Trichorhinophalangeal syndrome (TRPS) comprises TRPS I (caused by a heterozygous pathogenic variant in TRPS1) and TRPS II (caused by contiguous gene deletion of TRPS1, RAD21, and EXT1). Both types of TRPS are characterized by distinctive facial features; ectodermal features (fine, sparse, depigmented, and slow growing hair; dystrophic nails; and small breasts); and skeletal findings (short stature; short feet; brachydactyly with ulnar or radial deviation of the fingers; and early, marked hip dysplasia). TRPS II is characterized by multiple osteochondromas (typically first observed clinically on the scapulae and around the elbows and knees between ages 1 month and 6 years) and an increased risk of mild-to-moderate intellectual disability.

Prolidase deficiency is characterized by skin lesions (typically severe, chronic, recalcitrant, and painful skin ulcers of the lower extremities and telangiectasias of the face and hands), recurrent infections (particularly of the skin and respiratory tract), dysmorphic facial features, variable intellectual disability, and organomegaly (typically splenomegaly but occasionally associated with hepatomegaly) with elevated liver enzymes. Skeletal anomalies, chronic pulmonary disease, anemia, thrombocytopenia, hypergammaglobulinemia, and hypocomplementemia are observed in a minority of affected individuals. An association between prolidase deficiency and autoimmune conditions – particularly systemic lupus erythematosus (SLE) – has been described.

Hyperlysinemia type I is an autosomal recessive metabolic condition with variable clinical features. Some patients who present in infancy with nonspecific seizures, hypotonia, or mildly delayed psychomotor development have been found to have increased serum lysine and pipecolic acid on laboratory analysis. However, about 50% of probands are reported to be asymptomatic, and hyperlysinemia is generally considered to be a benign metabolic variant (summary by Tondo et al., 2013; Houten et al., 2013). The AASS gene encodes a bifunctional enzyme: lysine alpha-ketoglutarate reductase and saccharopine dehydrogenase. In hyperlysinemia type I, both enzymatic functions of AASS are defective; in hyperlysinemia type II, also known as saccharopinuria (268700), some of the first enzymatic function is retained (Cox, 1985; Cox et al., 1986).

3-methylglutaconyl-CoA hydratase deficiency is an inherited condition that causes neurological problems. Beginning in infancy to early childhood, children with this condition often have delayed development of mental and motor skills (psychomotor delay), speech delay, involuntary muscle cramping (dystonia), and spasms and weakness of the arms and legs (spastic quadriparesis). Affected individuals can also have optic atrophy, which is the breakdown (atrophy) of nerve cells that carry visual information from the eyes to the brain.\n\nIn some cases, signs and symptoms of 3-methylglutaconyl-CoA hydratase deficiency begin in adulthood, often in a person's twenties or thirties. These individuals have damage to a type of brain tissue called white matter (leukoencephalopathy). This damage likely contributes to progressive problems with speech (dysarthria), difficulty coordinating movements (ataxia), stiffness (spasticity), optic atrophy, and a decline in intellectual function (dementia).\n\nAffected individuals who show symptoms of 3-methylglutaconyl-CoA hydratase deficiency in childhood often go on to develop leukoencephalopathy and other neurological problems in adulthood.\n\nAll people with 3-methylglutaconyl-CoA hydratase deficiency accumulate large amounts of a substance called 3-methylglutaconic acid in their body fluids. As a result, they have elevated levels of acid in their blood (metabolic acidosis) and excrete large amounts of acid in their urine (aciduria). 3-methylglutaconyl-CoA hydratase deficiency is one of a group of metabolic disorders that can be diagnosed by the presence of increased levels 3-methylglutaconic acid in urine (3-methylglutaconic aciduria). People with 3-methylglutaconyl-CoA hydratase deficiency also have high urine levels of another acid called 3-methylglutaric acid.

