MedGen

Multiple acyl-CoA dehydrogenase deficiency (MADD) represents a clinical spectrum in which presentations can be divided into type I (neonatal onset with congenital anomalies), type II (neonatal onset without congenital anomalies), and type III (late onset). Individuals with type I or II MADD typically become symptomatic in the neonatal period with severe metabolic acidosis, which may be accompanied by profound hypoglycemia and hyperammonemia. Many affected individuals die in the newborn period despite metabolic treatment. In those who survive the neonatal period, recurrent metabolic decompensation resembling Reye syndrome and the development of hypertrophic cardiomyopathy can occur. Congenital anomalies may include dysmorphic facial features, large cystic kidneys, hypospadias and chordee in males, and neuronal migration defects (heterotopias) on brain MRI. Individuals with type III MADD, the most common presentation, can present from infancy to adulthood. The most common symptoms are muscle weakness, exercise intolerance, and/or muscle pain, although metabolic decompensation with episodes of rhabdomyolysis can also be seen. Rarely, individuals with late-onset MADD (type III) may develop severe sensory neuropathy in addition to proximal myopathy. [from GeneReviews]

Fukuyama congenital muscular dystrophy (FCMD) is characterized by hypotonia, symmetric generalized muscle weakness, and CNS migration disturbances that result in changes consistent with cobblestone lissencephaly with cerebral and cerebellar cortical dysplasia. Mild, typical, and severe phenotypes are recognized. Onset typically occurs in early infancy with poor suck, weak cry, and floppiness. Affected individuals have contractures of the hips, knees, and interphalangeal joints. Later features include myopathic facial appearance, pseudohypertrophy of the calves and forearms, motor and speech delays, intellectual disability, seizures, ophthalmologic abnormalities including visual impairment and retinal dysplasia, and progressive cardiac involvement after age ten years. Swallowing disturbance occurs in individuals with severe FCMD and in individuals older than age ten years, leading to recurrent aspiration pneumonia and death. [from GeneReviews]

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. [from GeneReviews]

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 a genetically heterogeneous autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and early death. The phenotype commonly includes cobblestone (type II) lissencephaly, cerebellar malformations, and retinal malformations. More variable features include macrocephaly or microcephaly, hypoplasia of midline brain structures, ventricular dilatation, microphthalmia, cleft lip/palate, and congenital contractures (Dobyns et al., 1989). Those with a more severe phenotype characterized as Walker-Warburg syndrome often die within the first year of life, whereas those characterized as having muscle-eye-brain disease may rarely acquire the ability to walk and to speak a few words. These are part of a group of disorders resulting from defective glycosylation of DAG1 (128239), collectively known as 'dystroglycanopathies' (Godfrey et al., 2007). Genetic Heterogeneity of Congenital Muscular Dystrophy-Dystroglycanopathy with Brain and Eye Anomalies (Type A) Muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is genetically heterogeneous and can be caused by mutation in other genes involved in DAG1 glycosylation: see MDDGA2 (613150), caused by mutation in the POMT2 gene (607439); MDDGA3 (253280), caused by mutation in the POMGNT1 gene (606822); MDDGA4 (253800), caused by mutation in the FKTN gene (607440); MDDGA5 (613153), caused by mutation in the FKRP gene (606596); MDDGA6 (613154), caused by mutation in the LARGE gene (603590); MDDGA7 (614643), caused by mutation in the ISPD gene (CRPPA; 614631); MDDGA8 (614830) caused by mutation in the GTDC2 gene (POMGNT2; 614828); MDDGA9 (616538), caused by mutation in the DAG1 gene (128239); MDDGA10 (615041), caused by mutation in the TMEM5 gene (RXYLT1; 605862); MDDGA11 (615181), caused by mutation in the B3GALNT2 gene (610194); MDDGA12 (615249), caused by mutation in the SGK196 gene (POMK; 615247); MDDGA13 (615287), caused by mutation in the B3GNT1 gene (B4GAT1; 605517); and MDDGA14 (615350), caused by mutation in the GMPPB gene (615320). [from OMIM]

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. [from GeneReviews]

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. [from GeneReviews]

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. [from GeneReviews]

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. [from GeneReviews]

Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies. [from GeneReviews]

Malonyl-CoA decarboxylase deficiency is an uncommon inherited metabolic disease. The characteristic phenotype is variable, but may include developmental delay in early childhood, seizures, hypotonia, diarrhea, vomiting, metabolic acidosis, hypoglycemia, ketosis, abnormal urinary compounds, lactic acidemia, and hypertrophic cardiomyopathy (Sweetman and Williams, 2001). [from OMIM]

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. [from SNOMEDCT_US]

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). [from OMIM]

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. [from GeneReviews]

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. [from GeneReviews]

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. [from GeneReviews]

The constitutional deletion of chromosome 1p36 results in a syndrome with multiple congenital anomalies and mental retardation (Shapira et al., 1997). Monosomy 1p36 is the most common terminal deletion syndrome in humans, occurring in 1 in 5,000 births (Shaffer and Lupski, 2000; Heilstedt et al., 2003). See also neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH; 616975), which shows overlapping features and is caused by heterozygous mutation in the RERE gene (605226) on proximal chromosome 1p36. See also Radio-Tartaglia syndrome (RATARS; 619312), caused by mutation in the SPEN gene (613484) on chromosome 1p36, which shows overlapping features. [from OMIM]

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). [from OMIM]

CASK disorders include a spectrum of phenotypes in both females and males. Two main types of clinical presentation are seen: Microcephaly with pontine and cerebellar hypoplasia (MICPCH), generally associated with pathogenic loss-of-function variants in CASK. X-linked intellectual disability (XLID) with or without nystagmus, generally associated with hypomorphic CASK pathogenic variants. MICPCH is typically seen in females with moderate-to-severe intellectual disability, progressive microcephaly with or without ophthalmologic anomalies, and sensorineural hearing loss. Most are able to sit independently; 20%-25% attain the ability to walk; language is nearly absent in most. Neurologic features may include axial hypotonia, hypertonia/spasticity of the extremities, and dystonia or other movement disorders. Nearly 40% have seizures by age ten years. Behaviors may include sleep disturbances, hand stereotypies, and self biting. MICPCH in males may occur with or without severe epileptic encephalopathy in addition to severe-to-profound developmental delay. When seizures are present they occur early and may be intractable. In individuals and families with milder (i.e., hypomorphic) pathogenic variants, the clinical phenotype is usually that of XLID with or without nystagmus and additional clinical features. Males have mild-to-severe intellectual disability, with or without nystagmus and other ocular features. Females typically have normal intelligence with some displaying mild-to-severe intellectual disability with or without ocular features. [from GeneReviews]

X-linked lissencephaly-2 (LISX2) is a developmental disorder characterized by structural brain anomalies, early-onset intractable seizures, severe psychomotor retardation, and ambiguous genitalia. Males are severely affected and often die within the first days or months of life, whereas females may be unaffected or have a milder phenotype (Bonneau et al., 2002). LISX2 is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from hydranencephaly and lissencephaly to Proud syndrome (300004) to infantile spasms without brain malformations (DEE1; 308350) to syndromic (309510) and nonsyndromic (300419) mental retardation (Kato et al., 2004; Wallerstein et al., 2008). For a general phenotypic description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (607432). [from OMIM]

MDDGB5 is an autosomal recessive congenital muscular dystrophy with impaired intellectual development and structural brain abnormalities (Brockington et al., 2001). 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., 2006). For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (613155). [from OMIM]