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Delayed CNS myelination

MedGen UID:
867393
Concept ID:
C4021758
Anatomical Abnormality
Synonym: Delay in central nervous system myelination
 
HPO: HP:0002188

Definition

Delayed myelination in the central nervous system. [from HPO]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • Delayed CNS myelination

Conditions with this feature

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.
Aicardi syndrome
MedGen UID:
61236
Concept ID:
C0175713
Disease or Syndrome
Aicardi syndrome is a neurodevelopmental disorder that affects primarily females. Initially it was characterized by a typical triad of agenesis of the corpus callosum, central chorioretinal lacunae, and infantile spasms. As more affected individuals have been ascertained, it has become clear that not all affected girls have all three features of the classic triad and that other neurologic and systemic defects are common, including other brain malformations, optic nerve abnormalities, other seizure types, intellectual disability of varying severity, and scoliosis.
Weaver syndrome
MedGen UID:
120511
Concept ID:
C0265210
Disease or Syndrome
EZH2-related overgrowth includes EZH2-related Weaver syndrome at one end of the spectrum and tall stature at the other. Although most individuals diagnosed with a heterozygous EZH2 pathogenic variant have been identified because of a clinical suspicion of Weaver syndrome, a minority have been identified through molecular genetic testing of family members of probands or individuals with overgrowth who did not have a clinical diagnosis of Weaver syndrome. Thus, the extent of the phenotypic spectrum associated with a heterozygous EZH2 pathogenic variant is not yet known. Weaver syndrome is characterized by tall stature, variable intellect (ranging from normal intellect to severe intellectual disability), characteristic facial appearance, and a range of associated clinical features including advanced bone age, poor coordination, soft doughy skin, camptodactyly of the fingers and/or toes, umbilical hernia, abnormal tone, and hoarse low cry in infancy. Brain MRI has identified abnormalities in a few individuals with EZH2-related overgrowth. Neuroblastoma occurs at a slightly increased frequency in individuals with a heterozygous EZH2 pathogenic variant but data are insufficient to determine absolute risk. There is currently no evidence that additional malignancies (including hematologic malignancies) occur with increased frequency.
Niemann-Pick disease, type A
MedGen UID:
78650
Concept ID:
C0268242
Disease or Syndrome
The phenotype of acid sphingomyelinase deficiency (ASMD) occurs along a continuum. Individuals with the severe early-onset form, infantile neurovisceral ASMD, were historically diagnosed with Niemann-Pick disease type A (NPD-A). The later-onset, chronic visceral form of ASMD is also referred to as Niemann-Pick disease type B (NPD-B). A phenotype with intermediate severity is also known as chronic neurovisceral ASMD (NPD-A/B). The most common presenting symptom in NPD-A is hepatosplenomegaly, usually detectable by age three months; over time the liver and spleen become massive in size. Psychomotor development progresses no further than the 12-month level, after which neurologic deterioration is relentless. Failure to thrive typically becomes evident by the second year of life. A classic cherry-red spot of the macula of the retina, which may not be present in the first few months, is eventually present in all affected children. Interstitial lung disease caused by storage of sphingomyelin in pulmonary macrophages results in frequent respiratory infections and often respiratory failure. Most children succumb before the third year of life. NPD-B generally presents later than NPD-A, and the manifestations are less severe. NPD-B is characterized by progressive hepatosplenomegaly, gradual deterioration in liver and pulmonary function, osteopenia, and atherogenic lipid profile. No central nervous system (CNS) manifestations occur. Individuals with NPD-A/B have symptoms that are intermediate between NPD-A and NPD-B. The presentation in individuals with NPD-A/B varies greatly, although all are characterized by the presence of some CNS manifestations. Survival to adulthood can occur in individuals with NPD-B and NPD-A/B.
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.
D-Glyceric aciduria
MedGen UID:
452447
Concept ID:
C0342765
Disease or Syndrome
D-glyceric aciduria is a rare autosomal recessive metabolic disorder with a highly variable phenotype. Some patients have an encephalopathic presentation, with severe mental retardation, seizures, microcephaly, and sometimes early death, whereas others have a mild phenotype with only mild speech delay or even normal development (summary by Sass et al., 2010).
Deficiency of malonyl-CoA decarboxylase
MedGen UID:
91001
Concept ID:
C0342793
Disease or Syndrome
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).
Myoclonic-astatic epilepsy
MedGen UID:
98284
Concept ID:
C0393702
Disease or Syndrome
A generalized myoclonic-atonic seizure is a type of generalized motor seizure characterized by a myoclonic jerk followed by an atonic motor component.
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.
Recombinant 8 syndrome
MedGen UID:
167070
Concept ID:
C0795822
Disease or Syndrome
Recombinant chromosome 8 syndrome (Rec8 syndrome) is a chromosomal disorder found among individuals of Hispanic descent with ancestry from the San Luis Valley of southern Colorado and northern New Mexico. Affected individuals typically have impaired intellectual development, congenital heart defects, seizures, a characteristic facial appearance with hypertelorism, thin upper lip, anteverted nares, wide face, and abnormal hair whorl, and other manifestations (Sujansky et al., 1993, summary by Graw et al., 2000).
Allan-Herndon-Dudley syndrome
MedGen UID:
208645
Concept ID:
C0795889
Disease or Syndrome
Allan-Herndon-Dudley syndrome (AHDS), an X-linked disorder, is characterized in males by neurologic findings (hypotonia and feeding difficulties in infancy, developmental delay / intellectual disability ranging from mild to profound) and later-onset pyramidal signs, extrapyramidal findings (dystonia, choreoathetosis, paroxysmal movement disorder, hypokinesia, masked facies), and seizures, often with drug resistance. Additional findings can include dysthyroidism (manifest as poor weight gain, reduced muscle mass, and variable cold intolerance, sweating, elevated heart rate, and irritability) and pathognomonic thyroid test results. Most heterozygous females are not clinically affected but may have minor thyroid test abnormalities.
Megalocornea-intellectual disability syndrome
MedGen UID:
162904
Concept ID:
C0796086
Disease or Syndrome
The cardinal findings of Neuhauser syndrome, also known as MMR syndrome, are impaired intellectual development or developmental delay, megalocornea, hypotonia, prominent forehead, micrognathia, prominent nasal bridge, and thin upper lip or carp-like mouth (Naritomi et al., 1997). Reviews Gutierrez-Amavizca et al. (2013) reviewed published reports and tabulated the clinical features of 35 patients with Neuhauser syndrome. Primary megalocornea and psychomotor delay were present in all patients. Characteristics observed in more than half of patients included hypotonia, growth retardation, abnormal electroencephalography (EEG) and/or seizures, micro- or macrocephaly, brain malformations such as cerebral atrophy and hypoplastic corpus callosum, craniofacial dysmorphisms, cardiac anomalies, osteoarticular abnormalities, and refractive errors. Additional features found at low frequency included primary hypothyroidism, recurrent infections, feeding difficulties, cerebral hypomyelination, dyslipidemia, sensorineural deafness, laryngomalacia, large fleshy and cup-shaped ears, obesity, and cryptorchidism. The authors stated that the classification suggested by Verloes et al. (1993) did not seem to be applicable, and proposed that the diagnosis of Neuhauser syndrome should be made in the presence of intellectual disability and megalocornea in the absence of elevated intraocular pressure, with at least 1 minor feature from among those observed in more than half of patients.
Methylmalonic acidemia with homocystinuria, type cblX
MedGen UID:
167111
Concept ID:
C0796208
Disease or Syndrome
Disorders of intracellular cobalamin metabolism have a variable phenotype and age of onset that are influenced by the severity and location within the pathway of the defect. The prototype and best understood phenotype is cblC; it is also the most common of these disorders. The age of initial presentation of cblC spans a wide range: In utero with fetal presentation of nonimmune hydrops, cardiomyopathy, and intrauterine growth restriction. Newborns, who can have microcephaly, poor feeding, and encephalopathy. Infants, who can have poor feeding and slow growth, neurologic abnormality, and, rarely, hemolytic uremic syndrome (HUS). Toddlers, who can have poor growth, progressive microcephaly, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures. Adolescents and adults, who can have neuropsychiatric symptoms, progressive cognitive decline, thromboembolic complications, and/or subacute combined degeneration of the spinal cord.
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).
Aminoacylase 1 deficiency
MedGen UID:
324393
Concept ID:
C1835922
Disease or Syndrome
Aminoacylase-1 deficiency (ACY1D) is a rare autosomal recessive inborn error of metabolism characterized by increased urinary excretion of specific N-actyl amino acids. Most patients show neurologic abnormalities such as intellectual disability, seizures, hypotonia, and motor delay (summary by Ferri et al., 2014).
Hereditary cryohydrocytosis with reduced stomatin
MedGen UID:
332390
Concept ID:
C1837206
Disease or Syndrome
Stomatin-deficient cryohydrocytosis with neurologic defects is an autosomal dominant disorder characterized by delayed psychomotor development, seizures, cataracts, and pseudohyperkalemia resulting from defects in the red blood cell membrane. The disorder combines the neurologic features of Glut1 deficiency syndrome-1 (GLUT1DS1; 606777), resulting from impaired glucose transport at the blood-brain barrier, and hemolytic anemia/pseudohyperkalemia with stomatocytosis, resulting from a cation leak in erythrocytes (summary by Bawazir et al., 2012). For a discussion of clinical and genetic heterogeneity of red cell stomatocyte disorders, see 194380.
Intellectual disability-brachydactyly-Pierre Robin syndrome
MedGen UID:
325196
Concept ID:
C1837564
Disease or Syndrome
Intellectual disability-brachydactyly-Pierre Robin syndrome is a rare developmental defect during embryogenesis syndrome characterized by mild to moderate intellectual disability and phsychomotor delay, Robin sequence (incl. severe micrognathia and soft palate cleft) and distinct dysmorphic facial features (e.g. synophris, short palpebral fissures, hypertelorism, small, low-set, and posteriorly angulated ears, bulbous nose, long/flat philtrum, and bow-shaped upper lip). Skeletal anomalies, such as brachydactyly, clinodactyly, small hands and feet, and oral manifestations (e.g. bifid, short tongue, oligodontia) are also associated. Additional features reported include microcephaly, capillary hemangiomas on face and scalp, ventricular septal defect, corneal clouding, nystagmus and profound sensorineural deafness.
Warburg micro syndrome 1
MedGen UID:
333142
Concept ID:
C1838625
Disease or Syndrome
RAB18 deficiency is the molecular deficit underlying both Warburg micro syndrome (characterized by eye, nervous system, and endocrine abnormalities) and Martsolf syndrome (characterized by similar – but milder – findings). To date Warburg micro syndrome comprises >96% of reported individuals with genetically defined RAB18 deficiency. The hallmark ophthalmologic findings are bilateral congenital cataracts, usually accompanied by microphthalmia, microcornea (diameter <10), and small atonic pupils. Poor vision despite early cataract surgery likely results from progressive optic atrophy and cortical visual impairment. Individuals with Warburg micro syndrome have severe to profound intellectual disability (ID); those with Martsolf syndrome have mild to moderate ID. Some individuals with RAB18 deficiency also have epilepsy. In Warburg micro syndrome, a progressive ascending spastic paraplegia typically begins with spastic diplegia and contractures during the first year, followed by upper-limb involvement leading to spastic quadriplegia after about age five years, often eventually causing breathing difficulties. In Martsolf syndrome infantile hypotonia is followed primarily by slowly progressive lower-limb spasticity. Hypogonadism – when present – manifests in both syndromes, in males as micropenis and/or cryptorchidism and in females as hypoplastic labia minora, clitoral hypoplasia, and small introitus.
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).
Chromosome 1p36 deletion syndrome
MedGen UID:
334629
Concept ID:
C1842870
Disease or Syndrome
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.
Spinocerebellar ataxia type 21
MedGen UID:
375311
Concept ID:
C1843891
Disease or Syndrome
Spinocerebellar ataxia-21 (SCA21) is an autosomal dominant neurologic disorder characterized by onset in the first decades of life of slowly progressive cerebellar ataxia, which is associated with cognitive impairment in most patients (summary by Delplanque et al., 2014). For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).
Fanconi anemia complementation group B
MedGen UID:
336901
Concept ID:
C1845292
Disease or Syndrome
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA.
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).
Spondyloepimetaphyseal dysplasia, Bieganski type
MedGen UID:
335350
Concept ID:
C1846148
Disease or Syndrome
X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL) is an X-linked recessive developmental disorder characterized by slowly progressive skeletal and neurologic abnormalities, including short stature, large and deformed joints, significant motor impairment, visual defects, and sometimes cognitive deficits. Affected individuals typically have normal early development in the first year or so of life, followed by development regression and the development of symptoms. Brain imaging shows white matter abnormalities consistent with hypomyelinating leukodystrophy (summary by Miyake et al., 2017).
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.
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency
MedGen UID:
344424
Concept ID:
C1855114
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.
Progressive encephalopathy with leukodystrophy due to DECR deficiency
MedGen UID:
346552
Concept ID:
C1857252
Disease or Syndrome
2,4-Dienoyl-CoA reductase deficiency (DECRD) is a rare autosomal recessive inborn error of metabolism resulting in mitochondrial dysfunction due to impaired production of NADPH, which is an essential cofactor for several mitochondrial enzymes. Affected individuals have a variable phenotype: some may have severe neurologic symptoms and metabolic dysfunction beginning in early infancy, whereas others may present with more subtle features, such as childhood-onset optic atrophy or intermittent muscle weakness. The variable severity is putatively dependent on the effect of the mutation on the NADK2 enzyme. Biochemical analysis typically shows hyperlysinemia, due to defective activity of the mitochondrial NADP(H)-dependent enzyme AASS (605113), which is usually a benign finding. More severe cases have increased C10:2-carnitine levels, due to defective activity of the enzyme DECR (DECR1; 222745) (summary by Houten et al., 2014 and Pomerantz et al., 2018).
Rhizomelic chondrodysplasia punctata type 1
MedGen UID:
347072
Concept ID:
C1859133
Disease or Syndrome
Rhizomelic chondrodysplasia punctata type 1 (RCDP1), a peroxisome biogenesis disorder (PBD) has a classic (severe) form and a nonclassic (mild) form. Classic (severe) RCDP1 is characterized by proximal shortening of the humerus (rhizomelia) and to a lesser degree the femur, punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities (chondrodysplasia punctata, or CDP), coronal clefts of the vertebral bodies, and cataracts that are usually present at birth or appear in the first few months of life. Birth weight, length, and head circumference are often at the lower range of normal; postnatal growth deficiency is profound. Intellectual disability is severe, and the majority of children develop seizures. Most affected children do not survive the first decade of life; a proportion die in the neonatal period. Nonclassic (mild) RCDP1 is characterized by congenital or childhood cataracts, CDP or infrequently, chondrodysplasia manifesting only as mild epiphyseal changes, variable rhizomelia, and milder intellectual disability and growth restriction than classic RCDP1.