Mevalonate kinase deficiency is a condition characterized by recurrent episodes of fever, which typically begin during infancy. Each episode of fever lasts about 3 to 6 days, and the frequency of the episodes varies among affected individuals. In childhood the fevers seem to be more frequent, occurring as often as 25 times a year, but as the individual gets older the episodes occur less often.\n\nMevalonate kinase deficiency has additional signs and symptoms, and the severity depends on the type of the condition. There are two types of mevalonate kinase deficiency: a less severe type called hyperimmunoglobulinemia D syndrome (HIDS) and a more severe type called mevalonic aciduria (MVA).\n\nPeople with MVA have signs and symptoms of the condition at all times, not just during episodes of fever. Affected children have developmental delay, problems with movement and balance (ataxia), recurrent seizures (epilepsy), progressive problems with vision, and failure to gain weight and grow at the expected rate (failure to thrive). Individuals with MVA typically have an unusually small, elongated head. In childhood or adolescence, affected individuals may develop eye problems such as inflammation of the eye (uveitis), a blue tint in the white part of the eye (blue sclera), an eye disorder called retinitis pigmentosa that causes vision loss, or clouding of the lens of the eye (cataracts). Affected adults may have short stature and may develop muscle weakness (myopathy) later in life. During fever episodes, people with MVA may have an enlarged liver and spleen (hepatosplenomegaly), lymphadenopathy, abdominal pain, diarrhea, and skin rashes. Children with MVA who are severely affected with multiple problems may live only into early childhood; mildly affected individuals may have a normal life expectancy.\n\nDuring episodes of fever, people with HIDS typically have enlargement of the lymph nodes (lymphadenopathy), abdominal pain, joint pain, diarrhea, skin rashes, and headache. Occasionally they will have painful sores called aphthous ulcers around their mouth. In females, these may also occur around the vagina. Rarely, people with HIDS develop a buildup of protein deposits (amyloidosis) in the kidneys that can lead to kidney failure. Fever episodes in individuals with HIDS can be triggered by vaccinations, surgery, injury, or stress. Most people with HIDS have abnormally high levels of immune system proteins called immunoglobulin D (IgD) and immunoglobulin A (IgA) in the blood. It is unclear why some people with HIDS have high levels of IgD and IgA and some do not. Elevated levels of these immunoglobulins do not appear to cause any signs or symptoms. Individuals with HIDS do not have any signs and symptoms of the condition between fever episodes and typically have a normal life expectancy.

Congenital disorder of glycosylation type IIc (CDG2C) is an autosomal recessive disorder characterized by moderate to severe psychomotor retardation, mild dysmorphism, and impaired neutrophil motility. It is a member of a group of disorders with a defect in the processing of protein-bound glycans. For a general overview of congenital disorders of glycosylation (CDGs), see CDG1A (212065) and CDG2A (212066). Frydman (1996) contended that the neutrophil defect in CDG2C, which has been referred to as 'leukocyte adhesion deficiency type II' (LAD2), is a manifestation of the disorder and that there are no cases of 'primary' LAD II. Etzioni and Harlan (1999) provided a comprehensive review of both leukocyte adhesion deficiency-1 (LAD1; 116920) and LAD2. While the functional neutrophil studies are similar in the 2 LADs, the clinical course is milder in LAD2. Furthermore, patients with LAD2 present other abnormal features, such as growth and mental retardation, which are related to the primary defect in fucose metabolism. Delayed separation of the umbilical cord occurs in LAD1. For a discussion of genetic heterogeneity of LAD, see 116920.

The creatine deficiency disorders (CDDs), inborn errors of creatine metabolism and transport, comprise three disorders: the creatine biosynthesis disorders guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency; and creatine transporter (CRTR) deficiency. Developmental delay and cognitive dysfunction or intellectual disability and speech-language disorder are common to all three CDDs. Onset of clinical manifestations of GAMT deficiency (reported in ~130 individuals) is between ages three months and two years; in addition to developmental delays, the majority of individuals have epilepsy and develop a behavior disorder (e.g., hyperactivity, autism, or self-injurious behavior), and about 30% have movement disorder. AGAT deficiency has been reported in 16 individuals; none have had epilepsy or movement disorders. Clinical findings of CRTR deficiency in affected males (reported in ~130 individuals) in addition to developmental delays include epilepsy (variable seizure types and may be intractable) and behavior disorders (e.g., attention deficit and/or hyperactivity, autistic features, impulsivity, social anxiety), hypotonia, and (less commonly) a movement disorder. Poor weight gain with constipation and prolonged QTc on EKG have been reported. While mild-to-moderate intellectual disability is commonly observed up to age four years, the majority of adult males with CRTR deficiency have been reported to have severe intellectual disability. Females heterozygous for CRTR deficiency are typically either asymptomatic or have mild intellectual disability, although a more severe phenotype resembling the male phenotype has been reported.

