia 3
MedGen UID:
1718444
Concept ID:
C5394289
Disease or Syndrome
Anauxetic dysplasia-3 (ANXD3) is characterized by severe short stature, brachydactyly, skin laxity, joint hypermobility, and joint dislocations. Radiographs show short metacarpals, broad middle phalanges, and metaphyseal irregularities. Most patients also exhibit motor and cognitive delays (Narayanan et al., 2019). For a discussion of genetic heterogeneity of anauxetic dysplasia, see ANXD1 (607095).
Diabetes mellitus, permanent neonatal 3
MedGen UID:
1717271
Concept ID:
C5394303
Disease or Syndrome
Permanent neonatal diabetes mellitus-3 (PNDM3) is characterized by the onset of mild to severe hyperglycemia within the first months of life, and requires lifelong therapy (summary by Babenko et al., 2006). Some patients also have neurologic features, including developmental delay and epilepsy (Proks et al., 2006; Babenko et al., 2006). The triad of developmental delay, epilepsy, and neonatal diabetes is known as DEND. For a discussion of genetic heterogeneity of permanent neonatal diabetes mellitus, see PNDM1 (606176).
Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities
MedGen UID:
1714862
Concept ID:
C5394311
Disease or Syndrome
Neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities (NEDASB) is an early-onset neurologic disorder characterized by global developmental delay, poor or absent speech and language development, and behavioral abnormalities reminiscent of autism spectrum disorder (ASD; 209850) or Angelman syndrome (AS; 105830). Additional features may include poor overall growth with small head circumference, axial hypotonia, spasticity, and seizures. Some patients have abnormal findings on brain imaging, including cerebral atrophy, cerebellar atrophy, and/or thin corpus callosum (summary by Mattioli et al., 2020).
Neurodevelopmental disorder with hypotonia, microcephaly, and seizures
MedGen UID:
1710110
Concept ID:
C5394312
Disease or Syndrome
Neurodevelopmental disorder with hypotonia, microcephaly, and seizures (NEDHYMS) is an autosomal recessive disorder characterized by global developmental delay with axial hypotonia, inability to sit or walk, and severely impaired intellectual development with absent language. Most patients develop early-onset intractable seizures that prevent normal development. Additional features include feeding difficulties with poor overall growth and microcephaly. Some patients may have spastic quadriplegia, poor eye contact due to cortical blindness, variable dysmorphic features, and nonspecific abnormalities on brain imaging (summary by Tan et al., 2020).
Retinal dystrophy with leukodystrophy
MedGen UID:
1715138
Concept ID:
C5394315
Disease or Syndrome
Retinal dystrophy and leukodystrophy (RDLKD) is a peroxisomal enzyme deficiency caused by impaired very long chain fatty acid (VLCFA) metabolism. Patients exhibit ataxia and spastic paraparesis as well as developmental delay, and may show facial dysmorphism (Ferdinandusse et al., 2017).
Skeletal dysplasia, mild, with joint laxity and advanced bone age
MedGen UID:
1711043
Concept ID:
C5394341
Disease or Syndrome
CSGALNACT1 deficiency is characterized by mild skeletal dysplasia, joint hypermobility, and advanced bone age. Shortness of long bones is evident prenatally, and patients exhibit short stature and relative macrocephaly. Advanced carpotarsal bone age and monkey-wrench appearance of the femur observed in infancy may disappear with age (Mizumoto et al., 2020).
Nizon-Isidor syndrome
MedGen UID:
1715748
Concept ID:
C5394350
Disease or Syndrome
Nizon-Isidor syndrome (NIZIDS) is a neurodevelopmental disorder characterized by global developmental delay, mildly delayed walking, poor speech and language, variably impaired intellectual development, and behavioral abnormalities, such as autistic features or attention deficit-hyperactivity disorder (ADHD). Some patients may have additional features, including nonspecific facial dysmorphism, gastrointestinal difficulties, distal hand anomalies, and thin corpus callosum on brain imaging (summary by Nizon et al., 2019).
Intellectual developmental disorder with autistic features and language delay, with or without seizures
MedGen UID:
1715081
Concept ID:
C5394447
Disease or Syndrome
Intellectual developmental disorder with autistic features and language delay, with or without seizures (IDDALDS), is a neurodevelopmental disorder characterized by global developmental delay, variable intellectual disability, impaired speech development, and behavioral abnormalities, most commonly on the autism spectrum. About half of patients develop seizures; brain imaging is typically normal. Additional features are highly variable, but may include chronic constipation, walking difficulties, and dysmorphic facial features (summary by Guo et al., 2019).
Neurodevelopmental, jaw, eye, and digital syndrome
MedGen UID:
1712714
Concept ID:
C5394477
Disease or Syndrome
Neurodevelopmental, jaw, eye, and digital syndrome (NEDJED) is characterized by phenotypic diversity, with patients exhibiting a range of overlapping phenotypes. Most patients show developmental delay ranging from mild to severe, and often have behavioral disorders as well. Brain imaging shows hypoplasia of the corpus callosum, prominence of lateral ventricles, and/or white matter abnormalities. Many patients have retro- or micrognathia, but mild prognathism has also been observed. Ocular anomalies are variably present, and may be severe and complex; however, some patients show only mild myopia. Abnormalities of fingers and toes include brachydactyly, clinodactyly, syndactyly, and contractures; polydactyly is rarely seen (Holt et al., 2019).
Cytochrome-c oxidase deficiency disease
MedGen UID:
1750917
Concept ID:
C5435656
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 1 (MC4DN1) is an autosomal recessive metabolic disorder characterized by rapidly progressive neurodegeneration and encephalopathy with loss of motor and cognitive skills between about 5 and 18 months of age after normal early development. Affected individuals show hypotonia, failure to thrive, loss of the ability to sit or walk, poor communication, and poor eye contact. Other features may include oculomotor abnormalities, including slow saccades, strabismus, ophthalmoplegia, and nystagmus, as well as deafness, apneic episodes, ataxia, tremor, and brisk tendon reflexes. Brain imaging shows bilateral symmetric lesions in the basal ganglia, consistent with a clinical diagnosis of Leigh syndrome (see 256000). Some patients may also have abnormalities in the brainstem and cerebellum. Laboratory studies usually show increased serum and CSF lactate and decreased levels and activity of mitochondrial respiratory complex IV in patient tissues. There is phenotypic variability, but death in childhood, often due to central respiratory failure, is common (summary by Tiranti et al., 1998; Tiranti et al., 1999; Teraoka et al., 1999; Poyau et al., 2000) Genetic Heterogeneity of Mitochondrial Complex IV Deficiency Most isolated COX deficiencies are inherited as autosomal recessive disorders caused by mutations in nuclear-encoded genes; mutations in the mtDNA-encoded COX subunit genes are relatively rare (Shoubridge, 2001; Sacconi et al., 2003). Mitochondrial complex IV deficiency caused by mutation in nuclear-encoded genes, in addition to MC4DN1, include MC4DN2 (604377), caused by mutation in the SCO2 gene (604272); MC4DN3 (619046), caused by mutation in the COX10 gene (602125); MC4DN4 (619048), caused by mutation in the SCO1 gene (603664); MC4DN5 (220111), caused by mutation in the LRPPRC gene (607544); MC4DN6 (615119), caused by mutation in the COX15 gene (603646); MC4DN7 (619051), caused by mutation in the COX6B1 gene (124089); MC4DN8 (619052), caused by mutation in the TACO1 gene (612958); MC4DN9 (616500), caused by mutation in the COA5 gene (613920); MC4DN10 (619053), caused by mutation in the COX14 gene (614478); MC4DN11 (619054), caused by mutation in the COX20 gene (614698); MC4DN12 (619055), caused by mutation in the PET100 gene (614770); MC4DN13 (616501), caused by mutation in the COA6 gene (614772); MC4DN14 (619058), caused by mutation in the COA3 gene (614775); MC4DN15 (619059), caused by mutation in the COX8A gene (123870); MC4DN16 (619060), caused by mutation in the COX4I1 gene (123864); MC4DN17 (619061), caused by mutation in the APOPT1 gene (616003); MC4DN18 (619062), caused by mutation in the COX6A2 gene (602009); MC4DN19 (619063), caused by mutation in the PET117 gene (614771); MC4DN20 (619064), caused by mutation in the COX5A gene (603773); and MC4DN21 (619065), caused by mutation in the COXFA4 gene (603883). Mitochondrial complex IV deficiency has been associated with mutations in several mitochondrial genes, including MTCO1 (516030), MTCO2 (516040), MTCO3 (516050), MTTS1 (590080), MTTL1 (590050), and MTTN (590010).
