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Limb hypertonia

MedGen UID:
333083
Concept ID:
C1838391
Finding
Synonyms: Hypertonia in limbs; Hypertonia in the limbs; Hypertonia of limbs; Hypertonia of the limbs; Hypertonia, limb; Hypertonia, limbs
 
HPO: HP:0002509

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVLimb hypertonia

Conditions with this feature

Propionic acidemia
MedGen UID:
75694
Concept ID:
C0268579
Disease or Syndrome
The spectrum of propionic acidemia (PA) ranges from neonatal-onset to late-onset disease. Neonatal-onset PA, the most common form, is characterized by a healthy newborn with poor feeding and decreased arousal in the first few days of life, followed by progressive encephalopathy of unexplained origin. Without prompt diagnosis and management, this is followed by progressive encephalopathy manifesting as lethargy, seizures, or coma that can result in death. It is frequently accompanied by metabolic acidosis with anion gap, lactic acidosis, ketonuria, hypoglycemia, hyperammonemia, and cytopenias. Individuals with late-onset PA may remain asymptomatic and suffer a metabolic crisis under catabolic stress (e.g., illness, surgery, fasting) or may experience a more insidious onset with the development of multiorgan complications including vomiting, protein intolerance, failure to thrive, hypotonia, developmental delays or regression, movement disorders, or cardiomyopathy. Isolated cardiomyopathy can be observed on rare occasion in the absence of clinical metabolic decompensation or neurocognitive deficits. Manifestations of neonatal and late-onset PA over time can include growth impairment, intellectual disability, seizures, basal ganglia lesions, pancreatitis, and cardiomyopathy. Other rarely reported complications include optic atrophy, hearing loss, premature ovarian insufficiency, and chronic renal failure.
6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
MedGen UID:
209234
Concept ID:
C0878676
Disease or Syndrome
Tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) comprises a genetically heterogeneous group of progressive neurologic disorders caused by autosomal recessive mutations in the genes encoding enzymes involved in the synthesis or regeneration of BH4. BH4 is a cofactor for phenylalanine hydroxylase (PAH; 612349), tyrosine hydroxylase (TH; 191290) and tryptophan hydroxylase (TPH1; 191060), the latter 2 of which are involved in neurotransmitter synthesis. The BH4-deficient HPAs are characterized phenotypically by hyperphenylalaninemia, depletion of the neurotransmitters dopamine and serotonin, and progressive cognitive and motor deficits (Dudesek et al., 2001). HPABH4A, caused by mutations in the PTS gene, represents the most common cause of BH4-deficient hyperphenylalaninemia (Dudesek et al., 2001). Other forms of BH4-deficient HPA include HPABH4B (233910), caused by mutation in the GCH1 gene (600225), HPABH4C (261630), caused by mutation in the QDPR gene (612676), and HPABH4D (264070), caused by mutation in the PCBD1 gene (126090). Niederwieser et al. (1982) noted that about 1 to 3% of patients with hyperphenylalaninemia have one of these BH4-deficient forms. These disorders are clinically and genetically distinct from classic phenylketonuria (PKU; 261600), caused by mutation in the PAH gene. Two additional disorders associated with BH4 deficiency and neurologic symptoms do not have overt hyperphenylalaninemia as a feature: dopa-responsive dystonia (612716), caused by mutation in the SPR gene (182125), and autosomal dominant dopa-responsive dystonia (DYT5; 128230), caused by mutation in the GCH1 gene. Patients with these disorders may develop hyperphenylalaninemia when stressed.
Deficiency of aromatic-L-amino-acid decarboxylase
MedGen UID:
220945
Concept ID:
C1291564
Disease or Syndrome
Aromatic L-amino acid decarboxylase deficiency (AADCD) is an autosomal recessive inborn error in neurotransmitter metabolism that leads to combined serotonin and catecholamine deficiency (Abeling et al., 2000). The disorder is clinically characterized by vegetative symptoms, oculogyric crises, dystonia, and severe neurologic dysfunction, usually beginning in infancy or childhood (summary by Brun et al., 2010).
Goldberg-Shprintzen syndrome
MedGen UID:
332131
Concept ID:
C1836123
Disease or Syndrome
Goldberg-Shprintzen syndrome (GOSHS) is an autosomal recessive multiple congenital anomaly syndrome characterized by impaired intellectual development, microcephaly, and dysmorphic facial features. Most patients also have Hirschsprung disease and/or gyral abnormalities of the brain, consistent with defects in migration of neural crest cells and neurons. Other features, such as megalocornea or urogenital anomalies, may also be present. Goldberg-Shprintzen syndrome has some resemblance to Mowat-Wilson syndrome (MOWS; 235730) but is genetically distinct (summary by Drevillon et al., 2013).
Amish lethal microcephaly
MedGen UID:
375938
Concept ID:
C1846648
Disease or Syndrome
Amish lethal microcephaly is characterized by severe congenital microcephaly and highly elevated 2-ketoglutarate or lactic acidosis. The occipitofrontal circumference is typically more than two standard deviations (occasionally >6 SD) below the mean; anterior and posterior fontanels are closed at birth and facial features are distorted. The average life span of an affected infant is between five and six months among the Lancaster Amish, although an affected Amish-Mennonite child was reported to be living with severe developmental delay at age seven years.
Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C
MedGen UID:
340761
Concept ID:
C1854990
Disease or Syndrome