Microphthalmia with brain and digit anomalies
MedGen UID:
355268
Concept ID:
C1864689
Disease or Syndrome
This syndrome has characteristics of anophthalmia or microphthalmia, retinal dystrophy, and/or myopia, associated in some cases with cerebral anomalies. It has been described in two families. Polydactyly may also be present. Linkage analysis allowed identification of mutations in the BMP4 gene, which has already been shown to play a role in eye development.
Developmental and epileptic encephalopathy, 4
MedGen UID:
436917
Concept ID:
C2677326
Disease or Syndrome
STXBP1 encephalopathy with epilepsy is characterized by early-onset encephalopathy with epilepsy (i.e., moderate-to-severe intellectual disability, refractory seizures, and ongoing epileptiform activity). The median age of onset of seizures is six weeks (range 1 day to 13 years). Seizure types can include infantile spasms; generalized tonic-clonic, clonic, or tonic seizures; and myoclonic, focal, atonic, and absence seizures. Epilepsy syndromes can include Ohtahara syndrome, West syndrome, Lennox-Gaustaut syndrome, and Dravet syndrome (not SCN1A-related), classic Rett syndrome (not MECP2-related), and atypical Rett syndrome (not CDKL5-related). The EEG is characterized by focal epileptic activity, burst suppression, hypsarrhythmia, or generalized spike-and-slow waves. Other findings can include abnormal tone, movement disorders (especially ataxia and dystonia), and behavior disorders (including autism spectrum disorder). Feeding difficulties are common.
ALG9 congenital disorder of glycosylation
MedGen UID:
443955
Concept ID:
C2931006
Disease or Syndrome
Congenital disorders of glycosylation (CDGs) that represent defects of dolichol-linked oligosaccharide assembly are classified as CDG type I. For a general description and a discussion of the classification of CDGs, see CDG1A (212065).
Chromosome 14q11-q22 deletion syndrome
MedGen UID:
462057
Concept ID:
C3150707
Disease or Syndrome
14q11.2 microdeletion syndrome is a recently described syndrome characterized by developmental delay, hypotonia and facial dysmorphism.
Infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly
MedGen UID:
462271
Concept ID:
C3150921
Disease or Syndrome
Infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly is a rare, central nervous system malformation syndrome characterized by progressive microcephaly with profound motor delay and intellectual disability, associated with hypertonia, spasticity, clonus, and seizures, with brain imaging revealing severe cerebral and cerebellar atrophy, and poor myelination.
Chromosome 17p13.1 deletion syndrome
MedGen UID:
462419
Concept ID:
C3151069
Disease or Syndrome
D-2-hydroxyglutaric aciduria 1
MedGen UID:
463405
Concept ID:
C3152055
Disease or Syndrome
D-2-hydroxyglutaric aciduria is a neurometabolic disorder first described by Chalmers et al. (1980). Clinical symptoms include developmental delay, epilepsy, hypotonia, and dysmorphic features. Mild and severe phenotypes were characterized (van der Knaap et al., 1999). The severe phenotype is homogeneous and is characterized by early infantile-onset epileptic encephalopathy and, often, cardiomyopathy. The mild phenotype has a more variable clinical presentation. Genetic Heterogeneity of D-2-Hydroxyglutaric Aciduria D-2-hydroxyglutaric aciduria-2 (D2HGA2; 613657) is caused by heterozygous mutation in the mitochondrial isocitrate dehydrogenase-2 gene (IDH2; 147650) on chromosome 15q26.
Methylmalonate semialdehyde dehydrogenase deficiency
MedGen UID:
481470
Concept ID:
C3279840
Disease or Syndrome
Methylmalonate semialdehyde dehydrogenase deficiency is a rare autosomal recessive inborn error of metabolism with a highly variable phenotype. Some patients may be asymptomatic, whereas others show global developmental delay, nonspecific dysmorphic features, and delayed myelination on brain imaging. Laboratory studies typically show increased urinary 3-hydroxyisobutyric acid, although additional metabolic abnormalities may also be observed (summary by Marcadier et al., 2013).
Microcephaly, epilepsy, and diabetes syndrome
MedGen UID:
481870
Concept ID:
C3280240
Disease or Syndrome
Primary microcephaly-epilepsy-permanent neonatal diabetes syndrome is a rare, genetic, neurologic disease characterized by congenital microcephaly, severe, early-onset epileptic encephalopathy (manifesting as intractable, myoclonic and/or tonic-clonic seizures), permanent, neonatal, insulin-dependent diabetes mellitus, and severe global developmental delay. Muscular hypotonia, skeletal abnormalities, feeding difficulties, and dysmorphic facial features (including narrow forehead, anteverted nares, small mouth with deep philtrum, tented upper lip vermilion) are frequently associated. Brain MRI reveals cerebral atrophy with cortical gyral simplification and aplasia/hypoplasia of the corpus callosum.
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.
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).
Coffin-Siris syndrome 1
MedGen UID:
482831
Concept ID:
C3281201
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.
Developmental and epileptic encephalopathy, 1
MedGen UID:
483052
Concept ID:
C3463992
Disease or Syndrome
Developmental and epileptic encephalopathy-1 (DEE1) is a severe form of epilepsy characterized by frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst patterns, characterized by high-voltage bursts alternating with almost flat suppression phases. Approximately 75% of DEE1 patients progress to tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG (Kato et al., 2007). DEE1 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 lissencephaly (LISX2; 300215) to Proud syndrome (300004) to infantile spasms without brain malformations (DEE) to syndromic (309510) and nonsyndromic (300419) mental retardation. Although males with ARX mutations are often more severely affected, female mutation carriers may also be affected (Kato et al., 2004; Wallerstein et al., 2008). Reviews Deprez et al. (2009) reviewed the genetics of epilepsy syndromes starting in the first year of life and included a diagnostic algorithm. Genetic Heterogeneity of Developmental and Epileptic Encephalopathy Also see DEE2 (300672), caused by mutation in the CDKL5 gene (300203); DEE3 (609304), caused by mutation in the SLC25A22 gene (609302); DEE4 (612164), caused by mutation in the STXBP1 gene (602926); DEE5 (613477), caused by mutation in the SPTAN1 gene (182810); DEE6A (607208), also known as Dravet syndrome, caused by mutation in the SCN1A gene (182389); DEE6B (619317), also caused by mutation in the SCN1A gene; DEE7 (613720), caused by mutation in the KCNQ2 gene (602235); DEE8 (300607), caused by mutation in the ARHGEF9 gene (300429); DEE9 (300088), caused by mutation in the PCDH19 gene (300460); DEE10 (613402), caused by mutation in the PNKP gene (605610); DEE11 (613721), caused by mutation in the SCN2A gene (182390); DEE12 (613722), caused by mutation in the PLCB1 gene (607120); DEE13 (614558), caused by mutation in the SCN8A gene (600702); DEE14 (614959), caused by mutation in the KCNT1 gene (608167); DEE15 (615006), caused by mutation in the ST3GAL3 gene (606494); DEE16 (615338), caused by mutation in the TBC1D24 gene (613577); DEE17 (615473), caused by mutation in the GNAO1 gene (139311); DEE18 (615476), caused by mutation in the SZT2 gene (615463); DEE19 (615744), caused by mutation in the GABRA1 gene (137160); DEE20 (300868), caused by mutation in the PIGA gene (311770); DEE21 (615833), caused by mutation in the NECAP1 gene (611623); DEE22 (300896), caused by mutation in the SLC35A2 gene (314375); DEE23 (615859), caused by mutation in the DOCK7 gene (615730); DEE24 (615871), caused by mutation in the HCN1 gene (602780); DEE25 (615905), caused by mutation in the SLC13A5 gene (608305); DEE26 (616056), caused by mutation in the KCNB1 gene (600397); DEE27 (616139), caused by mutation in the GRIN2B gene (138252); DEE28 (616211), caused by mutation in the WWOX gene (605131); DEE29 (616339), caused by mutation in the AARS gene (601065); DEE30 (616341), caused by mutation in the SIK1 gene (605705); DEE31A (616346) and DEE31B (620352), caused by mutation in the DNM1 gene (602377); DEE32 (616366), caused by mutation in the KCNA2 gene (176262); DEE33 (616409), caused by mutation in the EEF1A2 gene (602959); DEE34 (616645), caused by mutation in the SLC12A5 gene (606726); DEE35 (616647), caused by mutation in the ITPA gene (147520); DEE36 (300884), caused by mutation in the ALG13 gene (300776); DEE37 (616981), caused by mutation in the FRRS1L gene (604574); DEE38 (617020), caused by mutation in the ARV1 gene (611647); DEE39 (612949), caused by mutation in the SLC25A12 gene (603667); DEE40 (617065), caused by mutation in the GUF1 gene (617064); DEE41 (617105), caused by mutation in the SLC1A2 gene (600300); DEE42 (617106), caused by mutation in the CACNA1A gene (601011); DEE43 (617113), caused by mutation in the GABRB3 gene (137192); DEE44 (617132), caused by mutation in the UBA5 gene (610552); DEE45 (617153), caused by mutation in the GABRB1 gene (137190); DEE46 (617162), caused by mutation in the GRIN2D gene (602717); DEE47 (617166), caused by mutation in the FGF12 gene (601513); DEE48 (617276), caused by mutation in the AP3B2 gene (602166); DEE49 (617281), caused by mutation in the DENND5A gene (617278); DEE50 (616457) caused by mutation in the CAD gene (114010); DEE51 (617339), caused by mutation in the MDH2 gene (154100); DEE52 (617350), caused by mutation in the SCN1B gene (600235); DEE53 (617389), caused by mutation in the SYNJ1 gene (604297); DEE54 (617391), caused by mutation in the HNRNPU gene (602869); DEE55 (617599), caused by mutation in the PIGP gene (605938); DEE56 (617665), caused by mutation in the YWHAG gene (605356); DEE57 (617771), caused by mutation in the KCNT2 gene (610044); DEE58 (617830), caused by mutation in the NTRK2 gene (600456); DEE59 (617904), caused by mutation in the GABBR2 gene (607340); DEE60 (617929), caused by mutation in the CNPY3 gene (610774); DEE61 (617933), caused by mutation in the ADAM22 gene (603709); DEE62 (617938), caused by mutation in the SCN3A gene (182391); DEE63 (617976), caused by mutation in the CPLX1 gene (605032); DEE64 (618004), caused by mutation in the RHOBTB2 gene (607352); DEE65 (618008), caused by mutation in the CYFIP2 gene (606323); DEE66 (618067), caused by mutation in the PACS2 gene (610423); DEE67 (618141), caused by mutation in the CUX2 gene (610648); DEE68 (618201), caused by mutation in the TRAK1 gene (608112); DEE69 (618285), caused by mutation in the CACNA1E gene (601013); DEE70 (618298) caused by mutation in the PHACTR1 gene (608723); DEE71 (618328), caused by mutation in the GLS gene (138280); DEE72 (618374), caused by mutation in the NEUROD2 gene (601725); DEE73 (618379), caused by mutation in the RNF13 gene (609247); DEE74 (618396), caused by mutation in the GABRG2 gene (137164); DEE75 (618437), caused by mutation in the PARS2 gene (612036); DEE76 (618468), caused by mutation in the ACTL6B gene (612458); DEE77 (618548), caused by mutation in the PIGQ gene (605754); DEE78 (618557), caused by mutation in the GABRA2 gene (137140); DEE79 (618559), caused by mutation in the GABRA5 gene (137142); DEE80 (618580), caused by mutation in the PIGB gene (604122); DEE81 (618663), caused by mutation in the DMXL2 gene (612186); DEE82 (618721), caused by mutation in the GOT2 gene (138150); DEE83 (618744), caused by mutation in the UGP2 gene (191760); DEE84 (618792), caused by mutation in the UGDH gene (603370); DEE85 (301044), caused by mutation in the SMC1A gene (300040); DEE86 (618910), caused by mutation in the DALRD3 gene (618904); DEE87 (618916), caused by mutation in the CDK19 gene (614720); DEE88 (618959), caused by mutation in the MDH1 gene (152400); DEE89 (619124), caused by mutation in the GAD1 gene (605363); DEE90 (301058), caused by mutation in the FGF13 gene (300070); DEE91 (617711), caused by mutation in the PPP3CA gene (114105); DEE92 (617829), caused by mutation in the GABRB2 gene (600232); DEE93 (618012), caused by mutation in the ATP6V1A gene (607027); DEE94 (615369), caused by mutation in the CHD2 gene (602119); DEE95 (618143), caused by mutation in the PIGS gene (610271); DEE96 (619340), caused by mutation in the NSF gene (601633); DEE97 (619561), caused by mutation in the iCELF2 gene (602538); DEE98 (619605), caused by mutation in the ATP1A2 gene (182340); DEE99 (619606), caused by mutation in the ATP1A3 gene (182350); DEE100 (619777), caused by mutation in the FBXO28 gene (609100); DEE101 (619814), caused by mutation in the GRIN1 gene (138249); DEE102 (619881), caused by mutation in the SLC38A3 gene (604437); DEE103 (619913), caused by mutation in the KCNC2 gene (176256); DEE104 (619970), caused by mutation in the ATP6V0A1 gene (192130); DEE105 (619983), caused by mutation in the HID1 gene (605752); DEE106 (620028), caused by mutation in the UFSP2 gene (611482); DEE107 (620033), caused by mutation in the NAPB gene (
Fanconi anemia complementation group L
MedGen UID:
854018
Concept ID:
C3469528
Disease or Syndrome
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA.
Mitochondrial complex III deficiency nuclear type 1
MedGen UID:
762097
Concept ID:
C3541471
Disease or Syndrome
Autosomal recessive mitochondrial complex III deficiency is a severe multisystem disorder with onset at birth of lactic acidosis, hypotonia, hypoglycemia, failure to thrive, encephalopathy, and delayed psychomotor development. Visceral involvement, including hepatopathy and renal tubulopathy, may also occur. Many patients die in early childhood, but some may show longer survival (de Lonlay et al., 2001; De Meirleir et al., 2003). Genetic Heterogeneity of Mitochondrial Complex III Deficiency Mitochondrial complex III deficiency can be caused by mutation in several different nuclear-encoded genes. See MC3DN2 (615157), caused by mutation in the TTC19 gene (613814) on chromosome 17p12; MC3DN3 (615158), caused by mutation in the UQCRB gene (191330) on chromosome 8q; MC3DN4 (615159), caused by mutation in the UQCRQ gene (612080) on chromosome 5q31; MC3DN5 (615160), caused by mutation in the UQCRC2 gene (191329) on chromosome 16p12; MC3DN6 (615453), caused by mutation in the CYC1 gene (123980) on chromosome 8q24; MC3DN7 (615824), caused by mutation in the UQCC2 gene (614461) on chromosome 6p21; MC3DN8 (615838), caused by mutation in the LYRM7 gene (615831) on chromosome 5q23; MC3DN9 (616111), caused by mutation in the UQCC3 gene (616097) on chromosome 11q12; and MC3DN10 (618775), caused by mutation in the UQCRFS1 gene (191327) on chromosome 19q12. See also MTYCB (516020) for a discussion of a milder phenotype associated with isolated mitochondrial complex III deficiency and mutations in a mitochondrial-encoded gene.
Developmental and epileptic encephalopathy, 14
MedGen UID:
767109
Concept ID:
C3554195
Disease or Syndrome
KCNT1-related epilepsy is most often associated with two phenotypes: epilepsy of infancy with migrating focal seizures (EIMFS) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). EIMFS is characterized by seizures, typically focal and asynchronous, beginning in the first six months of life with associated developmental plateau or regression. Autonomic manifestations (e.g., perioral cyanosis, flushing, apnea) are common. Seizures are intractable to multiple anticonvulsants and progress to become nearly continuous by age six to nine months. ADNFLE is characterized by clusters of nocturnal motor seizures that vary from simple arousals to hyperkinetic events with tonic or dystonic features. Individuals with KCNT1-related ADNFLE are more likely to develop seizures at a younger age, have cognitive comorbidity, and display psychiatric and behavioral problems than individuals with ADNFLE resulting from other causes. Less common seizure phenotypes in individuals with KCNT1-related epilepsy include West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, leukodystrophy and/or leukoencephalopathy, focal epilepsy, and multifocal epilepsy. Additional neurologic features include hypotonia, microcephaly developing by age 12 months, strabismus, profound developmental delay, and additional movement disorders. Other systemic manifestations including pulmonary hemorrhage caused by prominent systemic-to-pulmonary collateral arteries or cardiac arrhythmia have been reported.
Microcephalic primordial dwarfism due to ZNF335 deficiency
MedGen UID:
767413
Concept ID:
C3554499