TBC1D24-related disorders comprise a continuum of features that were originally described as distinct, recognized phenotypes: DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures). Profound sensorineural hearing loss, onychodystrophy, osteodystrophy, intellectual disability / developmental delay, and seizures. Familial infantile myoclonic epilepsy (FIME). Early-onset myoclonic seizures, focal epilepsy, dysarthria, and mild-to-moderate intellectual disability. Progressive myoclonus epilepsy (PME). Action myoclonus, tonic-clonic seizures, progressive neurologic decline, and ataxia. Early-infantile epileptic encephalopathy 16 (EIEE16). Epileptiform EEG abnormalities which themselves are believed to contribute to progressive disturbance in cerebral function. Autosomal recessive nonsyndromic hearing loss, DFNB86. Profound prelingual deafness. Autosomal dominant nonsyndromic hearing loss, DFNA65. Slowly progressive deafness with onset in the third decade, initially affecting the high frequencies.

Childhood absence epilepsy (CAE, ECA), a subtype of idiopathic generalized epilepsy (EIG; 600669), is characterized by a sudden and brief impairment of consciousness that is accompanied by a generalized, synchronous, bilateral, 2.5- to 4-Hz spike and slow-wave discharge (SWD) on EEG. Seizure onset occurs between 3 and 8 years of age and seizures generally occur multiple times per day. About 70% of patients experience spontaneous remission of seizures, often around adolescence. There are no structural neuropathologic findings in patients with ECA (Crunelli and Leresche, 2002). Genetic Heterogeneity of Susceptibility to Childhood Absence Epilepsy The ECA1 locus has been mapped to chromosome 8q24; see also EIG1 (see 600669), which also maps to 8q24. Susceptibility to the development of childhood absence epilepsy may be conferred by variation in several genes: ECA2 (see 607681), conferred by variation in the GABRG2 gene (137164) on chromosome 5q31.1; ECA4 (611136), conferred by variation in the GABRA1 gene (137160) on chromosome 5q34; ECA5 (612269), conferred by variation in the GABRB3 gene (137192) on chromosome 15q12; and ECA6 (see 611942), conferred by variation in the CACNA1H gene (607904) on chromosome 16p13. See EIG11 (607628) for discussion of a locus previously designated ECA3 on chromosome 3q26.

Eiken syndrome (EKNS) is an autosomal recessive skeletal dysplasia characterized by delayed ossification of bones, epiphyseal dysplasia, and bone remodeling abnormalities. Type A1 brachydactyly (see 112500), supernumerary epiphyses of proximal phalanges and metacarpals, and failure of eruption of primary teeth have also been described. Defining radiologic features include delayed ossification of epiphyses and primary ossification centers of short tubular bones, modeling abnormalities of tubular bones, and angel-shaped phalanges (Jacob et al., 2019). See 603740 for a disorder with similar radiologic features.

Childhood seizures associated with febrile episodes are relatively common and represent the majority of childhood seizures. A febrile convulsion is defined as a seizure event in infancy or childhood, usually occurring between 6 months and 6 years of age, associated with fever but without any evidence of intracranial infection or defined pathologic or traumatic cause (Nabbout et al., 2002). Although the majority of patients do not develop epilepsy, the risk of developing subsequent afebrile seizures is 5 to 7 times higher in those with a history of febrile seizures compared to the general population (Annegers et al., 1987; Hedera et al., 2006). The FEB1 locus maps to chromosome 8q13-q21. Genetic Heterogeneity of Familial Febrile Seizures See FEB2 (602477), caused by mutation in the HCN2 gene (602781) on chromosome 19p13; FEB3A (604403), caused by mutation in the SCN1A gene (182389) on chromosome 2q24; FEB4 (604352), caused by mutation in the ADGRV1 gene (602851) on chromosome 5q14; FEB8 (607681), caused by mutation in the GABRG2 gene (137164) on chromosome 5q31; and FEB11 (614418), caused by mutation in the CPA6 gene (609562) on chromosome 8q13. Several loci for familial febrile seizures have been identified: see FEB3B (613863) on chromosome 2q24; FEB5 (609255) on chromosome 6q22-q24; FEB6 (609253) on chromosome 18p11; FEB7 (611515) on chromosome 21q22; FEB9 (611634) on chromosome 3p24.2-p23; and FEB10 (612637) on chromosome 3q26. A phenotype termed 'generalized epilepsy with febrile seizures plus' (GEFS+; 604233) is a clinical subset of familial febrile convulsions in which affected individuals later develop afebrile seizures. GEFS+ is associated with mutations in several genes. Deprez et al. (2009) provided a review of the genetics of epilepsy syndromes starting in the first year of life, and included a diagnostic algorithm.