Molybdenum cofactor deficiency (MoCD) represents a spectrum, with some individuals experiencing significant signs and symptoms in the neonatal period and early infancy (termed early-onset or severe MoCD) and others developing signs and symptoms in childhood or adulthood (termed late-onset or mild MoCD). Individuals with early-onset MoCD typically present in the first days of life with severe encephalopathy, including refractory seizures, opisthotonos, axial and appendicular hypotonia, feeding difficulties, and apnea. Head imaging may demonstrate loss of gray and white matter differentiation, gyral swelling, sulci injury (typically assessed by evaluating the depth of focal lesional injury within the sulci), diffusely elevated T2-weighted signal, and panlobar diffusion restriction throughout the forebrain and midbrain with relative sparring of the brain stem. Prognosis for early-onset MoCD is poor, with about 75% succumbing in infancy to secondary complications of their neurologic disability (i.e., pneumonia). Late-onset MoCD is typically characterized by milder symptoms, such as acute neurologic decompensation in the setting of infection. Episodes vary in nature but commonly consist of altered mental status, dystonia, choreoathetosis, ataxia, nystagmus, and fluctuating hypotonia and hypertonia. These features may improve after resolution of the inciting infection or progress in a gradual or stochastic manner over the lifetime. Brain imaging may be normal or may demonstrate T2-weighted hyperintense or cystic lesions in the globus pallidus, thinning of the corpus callosum, and cerebellar atrophy.
Autosomal recessive osteopetrosis 5
MedGen UID:
409627
Concept ID:
C1968603
Disease or Syndrome
Autosomal recessive osteopetrosis-5 is a form of infantile malignant osteopetrosis, characterized by defective osteoclast function resulting in decreased bone resorption and generalized osteosclerosis. Defective resorption causes development of densely sclerotic fragile bones and progressive obliteration of the marrow spaces and cranial foramina. Marrow obliteration is associated with extramedullary hematopoiesis and hepatosplenomegaly, and results in anemia and thrombocytopenia, whereas nerve entrapment accounts for progressive blindness and hearing loss. Other major manifestations include failure to thrive, pathologic fractures, and increased infection rate. Most affected children succumb to severe bone marrow failure and overwhelming infection in the first few years of life (Quarello et al., 2004).
Pontocerebellar hypoplasia type 2B
MedGen UID:
393505
Concept ID:
C2676466
Disease or Syndrome
TSEN54 pontocerebellar hypoplasia (TSEN54-PCH) comprises three PCH phenotypes (PCH2, 4, and 5) that share characteristic neuroradiologic and neurologic findings. The three PCH phenotypes (which differ mainly in life expectancy) were considered to be distinct entities before their molecular basis was known. PCH2. Children usually succumb before age ten years (those with PCH4 and 5 usually succumb as neonates). Children with PCH2 have generalized clonus, uncoordinated sucking and swallowing, impaired cognitive development, lack of voluntary motor development, cortical blindness, and an increased risk for rhabdomyolysis during severe infections. Epilepsy is present in approximately 50%. PCH4. Neonates often have seizures, multiple joint contractures ("arthrogryposis"), generalized clonus, and central respiratory impairment. PCH5 resembles PCH4 and has been described in one family.
Hereditary spastic paraplegia 50
MedGen UID:
442869
Concept ID:
C2752008
Disease or Syndrome
AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of neurodegenerative disorders characterized by a progressive, complex spastic paraplegia with onset typically in infancy or early childhood. Early-onset hypotonia evolves into progressive lower-extremity spasticity. The majority of children become nonambulatory and usually wheelchair bound. Over time spasticity progresses to involve the upper extremities, resulting in a spastic tetraplegia. Associated complications include dysphagia, contractures, foot deformities, dysregulation of bladder and bowel function, and a pseudobulbar affect. About 50% of affected individuals have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All have developmental delay. Speech development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe.
Adams-Oliver syndrome 2
MedGen UID:
481812
Concept ID:
C3280182
Disease or Syndrome
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.
Congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome
MedGen UID:
482486
Concept ID:
C3280856
Disease or Syndrome
ISQMR is a severe autosomal recessive disorder characterized by ichthyosis apparent from birth, profound psychomotor retardation with essentially no development, spastic quadriplegia, and seizures (summary by Aldahmesh et al., 2011).
Neonatal-onset encephalopathy with rigidity and seizures
MedGen UID:
482659
Concept ID:
C3281029
Disease or Syndrome
Lethal neonatal rigidity and multifocal seizure syndrome (RMFSL) is a severe autosomal recessive epileptic encephalopathy characterized by onset of rigidity and intractable seizures at or soon after birth. Affected infants achieve no developmental milestones and die within the first months or years of life (summary by Saitsu et al., 2014).
Juvenile onset Parkinson disease 19A
MedGen UID:
816141
Concept ID:
C3809811
Disease or Syndrome
DNAJC6 Parkinson disease is a complex early-onset neurologic disorder whose core features are typical parkinsonian symptoms including bradykinesia, resting tremor, rigidity, and postural instability. The majority of individuals have juvenile onset and develop symptoms before age 21 years. Developmental delay, intellectual disability, seizures, other movement disorders (e.g., dystonia, spasticity, myoclonus), and neuropsychiatric features occur in the majority of individuals with juvenile onset and often precede parkinsonism. The onset of parkinsonian features usually occurs toward the end of the first or beginning of the second decade and the disease course is rapidly progressive with loss of ambulation in mid-adolescence in the majority of individuals. Additional features include gastrointestinal manifestations and bulbar dysfunction. A minority of individuals with DNAJC6 Parkinson disease develop early-onset parkinsonism with symptom onset in the third to fourth decade and absence of additional neurologic features.
Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome
MedGen UID:
816301
Concept ID:
C3809971
Disease or Syndrome
Asparagine synthetase deficiency (ASD) mainly presents as a triad of congenital microcephaly, severe developmental delay, and axial hypotonia followed by spastic quadriplegia. Low cerebrospinal fluid (CSF) asparagine level can help the clinician in differentiating this disorder from others. In most cases age of onset of apnea, excessive irritability, and seizures is soon after birth. Affected individuals typically do not acquire any developmental milestones. Spastic quadriplegia can lead to severe contractures of the limbs and neurogenic scoliosis. Feeding difficulties (gastroesophageal reflux disease, frequent vomiting, swallowing dysfunction, and gastroesophageal incoordination) are a significant problem in most affected individuals. A majority have cortical blindness. MRI findings are nonspecific but may include generalized atrophy and simplified gyral pattern.
Aicardi-Goutieres syndrome 7
MedGen UID:
854829
Concept ID:
C3888244
Disease or Syndrome
Most characteristically, Aicardi-Goutières syndrome (AGS) manifests as an early-onset encephalopathy that usually, but not always, results in severe intellectual and physical disability. A subgroup of infants with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture highly suggestive of congenital infection. Otherwise, most affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development. Typically, they demonstrate the subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. Over time, as many as 40% develop chilblain skin lesions on the fingers, toes, and ears. It is becoming apparent that atypical, sometimes milder, cases of AGS exist, and thus the true extent of the phenotype associated with pathogenic variants in the AGS-related genes is not yet known.
Developmental and epileptic encephalopathy, 21
MedGen UID:
862867
Concept ID:
C4014430
Disease or Syndrome
Developmental and epileptic encephalopathy-21 (DEE21) is an autosomal recessive neurologic disorder characterized by the onset of intractable seizures in the first months of life. Affected individuals have severely impaired psychomotor development with poor head control and inability to fix and follow visually. Other features may include axial hypotonia, peripheral hypertonia, and cerebral atrophy or delayed myelination on brain imaging (summary by Alazami et al., 2014 and Alsahli et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Developmental and epileptic encephalopathy, 25
MedGen UID:
863058
Concept ID:
C4014621
Disease or Syndrome
Developmental and epileptic encephalopathy-25 with amelogenesis imperfecta (DEE25) is an autosomal recessive neurologic disorder characterized by the onset of refractory seizures in early infancy. Most patients present with seizures in the neonatal period, which is often associated with status epilepticus. However, there is phenotypic variability, and some patients have onset of seizures later in infancy. Affected individuals show global developmental delay with intellectual disability and poor speech and communication. The seizures may remit somewhat with age, but there are persistent neurologic symptoms, including ataxia, spasticity, and abnormal involuntary movements. In addition to neurologic deficits, patients also have dental anomalies with amelogenesis imperfecta (summary by Thevenon et al., 2014 and Schossig et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
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).
Cerebellar atrophy, visual impairment, and psychomotor retardation;
MedGen UID:
905041
Concept ID:
C4225172
Disease or Syndrome
Spastic paraplegia, intellectual disability, nystagmus, and obesity
MedGen UID:
924883
Concept ID:
C4284592
Disease or Syndrome
Spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO) is an autosomal dominant neurologic disorder characterized by rapid growth in infancy, global developmental delay, spastic paraplegia, variable ophthalmologic defects, and dysmorphic facial features (summary by Josifova et al., 2016).
COG4-congenital disorder of glycosylation
MedGen UID:
929221
Concept ID:
C4303552
Disease or Syndrome
An extremely rare form of carbohydrate deficient glycoprotein syndrome with, in the single reported case to date, seizures, some dysmorphic features, axial hypotonia, slight peripheral hypertonia and hyperreflexia.
Developmental and epileptic encephalopathy, 48
MedGen UID:
934604
Concept ID:
C4310637
Disease or Syndrome
Developmental and epileptic encephalopathy-48 (DEE48) is a severe autosomal recessive neurologic disorder characterized by global developmental delay with intellectual disability and absent speech; poor, if any, motor development; and onset of seizures usually in the first year of life, although later onset has been reported. Affected individuals have poor eye contact and may develop microcephaly and abnormal movements (summary by Assoum et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Shashi-Pena syndrome
MedGen UID:
934639
Concept ID:
C4310672
Disease or Syndrome
Shashi-Pena syndrome is a neurodevelopmental syndrome characterized by delayed psychomotor development, variable intellectual disability, hypotonia, facial dysmorphism, and some unusual features, including enlarged head circumference, glabellar nevus flammeus, and deep palmar creases. Some patients may also have atrial septal defect, episodic hypoglycemia, changes in bone mineral density, and/or seizures (summary by Shashi et al., 2016).
Developmental and epileptic encephalopathy, 46
MedGen UID:
934654
Concept ID:
C4310687
Disease or Syndrome