Disease or Syndrome
Primary microcephaly-10 (MCPH10) is an autosomal recessive disorder characterized by extremely small head size (-9 SD) at birth and death usually by 1 year of age. Neuropathologic examination shows severe loss of neurons as well as neuronal loss of polarity and abnormal dendritic maturation (summary by Yang et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).
SLC35A2-congenital disorder of glycosylation
MedGen UID:
813018
Concept ID:
C3806688
Disease or Syndrome
Congenital disorder of glycosylation type IIm, or developmental and epileptic encephalopathy-22 (DEE22), is an X-linked dominant severe neurologic disorder characterized by infantile-onset seizures, hypsarrhythmia on EEG, hypotonia, and developmental delay associated with severe intellectual disability and lack of speech. These features are consistent with developmental and epileptic encephalopathy (DEE). Brain malformations usually include cerebral and cerebellar atrophy. Additionally, some patients may have dysmorphic features or coarse facies (Ng et al., 2013; Kodera et al., 2013). For a general discussion of CDGs, see CDG1A (212065) and CDG2A (212066). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Mitochondrial DNA depletion syndrome 13
MedGen UID:
815922
Concept ID:
C3809592
Disease or Syndrome
FBXL4-related encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome is a multi-system disorder characterized primarily by congenital or early-onset lactic acidosis and growth failure, feeding difficulty, hypotonia, and developmental delay. Other neurologic manifestations can include seizures, movement disorders, ataxia, autonomic dysfunction, and stroke-like episodes. All affected individuals alive at the time they were reported (median age: 3.5 years) demonstrated significant developmental delay. Other findings can involve the heart (hypertrophic cardiomyopathy, congenital heart malformations, arrhythmias), liver (mildly elevated transaminases), eyes (cataract, strabismus, nystagmus, optic atrophy), hearing (sensorineural hearing loss), and bone marrow (neutropenia, lymphopenia). Survival varies; the median age of reported deaths was two years (range 2 days – 75 months), although surviving individuals as old as 36 years have been reported. To date FBXL4-related mtDNA depletion syndrome has been reported in 50 individuals.
Developmental and epileptic encephalopathy, 17
MedGen UID:
815936
Concept ID:
C3809606
Disease or Syndrome
Developmental and epileptic encephalopathy-17 (DEE17) is a severe neurologic disorder characterized by onset of intractable seizures in the first weeks or months of life. EEG often shows a burst-suppression pattern consistent with a clinical diagnosis of Ohtahara syndrome. Affected infants have very poor psychomotor development and may have brain abnormalities, such as cerebral atrophy or thin corpus callosum. Some patients may show involuntary movements (summary by Nakamura et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Microcephaly-thin corpus callosum-intellectual disability syndrome
MedGen UID:
816410
Concept ID:
C3810080
Disease or Syndrome
A rare, genetic, syndromic intellectual disability disease characterized by progressive postnatal microcephaly and global developmental delay, as well as moderate to profound intellectual disability, difficulty or inability to walk, pyramidal signs (including spasticity, hyperreflexia and extensor plantar response) and thin corpus callosum revealed by brain imaging. Ophthalmologic signs (including nystagmus, strabismus and abnormal retinal pigmentation), foot deformity and genital anomalies may also be associated.
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).
AHDC1-related intellectual disability - obstructive sleep apnea - mild dysmorphism syndrome
MedGen UID:
862856
Concept ID:
C4014419
Disease or Syndrome
The main features of Xia-Gibbs syndrome (XGS), present in a majority of affected individuals, include delayed motor milestones, speech delay with severely limited or absent speech, moderate-to-severe cognitive impairment, hypotonia, structural brain anomalies, and nonspecific dysmorphic features. Other features may include sleep apnea, movement disorders (ataxia, tremors, and bradykinesias) that often become apparent in childhood or adolescence, short stature, seizures, eye anomalies, behavioral concerns, autism spectrum disorder, scoliosis, and laryngomalacia.
Webb-Dattani syndrome
MedGen UID:
863145
Concept ID:
C4014708
Disease or Syndrome
Webb-Dattani syndrome is an autosomal recessive disorder characterized by frontotemporal hypoplasia, globally delayed development, and pituitary and hypothalamic insufficiency due to hypoplastic development of these brain regions. Patients present soon after birth with multiple pituitary hormonal deficiencies and subsequently develop microcephaly, seizures, and spasticity. Other features include postretinal blindness and renal abnormalities (summary by Webb et al., 2013).
Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome
MedGen UID:
863609
Concept ID:
C4015172
Disease or Syndrome
Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) is an autosomal recessive syndromic disorder characterized by onset of severe sideroblastic anemia in the neonatal period or infancy. Affected individuals show delayed psychomotor development with variable neurodegeneration. Recurrent periodic fevers without an infectious etiology occur throughout infancy and childhood; immunologic work-up shows B-cell lymphopenia and hypogammaglobulinemia. Other more variable features include sensorineural hearing loss, retinitis pigmentosa, nephrocalcinosis, and cardiomyopathy. Death in the first decade may occur (summary by Wiseman et al., 2013).
Fatty acyl-CoA reductase 1 deficiency
MedGen UID:
863781
Concept ID:
C4015344
Disease or Syndrome
Peroxisomal fatty acyl-CoA reductase-1 disorder (PFCRD) is an autosomal recessive disorder characterized by onset in infancy of severely delayed psychomotor development, growth retardation with microcephaly, and seizures. Some patients may have congenital cataracts and develop spasticity later in childhood. Biochemical studies tend to show decreased plasmalogen, consistent with a peroxisomal defect. The disorder is reminiscent of rhizomelic chondrodysplasia punctata (see, e.g., RCDP1, 215100), although the characteristic skeletal abnormalities observed in RCDP are absent (Buchert et al., 2014).
PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome
MedGen UID:
863794
Concept ID:
C4015357
Disease or Syndrome
PURA-related neurodevelopmental disorders include PURA syndrome, caused by a heterozygous pathogenic sequence variant in PURA, and 5q31.3 deletion syndrome, caused by a genomic 5q31.3 deletion encompassing all or part of PURA. PURA-related neurodevelopmental disorders are characterized by moderate-to-severe neurodevelopmental delay with absence of speech in most and lack of independent ambulation in many. Early-onset problems can include hypotonia, hypothermia, hypersomnolence, feeding difficulties, excessive hiccups, recurrent central and obstructive apneas, epileptic seizures, abnormal nonepileptic movements (dystonia, dyskinesia, and dysconjugate eye movements), and abnormal vision. Congenital heart defects, urogenital malformations, skeletal abnormalities, and endocrine disorders occur, but are less common.
Developmental and epileptic encephalopathy, 28
MedGen UID:
863956
Concept ID:
C4015519
Disease or Syndrome
Developmental and epileptic encephalopathy-28 (DEE28) is an autosomal recessive severe neurologic disorder characterized by the onset of refractory seizures in the first months of life. Affected individuals have severe axial hypotonia and profoundly impaired psychomotor development. More severely affected patients have acquired microcephaly, poor or absent visual contact, and retinal degeneration; early death may occur (summary by Mignot et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Trichothiodystrophy 3, photosensitive
MedGen UID:
865608
Concept ID:
C4017171
Disease or Syndrome
Trichothiodystrophy is a rare autosomal recessive disorder in which patients have brittle, sulfur-deficient hair that displays a diagnostic alternating light and dark banding pattern, called 'tiger tail banding,' under polarizing microscopy. TTD patients display a wide variety of clinical features, including cutaneous, neurologic, and growth abnormalities. Common additional clinical features are ichthyosis, intellectual/developmental disabilities, decreased fertility, abnormal characteristics at birth, ocular abnormalities, short stature, and infections. There are both photosensitive and nonphotosensitive forms of the disorder. Patients with TTD have not been reported to have a predisposition to cancer (summary by Faghri et al., 2008). For a discussion of genetic heterogeneity of TTD, see 601675.
Hypomyelinating leukodystrophy 13
MedGen UID:
896545
Concept ID:
C4225170
Disease or Syndrome
Hypomyelinating leukodystrophy-13 is an autosomal recessive neurodegenerative disorder characterized by infantile onset of delayed psychomotor development, axial hypotonia, and spasticity associated with delayed myelination and periventricular white matter abnormalities on brain imaging. More variable neurologic deficits, such as visual impairment, may also occur. Some patients may experience cardiac failure during acute illness (summary by Edvardson et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080.
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.
Spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome
MedGen UID:
900192
Concept ID:
C4225254
Disease or Syndrome
Spastic tetraplegia, thin corpus callosum, and progressive microcephaly is an autosomal recessive neurodevelopmental disorder characterized by onset of those features and severely impaired global development in early infancy. Most patients are unable to achieve independent walking or speech; some patients have seizures (summary by Srour et al., 2015 and Heimer et al., 2015).
Developmental and epileptic encephalopathy, 35
MedGen UID:
904159
Concept ID:
C4225256
Disease or Syndrome
Developmental and epileptic encephalopathy-35 (DEE35) is an autosomal recessive neurodegenerative disorder characterized by onset of seizures in the first months of life associated with essentially no normal development. Brain imaging shows a characteristic pattern consistent with lack of myelination of early structures, including the posterior limb of the internal capsule, brainstem tracts, and tracts to the primary visual and motor cortices. Many patients die in early childhood (summary by Kevelam et al., 2015) For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Developmental and epileptic encephalopathy, 34
MedGen UID:
899149
Concept ID:
C4225257
Disease or Syndrome
SLC12A5-related epilepsy of infancy with migrating focal seizures (SLC12A5-EIMFS), reported to date in nine children, is characterized by onset of seizures before age six months and either developmental delay or developmental regression with seizure onset. Of these nine children, six had severe developmental delay with no progress of abilities and three made notable neurodevelopmental progress. Eight had postnatal microcephaly and hypotonia. In most children epilepsy begins as focal motor seizures (typically involving head and eye deviation) that become multifocal and intractable to conventional anti-seizure medication (ASM).
Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome
MedGen UID:
895574
Concept ID:
C4225276
Disease or Syndrome
Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities (NEDHSB) is an autosomal recessive disorder characterized by severe neurologic impairment including impaired intellectual development, epilepsy, microcephaly, abnormal muscle tone, and sensorineural hearing loss. Most affected individuals are nonambulatory, cannot sit unassisted, and have no speech development. More variable features include feeding difficulties, poor growth, cortical visual impairment, spasticity, scoliosis, immunodeficiency, and thrombocytopenia (Tanaka et al., 2015).
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.
Houge-Janssens syndrome 2
MedGen UID:
899880
Concept ID:
C4225352
Disease or Syndrome
PPP2R1A-related neurodevelopmental disorder (NDD) is characterized by: severe, persistent hypotonia; developmental delay with variable intellectual outcomes, typically in the moderate-to-severe intellectual disability range; seizures (more commonly seen in individuals with microcephaly and/or severe intellectual disability); attention-deficit/hyperactivity disorder and other behavioral problems (anxiousness, repetitive movements, self-injurious or destructive behavior, and autism spectrum disorder); feeding and swallowing issues; and dysmorphic features of the head and face. A minority of affected individuals have ear anomalies, hearing loss, ptosis, generalized joint hypermobility, and patent ductus arteriosus. Brain MRI findings are nonspecific but typically include complete or partial agenesis of the corpus callosum. Nonprogressive ventriculomegaly may be seen in a subset of affected individuals and is often associated with specific pathogenic variants in PPP2R1A: c.544C>T (p.Arg182Trp) and c.547C>T (p.Arg183Trp).
Lipoyl transferase 1 deficiency
MedGen UID:
904073
Concept ID:
C4225379
Disease or Syndrome
Lipoyl transferase 1 deficiency is a very rare inborn error of metabolism disorder, with a highly variable phenotype, typically characterized by neonatal to infancy-onset of seizures, psychomotor delay, and abnormal muscle tone that may include hypo- and/or hypertonia, resulting in generalized weakness, dystonic movements, and/or progressive respiratory distress, associated with severe lactic acidosis and elevated lactate, ketoglutarate and 2-oxoacids in urine. Additional manifestations may include dehydration, vomiting, signs of liver dysfunction, extrapyramidal signs, spastic tetraparesis, brisk deep tendon reflexes, speech impairment, swallowing difficulties, and pulmonary hypertension.
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).
Mucopolysaccharidosis-plus syndrome
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).
Optic atrophy 11
MedGen UID:
934595
Concept ID:
C4310628
Disease or Syndrome
Optic atrophy-11 (OPA11) is an autosomal recessive disorder characterized by delayed psychomotor development, intellectual disability, ataxia, optic atrophy, and leukoencephalopathy on brain imaging. Laboratory studies are consistent with mitochondrial dysfunction (summary by Hartmann et al., 2016). For a discussion of genetic heterogeneity of optic atrophy, see OPA1 (165500).
Global developmental delay, absent or hypoplastic corpus callosum, and dysmorphic facies
MedGen UID:
934611
Concept ID:
C4310644
Disease or Syndrome
GDACCF is an intellectual disability syndrome apparent soon after birth with neonatal hypotonia, poor feeding, and respiratory insufficiency followed by delayed psychomotor development and intellectual disability with poor speech. Brain imaging shows aplasia or hypoplasia of the corpus callosum. Affected individuals have variable dysmorphic facial features, and some may have dysplastic, cystic kidneys or mild cardiac defects (summary by Stevens et al., 2016).
Myoclonus, intractable, neonatal
MedGen UID:
934625
Concept ID:
C4310658
Disease or Syndrome
Neonatal intractable myoclonus (NEIMY) is a severe neurologic disorder characterized by the onset of intractable myoclonic seizures soon after birth. Affected infants have intermittent apnea, abnormal eye movements, pallor of the optic nerve, and lack of developmental progress. Brain imaging shows a progressive leukoencephalopathy. Some patients may die in infancy. There is phenotypic and biochemical evidence of mitochondrial dysfunction (summary by Duis et al., 2016).
Periventricular nodular heterotopia 7
MedGen UID:
934636
Concept ID:
C4310669
Disease or Syndrome
Periventricular nodular heterotopia-7 (PVNH7) is a neurologic disorder characterized by abnormal neuronal migration during brain development resulting in delayed psychomotor development and intellectual disability; some patients develop seizures. Other features include cleft palate and 2-3 toe syndactyly (summary by Broix et al., 2016). For a phenotypic description and a discussion of genetic heterogeneity of periventricular heterotopia, see 300049.
Short stature-brachydactyly-obesity-global developmental delay syndrome
MedGen UID:
934656
Concept ID:
C4310689
Disease or Syndrome
A rare genetic, multiple congenital anomalies syndrome characterized by short stature, hand brachydactyly with hypoplastic distal phalanges, global development delay, intellectual disability, and more variably seizures, obesity, and craniofacial dysmorphism that includes microcephaly, high forehead, flat face, hypertelorism, deep set eyes, flat nasal bridge, averted nostrils, long philtrum, thin lip vermilion, and short neck.