PRRT2-associated paroxysmal movement disorders (PRRT2-PxMD) include paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC), and hemiplegic migraine (HM). In addition, PRRT2 pathogenic variants have been identified in other childhood-onset movement disorders and different types of seizures, suggesting that the understanding of the spectrum of PRRT2-PxMD is still evolving. The paroxysmal attacks in PKD are characterized by dystonia, choreoathetosis, and less commonly ballismus. The seizures of BFIE are usually focal with or without generalization. Thirty percent of PRRT2-associated PKD is associated with BFIE and is referred to as PKD/IC.

Any febrile seizures, familial in which the cause of the disease is a mutation in the ADGRV1 gene.

Generalized epilepsy with febrile seizures plus type 1 (GEFSP1) is an autosomal dominant neurologic disorder characterized by onset of seizures associated with fever in infancy or early childhood. There is wide phenotypic variability, even within families. In contrast to classic febrile seizures (see, e.g., FEB1, 121210), which affect approximately 3% of children under 6 years of age and typically spontaneously remit by age 6 years, patients with GEFSP1 either have febrile seizures extending beyond age 6 years or develop epilepsy with afebrile seizures. Other seizure types include absence seizures, partial seizures, myoclonic seizures, and atonic seizures. Some patients may have developmental delay after the onset of seizures (summary by Wallace et al., 1998 and Singh et al., 1999). 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 GEFS+ GEFS+ is a genetically heterogeneous disorder. See also GEFS+2 (604403), caused by mutation in the SCN1A gene (182389) on chromosome 2q24; GEFS+3 (see 607681), caused by mutation in the GABRG2 gene (137164) on chromosome 5q34; GEFS+5 (613060), associated with variation in the GABRD (137163) gene on chromosome 1p36; GEFS+9 (616172), caused by mutation in the STX1B gene (601485) on chromosome 16p11; GEFS+10 (618482), caused by mutation in the HCN1 gene (602780) on chromosome 5p12; GEFS+11 (602477), caused by mutation in the HCN2 gene (602781) on chromosome 19p13; and GEFS+12 (620755), caused by mutation in the SLC32A1 gene (616440) on chromosome 20q11. Several putative loci have also been identified; see GEFS+4 (609800), mapped to chromosome 2p24; GEFS+6 (612279), mapped to chromosome 8p23-p21; GEFS+7 (613863), mapped to chromosome 2q24; and GEFS+8 (613828), mapped to chromosome 6q16.3-q22.31.

SCN1A seizure disorders encompass a spectrum that ranges from simple febrile seizures and generalized epilepsy with febrile seizures plus (GEFS+) at the mild end to Dravet syndrome and intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC) at the severe end. Phenotypes with intractable seizures including Dravet syndrome are often associated with cognitive decline. Less commonly observed phenotypes include myoclonic astatic epilepsy (MAE), Lennox-Gastaut syndrome, infantile spasms, epilepsy with focal seizures, and vaccine-related encephalopathy and seizures. The phenotype of SCN1A seizure disorders can vary even within the same family.

An extremely rare form of hereditary episodic ataxia with characteristics of recurrent episodes of vertigo and ataxia lasting several hours.

MBD5 haploinsufficiency is a neurodevelopmental disorder characterized by developmental delay, intellectual disability, severe speech impairment, seizures, sleep disturbances, and abnormal behaviors. Most children lack speech entirely or have single words, short phrases, or short sentences. Seizures are present in more than 80% of children; onset is usually around age two years. Sleep disturbances, present in about 90%, can result in excessive daytime drowsiness. Abnormal behaviors can include autistic-like behaviors (80%) and self-injury and aggression (>60%).