GRIN2D-related developmental and epileptic encephalopathy (GRIN2D-related DEE) is characterized by mild-to-profound developmental delay or intellectual disability, epilepsy, abnormal muscle tone (hypotonia and spasticity), movement disorders (dystonia, dyskinesia, chorea), autism spectrum disorder, and cortical visual impairment. Additional findings can include sleep disorders and feeding difficulties. To date 22 individuals with GRIN2D-related DEE have been reported.
Developmental and epileptic encephalopathy, 38
MedGen UID:
934729
Concept ID:
C4310762
Disease or Syndrome
Developmental and epileptic encephalopathy-38 (DEE38) is an autosomal recessive neurologic and neurodegenerative disorder characterized by the onset of various type of seizures usually between about 4 and 7 months of age. Prior to the onset of seizures, most infants show severely impaired global development, hypotonia with poor head control, and visual inattention with roving eye movements and nystagmus. Seizures are usually refractory to treatment and associated with status epilepticus. Patients have little or no development with inability to walk or speak, spasticity or abnormal movements, and often cortical blindness. There is failure to thrive, and many require tube-feeding. Death in early childhood due to aspiration or intractable epilepsy may occur. The disorder is associated with a defect in GPI-anchoring of membrane-bound proteins (summary by Palmer et al., 2016; Davids et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Intellectual disability, autosomal dominant 42
MedGen UID:
934741
Concept ID:
C4310774
Mental or Behavioral Dysfunction
GNB1 encephalopathy (GNB1-E) is characterized by moderate-to-severe developmental delay / intellectual disability, structural brain abnormalities, and often infantile hypotonia and seizures. Other less common findings include dystonia, reduced vision, behavior issues, growth delay, gastrointestinal (GI) problems, genitourinary (GU) abnormalities in males, and cutaneous mastocytosis.
Heart and brain malformation syndrome
MedGen UID:
934760
Concept ID:
C4310793
Disease or Syndrome
Heart and brain malformation syndrome (HBMS) is a severe autosomal recessive multiple congenital anomaly syndrome characterized by profoundly delayed psychomotor development, dysmorphic facial features, microphthalmia, cardiac malformations, mainly septal defects, and brain malformations, including Dandy-Walker malformation (summary by Shaheen et al., 2016). Homozygous mutation in the SMG9 gene can also cause neurodevelopmental disorder with intention tremor, pyramidal signs, dyspraxia, and ocular anomalies (NEDITPDO; 619995), a less severe neurodevelopmental disorder.
Hyperphenylalaninemia due to DNAJC12 deficiency
MedGen UID:
1391882
Concept ID:
C4479270
Disease or Syndrome
Mild non-BH4-deficient hyperphenylalaninemia (HPANBH4) is an autosomal recessive disorder characterized by increased serum phenylalanine (HPA) usually detected by newborn screening and associated with highly variable neurologic defects, including movement abnormalities, such as dystonia, and variably impaired intellectual development. Laboratory analysis shows dopamine and serotonin deficiencies in the cerebrospinal fluid, and normal tetrahydrobiopterin (BH4) metabolism. Evidence suggests that treatment with BH4 and neurotransmitter precursors can lead to clinical improvement or even prevent the neurologic defects if started in infancy (summary by Anikster et al., 2017). The phenotype is highly variable: some patients may present with later onset of juvenile or young adult nonprogressive dopa-responsive parkinsonism reminiscent of early-onset Parkinson disease (168600). These patients benefit from treatment with L-dopa (summary by Straniero et al., 2017). In a review of HPA, Blau et al. (2018) noted that molecular screening for DNAJC12 mutations should be mandatory in patients in whom deficiencies of PAH (612349) and BH4 metabolism have been excluded.
Psychomotor regression-oculomotor apraxia-movement disorder-nephropathy syndrome
MedGen UID:
1621949
Concept ID:
C4539828
Disease or Syndrome
Birk-Landau-Perez syndrome (BILAPES) is an autosomal recessive syndromic developmental disorder characterized by global developmental delay apparent from infancy or early childhood. Some patients have developmental regression with loss of speech and motor skills, whereas other patients never achieve these milestones. More variable features may include hypotonia, poor overall growth, ataxia, dystonia, abnormal eye movements, and renal insufficiency (Perez et al., 2017; Kleyner et al., 2022).
Developmental and epileptic encephalopathy, 55
MedGen UID:
1622363
Concept ID:
C4539843
Disease or Syndrome
Developmental and epileptic encephalopathy-55 (DEE55) is an autosomal recessive neurologic disorder characterized by onset of refractory seizures in the first weeks or months of life. Affected individuals have an extremely poor outcome, with profoundly impaired intellectual development, absent speech, spastic quadriplegia, and dyskinetic movements. Most have cortical visual impairment and require a feeding tube. Brain imaging shows nonspecific abnormalities, including cerebral atrophy, thin corpus callosum, and abnormal signals in the white matter. Death in childhood may occur. Biochemically, the disorder is associated with impaired synthesis of GPI-anchored proteins (summary by Vetro et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures
MedGen UID:
1619876
Concept ID:
C4540192
Disease or Syndrome
NEMMLAS is an autosomal recessive multisystemic disorder characterized by delayed psychomotor development, intellectual disability, and abnormal motor function, including hypotonia, dystonia, ataxia, and spasticity. Patient tissues may show deficiencies in one or more of the mitochondrial oxidative phosphorylation (OXPHOS) enzymes, but this is not a constant finding (summary by Wortmann et al., 2017).
Microcephaly 22, primary, autosomal recessive
MedGen UID:
1635688
Concept ID:
C4693834
Disease or Syndrome