Developmental and epileptic encephalopathy, 44
MedGen UID:
934667
Concept ID:
C4310700
Disease or Syndrome
Developmental and epileptic encephalopathy-44 (DEE44) is an autosomal recessive neurologic disorder characterized by the onset of refractory infantile spasms or myoclonus usually in the first weeks or months of life, up to about 12 months of age. Affected infants may have normal or mildly delayed development before the onset of seizures, but thereafter show developmental stagnation and severe neurologic impairment. EEG in some patients shows hypsarrhythmia, consistent with a clinical diagnosis of West syndrome. Additional features include poor feeding and poor overall growth with microcephaly, axial hypotonia with peripheral hypertonia or spasticity, abnormal movements, limited eye contact, and profoundly impaired intellectual development with absent language. Many patients require tube feeding, and some die in childhood (summary by Muona et al., 2016; Colin et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Developmental and epileptic encephalopathy, 41
MedGen UID:
934684
Concept ID:
C4310717
Disease or Syndrome
Developmental and epileptic encephalopathy-41 (DEE41) is a neurologic disorder characterized by the onset of seizures in the first days or weeks of life. Affected infants show severely impaired psychomotor development with hypotonia, spasticity, lack of speech, poor visual fixation, feeding difficulties sometimes necessitating tube feeding, poor overall growth and microcephaly, and contractures. Brain imaging may show delayed myelination, thin corpus callosum, and cerebral atrophy (summary by the EPI4K Consortium, 2016). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Hermansky-Pudlak syndrome 10
MedGen UID:
934713
Concept ID:
C4310746
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.
Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart
MedGen UID:
934739
Concept ID:
C4310772
Disease or Syndrome
RERE-related disorders are characterized by neurodevelopmental problems with or without structural anomalies of the eyes, heart, kidneys, and genitourinary tract and mild sensorineural hearing loss. Hypotonia and feeding problems are common among affected individuals. Developmental delay and intellectual disability range from mild to profound. Behavior problems may include attention-deficit/hyperactivity disorder, self-injurious behavior, and autism spectrum disorder. A variety of eye anomalies (coloboma, optic nerve anomalies, microphthalmia, and/or Peter's anomaly) and vision issues (myopia, anisometropia, astigmatism, exotropia, esotropia) have been reported. Congenital heart defects, most commonly septal defects, have also been described. Genitourinary abnormalities include vesicoureteral reflux, and cryptorchidism and hypospadias in males. Sensorineural hearing loss can be unilateral or bilateral.
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.
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).
Intellectual disability, X-linked 104
MedGen UID:
934784
Concept ID:
C4310817
Disease or Syndrome
Any non-syndromic X-linked intellectual disability in which the cause of the disease is a mutation in the FRMPD4 gene.
Developmental and epileptic encephalopathy, 36
MedGen UID:
1382656
Concept ID:
C4317295
Disease or Syndrome
Developmental and epileptic encephalopathy-36 (DEE36) is an X-linked neurodevelopmental disorder characterized by the onset of seizures at a mean age of 6.5 months. Most patients present with infantile spasms associated with hypsarrhythmia on EEG, consistent with a clinical diagnosis of West syndrome. The seizures tend to be refractory to treatment, although some patients may respond to benzodiazepines or a ketogenic diet. Affected individuals have severely delayed psychomotor development with poor motor function, severe intellectual disability, poor or absent speech, and limited eye contact. More variable features include feeding difficulties sometimes requiring tube feeding, ocular defects including cortical visual impairment, dysmorphic facial features, and scoliosis or osteopenia. The vast majority of patients reported have been females, although rare affected males with a similar phenotype have been described. Most patients show normal N-glycosylation on transferrin isoelectric focusing, but some show abnormal N-glycosylation consistent with CDG type I (summary by Ng et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. For a discussion of the classification of CDGs, see CDG1A (212065).
Developmental and epileptic encephalopathy, 51
MedGen UID:
1372686
Concept ID:
C4479208
Disease or Syndrome
Developmental and epileptic encephalopathy-51 (DEE51) is an autosomal recessive severe neurodevelopmental disorder characterized by onset of intractable seizures and hypotonia in the first days or weeks of life. Affected individuals have severely delayed psychomotor development and may show abnormal movements. Brain imaging shows nonspecific abnormalities, such as cerebral atrophy, cerebellar atrophy, and delayed myelination. Laboratory studies showed increased lactate, suggesting mitochondrial dysfunction (summary by Ait-El-Mkadem et al., 2017). For a discussion of genetic heterogeneity of DEE, see 308350.
Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination
MedGen UID:
1377894
Concept ID:
C4479333
Disease or Syndrome
Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination is a syndromic form of severe to profound intellectual disability with onset of delayed psychomotor development and seizures in infancy. Affected children have hypotonia, feeding difficulties resulting in failure to thrive, and inability to speak or walk, and they tend to show repetitive stereotypic behaviors. Brain imaging shows cerebral atrophy and delayed myelination (summary by Schoch et al., 2017).
Intellectual disability, autosomal recessive 60
MedGen UID:
1373351
Concept ID:
C4479476
Mental or Behavioral Dysfunction
Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies
MedGen UID:
1380860
Concept ID:
C4479566
Disease or Syndrome
NMIHBA is a severe autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by global developmental delay apparent from infancy and profoundly impaired intellectual development. Affected individuals have microcephaly with accompanying dysmorphic features, truncal hypotonia, peripheral spasticity, and lack of independent ambulation or speech acquisition. Brain imaging shows variable abnormalities, including cortical atrophy, thin corpus callosum, cerebellar hypoplasia, and delayed myelination (summary by Zollo et al., 2017).
Neurodevelopmental disorder with involuntary movements
MedGen UID:
1374697
Concept ID:
C4479569
Disease or Syndrome
NEDIM is a neurodevelopmental and neurodegenerative disorder characterized by delayed psychomotor development and infantile or childhood onset of hyperkinetic involuntary movements, including chorea and athetosis. The abnormal movements can be severe, sometimes resulting in inability to sit, walk, speak, or eat. Hyperkinetic movements can be exacerbated by specific triggers, such as stress, illness, or high temperature. Some patients have brain abnormalities, such as cerebral atrophy or thin corpus callosum, and some patients may develop seizures (summary by Ananth et al., 2016 and Danti et al., 2017).
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.
Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities
MedGen UID:
1624694
Concept ID:
C4540052
Disease or Syndrome
NELABA is a severe autosomal recessive metabolic disorder characterized by onset at birth of progressive encephalopathy associated with increased serum lactate. Affected individuals have little or no psychomotor development and show brain abnormalities, including cerebral atrophy, cysts, and white matter abnormalities. Some patients die in infancy (summary by Habarou et al., 2017).
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).
Epileptic encephalopathy, infantile or early childhood, 1
MedGen UID:
1626137
Concept ID:
C4540199
Disease or Syndrome
Developmental and epileptic encephalopathy-91 (DEE91) is characterized by delayed psychomotor development apparent in infancy and resulting in severely to profoundly impaired intellectual development with poor or absent speech. Most patients never achieve independent walking. Patients typically have onset of refractory multifocal seizures between the first weeks and years of life, and some may show developmental regression. Additional features, such as hypotonia and cortical visual impairment, are more variable (summary by Myers et al., 2017). For a discussion of genetic heterogeneity of DEE, see 308350.
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).
Joubert syndrome 33
MedGen UID:
1615779
Concept ID:
C4540389
Disease or Syndrome
Joubert syndrome (JBTS) represents a classic ciliopathy characterized by hypotonia, ataxia, cognitive impairment, and a distinctive brain malformation, the 'molar tooth sign.' In addition, retinal dystrophy, cystic kidney disease, liver fibrosis, and polydactyly occur in a subset of patients (summary by Wheway et al., 2015). For a discussion of genetic heterogeneity of Joubert syndrome, see JBTS1 (213300).
Intellectual disability, autosomal dominant 52
MedGen UID:
1615839
Concept ID:
C4540478
Mental or Behavioral Dysfunction
Microcephaly 19, primary, autosomal recessive
MedGen UID:
1616860
Concept ID:
C4540488
Disease or Syndrome
Autosomal recessive primary microcephaly-19 (MCPH19) is a rare congenital brain defect resulting in a reduction of occipitofrontal head circumference by at least 3 standard deviations, severe developmental delay, failure to thrive, cortical blindness, and spasticity (DiStasio et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).
Neurodevelopmental disorder with severe motor impairment and absent language
MedGen UID:
1622162
Concept ID:
C4540496
Mental or Behavioral Dysfunction
NEDMIAL is a neurodevelopmental disorder characterized by delayed psychomotor development and hypotonia apparent from early infancy, resulting in feeding difficulties, ataxic gait or inability to walk, delayed or absent speech development, and impaired intellectual development, sometimes with behavioral abnormalities, such as hand-flapping. Additional common features may include sleep disorder, nonspecific dysmorphic facial features, and joint hyperlaxity (summary by Lessel et al., 2017 and Mannucci et al., 2021).
Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter
MedGen UID:
1621102
Concept ID:
C4540498
Disease or Syndrome
NDAGSCW is a neurodevelopmental disorder characterized by severely delayed psychomotor development apparent from infancy. Affected individuals have delayed and difficulty walking, intellectual disability, absent speech, and variable additional features, including hip dysplasia, tapering fingers, and seizures. Brain imaging shows decreased cortical white matter, often with decreased cerebellar white matter, thin corpus callosum, and thin brainstem (summary by Lamers et al., 2017).
Intellectual disability, autosomal dominant 56
MedGen UID:
1638835
Concept ID:
C4693389
Mental or Behavioral Dysfunction
Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities
MedGen UID:
1634867
Concept ID:
C4693567
Disease or Syndrome
Leukodystrophy, hypomyelinating, 16
MedGen UID:
1631337
Concept ID:
C4693779
Disease or Syndrome
Hypomyelinating leukodystrophy-16 is an autosomal dominant neurologic disorder characterized by onset of hypotonia, nystagmus, and mildly delayed motor development in infancy. Affected individuals have motor disabilities, including ataxic or broad-based gait, hyperreflexia, intention tremor, dysmetria, and a mild pyramidal syndrome. Some patients have cognitive impairment, whereas others may have normal cognition or mild intellectual disability with speech difficulties. Brain imaging typically shows hypomyelination, leukodystrophy, and thin corpus callosum (summary by Simons et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of hypomyelinating leukodystrophy, see 312080.
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.
Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome
MedGen UID:
1645614
Concept ID:
C4706421
Disease or Syndrome
Combined oxidative phosphorylation deficiency-12 (COXPD12) is an autosomal recessive mitochondrial neurologic disorder characterized by onset in infancy of hypotonia and delayed psychomotor development, or early developmental regression, associated with T2-weighted hyperintensities in the deep cerebral white matter, brainstem, and cerebellar white matter. Serum lactate is increased due to a defect in mitochondrial respiration. There are 2 main phenotypic groups: those with a milder disease course and some recovery of skills after age 2 years, and those with a severe disease course resulting in marked disability (summary by Steenweg et al., 2012). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
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).
Glycosylphosphatidylinositol biosynthesis defect 18
MedGen UID:
1648478
Concept ID:
C4748357
Disease or Syndrome
DEE95 is a severe autosomal recessive developmental disorder characterized by severely impaired global development, hypotonia, weakness, ataxia, coarse facial features, and intractable seizures. More variable features may include abnormalities of the hands and feet, inguinal hernia, and feeding difficulties. The disorder is part of a group of similar neurologic disorders resulting from biochemical defects in the glycosylphosphatidylinositol (GPI) biosynthetic pathway (summary by Nguyen et al., 2018). 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).
Periventricular nodular heterotopia 8
MedGen UID:
1648287
Concept ID:
C4748602
Disease or Syndrome
Periventricular nodular heterotopia-8 (PVNH8) is a neurologic disorder characterized by abnormal neuronal migration during brain development, resulting in delayed psychomotor development. Three patients have been reported (Ge et al., 2016). For a phenotypic description and a discussion of genetic heterogeneity of periventricular heterotopia, see PVNH1 (300049).
Inflammatory bowel disease, immunodeficiency, and encephalopathy
MedGen UID:
1648434
Concept ID:
C4748708
Disease or Syndrome
A rare genetic disease characterized by infantile onset of severe inflammatory bowel disease manifesting with bloody diarrhea and failure to thrive, and central nervous system disease with global developmental delay and regression, impaired speech, hypotonia, hyperreflexia, and epilepsy. Brain imaging shows global cerebral atrophy, thin corpus callosum, delayed myelination, and posterior leukoencephalopathy. Cases with recurrent infections and impaired T-cell responses to stimulation, as well as decreased T-cell subsets, have been reported.
Developmental and epileptic encephalopathy, 70
MedGen UID:
1648407
Concept ID:
C4749023
Disease or Syndrome
Developmental and epileptic encephalopathy-70 (DEE70) is neurologic disorder characterized by the onset of epileptic spasms or seizures in the first months of life. EEG may show hypsarrhythmia, consistent with a clinical diagnosis of West syndrome. Affected individuals show severely delayed psychomotor development with impaired or absent walking and language skills; intellectual impairment ranges from moderate to severe (summary by Hamada et al., 2018). For a discussion of genetic heterogeneity of DEE, see 308350.
Intellectual disability-strabismus syndrome
MedGen UID:
1665943
Concept ID:
C4750838
Disease or Syndrome
Neurodevelopmental disorder with brain abnormalities, poor growth, and dysmorphic facies (NEDBGF) is an autosomal recessive disorder characterized by global developmental delay with delayed walking, impaired intellectual development, and speech delay apparent from infancy or early childhood. Most patients have dysmorphic facial features, often with microcephaly and strabismus, and white matter abnormalities on brain imaging. More variable features may include teeth anomalies, distal joint contractures, spasticity, peripheral neuropathy, and behavioral problems (summary by Sharkia et al., 2019).
Congenital disorder of glycosylation with defective fucosylation 2
MedGen UID:
1676187
Concept ID:
C5193028
Disease or Syndrome
Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis
MedGen UID:
1682670
Concept ID:
C5193033
Disease or Syndrome
Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development
MedGen UID:
1673640
Concept ID:
C5193037
Disease or Syndrome