Mutations in the GABRG2 gene cause a spectrum of seizure disorders, ranging from early-onset isolated febrile seizures (FS) to childhood absence epilepsy (CAE) to generalized epilepsy with febrile seizures plus, type 3 (GEFS+3), which tends to represent a more severe phenotype. Patients with isolated febrile seizures usually have onset in the first year of life and show spontaneous remission by age 6 years. Many of these patients may later develop absence seizures, which may also spontaneously remit, whereas a few may continue to have various types of febrile and afebrile seizures that persist beyond childhood, consistent with GEFS+. There is phenotypic variability in the seizure type, even within a family carrying the same mutation, suggesting that other loci may be involved (summary by Singh et al., 1999 and Marini et al., 2003). For a phenotypic description and a discussion of genetic heterogeneity of familial febrile seizures, see 121210. For a general phenotypic description and a discussion of genetic heterogeneity of GEFS+, see 604233. For a phenotypic description and discussion of genetic heterogeneity of childhood absence epilepsy, see 600131.

SATB2-associated syndrome (SAS) is a multisystem disorder characterized by significant neurodevelopmental compromise with limited to absent speech, behavioral issues, and craniofacial anomalies. All individuals described to date have manifest developmental delay / intellectual disability, with severe speech delay. Affected individuals often have hypotonia and feeding difficulties in infancy. Behavioral issues may include autistic features, hyperactivity, and aggressiveness. Craniofacial anomalies may include palatal abnormalities (cleft palate, high-arched palate, and bifid uvula), micrognathia, and abnormal shape or size of the upper central incisors. Less common features include skeletal anomalies (osteopenia, pectus deformities, kyphosis/lordosis, and scoliosis), growth restriction, strabismus/refractive errors, congenital heart defects, genitourinary anomalies, and epilepsy. While dysmorphic features have been described in individuals with this condition, these features are not typically distinctive enough to allow for a clinical diagnosis of SAS.

For a general phenotypic description and a discussion of genetic heterogeneity of idiopathic generalized epilepsy, see 600669. Juvenile myoclonic epilepsy is a subtype of idiopathic generalized epilepsy; see 254770 for a general phenotypic description and a discussion of genetic heterogeneity of JME.

Idiopathic generalized epilepsy (EIG) is a broad term that encompasses several common seizure phenotypes, classically including childhood absence epilepsy (CAE, ECA), juvenile absence epilepsy (JAE), and juvenile myoclonic epilepsy (JME, EJM) (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). Generalized epilepsy with febrile seizures plus (GEFS+) shows phenotypic overlap with IGE, and includes patients with early-onset febrile seizures who later develop various types of febrile and afebrile seizures, such as those observed in EIG (summary by Singh et al., 1999). For a general phenotypic description and a discussion of genetic heterogeneity of EIG, see 600669. For a general phenotypic description and a discussion of genetic heterogeneity of GEFS+, see 604233. For a general phenotypic description and a discussion of genetic heterogeneity of EJM, see 254770.

Patients with isolated febrile seizures (FEB3B) usually have onset between ages 5 months to 4 years and show spontaneous remission by age 6 years (summary by Singh et al., 2009), whereas patients with GEFS+ continue to have various types of febrile and afebrile seizures later in life (summary by Singh et al., 1999). For a general phenotypic description and a discussion of genetic heterogeneity of GEFS+, see 604233. For a phenotypic description and a discussion of genetic heterogeneity of familial febrile seizures, see 121210.

Developmental and epileptic encephalopathy-39 with leukodystrophy (DEE39) is an autosomal recessive neurologic syndrome characterized clinically by global developmental delay apparent in early infancy, early-onset seizures, hypotonia with poor motor function, and hypomyelination on brain imaging. Other features include absent speech and inability to walk; spasticity and hyperreflexia has also been reported. Although there is significant hypomyelination on brain imaging, the disorder was not classified as a primary leukodystrophy. The myelination defect was thought to stem from primary neuronal dysfunction due to impaired mitochondrial transport activity (summary by Wibom et al., 2009 and Falk et al., 2014). However, serial brain imaging in a patient with DEE39 by Kavanaugh et al. (2019) suggested that the mechanism of disease is consistent with a leukoaxonopathy type of leukodystrophy. For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Any generalized epilepsy in which the cause of the disease is a mutation in the CASR gene.