Myopathy, congenital, with diaphragmatic defects, respiratory insufficiency, and dysmorphic facies
MedGen UID:
1764743
Concept ID:
C5436530
Disease or Syndrome
Congenital myopathy with diaphragmatic defects, respiratory insufficiency, and dysmorphic facies (MYODRIF) is an autosomal recessive muscle disorder. Affected individuals present at birth with hypotonia and respiratory insufficiency associated with high diaphragmatic dome on imaging. Other features include poor overall growth, pectus excavatum, dysmorphic facies, and renal anomalies in some. The severity of the disorder is highly variable: some patients may have delayed motor development with mildly decreased endurance, whereas others have more severe hypotonia associated with distal arthrogryposis and lung hypoplasia, resulting in early death (summary by Watson et al., 2016 and Lopes et al., 2018).
Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type b, 15
MedGen UID:
1755743
Concept ID:
C5436552
Disease or Syndrome
Deeah syndrome
MedGen UID:
1756624
Concept ID:
C5436579
Disease or Syndrome
DEEAH syndrome is an autosomal recessive multisystemic disorder with onset in early infancy. Affected individuals usually present in the perinatal period with respiratory insufficiency, apneic episodes, and generalized hypotonia. The patients have failure to thrive and severely impaired global development with poor acquisition of motor, cognitive, and language skills. Other common features include endocrine, pancreatic exocrine, and autonomic dysfunction, as well as hematologic disturbances, mainly low hemoglobin. Patients also have dysmorphic and myopathic facial features. Additional more variable features include seizures, undescended testes, and distal skeletal anomalies. Death in early childhood may occur (summary by Schneeberger et al., 2020).
Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia
MedGen UID:
1776912
Concept ID:
C5436585
Disease or Syndrome
Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia (NEDDISH) is an autosomal recessive disorder characterized by global developmental delay and mildly to severely impaired intellectual development with poor speech and language acquisition. Some patients may have early normal development with onset of the disorder in the first years of life. More variable neurologic abnormalities include hypotonia, seizures, apnea, mild signs of autonomic or peripheral neuropathy, and autism. Aside from dysmorphic facial features and occasional findings such as scoliosis or undescended testes, other organ systems are not involved (summary by Schneeberger et al., 2020).
Combined oxidative phosphorylation deficiency 50
MedGen UID:
1753519
Concept ID:
C5436623
Disease or Syndrome
Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities
MedGen UID:
1736667
Concept ID:
C5436628
Disease or Syndrome
Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA) is an autosomal recessive disorder characterized by impaired psychomotor development apparent in infancy. Affected individuals show poor overall growth, progressive microcephaly, and axial hypotonia, with later onset of spasticity. The disorder is progressive. Some patients show normal early development, but later have regression of motor, cognitive, and language skills. More variable features include seizures, joint contractures, ocular disturbances, episodic respiratory failure, and nonspecific dysmorphic facial features. The intellectual impairment is variable, ranging from poor visual contact with inability to walk or speak to milder intellectual disability with the ability to say some words. Brain imaging shows variable white matter abnormalities, including thin corpus callosum and poor myelination (summary by Husain et al., 2020).
Vissers-Bodmer syndrome
MedGen UID:
1776566
Concept ID:
C5436647
Disease or Syndrome
Vissers-Bodmer syndrome (VIBOS) is characterized by global developmental delay with variably impaired intellectual development, speech delay, motor delay, and behavioral abnormalities apparent from infancy. The phenotype is highly variable: some individuals have only mild learning difficulties, whereas others have severe cognitive impairment with IQ in the 50s. Many patients have behavioral abnormalities, including autism spectrum disorder, ADD, ADHD, obsessive-compulsive disorder, and impulsivity. Other common features include growth impairment abnormalities, hypotonia, and distal skeletal defects, such as foot and hand deformities. Less common features include seizures, brain abnormalities on MRI, feeding problems, and joint hypermobility. Most individuals have dysmorphic facial features, but there is no recognizable gestalt (summary by Vissers et al., 2020).
Spinal muscular atrophy, infantile, James type
MedGen UID:
1764556
Concept ID:
C5436669
Disease or Syndrome
The phenotypic spectrum of GARS1-associated axonal neuropathy ranges from GARS1 infantile-onset SMA (GARS1-iSMA) to GARS1 adolescent- or early adult-onset hereditary motor/sensory neuropathy (GARS1-HMSN). GARS1-iSMA. Age of onset ranges from the neonatal period to the toddler years. Initial manifestations are typically respiratory distress, poor feeding, and muscle weakness (distal greater than proximal). Weakness is slowly progressive, ultimately requiring mechanical ventilation and feeding via gastrostomy tube. GARS1-HMSN. Age of onset is most commonly during the second decade (range eight to 36 years). Initial manifestations are typically muscle weakness in the hands sometimes with sensory deficits. Lower limb involvement (seen in ~50% of individuals) ranges from weakness and atrophy of the extensor digitorum brevis and weakness of toe dorsiflexors to classic peroneal muscular atrophy with foot drop and a high steppage gait.
Neurodevelopmental disorder with speech impairment and dysmorphic facies
MedGen UID:
1758434
Concept ID:
C5436699
Disease or Syndrome
Neurodevelopmental disorder with speech impairment and dysmorphic facies (NEDSID) is characterized by developmental delay associated with mild to moderately impaired intellectual development or learning difficulties, behavioral or psychiatric abnormalities, and delayed speech and language acquisition. Additional features include dysmorphic facies, distal limb anomalies, gastrointestinal problems or feeding difficulties, and hypotonia. The phenotypic features and severity of the disorder are variable (summary by Kummeling et al., 2021).
Mitochondrial complex 4 deficiency, nuclear type 19
MedGen UID:
1729504
Concept ID:
C5436723
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 19 (MC4DN19) is an autosomal recessive multisystem metabolic disorder characterized by the onset of symptoms in infancy or early childhood. Affected individuals show global developmental delay and developmental regression with a loss of acquired motor and language skills. Additional features include motor dysfunction, such as hypokinesia and pyramidal signs. More variable features may include recurrent infections with immunodeficiency and possibly protein-losing enteropathy. Serum lactate is increased; T2-weighted lesions in the medulla oblongata have also been reported. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV (Renkema et al., 2017). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Mitochondrial complex 4 deficiency, nuclear type 21
MedGen UID:
1732562
Concept ID:
C5436727
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 21 (MC4DN21) is an autosomal recessive multisystem metabolic disorder characterized by the onset of symptoms in infancy. Affected individuals present with congenital lactic acidosis and later show global developmental delay with delayed speech and learning disabilities. Additional features include motor dysfunction manifest as spasticity, dystonia, and pyramidal tract signs. Ataxia, peripheral neuropathy, and seizures may also occur. Brain imaging shows T2-weighted hyperintensities in subcortical regions, consistent with a clinical diagnosis of Leigh syndrome (see 256000). Patient tissues show variably decreased levels and activity of mitochondrial respiratory complex IV (Pitceathly et al., 2013). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Hearing loss, autosomal dominant 78