Developmental and epileptic encephalopathy, 64
MedGen UID:
1633501
Concept ID:
C4693899
Disease or Syndrome
Developmental and epileptic encephalopathy-64 (DEE64) is a neurodevelopmental disorder characterized by onset of seizures usually in the first year of life and associated with intellectual disability, poor motor development, and poor or absent speech. Additional features include hypotonia, abnormal movements, and nonspecific dysmorphic features. The severity is variable: some patients are unable to speak, walk, or interact with others as late as the teenage years, whereas others may have some comprehension (summary by Straub et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Combined oxidative phosphorylation defect type 21
MedGen UID:
1638633
Concept ID:
C4706316
Disease or Syndrome
Combined oxidative phosphorylation deficiency-21 (COXPD21) is an autosomal recessive disorder characterized either by onset within the first months of life of severe hypotonia, failure to thrive, epilepsy and early death or by onset after 6 months of life with a milder course and longer survival (summary by Zheng et al., 2022). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Neurodevelopmental disorder with cerebellar atrophy and with or without seizures
MedGen UID:
1648373
Concept ID:
C4748032
Disease or Syndrome
Neurodevelopmental disorder with cerebellar atrophy and with or without seizures (NEDCAS) is an autosomal recessive disorder characterized by intellectual disability associated with ataxia (summary by Engel et al., 2023).
Neurodevelopmental disorder with spasticity and poor growth
MedGen UID:
1648309
Concept ID:
C4748081
Disease or Syndrome
Neurodevelopmental disorder with spasticity and poor growth (NEDSG) is an autosomal recessive disorder characterized by severe early-onset encephalopathy with progressive microcephaly (Nahorski et al., 2018).
Spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits
MedGen UID:
1648308
Concept ID:
C4748120
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 26
MedGen UID:
1648283
Concept ID:
C4748809
Disease or Syndrome
Pontocerebellar hypoplasia type 10
MedGen UID:
1676575
Concept ID:
C5190575
Disease or Syndrome
Pontocerebellar hypoplasia type 10 is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by severely delayed psychomotor development, progressive microcephaly, spasticity, seizures, and brain abnormalities, including brain atrophy and delayed myelination. Some patients have dysmorphic features and an axonal sensorimotor neuropathy (summary by Karaca et al., 2014 and Schaffer et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).
Neurodevelopmental disorder with seizures and speech and walking impairment
MedGen UID:
1672912
Concept ID:
C5193119
Disease or Syndrome
Neurodevelopmental disorder with seizures and speech and walking impairment (NEDSSWI) is an autosomal recessive disorder with onset in infancy. Patients show global developmental delay, particularly of speech acquisition, as well as walking difficulties due to hypotonia, hypertonia, spasticity, or poor coordination. Other features include seizures, mild dysmorphic features, and variable short stature. The pregnancies tend to be complicated by hyper- or hypotension (summary by Ganapathi et al., 2019).
Neurodevelopmental disorder with visual defects and brain anomalies
MedGen UID:
1684774
Concept ID:
C5231404
Disease or Syndrome
Neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA) is characterized by global developmental delay with impaired intellectual development and speech delay, variable visual defects, including retinitis pigmentosa and optic atrophy, hypotonia or hypertonia, and variable structural brain abnormalities. Other nonspecific features may be found (summary by Okur et al., 2019).
Neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities
MedGen UID:
1708579
Concept ID:
C5394517
Disease or Syndrome
Neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities (NEDSHBA) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay, severe to profound intellectual impairment, early-onset refractory seizures, hypotonia, failure to thrive, and progressive microcephaly. Brain imaging shows cerebral atrophy, thin corpus callosum, and myelination defects. Death in childhood may occur (summary by Marafi et al., 2020).
Mitochondrial complex 1 deficiency, nuclear type 36
MedGen UID:
1773965
Concept ID:
C5436935
Disease or Syndrome
Mitochondrial complex I deficiency nuclear type 36 (MC1DN36) is an autosomal recessive metabolic disorder characterized by global developmental delay, hypotonia, and failure to thrive apparent from infancy or early childhood. Affected individuals usually do not acquire ambulation, show progressive spasticity, and have impaired intellectual development with absent speech. More variable features may include pale optic discs, poor eye contact, seizures, and congenital heart defects. Laboratory studies show increased serum lactate; metabolic acidosis may occur during stress or infection. Brain imaging shows T2-weighted abnormalities in the basal ganglia and brainstem, consistent with a clinical diagnosis of Leigh syndrome (see 256000). Patient tissue showed isolated mitochondrial complex I deficiency. Death may occur in childhood (Alahmad et al., 2020). For a discussion of genetic heterogeneity of mitochondrial complex I deficiency, see 252010.
Developmental and epileptic encephalopathy, 90
MedGen UID:
1786502
Concept ID:
C5542345
Disease or Syndrome
Developmental and epileptic encephalopathy-90 (DEE90) is an X-linked neurologic disorder characterized by onset of refractory seizures in the first days or months of life. Although most patients have focal seizures associated with oromotor automatisms and apnea, various seizure types may occur, including epileptic spasms, generalized tonic-clonic, and absence. EEG shows multifocal discharges; hypsarrhythmia, intermittent burst suppression, and slow spike-wave background resembling Lennox-Gastaut syndrome may also be observed. Affected individuals have global developmental delay with variable severity, but it is usually profound or severe. Some are unable to walk or speak, whereas others may achieve some milestones and show autistic features (summary by Fry et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