KCNQ2-related disorders represent a continuum of overlapping neonatal epileptic phenotypes ranging from self-limited familial neonatal epilepsy (SLFNE) at the mild end to neonatal-onset developmental and epileptic encephalopathy (NEO-DEE) at the severe end. Additional, less common phenotypes consisting of neonatal encephalopathy with non-epileptic myoclonus, infantile or childhood-onset developmental and epileptic encephalopathy (DEE), and isolated intellectual disability (ID) without epilepsy have also been described. KCNQ2-SLFNE is characterized by seizures that start in otherwise healthy infants between two and eight days after term birth and spontaneously disappear between the first and the sixth to 12th month of life. There is always a seizure-free interval between birth and the onset of seizures. Seizures are characterized by sudden onset with prominent motor involvement, often accompanied by apnea and cyanosis; video EEG identifies seizures as focal onset with tonic stiffening of limb(s) and some migration during each seizure's evolution. About 30% of individuals with KCNQ2-SLFNE develop epileptic seizures later in life. KCNQ2-NEO-DEE is characterized by multiple daily seizures beginning in the first week of life that are mostly tonic, with associated focal motor and autonomic features. Seizures generally cease between ages nine months and four years. At onset, EEG shows a burst-suppression pattern or multifocal epileptiform activity; early brain MRI can show basal ganglia hyperdensities and later MRIs may show white matter or general volume loss. Moderate-to-profound developmental impairment is present.

AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of neurodegenerative disorders characterized by a progressive, complex spastic paraplegia with onset typically in infancy or early childhood. Early-onset hypotonia evolves into progressive lower-extremity spasticity. The majority of children become nonambulatory and usually wheelchair bound. Over time spasticity progresses to involve the upper extremities, resulting in a spastic tetraplegia. Associated complications include dysphagia, contractures, foot deformities, dysregulation of bladder and bowel function, and a pseudobulbar affect. About 50% of affected individuals have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All have developmental delay. Speech development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe.

Keppen-Lubinsky syndrome (KPLBS) is a rare disorder characterized by severely delayed psychomotor development, hypertonia, hyperreflexia, generalized lipodystrophy giving an aged appearance, and distinctive dysmorphic features, including microcephaly, prominent eyes, narrow nasal bridge, and open mouth (summary by Masotti et al., 2015).

Hyperphosphatasia with impaired intellectual development syndrome-3 (HPMRS3) is an autosomal recessive disorder characterized by severe intellectual disability, hypotonia with poor motor development, poor speech, and increased serum alkaline phosphatase (summary by Hansen et al., 2013). However, the severity of the disorder can also vary to include more mild intellectual impairment (Krawitz et al., 2013). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of HPMRS, see HPMRS1 (239300). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

Familial febrile seizures-11 is an autosomal recessive seizure disorder characterized by early childhood onset of simple or complex seizures associated with fever. These seizures usually remit later in childhood with no neurologic sequelae (summary by Salzmann et al., 2012). For a general description and a discussion of genetic heterogeneity of familial febrile seizures, see FEB1 (121210).

SCN8A-related epilepsy with encephalopathy is characterized by developmental delay, seizure onset in the first 18 months of life (mean 4 months), and intractable epilepsy characterized by multiple seizure types (generalized tonic-clonic seizures, infantile spasms, and absence and focal seizures). Epilepsy syndromes can include Lennox-Gastaut syndrome, West syndrome, and epileptic encephalopathies (e.g., Dravet syndrome). Hypotonia and movement disorders including dystonia, ataxia, and choreoathetosis are common. Psychomotor development varies from normal prior to seizure onset (with subsequent slowing or regression after seizure onset) to abnormal from birth. Intellectual disability, present in all, ranges from mild to severe (in ~50% of affected individuals). Autistic features are noted in some. Sudden unexpected death in epilepsy (SUDEP) of unknown cause has been reported in approximately 10% of published cases. To date SCN8A-related epilepsy with encephalopathy has been reported in the literature in about 50 individuals.

CHD2-related neurodevelopmental disorders are characterized by early-onset epileptic encephalopathy (i.e., refractory seizures and cognitive slowing or regression associated with frequent ongoing epileptiform activity). Seizure onset is typically between ages six months and four years. Seizure types typically include drop attacks, myoclonus, and rapid onset of multiple seizure types associated with generalized spike-wave on EEG, atonic-myoclonic-absence seizures, and clinical photosensitivity. Intellectual disability and/or autism spectrum disorders are common.