MedGen UID:
1777362
Concept ID:
C5436768
Disease or Syndrome
Autosomal dominant deafness-78 (DFNA78) is characterized by profound congenital bilateral sensorineural hearing loss affecting all frequencies. Some patients may have mild motor delay early in life due to vestibular dysfunction, although the motor skills catch up with age. Affected individuals do not have systemic or other neurologic manifestations (summary by Mutai et al., 2020).
Osteogenesis imperfecta, type 21
MedGen UID:
1723598
Concept ID:
C5436875
Disease or Syndrome
Osteogenesis imperfecta type XXI (OI21) is a progressively deforming disorder, characterized by multiple fractures that often occur after minor trauma. Fractures may be present at birth in some affected individuals. Patients exhibit disproportionate short stature and scoliosis, and are often wheelchair-bound by adulthood (van Dijk et al., 2020).
Lessel-Kreienkamp syndrome
MedGen UID:
1762595
Concept ID:
C5436892
Disease or Syndrome
Lessel-Kreienkamp syndrome (LESKRES) is a neurodevelopmental disorder characterized by global developmental delay with intellectual disability and speech and language delay apparent from infancy or early childhood. The severity of the disorder is highly variable: some patients have mildly delayed walking and mild cognitive deficits, whereas others are nonambulatory and nonverbal. Most have behavioral disorders. Additional features, including seizures, hypotonia, gait abnormalities, visual defects, cardiac defects, and nonspecific dysmorphic facial features may also be present (summary by Lessel et al., 2020).
Inflammatory bowel disease (infantile ulcerative colitis) 31, autosomal recessive
MedGen UID:
1783277
Concept ID:
C5444224
Disease or Syndrome
Infantile ulcerative colitis (IBD31) is characterized by the presence of ulcers throughout the colon and rectum with normal-appearing ileum. Affected infants present with recurrent bloody diarrhea with anemia and leukocytosis, with extensive lymphoplasmocytic infiltration, cryptitis, and apoptotic crypt abcesses throughout the colon and rectum (Zhang et al., 2021). Infantile bowel disease has also been referred to as very-early-onset IBD (VEOIBD). For a general description and discussion of genetic heterogeneity of inflammatory bowel disease, including Crohn disease (CD) and ulcerative colitis, see IBD1 (266600).
Goldblatt syndrome
MedGen UID:
1784281
Concept ID:
C5542277
Disease or Syndrome
Odontochondrodysplasia-1 (ODCD1) is characterized by mesomelic shortening of tubular bones, ligamentous laxity, and scoliosis, in association with dentinogenesis imperfecta involving both primary and secondary dentition. Affected individuals show variable severity. Radiologic features include trident pelvis, posteriorly flattened vertebrae, and brachydactyly with cone-shaped epiphyses (Maroteaux et al., 1996). Clinical variability and extraskeletal manifestations have been observed (Wehrle et al., 2019). Genetic Heterogeneity of Odontochondrodysplasia Odontochondrodysplasia-2 with hearing loss and diabetes (ODCD2; 619269) is caused by mutation in the TANGO1 gene (MIA3; 613455) on chromosome 1q41.
Neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities
MedGen UID:
1781967
Concept ID:
C5543020
Disease or Syndrome
Childhood-onset neurodegeneration with hypotonia, respiratory insufficiency, and brain imaging abnormalities (CONRIBA) is characterized by severe global developmental delay apparent in infancy or early childhood. Affected individuals have hypotonia with impaired motor development, respiratory insufficiency, and feeding difficulties requiring intervention. Intellectual and speech development is also delayed, and most have visual defects, including cortical visual blindness, nystagmus, and esotropia. The disorder is progressive, as manifest by developmental regression consistent with neurodegeneration. Although overt seizures are not observed, some patients may have episodic hypertonia or apnea, and EEG may show nonspecific abnormalities. Brain imaging shows unique diffusion restriction signal abnormalities affecting the brainstem, cerebellum, and corticospinal tracts. Early death may occur (summary by Polovitskaya et al., 2020).
Proteasome-associated autoinflammatory syndrome 4
MedGen UID:
1780127
Concept ID:
C5543053
Disease or Syndrome
Proteasome-associated autoinflammatory syndrome-4 (PRAAS4) is an autosomal recessive immunologic disorder characterized by onset of panniculitis and erythematous skin lesions in early infancy. Additional features include hepatosplenomegaly, lymphadenopathy, fever, generalized lipodystrophy, myositis, and joint contractures, as well as delayed motor and speech development. Autoimmune features, such as hemolytic anemia, may also occur. Laboratory studies show elevation of acute phase reactants and abnormal activation of the type I interferon response. Treatment with the JAK (see 147795) inhibitor ruxolitinib may result in clinical improvement (summary by de Jesus et al., 2019). For a discussion of genetic heterogeneity of PRAAS, see PRAAS1 (256040).
Neurofacioskeletal syndrome with or without renal agenesis
MedGen UID:
1778926
Concept ID:
C5543070
Disease or Syndrome
Neurofacioskeletal syndrome with or without renal agenesis (NFSRA) is characterized by developmental delay and/or intellectual disability; corpus callosum hypoplasia or agenesis; facial dysmorphism, including upslanting palpebral fissures, broad nasal tip, and wide mouth; and skeletal abnormalities, including short stature, scoliosis, and flexion contractures, with broad fingertips and/or toes. Renal agenesis, unilateral or bilateral, has also been observed in some patients (Schneeberger et al., 2020).
Deafness, congenital, and adult-onset progressive leukoencephalopathy
MedGen UID:
1784506
Concept ID:
C5543087
Disease or Syndrome
Congenital deafness and adult-onset progressive leukoencephalopathy (DEAPLE) is an autosomal recessive complex neurodegenerative disorder characterized by congenital neurosensory deafness followed by onset of neurodegenerative symptoms, including pyramidal signs and cognitive decline, in young adulthood. Some patients may have mild developmental delay or learning difficulties in childhood, but most can function independently. The onset of motor and cognitive decline in adulthood can be rapid and may result in early death. Brain imaging shows diffuse white matter abnormalities affecting various brain regions, consistent with a progressive leukoencephalopathy. More variable additional features may include visual impairment and axonal peripheral neuropathy (summary by Scheidecker et al., 2019).
Developmental delay with dysmorphic facies and dental anomalies
MedGen UID:
1785587
Concept ID:
C5543197
Disease or Syndrome
Developmental delay with dysmorphic facies and dental anomalies (DEFDA) is characterized by generally mild global developmental delay with variably impaired intellectual development, walking by 2 to 3 years, and slow language acquisition. The severity of the disorder ranges from moderate cognitive deficits to mild learning difficulties or behavioral abnormalities. Most patients have dysmorphic facial features, often with abnormal dentition and nonspecific visual defects, such as myopia, astigmatism, and strabismus. Although rare, involvement of other systems, such as skeletal, cardiac, and gastrointestinal, may be present (summary by den Hoed et al., 2021).
Kohlschutter-Tonz syndrome-like
MedGen UID:
1781649
Concept ID:
C5543202
Disease or Syndrome
Kohlschutter-Tonz syndrome-like (KTZSL) is characterized by global developmental delay with moderately to severely impaired intellectual development, poor or absent speech, and delayed motor skills. Although the severity of the disorder varies, many patients are nonverbal and have hypotonia with inability to sit or walk. Early-onset epilepsy is common and may be refractory to treatment, leading to epileptic encephalopathy and further interruption of developmental progress. Most patients have feeding difficulties with poor overall growth and dysmorphic facial features, as well as significant dental anomalies resembling amelogenesis imperfecta. The phenotype is reminiscent of Kohlschutter-Tonz syndrome (KTZS; 226750). More variable features of KTZSL include visual defects, behavioral abnormalities, and nonspecific involvement of other organ systems (summary by den Hoed et al., 2021).
Short stature, oligodontia, dysmorphic facies, and motor delay
MedGen UID:
1787876
Concept ID:
C5543206
Disease or Syndrome