Aside from the clinical features of infantile cataract, skin abnormalities, and impaired intellectual development, CASGID is characterized by strikingly high intracerebral and urinary glutamate excess with almost undetectable glutamine. A gain-of-function mutation in the GLS gene was found (see MOLECULAR GENETICS) (Rumping et al., 2019). GLS loss of function is implicated in developmental and epileptic encephalopathy-71 (DEE71; 618328) and a syndrome of global developmental delay and progressive ataxia (GDPAG; 618412).
Galloway-Mowat syndrome 8
MedGen UID:
1675829
Concept ID:
C5193045
Disease or Syndrome
Galloway-Mowat syndrome-8 is an autosomal recessive disorder characterized by impaired psychomotor development, poor overall growth with microcephaly, and early-onset progressive nephrotic syndrome associated with focal segmental glomerulosclerosis on renal biopsy. Some patients may have seizures, and some may die in childhood (summary by Fujita et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of GAMOS, see GAMOS1 (251300).
Houge-Janssens syndrome 3
MedGen UID:
1677130
Concept ID:
C5193048
Disease or Syndrome
Houge-Janssens syndrome-3 (HJS3) is characterized by global developmental delay apparent from infancy. The phenotype is highly variable: patients may have hypotonia, behavioral abnormalities, and abnormalities on brain imaging, including enlarged ventricles, thin corpus callosum, and sometimes small brainstem. Many develop seizures, sometimes refractory, and some may have nonspecific dysmorphic features. Intellectual impairment can vary from mild to profound, and some patients may benefit from special education and respond well to speech therapy (summary by Reynhout et al., 2019). For a discussion of genetic heterogeneity of HJS, see HJS1 (616355).
Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination
MedGen UID:
1684142
Concept ID:
C5193057
Disease or Syndrome
A rare, genetic, neurometabolic disease characterized by microcephaly, short stature, epilepsy, cerebral hypomyelination, severe global developmental delay, and progressive spasticity. Macrocytic anemia and hyperthermia have also been reported in association. Brain imaging reveals delayed myelination with minimal progression over time, mild cerebellar atrophy and/or thin corpus callosum.
Developmental and epileptic encephalopathy, 72
MedGen UID:
1681879
Concept ID:
C5193063
Disease or Syndrome
Developmental and epileptic encephalopathy-72 (DEE72) is neurologic disorder characterized by the onset of infantile spasms around 5 months of age. The seizures tend to be refractory to treatment. EEG may show hypsarrhythmia, consistent with a clinical diagnosis of West syndrome. Affected individuals show severely delayed psychomotor development with impaired or absent walking and language skills. Additional more variable features include hyperkinetic movements and cortical visual impairment (summary by Sega et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Developmental and epileptic encephalopathy, 73
MedGen UID:
1681654
Concept ID:
C5193065
Disease or Syndrome
Developmental and epileptic encephalopathy-73 (DEE73) is a neurologic disorder characterized by the onset of refractory seizures in the first months of life. Affected individuals meet almost no developmental milestones: they have hypotonia and are unable to walk, speak, or feed properly. They have poor overall growth with small head circumference and dysmorphic facial features. Additional manifestations include cortical visual impairment with roving eye movements and variable hearing loss (summary by Edvardson et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Developmental and epileptic encephalopathy, 74
MedGen UID:
1680535
Concept ID:
C5193074
Disease or Syndrome
Developmental and epileptic encephalopathy-74 (DEE74) is neurologic disorder characterized by the onset of refractory seizures in the first months of life. Seizure types are variable and include infantile spasms, myoclonic, tonic, atonic, and absence, often with secondary generalization. Affected individuals have severe global developmental delay with hypotonia, severe motor impairment, roving eye movements, and absent language (summary by Shen et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Developmental delay with or without dysmorphic facies and autism
MedGen UID:
1679263
Concept ID:
C5193106
Disease or Syndrome
Developmental delay with or without dysmorphic facies and autism (DEDDFA) is a complex neurodevelopmental disorder apparent from infancy or early childhood and associated with variably impaired intellectual development. Some patients may be severely affected with no speech and inability to walk, whereas others may be able to attend special schools or have normal intellectual function associated with autism spectrum disorder and mild speech delay. Genetic analysis has suggested that the phenotype can be broadly categorized into 2 main groups. Patients with TRRAP mutations affecting residues 1031-1159 have a more severe disorder, often with multisystem involvement, including renal, cardiac, and genitourinary systems, as well as structural brain abnormalities. Patients with mutations outside of that region tend to have a less severe phenotype with a higher incidence of autism and usually no systemic involvement. Patients in both groups usually have somewhat similar dysmorphic facial features, such as upslanting palpebral fissures, hypertelorism, low-set ears, and broad or depressed nasal bridge, although these features are highly variable (summary by Cogne et al., 2019).
Developmental and epileptic encephalopathy, 76
MedGen UID:
1673011
Concept ID:
C5193113
Disease or Syndrome
Developmental and epileptic encephalopathy-76 (DEE76) is an autosomal recessive neurodevelopmental disorder characterized by early-onset, usually refractory, seizures, severely delayed global development, hypotonia, peripheral spasticity, and abnormalities on brain imaging, mainly cerebral atrophy and delayed myelination. Some patients may have additional features, such as scoliosis or microcephaly. The disorder may result in death in childhood (summary by Bell et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Hypopigmentation, organomegaly, and delayed myelination and development
MedGen UID:
1684826
Concept ID:
C5203300
Disease or Syndrome
Hypopigmentation, organomegaly, and delayed myelination and development (HOD) is characterized by hypopigmented skin and hair with normally pigmented irides; organomegaly including enlargement of liver, kidney, and spleen; and delayed myelination on brain MRI accompanied by developmental delay in both gross and fine motor skills. Biopsy findings from skin and other organs are consistent with a lysosomal storage disorder (Nicoli et al., 2019).
Glycosylphosphatidylinositol biosynthesis defect 21
MedGen UID:
1684749
Concept ID:
C5231419
Disease or Syndrome
Neurodevelopmental disorder with brain anomalies, seizures, and scoliosis (NEDBSS) is an autosomal recessive disorder characterized by severely impaired psychomotor development, hypotonia, seizures, and structural brain anomalies, including thin corpus callosum and cerebellar atrophy. Other features include scoliosis, dysmorphic facies, and visual impairment. Affected individuals are usually unable to walk or speak and may require tube feeding in severe cases. The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis (summary by Knaus et al., 2019). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities
MedGen UID:
1684818
Concept ID:
C5231423
Disease or Syndrome
Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities (NEDHIB) is characterized by early-onset hypotonia, delayed walking, poor speech, and impaired intellectual development. Additional features may include feeding difficulties, dysmorphic features, and visual defects. Brain imaging tends to show delayed myelination, thin corpus callosum, and/or enlarged ventricles. The severity of the disorder is highly variable; initial evidence suggests that the severity may depend on the type of mutation (summary by Haijes et al., 2019).
Snijders blok-fisher syndrome
MedGen UID:
1684801
Concept ID:
C5231424
Disease or Syndrome
Snijders Blok-Fisher syndrome (SNIBFIS) is a neurodevelopmental disorder characterized by global developmental delay, hypotonia, variable impaired intellectual development, and specifically impaired speech and language acquisition. Patients achieve independent ambulation and most have mildly to moderately impaired cognition with autistic features, although a few may develop seizures and have a more severe phenotype. Dysmorphic features include abnormal, cupped, or prominent ears and ocular anomalies. Mutations usually occur de novo, although 1 family with autosomal dominant inheritance has been reported (summary by Snijders Blok et al., 2019).
Intellectual developmental disorder with impaired language and dysmorphic facies
MedGen UID:
1684804
Concept ID:
C5231444
Disease or Syndrome
Intellectual developmental disorder with impaired language and dysmorphic facies (IDDILF) is an autosomal dominant disorder characterized by global developmental delay apparent from infancy, impaired language development, and dysmorphic facial features, including hypertelorism, epicanthal folds, and abnormal palpebral fissures. Some patients may have additional findings, including feeding difficulties, mild cardiac or genitourinary defects, and distal skeletal anomalies (summary by Balak et al., 2019).
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 speech delay, autism, and dysmorphic facies
MedGen UID:
1684848
Concept ID:
C5231456
Disease or Syndrome
Leukodystrophy, hypomyelinating, 19, transient infantile
MedGen UID:
1684698
Concept ID:
C5231463
Disease or Syndrome
Transient infantile hypomyelinating leukodystrophy-19 (HLD19) is a disorder characterized by onset of transient neurologic abnormalities in early infancy, with resolution within the first or second decades. Affected individuals typically present in the newborn period or in early infancy with nystagmus and motor deficits associated with marked hypomyelination on brain imaging. Both neurologic impairment and abnormal brain imaging spontaneously resolve during childhood. Most patients have normal cognition and can attend regular schools, although some may have persistent neurologic deficits, such as gait ataxia, speech pronunciation defects, and/or mild cognitive impairment (summary by Yan et al., 2019). For a discussion of genetic heterogeneity of HLD, see 312080.
Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies
MedGen UID:
1684772
Concept ID:
C5231481
Disease or Syndrome
Wieacker-Wolff syndrome, female-restricted
MedGen UID:
1715791
Concept ID:
C5393303
Disease or Syndrome
Female-restricted Wieacker-Wolff syndrome (WRWFFR) is an X-linked dominant syndromic form of neurogenic arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. Affected individuals have decreased fetal movements causing the development of contractures in utero and resulting in AMC and diffuse contractures involving the large and small joints apparent at birth. There is global developmental delay with difficulty walking or inability to walk, hypotonia that often evolves to spasticity, and variably impaired intellectual development with poor or absent speech and language. Dysmorphic facial features, including hypotonic facies, ptosis, microretrognathia, and small mouth, are seen in most patients. Seizures are uncommon; some patients have evidence of a peripheral motor neuropathy with distal muscle weakness. The level of X inactivation in lymphocytes and fibroblasts is often skewed, but may not predict the severity of the phenotype. Most cases occur sporadically; rare X-linked dominant inheritance has been reported in families (summary by Frints et al., 2019).
Developmental and epileptic encephalopathy, 84
MedGen UID:
1720141
Concept ID:
C5394081
Disease or Syndrome
Developmental and epileptic encephalopathy-84 (DEE84) is an autosomal recessive neurologic disorder characterized by onset of refractory seizures in the first months or years of life. Affected individuals have severely impaired global development with impaired intellectual development, absent speech, and inability to walk. Other features include axial hypotonia, peripheral spasticity, feeding difficulties that sometimes necessitate tube feeding, and mild dysmorphic facial features. Brain imaging may show nonspecific findings such as cerebral/cerebellar atrophy and/or hypomyelination. The severity of the disorder is variable (summary by Hengel et al., 2020). For a discussion of genetic heterogeneity of DEE, see 308350.
Sandestig-stefanova syndrome
MedGen UID:
1718072
Concept ID:
C5394118
Disease or Syndrome
Sandestig-Stefanova syndrome (SANDSTEF) is an autosomal recessive developmental syndrome characterized by pre- and postnatal microcephaly, trigonocephaly, congenital cataract, microphthalmia, facial gestalt, camptodactyly, loss of periventricular white matter, thin corpus callosum, delayed myelinization, and poor prognosis (Sandestig 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).
Rhizomelic limb shortening with dysmorphic features
MedGen UID:
1720321
Concept ID:
C5394173
Disease or Syndrome
Rhizomelic limb shortening with dysmorphic features (RLSDF) is characterized by rhizomelic shortening of the extremities, predominantly of the upper limbs, and variable dysmorphic features, including macrocephaly, prominent forehead, hypertelorism, depressed or broad nasal bridge, and micrognathia. Hearing loss has also been observed (Sajan et al., 2019; Pagnamenta et al., 2023).
Epilepsy, early-onset, with or without developmental delay
MedGen UID:
1709942
Concept ID:
C5394228
Disease or Syndrome
Early-onset epilepsy-2 with or without developmental delay (EPEO2) is an autosomal dominant neurologic disorder characterized by the onset of generalized tonic-clonic seizures in the first days, months, or years of life. The severity is highly variable: some patients have normal psychomotor development and normal brain imaging, whereas others may show developmental delay associated with abnormalities on brain imaging (summary by Yu et al., 2019). For a discussion of genetic heterogeneity of EPEO, see 617290.
Combined oxidative phosphorylation deficiency 43
MedGen UID:
1718250
Concept ID:
C5394284
Disease or Syndrome
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).
Seizures, early-onset, with neurodegeneration and brain calcifications
MedGen UID:
1713658
Concept ID:
C5394359
Disease or Syndrome
Early-onset seizures with neurodegeneration and brain calcifications (SENEBAC) is an autosomal recessive encephalopathy characterized by onset of refractory seizures in the first year of life. Affected individuals tend to have normal or mildly delayed development early in life, but show significant and progressive developmental regression associated with seizure onset. Features include hypotonia, peripheral spasticity, poor eye contact, and absent speech. Most require tube feeding; death in childhood may occur. Brain imaging shows cerebral atrophy, loss of white matter, and punctate calcifications, suggestive of abnormal neuroinflammation (summary by Smith et al., 2020 and Dong et al., 2020).
Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome
MedGen UID:
1719567
Concept ID:
C5394367
Disease or Syndrome
Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (LEUDEN) is characterized by global developmental delay apparent in early childhood, followed by episodic neurologic regression or decompensation associated with systemic stress, such as febrile infection. Affected individuals have hypotonia, gait difficulties or ataxia, poor or absent speech with dysarthria, and variable motor abnormalities, including spasticity, dystonia, extrapyramidal signs, and tremor. Many patients have seizures. Brain imaging shows diffuse white matter abnormalities, poor myelination, thin corpus callosum, and generalized cerebral atrophy with enlarged ventricles. The clinical features of the disorder and the abnormal brain imaging findings are progressive (summary by Mao et al., 2020).
Microcephaly, developmental delay, and brittle hair syndrome
MedGen UID:
1718781
Concept ID:
C5394425
Disease or Syndrome
Microcephaly, developmental delay, and brittle hair syndrome (MDBH) is a multisystem disorder with clinical variability. Affected individuals show cognitive and motor disabilities, as well as some degree of fine, brittle hair with microscopic shaft abnormalities. Other shared features include failure to thrive in early childhood and short stature, with some patients exhibiting feeding difficulties and hepatic steatosis (Kuo et al., 2019).
Developmental and epileptic encephalopathy, 87
MedGen UID:
1719688
Concept ID:
C5394501
Disease or Syndrome
Developmental and epileptic encephalopathy-87 (DEE87) is a neurologic disorder characterized by global developmental delay, hypotonia, and onset of frequent refractory seizures or infantile spasms between 6 and 15 months of age. Affected individuals have severely impaired motor and cognitive development with little or absent speech and poor visual tracking. More variable features include facial dysmorphisms, joint laxity, and nonspecific brain imaging findings (summary by Chung et al., 2020).
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).
Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies
MedGen UID:
1759589
Concept ID:
C5436646
Disease or Syndrome
IDDEBF is a severe disorder characterized by impaired intellectual development, epilepsy, behavioral abnormalities, and coarse facies. Brain MRI findings may include delayed myelination in the deep parietal lobes (Kvarnung et al., 2018).
Myopathy, epilepsy, and progressive cerebral atrophy
MedGen UID:
1759100
Concept ID:
C5436652
Disease or Syndrome
Myopathy, epilepsy, and progressive cerebral atrophy (MEPCA) is a severe autosomal recessive disorder with onset in utero or at birth. Affected individuals have hypotonia with respiratory or feeding difficulties apparent from birth and often associated with contractures of the large joints. There is little spontaneous movement: skeletal muscle biopsy and electrophysiologic studies are consistent with a myopathy or myasthenic disorder. Patients also develop refractory seizures with burst-suppression pattern or hypsarrhythmia on EEG. Brain imaging shows progressive cerebral atrophy and myelination defects. All patients reported to date died within the first year of life (summary by Schorling et al., 2017).
Neurodevelopmental disorder with microcephaly, seizures, and brain atrophy
MedGen UID:
1755716
Concept ID:
C5436747
Disease or Syndrome
Neurodevelopmental disorder with microcephaly, seizures, and brain atrophy (NEDMISB) is an autosomal recessive disorder characterized by severe global developmental delay, developmental regression with loss of milestones, severe microcephaly, and brain abnormalities, primarily cerebral atrophy and hypoplasia of the corpus callosum. Affected individuals develop seizures in the first year of life; eventually they are unable to sit, feed, or communicate, and may be unresponsive to stimuli. Other features include muscle weakness, spasticity with hyperreflexia, irritability, and contractures (Coulter et al., 2020).
Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy
MedGen UID:
1765507
Concept ID:
C5436781
Disease or Syndrome
Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy (DIGFAN) is a complex neurologic disorder characterized by impaired motor and intellectual development, hypotonia, poor overall growth, usually with short stature and microcephaly, and subtly dysmorphic facial features. Affected individuals have distal muscle weakness and muscle atrophy resulting in delayed acquisition of motor skills and persistent gait abnormalities. Although many patients have clinical and/or electrophysiologic features consistent with an axonal sensorimotor peripheral neuropathy, such as hyporeflexia, impaired sensation, foot drop, and pes cavus, the signs and severity are highly variable. Additional features may include hearing loss, pigmentary retinopathy, and abnormalities on brain imaging, including cerebral or cerebellar atrophy, hypomyelination, and lesions in the basal ganglia or brainstem. In some instances, the same mutation may result in different phenotypic manifestations (CMT2Z or DIGFAN syndrome), which highlights the expanding clinical spectrum associated with MORC2 mutations and may render classification of patients into one or the other disorder challenging (summary by Guillen Sacoto et al., 2020).
Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities
MedGen UID:
1731507
Concept ID:
C5436783
Disease or Syndrome
Neurodevelopmental disorder with microcephaly, language delay, and gait abnormalities (NEDMILG) is an autosomal recessive disorder characterized by global developmental delay apparent in infancy. Affected individuals have delayed walking with variable gait abnormalities, impaired intellectual development with poor or absent speech and language, and progressive microcephaly. More variable features include hypotonia, early-onset seizures, and a peripheral demyelinating or axonal peripheral sensorimotor neuropathy. The disease follows a neurodegenerative course in many patients; clinical features suggest involvement of both the central and peripheral nervous systems (Manole et al., 2020).
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).
Neurodevelopmental disorder with or without autism or seizures
MedGen UID:
1784023
Concept ID:
C5543225
Disease or Syndrome
CUL3-related neurodevelopmental disorder is a condition that affects neurological and physical development. Children with CUL3-related neurodevelopmental disorder may have intellectual disability or specific learning disorders. They may also experience delayed development of speech and motor skills, such as sitting and walking. Some individuals with this condition may have autism spectrum disorder, a developmental condition that affects communication and social skills. \n\nMovement abnormalities can also occur in people with CUL3-related neurodevelopmental disorder. Affected individuals may have weak muscle tone (hypotonia) in childhood. In adulthood, they may develop involuntary muscle tensing (dystonia), rhythmic shaking (tremor), or other uncontrolled movements (spasms). \n\nPeople with CUL3-related neurodevelopmental disorder can have distinctive facial features, including a long, triangular-shaped face; a large forehead; a large, rounded nose; small ears; deep-set eyes; or a pointed chin. Some affected individuals have a larger than normal head (macrocephaly). \n\nMany people with CUL3-related neurodevelopmental disorder have hand and foot abnormalities. Hand abnormalities can include small pinky (fifth) fingers that curve inward (clinodactyly), narrow thumbs, underdevelopment of the muscle at the base of the thumb (thenar hypoplasia), or a single crease across the palm of the hand. Foot abnormalities can include high arches of the feet (pes cavus); bunions; fusion of the skin between some toes (cutaneous syndactyly); or joint deformities (contractures) in the ankles, feet, or toes. A few individuals with CUL3-related neurodevelopmental disorder have an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). \n\nSome affected infants have a backflow of stomach acids into the esophagus (gastroesophageal reflux disease or GERD), which tends to go away after childhood. Rarely, recurrent seizures (epilepsy), congenital heart abnormalities, or genitourinary abnormalities occur in people with CUL3-related neurodevelopmental disorder. 
Spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis
MedGen UID:
1780157
Concept ID:
C5543257
Disease or Syndrome
SHILCA is characterized by early-onset retinal degeneration in association with sensorineural hearing loss, short stature, vertebral anomalies, and epiphyseal dysplasia, as well as motor and intellectual delay. Delayed myelination, leukoencephalopathy, and hypoplasia of the corpus callosum and cerebellum have been observed on brain MRI (Bedoni et al., 2020).
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).
Pontocerebellar hypoplasia, type 15
MedGen UID:
1781311
Concept ID:
C5543326
Disease or Syndrome
Pontocerebellar hypoplasia type 15 (PCH15) 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 spastic quadriplegia, early-onset seizures, and chronic anemia and thrombocytopenia. Brain imaging shows pontocerebellar hypoplasia and partial agenesis of the corpus callosum (summary by et al., 2021). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1A (607596).
Pontocerebellar hypoplasia, type 1F
MedGen UID:
1785905
Concept ID:
C5543331
Disease or Syndrome
Pontocerebellar hypoplasia type 1F (PCH1F) is an autosomal recessive neurologic disorder characterized by hypotonia, global developmental delay, poor overall growth, and dysmorphic facial features. Brain imaging shows pontocerebellar hypoplasia, thin corpus callosum, cerebral atrophy, and delayed myelination (summary by Somashekar et al., 2021). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1A (607596).
Neurodevelopmental disorder with infantile epileptic spasms
MedGen UID:
1781627
Concept ID:
C5543538
Disease or Syndrome
Neurodevelopmental disorder with infantile epileptic spasms (NEDIES) is characterized by onset of severe and frequent epileptic spasms within the first year of life. Affected individuals have global developmental delay with delayed walking and poor or absent speech. More variable features may include poor overall growth, high-arched palate, and delayed myelination on brain imaging (summary by Fatima et al., 2021).
Focal segmental glomerulosclerosis and neurodevelopmental syndrome
MedGen UID:
1794148
Concept ID:
C5561938
Disease or Syndrome
Focal segmental glomerulosclerosis and neurodevelopmental syndrome (FSGSNEDS) is characterized by global developmental delay and renal dysfunction manifest as proteinuria and nephrotic syndrome apparent from infancy or early childhood. Some patients present with renal disease, whereas others present with developmental delay and develop renal disease later in childhood. Renal biopsy shows focal segmental glomerulosclerosis (FSGS), but the course of the disease is variable: some patients have transient proteinuria and others require renal transplant. Neurodevelopmental features are also variable, with some patients having only mildly impaired intellectual development, and others having a severe developmental disorder associated with early-onset refractory seizures or epileptic encephalopathy. Additional features, including feeding difficulties, poor overall growth, and nonspecific dysmorphic facial features, are commonly observed (summary by Assoum et al., 2018 and Weng et al., 2021).
Aicardi-Goutieres syndrome 9
MedGen UID:
1794176
Concept ID:
C5561966
Disease or Syndrome
Aicardi-Goutieres syndrome-9 (AGS9) is a type I interferonopathy characterized by severe developmental delay and progressive neurologic deterioration. Patients present in infancy with irritability and spasticity. Brain imaging shows diffusely abnormal white matter, cerebral atrophy, and intracranial calcification. Premature death has been associated with renal and/or hepatic failure (Uggenti et al., 2020). For a general phenotypic description and discussion of genetic heterogeneity of Aicardi-Goutieres syndrome, see AGS1 (225750).
Neurodevelopmental disorder with hypotonia and dysmorphic facies
MedGen UID:
1794184
Concept ID:
C5561974
Disease or Syndrome
Neurodevelopmental disorder with hypotonia and dysmorphic facies (NEDHYDF) is characterized by global developmental delay and hypotonia apparent from birth. Affected individuals have variably impaired intellectual development, often with speech delay and delayed walking. Seizures are generally not observed, although some patients may have single seizures or late-onset epilepsy. Most patients have prominent dysmorphic facial features. Additional features may include congenital cardiac defects (without arrhythmia), nonspecific renal anomalies, joint contractures or joint hyperextensibility, dry skin, and cryptorchidism. There is significant phenotypic variability in both the neurologic and extraneurologic manifestations (summary by Tan et al., 2022).
Neurodevelopmental disorder with hypotonia and brain abnormalities
MedGen UID:
1794187
Concept ID:
C5561977
Disease or Syndrome
Neurodevelopmental disorder with hypotonia and brain abnormalities (NEDHYBA) is characterized by impaired development of motor skills, cognitive function, and speech acquisition beginning in infancy or early childhood. Some affected individuals may have feeding difficulties, seizures, behavioral abnormalities, and nonspecific dysmorphic facial features. Brain imaging shows variable abnormalities, including corpus callosum defects, cerebellar defects, and decreased white matter volume. There is significant phenotypic variability (summary by Duncan et al., 2021).
Neurodevelopmental disorder with seizures and brain abnormalities
MedGen UID:
1794189
Concept ID:
C5561979
Disease or Syndrome
Neurodevelopmental disorder with seizures and brain abnormalities (NEDSBA) is an autosomal recessive neurologic disorder characterized by global developmental delay and onset of seizures in the first months of life associated with structural brain defects on brain imaging. Additional features may include pigmentary retinopathy with poor visual fixation and spasticity (summary by Duncan et al., 2021).
Intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies
MedGen UID:
1794207
Concept ID:
C5561997
Disease or Syndrome
Intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies (IDDHISD) is characterized by global developmental delay with impaired intellectual development and poor or absent speech, hypotonia, ophthalmologic abnormalities, and nonspecific dysmorphic features. Some affected individuals have seizures, and a few have involvement of other organ systems (Goodman 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).
Developmental and epileptic encephalopathy 99
MedGen UID:
1794228
Concept ID:
C5562018
Disease or Syndrome
Developmental and epileptic encephalopathy-99 (DEE99) is characterized by onset of seizures in early childhood associated with global developmental delay and severely impaired intellectual development. Other features may include hypotonia, quadriparesis, nystagmus, and apnea. Brain imaging may be normal or show nonspecific and variable abnormalities, including cerebral atrophy and polymicrogyria. The severity is variable; some patients die of refractory status epilepticus (summary by Vetro et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Galloway-Mowat syndrome 10
MedGen UID:
1794230
Concept ID:
C5562020
Disease or Syndrome
Galloway-Mowat syndrome-10 (GAMOS10) is a severe autosomal recessive disorder characterized by onset of symptoms soon after birth. Affected individuals have progressive renal dysfunction with proteinuria associated with diffuse mesangial sclerosis (DMS) on renal biopsy. Other features include global developmental delay, microcephaly, hypothyroidism, arachnodactyly, and dysmorphic facial features. Some patients may have seizures or abnormalities on brain imaging. All reported patients have died in infancy (summary by Arrondel et al., 2019 and Schmidt et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of GAMOS, see GAMOS1 (251300).
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).
Trichothiodystrophy 8, nonphotosensitive
MedGen UID:
1794267
Concept ID:
C5562057
Disease or Syndrome
Nonphotosensitive trichothiodystrophy-8 (TTD8) is characterized by brittle hair and nails and scaly skin, accompanied by failure to thrive, microcephaly, and neuromotor developmental delay. Hair analysis shows low sulfur content, and skin fibroblasts demonstrate normal DNA repair efficiency after UV irradiation (Botta et al., 2021). For a general phenotypic description and discussion of genetic heterogeneity of trichothiodystrophy, see TTD1 (601675).
Combined oxidative phosphorylation deficiency 29
MedGen UID:
1799030
Concept ID:
C5567607
Disease or Syndrome
A rare mitochondrial oxidative phosphorylation disorder with characteristics of microcephaly, global developmental delay, spastic-dystonic movement disorder, intractable seizures, optic atrophy, autonomic dysfunction and peripheral neuropathy. Serum lactate is increased, and muscle biopsy shows decreased activity of mitochondrial respiratory complexes I and III. Brain imaging reveals progressive cerebellar atrophy and delayed myelination.
Combined oxidative phosphorylation defect type 26
MedGen UID:
1799164
Concept ID:
C5567741
Disease or Syndrome
Peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay (PNSED) is an autosomal recessive multisystemic disorder with highly variable manifestations, even within the same family. Some patients present in infancy with hypotonia and global developmental delay with poor or absent motor skill acquisition and poor growth, whereas others present as young adults with exercise intolerance and muscle weakness. All patients have signs of a peripheral neuropathy, usually demyelinating, with distal muscle weakness and atrophy and distal sensory impairment; many become wheelchair-bound. Additional features include spasticity, extensor plantar responses, contractures, cerebellar signs, seizures, short stature, and rare involvement of other organ systems, including the heart, pancreas, and kidney. Biochemical analysis may show deficiencies in mitochondrial respiratory complex enzyme activities in patient tissue, although this is not always apparent. Lactate is frequently increased, suggesting mitochondrial dysfunction (Powell et al., 2015; Argente-Escrig et al., 2022). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