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.
Pontocerebellar hypoplasia, type 16
MedGen UID:
1794197
Concept ID:
C5561987
Disease or Syndrome
Pontocerebellar hypoplasia type 16 (PCH16) is an autosomal recessive severe neurodevelopmental disorder characterized by hypotonia and severe global developmental delay apparent from early infancy. Although the severity of the disorder is variable, most affected individuals achieve only a few, if any, developmental milestones. Most are unable to walk or speak, have eye abnormalities with poor visual contact, and develop early-onset epilepsy. Other features may include stereotypic movements, spasticity, and progressive microcephaly. Brain imaging shows pontocerebellar hypoplasia, often with thin corpus callosum, atrophy of the thalamus and basal ganglia, enlarged ventricles, and white matter abnormalities (summary by Ucuncu et al., 2020). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1A (607596).
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).
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).
Chilton-Okur-Chung neurodevelopmental syndrome
MedGen UID:
1803276
Concept ID:
C5677022
Disease or Syndrome
Chilton-Okur-Chung neurodevelopmental syndrome (CHOCNS) is characterized mainly by global developmental delay with variably impaired intellectual development and occasional speech delay. Most patients have behavioral abnormalities, including autism spectrum disorder, ADHD, and aggression. About half of patients have dysmorphic facial features, and about half have nonspecific brain abnormalities, including thin corpus callosum. Rare involvement of other organ systems may be present. At least 1 child with normal development at age 2.5 years has been reported (Chilton et al., 2020).
Developmental and epileptic encephalopathy 106
MedGen UID:
1823985
Concept ID:
C5774212
Disease or Syndrome
Developmental and epileptic encephalopathy-106 (DEE106) is an autosomal recessive disorder characterized by the onset of various types of frequent, often refractory, seizures within the first year of life. Affected individuals demonstrate profound global developmental delay with limited ability to move and severely impaired intellectual development with absent speech. Nonspecific brain abnormalities may be observed on MRI (Ni et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties
MedGen UID:
1824001
Concept ID:
C5774228
Disease or Syndrome
Neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties (NEDSFF) is an autosomal recessive disorder characterized by distinct craniofacial features, multisystem dysfunction, profound neurodevelopmental delays, and neonatal death (Shankar et al., 2022).
Tessadori-Van Haaften neurodevelopmental syndrome 3
MedGen UID:
1824083
Concept ID:
C5774310
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).
Neurodegeneration and seizures due to copper transport defect
MedGen UID:
1841021
Concept ID:
C5830385
Disease or Syndrome
Neurodegeneration and seizures due to copper transport defect (NSCT) is an autosomal recessive disorder of copper transport characterized by hypotonia, global developmental delay, seizures, and rapid brain atrophy (summary by Dame et al., 2023).
Cortical dysplasia, complex, with other brain malformations 12
MedGen UID:
1841043
Concept ID:
C5830407
Disease or Syndrome
Complex cortical dysplasia with other brain malformations-12 (CDCBM12) is an autosomal recessive disorder of developmental neuronal migration characterized by severe to profound neurodevelopmental delay with absent speech, central hypotonia, peripheral spasticity, cortical visual impairment, and dysmorphic craniofacial features. Affected individuals usually have feeding difficulties and show minimal developmental progress of motor or cognitive skills. Most have microcephaly and develop early-onset refractory seizures. Brain imaging shows cortical abnormalities, such as lissencephaly and pachygyria, as well as other brain malformations, including thin or absent corpus callosum, dysplastic basal ganglia, and mild cerebellar hypoplasia. Due to the function of CAMSAP1 in microtubule stability and maintenance, this disorder can be classified as a 'tubulinopathy' (Khalaf-Nazzal et al., 2022). For a discussion of genetic heterogeneity of CDCBM, see CDCBM1 (614039).
Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities
MedGen UID:
1841069
Concept ID:
C5830433
Disease or Syndrome
Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities (NDDRSB) is a severe autosomal recessive disorder characterized by onset of these features in infancy. Affected individuals present with respiratory failure requiring intubation soon after birth; some die due to cardiorespiratory insufficiency. Those that survive show severe global developmental delay, refractory myoclonic seizures, hyperkinetic movements with exaggerated startle response, and microcephaly with dysmorphic features. Additional findings may include sensorineural hearing loss and ocular defects. Brain imaging shows variable abnormalities consistent with progressive neurodegeneration (Cali et al., 2022).
GTP cyclohydrolase I deficiency with hyperphenylalaninemia
MedGen UID:
988270
Concept ID:
CN305333
Disease or Syndrome
GTP-cyclohydrolase I deficiency, an autosomal recessive genetic disorder, is one of the causes of malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency. Not only does tetrahydrobiopterin deficiency cause hyperphenylalaninemia, it is also responsible for defective neurotransmission of monoamines because of malfunctioning tyrosine and tryptophan hydroxylases, both tetrahydrobiopterin-dependent hydroxylases.