SOFM is characterized by marked short stature, oligodontia, mild facial dysmorphism, and motor delay. Endosteal hyperostosis has also been observed, and patients may exhibit some features of progeria (Terhal et al., 2020; Beauregard-Lacroix et al., 2020).
Neurodevelopmental disorder with or without autism or seizures
MedGen UID:
1784023
Concept ID:
C5543225
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 37
MedGen UID:
1783339
Concept ID:
C5543281
Disease or Syndrome
Cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome
MedGen UID:
1780242
Concept ID:
C5543287
Disease or Syndrome
CIMDAG syndrome is a multisystemic disorder characterized by severely impaired psychomotor development and hematologic abnormalities apparent from early infancy. Affected individuals show poor overall growth with microcephaly, impaired intellectual development, poor or absent speech, poor eye contact, and motor problems, such as inability to walk, hypotonia, and spasticity. Brain imaging typically shows cerebral and cerebellar atrophy, thin corpus callosum, and delayed myelination. The associated hematologic abnormalities are variable, but are mostly consistent with congenital dyserythropoietic anemia (CDA) (summary by Rodger et al., 2020 and Seu et al., 2020).
NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, CATARACTS, AND CEREBELLAR HYPOPLASIA
MedGen UID:
1781371
Concept ID:
C5543306
Disease or Syndrome
Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia (NEDSCAC) is an autosomal recessive disorder characterized by global developmental delay with variably impaired intellectual development. More severely affected individuals are nonverbal and do not achieve independent ambulation, whereas others develop some speech and can walk, or show regression later in childhood. Common features include axial hypotonia, peripheral spasticity, dystonia, cataracts, and seizures. Brain imaging usually shows cerebellar hypoplasia with variable additional abnormalities, such as thin corpus callosum, cerebral atrophy, and hypomyelination (summary by Meng et al., 2021).
Pontocerebellar hypoplasia, type 14
MedGen UID:
1778516
Concept ID:
C5543322
Disease or Syndrome
Pontocerebellar hypoplasia type 14 (PCH14) is a severe autosomal recessive neurodevelopmental disorder characterized by congenital onset of progressive microcephaly and poor or absent psychomotor development with severely impaired intellectual development apparent from birth. Other features may include hypotonia, spastic quadriplegia, and early-onset seizures. Brain imaging shows pontocerebellar hypoplasia, agenesis or partial agenesis of the corpus callosum, and sometimes a simplified gyral pattern. Early death may occur (summary by et al., 2021). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1A (607596).
RADIO-TARTAGLIA SYNDROME
MedGen UID:
1778557
Concept ID:
C5543339
Disease or Syndrome
Radio-Tartaglia syndrome (RATARS) is a neurodevelopmental disorder characterized by global developmental delay with impaired intellectual development, speech delay, and variable behavioral abnormalities. Affected individuals show hypotonia, mild motor difficulties, and craniofacial dysmorphism. Brain imaging may show nonspecific defects; rare patients have seizures or pyramidal signs. A subset of individuals may have congenital heart defects, precocious puberty, and obesity in females. Some of the features are similar to those observed in patients with chromosome 1p36 deletion syndrome (607872) (summary by Radio et al., 2021).
BURATTI-HAREL SYNDROME
MedGen UID:
1788293
Concept ID:
C5543351
Disease or Syndrome
Buratti-Harel syndrome (BURHAS) is a neurodevelopmental disorder characterized by infantile hypotonia, global developmental delay, mild motor and speech delay, and mild to moderately impaired intellectual development. Some patients are able to attend special schools and show learning difficulties, whereas others are more severely affected. Patients have prominent dysmorphic facial features, including hypertelorism, downslanting palpebral fissures, strabismus, and small low-set ears. Additional features may include laryngomalacia with feeding difficulties and distal skeletal anomalies (summary by Buratti et al., 2021).
BDV SYNDROME
MedGen UID:
1785671
Concept ID:
C5543403
Disease or Syndrome
BDV syndrome (BDVS) is an autosomal recessive disorder characterized by early-onset profound obesity, hyperphagia, and moderately impaired intellectual development accompanied by infantile hypotonia and other endocrine disorders including hypogonadotropic hypogonadism, hypothyroidism, and insulin resistance (summary by Bosch et al., 2021).
NEURODEVELOPMENTAL DISORDER WITH CEREBELLAR ATROPHY AND MOTOR DYSFUNCTION
MedGen UID:
1781936
Concept ID:
C5543427
Disease or Syndrome
Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (NEDCAM) is an autosomal recessive disorder characterized by global developmental delay with prominent motor abnormalities, mainly axial hypotonia, gait ataxia, and appendicular spasticity. Affected individuals have cognitive impairment and speech delay; brain imaging shows cerebellar atrophy. The severity is variable (summary by Kour et al., 2021).
Spinocerebellar ataxia, autosomal recessive 29
MedGen UID:
1788435
Concept ID:
C5543595
Disease or Syndrome
Autosomal recessive spinocerebellar ataxia-29 (SCAR29) is a progressive neurodegenerative disorder characterized by delayed motor development in early infancy followed by difficulty walking due to an ataxic gait or inability to walk, hypotonia, and variably impaired intellectual development. Other features include dysarthria, nystagmus, peripheral spasticity, nystagmus, and visual impairment. Brain imaging typically shows atrophy of the cerebellar vermis, but other abnormalities may also be present. Some patients are wheelchair-bound and/or nonverbal (summary by Sanderson et al., 2021) In a review of the pathogenesis of disorders with prominent dystonia as a feature, Monfrini et al. (2021) classified SCAR29 as belonging to a group of neurologic disorders termed 'HOPS-associated neurologic disorders' (HOPSANDs), which are caused by mutations in genes encoding various components of the autophagic/endolysosomal system, including VPS41.
Dyskinesia with orofacial involvement, autosomal dominant
MedGen UID:
1790407
Concept ID:
C5551343
Disease or Syndrome
ADCY5 dyskinesia is a hyperkinetic movement disorder (more prominent in the face and arms than the legs) characterized by infantile to late-adolescent onset of chorea, athetosis, dystonia, myoclonus, or a combination of these. To date, affected individuals have had overlapping (but not identical) manifestations with wide-ranging severity. The facial movements are typically periorbital and perioral. The dyskinesia is prone to episodic or paroxysmal exacerbation lasting minutes to hours, and may occur during sleep. Precipitating factors in some persons have included emotional stress, intercurrent illness, sneezing, or caffeine; in others, no precipitating factors have been identified. In some children, severe infantile axial hypotonia results in gross motor delays accompanied by chorea, sometimes with language delays. The overall tendency is for the abnormal movements to stabilize in early middle age, at which point they may improve in some individuals; less commonly, the abnormal movements are slowly progressive, increasing in severity and frequency.
Neuroocular syndrome
MedGen UID:
1790414
Concept ID:
C5551362
Disease or Syndrome
Neuroocular syndrome (NOC) encompasses a broad spectrum of overlapping anomalies, with developmental delay or impaired intellectual development as a consistent finding. Eye abnormalities show marked variability in the type and severity of defects, and include anophthalmia, microphthalmia, and coloboma. Other common systemic features include congenital heart and kidney defects, hypotonia, failure to thrive, and microcephaly (summary by Chowdhury et al., 2021).
Charcot-Marie-Tooth Disease, axonal, type 2GG
MedGen UID:
1794143
Concept ID:
C5561933
Disease or Syndrome
Charcot-Marie-Tooth disease type 2GG (CMT2GG) is an autosomal dominant axonal peripheral neuropathy characterized by slowly progressive distal muscle weakness and atrophy primarily affecting the lower limbs and causing difficulty walking. The onset is usually in adulthood, although rare patients may have mild symptoms from childhood. Some individuals may also have involvement of the hands. Although most patients have hypo- or areflexia at the ankles, distal sensory impairment is not always present, indicating a spectrum of disease encompassing both distal hereditary neuropathy and axonal CMT. Electrophysiologic studies are consistent with a axonal process (summary by Mendoza-Ferreira et al., 2020). For a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).