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.
Charcot-Marie-Tooth disease, demyelinating, IIA 1I
MedGen UID:
1811493
Concept ID:
C5676914
Disease or Syndrome
Demyelinating Charcot-Marie-Tooth disease type 1I (CMT1I) is a neurologic disorder characterized predominantly by delayed motor development in the first years of life associated with gait abnormalities, sensory ataxia, hyporeflexia, and distal sensory impairment due to a sensorimotor peripheral neuropathy that mainly affects the lower limbs. The disorder is progressive, and some may have upper limb involvement. A subset of patients has central nervous system involvement that manifests as global developmental delay with impaired intellectual development and speech difficulties. Other features may include spasticity, hyperreflexia, tremor, dysmetria, seizures, or cerebellar findings. Brain imaging may be normal or show nonspecific abnormalities, such as white matter signal changes and delayed myelination (summary by Djordjevic et al., 2021). For a discussion of genetic heterogeneity of autosomal dominant Charcot-Marie-Tooth disease type 1, see CMT1B (118200).
Developmental and epileptic encephalopathy 100
MedGen UID:
1809351
Concept ID:
C5676932
Disease or Syndrome
Developmental and epileptic encephalopathy-100 (DEE100) is a severe neurologic disorder characterized by global developmental delay and onset of variable types of seizures in the first months or years of life. Most patients have refractory seizures and show developmental regression after seizure onset. Affected individuals have ataxic gait or inability to walk and severe to profoundly impaired intellectual development, often with absent speech. Additional more variable features may include axial hypotonia, hyperkinetic movements, dysmorphic facial features, and brain imaging abnormalities (summary by Schneider et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
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).
3-methylglutaconic aciduria, type VIIA
MedGen UID:
1813022
Concept ID:
C5676967
Disease or Syndrome
3-Methylglutaconic aciduria (MGCA7) is an inborn error of metabolism characterized primarily by increased levels of 3-methylglutaconic acid (3-MGA) associated with variable neurologic deficits and neutropenia. The phenotype is highly variable: most patients have infantile onset of a severe progressive encephalopathy with various movement abnormalities and delayed psychomotor development. Other common variable features include seizures, recurrent infections due to neutropenia, anemia, and brain imaging abnormalities (Wortmann et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA1 (250950).
Dentici-Novelli neurodevelopmental syndrome
MedGen UID:
1810366
Concept ID:
C5676987
Disease or Syndrome
Dentici-Novelli neurodevelopmental syndrome (DENNED) is an autosomal recessive disorder characterized by global developmental delay with impaired intellectual development apparent from infancy. The severity of the phenotype is highly variable: more severely affected individuals have axial hypotonia, peripheral spasticity, microcephaly, early-onset seizures, brain imaging abnormalities, and are unable to walk or speak. Those with a less severe phenotype may achieve some developmental goals and show less severe intellectual disability (Dentici et al., 2022).
Osteoporosis, childhood- or juvenile-onset, with developmental delay
MedGen UID:
1802083
Concept ID:
C5676992
Disease or Syndrome
Childhood- or juvenile-onset osteoporosis with developmental delay (OPDD) is characterized by evidence of osteopenia or osteoporosis, with recurrent fractures following minor trauma in some patients. Developmental delay is variable, and includes mild intellectual or learning disabilities as well as wide-based gait and/or gross motor delays. Microcephaly is present in some patients (Marom et al., 2021).
Developmental and epileptic encephalopathy 103
MedGen UID:
1809962
Concept ID:
C5677002
Disease or Syndrome
Developmental and epileptic encephalopathy-103 (DEE103) is characterized by onset of various types of seizures in the first year of life, most of which are refractory to treatment. Affected individuals show global developmental delay with impaired intellectual development ranging from mild to severe. Additional features may include hypotonia, ataxia, and behavioral abnormalities, including autism and hyperactivity (Schwarz et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Glycosylphosphatidylinositol biosynthesis defect 25
MedGen UID:
1823964
Concept ID:
C5774191
Disease or Syndrome
Glycosylphosphatidylinositol biosynthesis defect-25 (GPIBD25) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay, brain anomalies, hypotonia, and contractures (Salian et al., 2022). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Liver disease, severe congenital
MedGen UID:
1823968
Concept ID:
C5774195
Disease or Syndrome
Severe congenital liver disease (SCOLIV) is an autosomal recessive disorder characterized by the onset of progressive hepatic dysfunction usually in the first years of life. Affected individuals show feeding difficulties with failure to thrive and features such as jaundice, hepatomegaly, and abdominal distension. Laboratory workup is consistent with hepatic insufficiency and may also show coagulation defects, anemia, or metabolic disturbances. Cirrhosis and hypernodularity are commonly observed on liver biopsy. Many patients die of liver failure in early childhood (Moreno Traspas et al., 2022).
Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment
MedGen UID:
1823998
Concept ID:
C5774225
Disease or Syndrome
Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment (NEDMVIC) is an autosomal recessive disorder characterized by global developmental delay, impaired intellectual development, facial dysmorphism, and microcephaly (Ziegler et al., 2022).
Neurodevelopmental disorder with facial dysmorphism, absent language, and pseudo-pelger-huet anomaly
MedGen UID:
1824005
Concept ID:
C5774232
Disease or Syndrome
Neurodevelopmental disorder with facial dysmorphism, absent language, and pseudo-Pelger-Huet anomaly (NEDFLPH) is an autosomal recessive disorder characterized by global developmental delay with severely impaired intellectual development. Affected individuals often have behavioral abnormalities and may have variable findings on brain imaging, such as thin corpus callosum. Laboratory studies show nuclear lobulation defects in a subset of neutrophils, indicating a pseudo-Pelger-Huet anomaly (see 169400) and suggesting defects in the integrity of the nuclear envelope, where TMEM147 localizes (Thomas et al., 2022).
Neurodevelopmental disorder with eye movement abnormalities and ataxia
MedGen UID:
1824014
Concept ID:
C5774241
Disease or Syndrome
Neurodevelopmental disorder with eye movement abnormalities and ataxia (NEDEMA) is characterized by global developmental delay apparent from infancy. Affected individuals show delayed walking with an unsteady gait, variably impaired intellectual development, learning disabilities, and speech difficulties. Abnormal eye movements, which are often noted in early childhood, include opsoclonus, nystagmus, and strabismus. Some patients have seizures, which may be refractory (Lu et al., 2022).
Neurodevelopmental disorder with speech impairment and with or without seizures
MedGen UID:
1824025
Concept ID:
C5774252
Disease or Syndrome
Neurodevelopmental disorder with speech impairment and with or without seizures (NEDSIS) is a phenotypically heterogeneous neurologic disorder whose severity appears to depend on the functional effect of the CACNA1I mutation. Severely affected individuals present in infancy with profound global developmental delay, hypotonia, delayed or absent walking, absent speech, feeding difficulties, cortical visual impairment, and onset of hyperexcitability and seizures in the first months or years of life. They achieve little or no developmental progress and may be tube-fed. Mutations in these individuals occurred de novo. In contrast, a milder phenotype associated with an inherited mutation has been found in a family with mild to moderate cognitive impairment and mild speech delay, usually without seizures (El Ghaleb et al., 2021).
Developmental and epileptic encephalopathy 109
MedGen UID:
1824036
Concept ID:
C5774263
Disease or Syndrome
Developmental and epileptic encephalopathy-109 (DEE109) is characterized by the onset of various types of seizures in the first months or years of life. Affected individuals show developmental delay before and concurrent with the onset of seizures. Features include impaired intellectual development with poor speech, ataxic gait, coordination problems, and behavioral abnormalities (Manivannan et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Congenital disorder of glycosylation, type IIy
MedGen UID:
1824067
Concept ID:
C5774294
Disease or Syndrome
Congenital disorder of glycosylation type IIy (CDG2Y) is an autosomal recessive multisystemic congenital disorder characterized by poor overall growth and global developmental delay with impaired intellectual development. Other features may include hypotonia, seizures, brain imaging abnormalities, dysmorphic features, and various skeletal defects. Laboratory studies show a subtle type II glycosylation defect of serum transferrin (Tambe et al., 2020). For a general discussion of CDGs, see CDG1A (212065).
Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia
MedGen UID:
1824071
Concept ID:
C5774298
Disease or Syndrome
Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia (NEDFIH) is an autosomal recessive disorder characterized by these features and moderate to severe global developmental delay. Affected individuals show episodic regression during periods of stress, including seizures or infection, the latter of which may be associated with lymphopenia. Brain imaging shows diminished white matter volume, enlarged ventricles, and thin corpus callosum (Muffels et al., 2023).
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).
Developmental delay with hypotonia, myopathy, and brain abnormalities
MedGen UID:
1840906
Concept ID:
C5830270
Disease or Syndrome
Developmental delay with hypotonia, myopathy, and brain abnormalities (DEDHMB) is an autosomal recessive disorder characterized by global developmental delay and muscle weakness apparent in infancy. Affected individuals show severe motor delay and may not achieve independent walking due to central hypotonia and skeletal muscle myopathy. Some have poor overall growth with microcephaly, subtle dysmorphic features, and delayed language acquisition. Brain imaging shows cerebral atrophy, thinning of the corpus callosum, and delayed myelination (Shamseldin et al., 2016; Kotecha et al., 2021).
Neurodevelopmental disorder with poor growth and behavioral abnormalities
MedGen UID:
1840909
Concept ID:
C5830273
Disease or Syndrome
Neurodevelopmental disorder with poor growth and behavioral abnormalities (NEDGBA) is an autosomal recessive disorder characterized by global developmental delay, moderately to severely impaired intellectual development, often with absent speech, and behavioral abnormalities, including hyperactivity, short attention span, and ADHD. Affected individuals show failure to thrive with poor overall growth; some have microcephaly. Additional features may include nonspecific facial dysmorphism, hypotonia, and feeding difficulties (Vogt et al., 2022; Meng et al., 2023).
Leukodystrophy, hypomyelinating, 25
MedGen UID:
1840911
Concept ID:
C5830275
Disease or Syndrome
Hypomyelinating leukodystrophy-25 (HLD25) is an autosomal recessive disorder characterized by horizontal nystagmus, hypotonia, and global developmental delay apparent soon after birth or in infancy. Most patients show gradual clinical improvement over time with resolution of the nystagmus in early childhood. Many achieve developmental milestones and may have normal cognition, although the severity of the disorder varies and some patients may have persistent neurologic deficits, such as ataxia or intellectual disability. Brain imaging shows hypomyelination that may also improve with time (Yan et al., 2022; do Rosario et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080.
Leukodystrophy, hypomyelinating, 26, with chondrodysplasia
MedGen UID:
1840948
Concept ID:
C5830312
Disease or Syndrome
Hypomyelinating leukodystrophy-26 with chondrodysplasia (HLD26) is characterized by severe psychomotor delay, predominantly involving motor and expressive language development, with cerebral and cerebellar atrophy and corpus callosum hypoplasia. In addition, patients show pre- and postnatal growth retardation, early-onset scoliosis, and dislocations of large joints (Guasto et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see HLD1 (312080).
Neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities
MedGen UID:
1841049
Concept ID:
C5830413
Disease or Syndrome
Neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities (NEDMSBA) is an autosomal recessive disorder characterized by global developmental delay, hypotonia, delayed or absent walking, impaired intellectual development, and poor or absent speech, apparent from early infancy. Affected individuals have postnatal progressive microcephaly and may show poor overall growth and dysmorphic facial features. Additional more variable features include cortical visual impairment, seizures, hypotonia, spasticity, and sensorineural deafness. Brain imaging is abnormal in most patients, showing myelination defects, cortical atrophy, or thin corpus callosum. There is phenotypic variability, even within families (Bogershausen et al., 2022; Lin et al., 2022).
Intellectual developmental disorder, autosomal dominant 71, with behavioral abnormalities
MedGen UID:
1841073
Concept ID:
C5830437
Mental or Behavioral Dysfunction
Autosomal dominant intellectual developmental disorder-71 with behavioral abnormalities (MRD71) is a neurodevelopmental disorder characterized by global developmental delay with hypotonia, speech delay, and variably impaired cognitive development. Almost all affected individuals show marked behavioral manifestations, including autism spectrum disorder (ASD), ADHD, hypersensitivity, and aggression. Many have dysmorphic features, although there is not a common gestalt (Harris et al., 2021).
Intellectual developmental disorder, autosomal recessive 79
MedGen UID:
1841189
Concept ID:
C5830553
Disease or Syndrome
Autosomal recessive intellectual developmental disorder-79 (MRT79) is characterized by global developmental delay apparent from infancy. Affected individuals have mildly delayed walking with an ataxic gait and severely impaired intellectual development with poor or absent speech. Additional features may include postnatal microcephaly and dysmorphic features (Van Bergen et al., 2022).
Neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities
MedGen UID:
1841232
Concept ID:
C5830596
Disease or Syndrome
Neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities (NEDMLOB) is an autosomal recessive neurologic disorder characterized by the onset of features in infancy or early childhood. Affected individuals show hypotonia, severe motor delay with ataxic gait or sometimes an inability to achieve walking, and impaired intellectual development with speech and language delay. Ocular defects can include optic atrophy, nystagmus, strabismus, and retinal dystrophy. Additional features may include seizures (in some), dysmorphic facial features, poor overall growth, and variable brain imaging abnormalities (Tepe et al., 2023).
Congenital disorder of deglycosylation 1
MedGen UID:
989503
Concept ID:
CN306977
Disease or Syndrome
Individuals with NGLY1-related congenital disorder of deglycosylation (NGLY1-CDDG) typically display a clinical tetrad of developmental delay / intellectual disability in the mild to profound range, hypo- or alacrima, elevated liver transaminases that may spontaneously resolve in childhood, and a complex hyperkinetic movement disorder that can include choreiform, athetoid, dystonic, myoclonic, action tremor, and dysmetric movements. About half of affected individuals will develop clinical seizures. Other findings may include obstructive and/or central sleep apnea, oral motor defects that affect feeding ability, auditory neuropathy, constipation, scoliosis, and peripheral neuropathy.