Professional guidelines

PubMed

Olver J, Esquenazi A, Fung VS, Singer BJ, Ward AB; Cerebral Palsy Institute
Eur J Neurol 2010 Aug;17 Suppl 2:57-73. doi: 10.1111/j.1468-1331.2010.03128.x. PMID: 20633179
Fehlings D, Novak I, Berweck S, Hoare B, Stott NS, Russo RN; Cerebral Palsy Institute
Eur J Neurol 2010 Aug;17 Suppl 2:38-56. doi: 10.1111/j.1468-1331.2010.03127.x. PMID: 20633178

Recent clinical studies

Etiology

Chow JW, Stokic DS
Int J Rehabil Res 2023 Sep 1;46(3):238-247. Epub 2023 Jun 22 doi: 10.1097/MRR.0000000000000590. PMID: 37345412
Trompetto C, Marinelli L, Mori L, Bragazzi N, Maggi G, Cotellessa F, Puce L, Vestito L, Molteni F, Gasperini G, Farina N, Bissolotti L, Sciarrini F, Millevolte M, Balestrieri F, Restivo DA, Chisari C, Santamato A, Del Felice A, Manganotti P, Serrati C, Currà A
Toxins (Basel) 2023 May 13;15(5) doi: 10.3390/toxins15050335. PMID: 37235369Free PMC Article
Spiegel R, Schwahn BC, Squires L, Confer N
J Inherit Metab Dis 2022 May;45(3):456-469. Epub 2022 Mar 3 doi: 10.1002/jimd.12488. PMID: 35192225Free PMC Article
Owen MJ, Lenberg J, Feigenbaum A, Gold J, Chau K, Bezares-Orin Z, Ding Y, Chowdhury S, Kingsmore SF
Cold Spring Harb Mol Case Stud 2021 Jun;7(3) Epub 2021 Jun 11 doi: 10.1101/mcs.a006091. PMID: 34117075Free PMC Article
Dunne JW, Gracies JM, Hayes M, Zeman B, Singer BJ; Multicentre Study Group
Clin Rehabil 2012 Sep;26(9):787-97. Epub 2012 Feb 3 doi: 10.1177/0269215511432016. PMID: 22308557

Diagnosis

Chow JW, Stokic DS
Int J Rehabil Res 2023 Sep 1;46(3):238-247. Epub 2023 Jun 22 doi: 10.1097/MRR.0000000000000590. PMID: 37345412
Spiegel R, Schwahn BC, Squires L, Confer N
J Inherit Metab Dis 2022 May;45(3):456-469. Epub 2022 Mar 3 doi: 10.1002/jimd.12488. PMID: 35192225Free PMC Article
Mailhan L, Schnitzler A, Genêt F, Gatin L, Calé F, Geffrier A, Denormandie P
Hand Surg Rehabil 2022 Feb;41S:S132-S136. Epub 2021 Aug 23 doi: 10.1016/j.hansur.2019.03.008. PMID: 34438111
Olver J, Esquenazi A, Fung VS, Singer BJ, Ward AB; Cerebral Palsy Institute
Eur J Neurol 2010 Aug;17 Suppl 2:57-73. doi: 10.1111/j.1468-1331.2010.03128.x. PMID: 20633179
Fehlings D, Novak I, Berweck S, Hoare B, Stott NS, Russo RN; Cerebral Palsy Institute
Eur J Neurol 2010 Aug;17 Suppl 2:38-56. doi: 10.1111/j.1468-1331.2010.03127.x. PMID: 20633178