NEURODEVELOPMENTAL DISORDER WITH MOTOR AND SPEECH DELAY AND BEHAVIORAL ABNORMALITIES
MedGen UID:
1794164
Concept ID:
C5561954
Disease or Syndrome
Neurodevelopmental disorder with motor and speech delay and behavioral abnormalities (NEDMOSBA) is an autosomal recessive disorder characterized by global developmental delay apparent from early childhood. There is significant phenotypic variability: some patients achieve walking and talking after a few years, whereas others develop spastic tetraplegia with inability to walk independently and never gain proper speech. Affected individuals may have variable additional features, including poor overall growth, hypotonia, tremor, ocular anomalies, seizures, and nonspecific dysmorphic facial features (summary by Polla et al., 2021).
VISS SYNDROME
MedGen UID:
1794165
Concept ID:
C5561955
Disease or Syndrome
VISS syndrome is a generalized connective tissue disorder characterized by early-onset thoracic aortic aneurysm and other connective tissue findings, such as aneurysm and tortuosity of other arteries, joint hypermobility, skin laxity, and hernias, as well as craniofacial dysmorphic features, structural cardiac defects, skeletal anomalies, and motor developmental delay (Van Gucht et al., 2021). Immune dysregulation has been observed in some patients (Ziegler et al., 2021).
DEVELOPMENTAL DELAY, IMPAIRED SPEECH, AND BEHAVIORAL ABNORMALITIES
MedGen UID:
1794167
Concept ID:
C5561957
Disease or Syndrome
Developmental delay, impaired speech, and behavioral abnormalities (DDISBA) is characterized by global developmental delay apparent from early childhood. Intellectual disability can range from mild to severe. Additional variable features may include dysmorphic facial features, seizures, hypotonia, motor abnormalities such as Tourette syndrome or dystonia, and hearing loss (summary by Cousin et al., 2021).
Chopra-Amiel-Gordon syndrome
MedGen UID:
1794185
Concept ID:
C5561975
Disease or Syndrome
Chopra-Amiel-Gordon syndrome (CAGS) is an autosomal dominant disorder characterized by developmental delay and/or impaired intellectual development, speech delay, facial dysmorphism, and variable other features, including recurrent bacterial infections, ophthalmologic abnormalities, and nonspecific brain abnormalities (Chopra et al., 2021).
MUSCULAR DYSTROPHY, CONGENITAL HEARING LOSS, AND OVARIAN INSUFFICIENCY SYNDROME
MedGen UID:
1794190
Concept ID:
C5561980
Disease or Syndrome
Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome (MDHLO) is an autosomal recessive systemic disorder characterized by progressive muscle weakness, sensorineural hearing loss, and endocrine abnormalities, mainly primary amenorrhea due to ovarian insufficiency. Features of the disorder appear soon after birth, although endocrine anomalies are not noted until puberty. The severity of the phenotype is variable: some patients may lose ambulation and have significant respiratory insufficiency, whereas others retain the ability to walk (Foley et al., 2020).
DEVELOPMENTAL DELAY WITH OR WITHOUT INTELLECTUAL IMPAIRMENT OR BEHAVIORAL ABNORMALITIES
MedGen UID:
1794214
Concept ID:
C5562004
Disease or Syndrome
Developmental delay with or without intellectual impairment or behavioral abnormalities (DDIB) is an autosomal dominant disorder with a nonspecific phenotype of developmental delay. Additional features may include neonatal feeding problems, hypotonia, and dysmorphic facial features (Dulovic-Mahlow et al., 2019; van Woerden et al., 2021).
NEURODEVELOPMENTAL DISORDER WITH IMPAIRED LANGUAGE AND ATAXIA AND WITH OR WITHOUT SEIZURES
MedGen UID:
1794216
Concept ID:
C5562006
Disease or Syndrome
Neurodevelopmental disorder with impaired language and ataxia and with or without seizures (NEDLAS) is characterized by axial hypotonia and global developmental delay apparent in early infancy. Affected individuals have delayed walking with gait ataxia and poor language development. Behavioral abnormalities also commonly occur. The severity is highly variable: a subset of patients have a more severe phenotype with early-onset seizures resembling epileptic encephalopathy, inability to walk or speak, and hypomyelination on brain imaging (summary by Stolz et al., 2021).
Joubert syndrome 40
MedGen UID:
1794217
Concept ID:
C5562007
Disease or Syndrome
Joubert syndrome-40 (JBTS40) is an autosomal recessive neurodevelopmental disorder characterized by developmental delay, postaxial polydactyly, subtle midline notching or clefting of the upper lip, hypotonia, and the 'molar tooth sign' on brain imaging. Affected individuals do not exhibit retinal or renal anomalies, or significant obesity (Zhongling et al., 2021). For a discussion of genetic heterogeneity of Joubert syndrome, see JBTS1 (213300).
Dyskinesia with orofacial involvement, autosomal recessive
MedGen UID:
1794246
Concept ID:
C5562036
Disease or Syndrome
Autosomal recessive dyskinesia with orofacial involvement (DSKOR) is characterized by the onset of abnormal involuntary movements, mainly affecting the limbs and causing walking difficulties, in the first decade. The severity is variable; some patients have orofacial dyskinesia resulting in speech difficulties, or develop neuropsychiatric features, including anxiety and social withdrawal. Cardiomyopathy has rarely been described and may be a manifestation of the disorder (summary by Bohlega et al., 2019).
NEURODEVELOPMENTAL DISORDER, NONPROGRESSIVE, WITH SPASTICITY AND TRANSIENT OPISTHOTONUS
MedGen UID:
1794250
Concept ID:
C5562040
Disease or Syndrome
Nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus (NEDSTO) is an autosomal recessive complex neurologic disorder characterized by delay of gross motor milestones, particularly walking, associated with axial hypotonia and peripheral spasticity apparent from infancy or early childhood. Affected individuals often show transient opisthotonic posturing in infancy, and later show abnormal involuntary movements, including chorea, dystonia, and dyspraxia. Some patients have impaired intellectual development, although the severity is highly variable; most have speech delay and articulation difficulties and a happy overall demeanor. Brain imaging shows myelination defects in some patients. The disorder is nonprogressive, and many patients may catch up developmentally in the second or third decades (summary by Wagner et al., 2020).
Spastic paraplegia 85, autosomal recessive
MedGen UID:
1794263
Concept ID:
C5562053
Disease or Syndrome
Autosomal recessive spastic paraplegia-85 (SPG85) is a neurologic disorder characterized by the onset of motor symptoms in the first few years of life. Affected individuals have spasticity and hyperreflexia of the lower limbs resulting in gait abnormalities. Older patients may have upper limb involvement and demonstrate axonal polyneuropathy. Additional features include optic atrophy, dysarthria, dysphagia, ataxia, and urinary incontinence. Brain imaging may show cerebellar atrophy (summary by Wagner et al., 2019). For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).
Developmental delay with variable neurologic and brain abnormalities
MedGen UID:
1794270
Concept ID:
C5562060
Disease or Syndrome
Developmental delay with variable neurologic and brain abnormalities (DENBA) is characterized most often by motor and speech delay apparent from early childhood. Most patients have delayed walking and variably impaired intellectual development. Additional neurologic features may include seizures, spasticity, and ocular abnormalities. Brain imaging often shows thin corpus callosum and may show white matter atrophy, myelination abnormalities, or enlarged ventricles. The severity of the disorder and clinical manifestations are highly variable (summary by Malhotra et al., 2021).
Ferguson-Bonni neurodevelopmental syndrome
MedGen UID:
1794275
Concept ID:
C5562065
Disease or Syndrome
Ferguson-Bonni neurodevelopmental syndrome (FERBON) is an autosomal recessive disorder characterized by global developmental delay, impaired intellectual development, and hypotonia with early motor delay. Additional features may include dysmorphic facies, mild skeletal abnormalities, and hearing loss (summary by Ferguson et al., 2022).
Congenital disorder of glycosylation, type Iw, autosomal dominant