Professional guidelines

PubMed

Forcadela M, Rocchi C, San Martin D, Gibbons EL, Wells D, Woodhall MR, Waters PJ, Huda S, Hamid S
Neurol Neuroimmunol Neuroinflamm 2024 Jan;11(1) Epub 2023 Nov 17 doi: 10.1212/NXI.0000000000200183. PMID: 37977848Free PMC Article
Gilbert EAB, Livingston J, Flores EG, Khan M, Kandavel H, Morshead CM
Brain Res 2024 Jan 1;1822:148648. Epub 2023 Oct 26 doi: 10.1016/j.brainres.2023.148648. PMID: 37890574
Benard-Seguin E, Costello F
Curr Opin Neurol 2023 Feb 1;36(1):10-18. Epub 2022 Dec 5 doi: 10.1097/WCO.0000000000001128. PMID: 36630210

Recent clinical studies

Etiology

Liasis A, Bamiou DE, Campbell P, Sirimanna T, Boyd S, Towell A
Neuropediatrics 2003 Feb;34(1):23-9. doi: 10.1055/s-2003-38622. PMID: 12690564
Kinney HC, Brody BA, Finkelstein DM, Vawter GF, Mandell F, Gilles FH
J Neuropathol Exp Neurol 1991 Jan;50(1):29-48. doi: 10.1097/00005072-199101000-00003. PMID: 1985152
Johnson MD, Glick AD, Whetsell WO Jr
Clin Neuropathol 1989 Jan-Feb;8(1):28-34. PMID: 2706841

Diagnosis

Liasis A, Bamiou DE, Campbell P, Sirimanna T, Boyd S, Towell A
Neuropediatrics 2003 Feb;34(1):23-9. doi: 10.1055/s-2003-38622. PMID: 12690564
Johnson MD, Glick AD, Whetsell WO Jr
Clin Neuropathol 1989 Jan-Feb;8(1):28-34. PMID: 2706841

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