Therapy

Chow JW, Stokic DS
Int J Rehabil Res 2023 Sep 1;46(3):238-247. Epub 2023 Jun 22 doi: 10.1097/MRR.0000000000000590. PMID: 37345412
Trompetto C, Marinelli L, Mori L, Bragazzi N, Maggi G, Cotellessa F, Puce L, Vestito L, Molteni F, Gasperini G, Farina N, Bissolotti L, Sciarrini F, Millevolte M, Balestrieri F, Restivo DA, Chisari C, Santamato A, Del Felice A, Manganotti P, Serrati C, Currà A
Toxins (Basel) 2023 May 13;15(5) doi: 10.3390/toxins15050335. PMID: 37235369Free PMC Article
Bonikowski M, Sławek J
Neurol Neurochir Pol 2021;55(2):158-164. Epub 2021 Apr 16 doi: 10.5603/PJNNS.a2021.0032. PMID: 33861462
Sätilä H
Toxins (Basel) 2020 Jul 6;12(7) doi: 10.3390/toxins12070440. PMID: 32640636Free PMC Article
Olver J, Esquenazi A, Fung VS, Singer BJ, Ward AB; Cerebral Palsy Institute
Eur J Neurol 2010 Aug;17 Suppl 2:57-73. doi: 10.1111/j.1468-1331.2010.03128.x. PMID: 20633179

Prognosis

Spiegel R, Schwahn BC, Squires L, Confer N
J Inherit Metab Dis 2022 May;45(3):456-469. Epub 2022 Mar 3 doi: 10.1002/jimd.12488. PMID: 35192225Free PMC Article
Li X, Peng B, Hou C, Li J, Zeng Y, Wu W, Liao Y, Tian Y, Chen WX
BMC Med Genet 2020 Nov 5;21(1):217. doi: 10.1186/s12881-020-01149-0. PMID: 33153448Free PMC Article
Hoarau X, Richer E, Dehail P, Cuny E
Brain Inj 2012;26(12):1451-63. Epub 2012 Jun 22 doi: 10.3109/02699052.2012.694564. PMID: 22725634
Hoarau X, Richer E, Dehail P, Cuny E
Brain Inj 2012;26(7-8):927-40. Epub 2012 Jun 5 doi: 10.3109/02699052.2012.661913. PMID: 22668125
Garcia-Cazorla A, Duarte S, Serrano M, Nascimento A, Ormazabal A, Carrilho I, Briones P, Montoya J, Garesse R, Sala-Castellvi P, Pineda M, Artuch R
Mitochondrion 2008 Jun;8(3):273-8. Epub 2008 May 21 doi: 10.1016/j.mito.2008.05.001. PMID: 18558519

Clinical prediction guides

Trompetto C, Marinelli L, Mori L, Bragazzi N, Maggi G, Cotellessa F, Puce L, Vestito L, Molteni F, Gasperini G, Farina N, Bissolotti L, Sciarrini F, Millevolte M, Balestrieri F, Restivo DA, Chisari C, Santamato A, Del Felice A, Manganotti P, Serrati C, Currà A
Toxins (Basel) 2023 May 13;15(5) doi: 10.3390/toxins15050335. PMID: 37235369Free PMC Article
He P, Wang Q, Hong X, Yuan H
Am J Med Genet A 2023 Jan;191(1):70-76. Epub 2022 Oct 11 doi: 10.1002/ajmg.a.62988. PMID: 36218002
Chow JW, Stokic DS
Arch Phys Med Rehabil 2019 Jun;100(6):1091-1101. Epub 2018 Nov 14 doi: 10.1016/j.apmr.2018.10.014. PMID: 30447195
Bravo-Esteban E, Taylor J, Abián-Vicén J, Albu S, Simón-Martínez C, Torricelli D, Gómez-Soriano J
NeuroRehabilitation 2013;33(4):531-43. doi: 10.3233/NRE-131000. PMID: 24018366
Dunne JW, Gracies JM, Hayes M, Zeman B, Singer BJ; Multicentre Study Group
Clin Rehabil 2012 Sep;26(9):787-97. Epub 2012 Feb 3 doi: 10.1177/0269215511432016. PMID: 22308557

Recent systematic reviews

He P, Wang Q, Hong X, Yuan H
Am J Med Genet A 2023 Jan;191(1):70-76. Epub 2022 Oct 11 doi: 10.1002/ajmg.a.62988. PMID: 36218002
Varvarousis DN, Martzivanou C, Dimopoulos D, Dimakopoulos G, Vasileiadis GI, Ploumis A
Toxicon 2021 Nov;203:74-84. Epub 2021 Oct 7 doi: 10.1016/j.toxicon.2021.09.020. PMID: 34626599

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