MedGen UID:
1794278
Concept ID:
C5562068
Disease or Syndrome
Autosomal dominant congenital disorder of glycosylation type Iw (CDG1WAD) is characterized by variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features; about half of patients have impaired intellectual development. Additional features include increased muscle tone and muscle cramps (Wilson et al., 2021).
Leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy
MedGen UID:
1794284
Concept ID:
C5562074
Disease or Syndrome
Hypomyelinating leukodystrophy-23 with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy (HLD23) is an autosomal recessive neurodegenerative disorder with systemic manifestations. Affected individuals show delayed motor development and ataxic gait in early childhood that progresses to spastic paraplegia with loss of ambulation in the first decades of life. Additional features include progressive sensorineural hearing loss resulting in deafness, hepatic dysfunction with elevated liver enzymes, and dilated cardiomyopathy that ultimately results in death in the first or second decades. Brain imaging shows hypomyelination, diffuse white matter abnormalities consistent with leukodystrophy, and thin corpus callosum (summary by Sferra et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080.
Dyskinesia, limb and orofacial, infantile-onset
MedGen UID:
1798887
Concept ID:
C5567464
Disease or Syndrome
Infantile-onset limb and orofacial dyskinesia is an autosomal recessive neurologic disorder characterized by delayed motor development and onset of a hyperkinetic movement disorder in the first year of life. The disorder results in impaired walking and orofacial dyskinesia with difficulty talking; the severity is variable (summary by Diggle et al., 2016).
Progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome
MedGen UID:
1800305
Concept ID:
C5568882
Disease or Syndrome
A rare genetic multiple congenital anomalies/dysmorphic syndrome with characteristics of global developmental delay and intellectual disability, progressive spondyloepimetaphyseal dysplasia, short stature, short fourth metatarsals and dysmorphic craniofacial features (including microcephaly, hypertelorism, epicanthal folds, mild ptosis, strabismus, malar hypoplasia, short nose, depressed nasal bridge, full lips, small, low-set ears and short neck). Craniosynostosis, generalized hypotonia, as well as asymmetry of the cerebral hemispheres and mild thinning of the corpus callosum on brain imaging have also been described.
Charcot-Marie-Tooth disease axonal type 2Z
MedGen UID:
1800448
Concept ID:
C5569025
Disease or Syndrome
Charcot-Marie-Tooth disease type 2Z (CMT2Z) is an autosomal dominant axonal peripheral neuropathy characterized by onset, usually in the first decade, of distal lower limb muscle weakness and sensory impairment. The disorder is progressive, and affected individuals tend to develop upper limb and proximal muscle involvement in an asymmetric pattern, resulting in severe disability late in adulthood. Rare occurrence of global developmental delay with impaired intellectual development or learning difficulties has been observed. In some instances, the same mutation may result in different phenotypic manifestations (CMT2Z or DIGFAN), which highlights the clinical spectrum associated with MORC2 mutations and may render the classification of patients into one or the other disorder challenging (summary by Sevilla et al., 2016, Ando et al., 2017, Guillen Sacoto et al., 2020). For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).
Acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome
MedGen UID:
1800507
Concept ID:
C5569084
Disease or Syndrome
Autosomal recessive spinocerebellar ataxia-21 is a neurologic disorder characterized by onset of cerebellar ataxia associated with cerebellar atrophy in early childhood. Affected individuals also have recurrent episodes of liver failure in the first decade, resulting in chronic liver fibrosis, as well as later onset of a peripheral neuropathy. Mild learning disabilities may also occur (summary by Schmidt et al., 2015). The phenotype is highly variable: all patients appear to have episodic and severe liver dysfunction in early childhood that tends to resolve with age. Affected individuals also show mild developmental or language delay and/or later onset of variable neurologic features, such as motor dysfunction (summary by Lenz et al., 2018).
Congenital nonprogressive myopathy with Moebius and Robin sequences
MedGen UID:
1804638
Concept ID:
C5676876
Disease or Syndrome
Carey-Fineman-Ziter syndrome-1 (CFZS1) is a multisystem congenital disorder characterized by hypotonia, Moebius sequence (bilateral congenital facial palsy with impairment of ocular abduction), Pierre Robin complex (micrognathia, glossoptosis, and high-arched or cleft palate), delayed motor milestones, and failure to thrive. More variable features include dysmorphic facial features, brain abnormalities, and intellectual disability. It has been postulated that many clinical features in CFZS1 may be secondary effects of muscle weakness during development or brainstem anomalies (summary by Pasetti et al., 2016). Di Gioia et al. (2017) determined that CFZS1 represents a slowly progressive congenital myopathy resulting from a defect in myoblast fusion. Genetic Heterogeneity of Carey-Fineman-Ziter Syndrome Carey-Fineman-Ziter syndrome-2 (CFZS2) is caused by mutation in the MYMX gene (619912) on chromosome 6p21.
Intellectual disability, autosomal dominant 40
MedGen UID:
1810363
Concept ID:
C5676894
Disease or Syndrome
Neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features (NEDHILD) is a rare neurodevelopmental disorder associated with impaired intellectual development, speech and language impairment, microcephaly, seizures, hypotonia, ophthalmologic issues, constipation/gastroesophageal reflux, and behavioral problems, including autism and sleep disturbances (summary by Garrity et al., 2021).
Neurodevelopmental disorder with or without variable movement or behavioral abnormalities
MedGen UID:
1802087
Concept ID:
C5676908
Disease or Syndrome
Neurodevelopmental disorder with or without variable movement or behavioral abnormalities (NEDMAB) is an autosomal dominant disorder characterized by mildly to severely impaired intellectual development and, in some patients, movement abnormalities consisting of tremors, cerebellar ataxia, or extrapyramidal symptoms. Movement abnormalities have onset in childhood or adolescence. Other variable features include autism spectrum disorder or autistic features and epilepsy.
Stuve-Wiedemann syndrome 2
MedGen UID:
1805977
Concept ID:
C5676919
Disease or Syndrome
Stuve-Wiedemann syndrome-2 (STWS2) is an autosomal recessive lethal skeletal dysplasia characterized by short stature, small chest, bowing of the long bones, and neonatal cardiopulmonary and autonomous dysfunction. Additional variable features include congenital thrombocytopenia, eczematoid dermatitis, renal anomalies, and defective acute-phase response (Chen et al., 2020). For a general phenotypic description and discussion of genetic heterogeneity of Stuve-Wiedemann syndrome, see STWS1 (601559).
Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism
MedGen UID:
1808634
Concept ID:
C5676924
Disease or Syndrome
Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism (CDIDHH) is characterized by delayed motor development, ataxia, severe progressive scoliosis, moderate to severe intellectual disability, and delayed sexual development. Cerebellar hypoplasia has been observed in some patients (Whittaker et al., 2021).
Kury-Isidor syndrome
MedGen UID:
1807460
Concept ID:
C5676925
Disease or Syndrome
Kury-Isidor syndrome (KURIS) is a neurodevelopmental disorder with a highly variable phenotype. It is characterized mainly by mild global developmental delay apparent from infancy or early childhood with walking delayed by a few years and speech delay, often with language deficits. Intellectual development may be mildly delayed, borderline, or even normal; most patients have behavioral problems, including autism. Additional variable systemic features may include poor overall growth, hypotonia, distal skeletal anomalies, seizures, and nonspecific dysmorphic facial features (summary by Kury et al., 2022).
Macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin
MedGen UID:
1802903
Concept ID:
C5676928
Disease or Syndrome
Macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin (MNDLFH) is characterized by clinically significant pharyngeal lymphoid hypertrophy, with adenoid overgrowth, frequent upper airway infections, and sleep apnea. Macrocephaly without structural brain abnormalities is present, and patients exhibit increased weight for height as well as delayed gross motor and impaired intellectual development; autistic features and attention-deficit hyperactivity disorder have also been reported. An increased fraction of fetal hemoglobin has been observed in some patients (Ohishi et al., 2020; von der Lippe et al., 2022).
Immunodeficiency 96
MedGen UID:
1810465
Concept ID:
C5676930
Disease or Syndrome
Immunodeficiency-96 (IMD96) is an autosomal recessive disorder characterized by onset of recurrent, usually viral, respiratory infections in infancy or early childhood. Other infections, including gastrointestinal and urinary tract infections, may also occur. Laboratory studies show hypogammaglobulinemia, lymphopenia with increased gamma/delta T cells, and erythrocyte macrocytosis. The disorder results from defective cellular DNA repair (summary by Maffucci et al., 2018).
Congenital disorder of deglycosylation 2
MedGen UID:
1809253
Concept ID:
C5676931
Disease or Syndrome
Congenital disorder of deglycosylation-2 (CDDG2) is an autosomal recessive disorder with variable associated features such as dysmorphic facies, impaired intellectual development, and brain anomalies, including polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and cerebellar vermis (Maia et al., 2022). For a discussion of genetic heterogeneity of congenital disorder of deglycosylation, see CDGG1 (615273).
Neurodevelopmental disorder with neuromuscular and skeletal abnormalities
MedGen UID:
1803456
Concept ID:
C5676965
Disease or Syndrome
Neurodevelopmental disorder with neuromuscular and skeletal abnormalities (NEDNMS) is an autosomal recessive disorder characterized by global developmental delay apparent from infancy or early childhood. The severity of the disorder is highly variable. Affected individuals show impaired intellectual development and motor delay associated with either severe hypotonia or hypertonia and spasticity. Most affected individuals have skeletal defects and dysmorphic facial features. Some may have ocular or auditory problems, peripheral neuropathy, behavioral abnormalities, and nonspecific findings on brain imaging (Kurolap et al., 2022).
Intellectual developmental disorder with or without peripheral neuropathy
MedGen UID:
1807523
Concept ID:
C5676969
Disease or Syndrome
Intellectual developmental disorder with or without peripheral neuropathy (IDDPN) is an autosomal recessive neurologic disorder characterized by global developmental delay with mildly impaired intellectual development apparent from infancy or early childhood. Affected individuals have hypotonia and delayed walking with an unsteady gait and frequent falls. Some patients develop a progressive length-dependent sensorimotor peripheral neuropathy. Additional features may include dysarthria and subtle dysmorphic facial features (Diaz et al., 2020).
Autoinflammatory-pancytopenia syndrome due to DNASE2 deficiency
MedGen UID:
1803642
Concept ID:
C5676977
Disease or Syndrome
Autoinflammatory-pancytopenia syndrome (AIPCS) is an autosomal recessive disorder characterized by severe anemia and thrombocytopenia apparent from early infancy, hepatosplenomegaly, and recurrent fevers associated with a hyperinflammatory state. Additional systemic features may include chronic diarrhea, proteinuria with renal disease, liver fibrosis with elevated liver enzymes, deforming arthropathy, and vasculitic skin lesions. Some patients may have motor delay or learning difficulties associated with subcortical white matter lesions on brain imaging. Laboratory studies show increased levels of proinflammatory cytokines and increased expression of interferon-stimulated genes (ISGs), consistent with a type I interferonopathy (Rodero et al., 2017). Treatment with a JAK (see 147795) inhibitor (baricitinib) may be effective (Hong et al., 2020).
Parenti-Mignot neurodevelopmental syndrome
MedGen UID:
1808333
Concept ID:
C5676984
Disease or Syndrome
Parenti-Mignot neurodevelopmental syndrome (PMNDS) is an autosomal dominant neurodevelopmental disorder frequently characterized by impaired intellectual development, speech delay, motor delay, behavioral problems, and epilepsy (Parenti et al., 2021).
Neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures
MedGen UID:
1810140
Concept ID:
C5676986
Disease or Syndrome
Neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures (NEDMHS) is an autosomal recessive disorder characterized by global developmental delay and impaired intellectual development apparent from infancy. Affected individuals have hypotonia with poor or absent motor skills, feeding difficulties with poor overall growth, microcephaly, mild dysmorphic features, and early-onset seizures. Additional variable features, such as nystagmus, cortical blindness, and spasticity, may also occur. Patients with this disorder tend to have recurrent respiratory infections, likely due to aspiration, that may lead to death in childhood (Arnadottir et al., 2022).
Pontocerebellar hypoplasia, IIA 17
MedGen UID:
1809583
Concept ID:
C5676999
Disease or Syndrome
Pontocerebellar hypoplasia type 17 (PCH17) is a severe autosomal recessive developmental disorder characterized by neonatal hypotonia, severe feeding difficulties, and respiratory insufficiency. Brain imaging shows cerebellar and brainstem hypoplasia. Most affected individuals die in infancy. Those who survive show variable developmental delay. Other features of the disorder include distal hypertonia, poor overall growth, visual defects, autonomic problems, dysmorphic features, and seizures (Coolen et al., 2022). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1A (607596).
Intellectual developmental disorder, autosomal dominant 67
MedGen UID:
1805690
Concept ID:
C5677006
Mental or Behavioral Dysfunction
Autosomal dominant intellectual developmental disorder-67 (MRD67) is characterized by global developmental delay with variably impaired intellectual development apparent from infancy or early childhood. Additional features may include behavioral abnormalities, such as autism spectrum disorder (ASD) and ADHD, as well as language and sleeping difficulties. Brain imaging is normal (Ismail et al., 2022).
Tessadori-Van Haaften neurodevelopmental syndrome 3
MedGen UID:
1811418
Concept ID:
C5677015
Disease or Syndrome
Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-3 (TEBIVANED3) is characterized by global developmental delay with poor overall growth, impaired intellectual development, and speech difficulties. More variable features include hypotonia, microcephaly, and dysmorphic facies. The severity and manifestations of the disorder are highly variable (Tessadori et al., 2022). For a discussion of genetic heterogeneity of Tessadori-Bicknell-van Haaften neurodevelopmental disorder, see TEBIVANED1 (619758).
ACCES syndrome
MedGen UID:
1804308
Concept ID:
C5677019
Disease or Syndrome
Aplasia cutis congenita and ectrodactyly skeletal syndrome (ACCES) is characterized by highly variable expressivity, even within the same family. Most patients exhibit scalp defects, whereas ectrodactyly is less common; however, more variable and less obvious digital and skeletal anomalies are often present. Early growth deficiency and neurodevelopmental delay are also commonly seen (Schnur et al., 2021).
Cerebrofaciothoracic dysplasia
MedGen UID:
1808104
Concept ID:
C5677021
Disease or Syndrome
Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-1 (CFSMR1) is characterized by cranial involvement with macrocrania at birth, brachycephaly, anomalies of middle fossa structures including hypoplasia of corpus callosum, enlargement of septum pellucidum, and dilated lateral ventricles, as well as cortical atrophy and hypodensity of the gray matter. Facial dysmorphisms include flat face, hypertelorism, epicanthal folds, synophrys, broad nasal bridge, cleft lip and cleft palate, and low-set posteriorly rotated ears. Patients also exhibit short neck and multiple costal and vertebral anomalies. The face is rather characteristic, and various authors have consistently reported affable/friendly personality, despite intellectual delay (summary by Alanay et al., 2014). Genetic Heterogeneity of Craniofacial Dysmorphism, Skeletal Anomalies, and Mental Retardation Syndrome CFSMR2 (616994) is caused by mutation in the RAB5IF gene (619960) on chromosome 20q11.

Recent clinical studies

Etiology

Kretch KS, Koziol NA, Marcinowski EC, Kane AE, Inamdar K, Brown ED, Bovaird JA, Harbourne RT, Hsu LY, Lobo MA, Dusing SC
Dev Psychobiol 2022 Jan;64(1):e22233. doi: 10.1002/dev.22233. PMID: 35050510
Gabis LV, Attia OL, Roth-Hanania R, Foss-Feig J
Res Dev Disabil 2020 Sep;104:103702. Epub 2020 Jun 20 doi: 10.1016/j.ridd.2020.103702. PMID: 32570001
Veldman SL, Jones RA, Chandler P, Robinson LE, Okely AD
J Paediatr Child Health 2020 Apr;56(4):571-576. Epub 2019 Nov 9 doi: 10.1111/jpc.14684. PMID: 31705779
Shriberg LD, Campbell TF, Mabie HL, McGlothlin JH
Clin Linguist Phon 2019;33(8):737-756. doi: 10.1080/02699206.2019.1595733. PMID: 31221011Free PMC Article
Hatakenaka Y, Kotani H, Yasumitsu-Lovell K, Suzuki K, Fernell E, Gillberg C
Pediatr Neurol 2016 Jan;54:55-63. doi: 10.1016/j.pediatrneurol.2015.09.008. PMID: 26706480

Diagnosis

Vats P, Polipalli SK, Yuvaraj P, Kapoor S
Neurol India 2020 Jul-Aug;68(4):919-921. doi: 10.4103/0028-3886.293457. PMID: 32859844
Gabis LV, Attia OL, Roth-Hanania R, Foss-Feig J
Res Dev Disabil 2020 Sep;104:103702. Epub 2020 Jun 20 doi: 10.1016/j.ridd.2020.103702. PMID: 32570001
Veldman SL, Jones RA, Chandler P, Robinson LE, Okely AD
J Paediatr Child Health 2020 Apr;56(4):571-576. Epub 2019 Nov 9 doi: 10.1111/jpc.14684. PMID: 31705779
Shriberg LD, Campbell TF, Mabie HL, McGlothlin JH
Clin Linguist Phon 2019;33(8):737-756. doi: 10.1080/02699206.2019.1595733. PMID: 31221011Free PMC Article
Hatakenaka Y, Kotani H, Yasumitsu-Lovell K, Suzuki K, Fernell E, Gillberg C
Pediatr Neurol 2016 Jan;54:55-63. doi: 10.1016/j.pediatrneurol.2015.09.008. PMID: 26706480

Therapy

Namasivayam AK, Huynh A, Granata F, Law V, van Lieshout P
Pediatr Res 2021 Feb;89(3):613-621. Epub 2020 May 1 doi: 10.1038/s41390-020-0924-4. PMID: 32357364Free PMC Article
Ferrante R, Hendershot S, Baranet K, Barbosa G, Carey H, Maitre N, Lo W, Pan J, Heathcock J
Pediatr Phys Ther 2019 Apr;31(2):217-224. doi: 10.1097/PEP.0000000000000594. PMID: 30865149Free PMC Article
Gorgon EJR
Phys Ther 2018 Jun 1;98(6):480-493. doi: 10.1093/ptj/pzy009. PMID: 29351642
Harbourne RT, Ryalls B, Stergiou N
Phys Occup Ther Pediatr 2014 May;34(2):197-212. Epub 2013 Aug 1 doi: 10.3109/01942638.2013.820252. PMID: 23901882
Meijer IA, Vanasse M, Nizard S, Robitaille Y, Rossignol E
Muscle Nerve 2014 Jan;49(1):134-8. Epub 2013 Nov 22 doi: 10.1002/mus.23968. PMID: 23893323

Prognosis

Kretch KS, Koziol NA, Marcinowski EC, Kane AE, Inamdar K, Brown ED, Bovaird JA, Harbourne RT, Hsu LY, Lobo MA, Dusing SC
Dev Psychobiol 2022 Jan;64(1):e22233. doi: 10.1002/dev.22233. PMID: 35050510
Duchan E
FP Essent 2021 Nov;510:11-16. PMID: 34709024
Namasivayam AK, Huynh A, Granata F, Law V, van Lieshout P
Pediatr Res 2021 Feb;89(3):613-621. Epub 2020 May 1 doi: 10.1038/s41390-020-0924-4. PMID: 32357364Free PMC Article
Harris SR
Can Fam Physician 2016 Aug;62(8):629-32. PMID: 27521388Free PMC Article
Hatakenaka Y, Kotani H, Yasumitsu-Lovell K, Suzuki K, Fernell E, Gillberg C
Pediatr Neurol 2016 Jan;54:55-63. doi: 10.1016/j.pediatrneurol.2015.09.008. PMID: 26706480

Clinical prediction guides

Duchan E
FP Essent 2021 Nov;510:11-16. PMID: 34709024
Hedgecock JB, Dannemiller LA, Shui AM, Rapport MJ, Katz T
Phys Ther 2018 Apr 1;98(4):251-259. doi: 10.1093/ptj/pzy006. PMID: 29325143
Ansar M, Riazuddin S, Sarwar MT, Makrythanasis P, Paracha SA, Iqbal Z, Khan J, Assir MZ, Hussain M, Razzaq A, Polla DL, Taj AS, Holmgren A, Batool N, Misceo D, Iwaszkiewicz J, de Brouwer APM, Guipponi M, Hanquinet S, Zoete V, Santoni FA, Frengen E, Ahmed J, Riazuddin S, van Bokhoven H, Antonarakis SE
Genet Med 2018 Jul;20(7):778-784. Epub 2017 Aug 24 doi: 10.1038/gim.2017.113. PMID: 28837161
Harris SR
Can Fam Physician 2016 Aug;62(8):629-32. PMID: 27521388Free PMC Article
Malerba KH, Tecklin JS
Phys Ther 2013 Jun;93(6):833-41. Epub 2013 Feb 21 doi: 10.2522/ptj.20110376. PMID: 23431212

Recent systematic reviews

Muthusamy S, Wagh D, Tan J, Bulsara M, Rao S
JAMA Pediatr 2022 Oct 1;176(10):980-989. doi: 10.1001/jamapediatrics.2022.3079. PMID: 36036913Free PMC Article
Marbán-Castro E, Vazquez Guillamet LJ, Pantoja PE, Casellas A, Maxwell L, Mulkey SB, Menéndez C, Bardají A
Int J Environ Res Public Health 2022 Jun 14;19(12) doi: 10.3390/ijerph19127319. PMID: 35742566Free PMC Article
De Roubaix A, Van de Velde D, Roeyers H, Van Waelvelde H
Eur J Paediatr Neurol 2021 Jan;30:29-57. Epub 2020 Dec 13 doi: 10.1016/j.ejpn.2020.12.003. PMID: 33385976
Caesar R, Colditz PB, Cioni G, Boyd RN
Dev Med Child Neurol 2021 Apr;63(4):387-395. Epub 2020 Nov 13 doi: 10.1111/dmcn.14730. PMID: 33185285
Miller L, Ziviani J, Boyd RN
Phys Occup Ther Pediatr 2014 Feb;34(1):90-111. Epub 2013 Mar 11 doi: 10.3109/01942638.2013.771720. PMID: 23477639

Supplemental Content

Table of contents

    Clinical resources

    Consumer resources

    Recent activity

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...
    Support Center