Developmental delay with autism spectrum disorder and gait instability is a rare, genetic, neurological disorder characterized by infant hypotonia and feeding difficulties, global development delay, mild to moderated intellectual disability, delayed independent ambulation, broad-based gait with arms upheld and flexed at the elbow with brisk walking or running, and limited language skills. Behavior patterns are highly variable and range from sociable and affectionate to autistic behavior.

PDE4D haploinsufficiency syndrome is a rare syndromic intellectual disability characterized by developmental delay, intellectual disability, low body mass index, long arms, fingers and toes, prominent nose and small chin.

A temporal lobe epilepsy that has material basis in variation in the chromosome region 3q25-q26.

Developmental and epileptic encephalopathy-19 (DEE19) is a neurologic disorder characterized by the onset of various types of seizures in the first year of life, usually between 8 and 12 months of age. Seizures are often triggered by fever, and status epilepticus may occur. Affected individuals subsequently show mildly to moderately impaired intellectual development. Brain imaging is typically normal. The clinical phenotype is similar to that of Dravet syndrome (DRVT; 607208) (summary by Carvill et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Developmental and epileptic encephalopathy-24 (DEE24) is a neurologic disorder characterized by onset of refractory seizures in infancy, severely impaired global development, intellectual disability, and behavioral abnormalities. Most patients have onset of variable types of seizures between 4 and 13 months of age, but earlier onset in the first days of life has also been reported. Seizures are often triggered by fever, at least initially; status epilepticus may occur (summary by Nava et al., 2014 and Marini et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth / intellectual disability syndrome characterized by length/height and/or head circumference =2 SD above the mean for age and sex, obesity / increased weight, intellectual disability that ranges from mild to severe, joint hypermobility, hypotonia, behavioral/psychiatric issues, kyphoscoliosis, and seizures. Individuals with TBRS have subtle dysmorphic features, including a round face with coarse features, thick horizontal low-set eyebrows, narrow (as measured vertically) palpebral fissures, and prominent upper central incisors. The facial gestalt is most easily recognizable in the teenage years. TBRS may be associated with an increased risk of developing acute myeloid leukemia. There are less clear associations with aortic root dilatation and increased risk of other hematologic and solid tumors.

SETBP1 haploinsufficiency disorder (SETBP1-HD) is characterized by hypotonia and mild motor developmental delay; intellectual abilities ranging from normal to severe disability; speech and language disorder; behavioral problems (most commonly attention/concentration deficits and hyperactivity, impulsivity), and refractive errors and strabismus. Typically children with SETBP1-HD whose intellect is in the normal or borderline range (IQ 80-90) were diagnosed following genetic testing for behavioral problems and/or severe speech and language disorders (respectively: the inability to produce sounds in words correctly, and deficits in the understanding and/or expression of words and sentences). To date, 47 individuals with SETBP1-HD have been reported.

Generalized epilepsy with febrile seizures plus-9 is an autosomal dominant neurologic disorder characterized by onset of febrile and/or afebrile seizures in early childhood, usually before age 3 years. Seizure types are variable and include generalized tonic-clonic, atonic, myoclonic, complex partial, and absence. Most patients have remission of seizures later in childhood with no residual neurologic deficits, but rare patients may show mild developmental delay or mild intellectual disabilities (summary by Schubert et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of GEFS+, see 604233.

Developmental and epileptic encephalopathy-32 (DEE32) is a neurologic disorder characterized by the onset of various seizure types, including febrile and myoclonic seizures, between about 5 and 17 months of age after normal early development. Thereafter, patients manifest global developmental delay or developmental regression with impaired intellectual development and poor or absent speech. Some may be able to attend special schools. Other features include ataxia with difficulty walking, deficient fine motor skills, tremor, and dysarthria. The seizures are initially refractory in some cases, but may remit later during childhood; however, neurologic deficits persist (summary by Syrbe et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Shashi-Pena syndrome is a neurodevelopmental syndrome characterized by delayed psychomotor development, variable intellectual disability, hypotonia, facial dysmorphism, and some unusual features, including enlarged head circumference, glabellar nevus flammeus, and deep palmar creases. Some patients may also have atrial septal defect, episodic hypoglycemia, changes in bone mineral density, and/or seizures (summary by Shashi et al., 2016).

Any autosomal recessive non-syndromic intellectual disability in which the cause of the disease is a mutation in the MBOAT7 gene.

GNB1 encephalopathy (GNB1-E) is characterized by moderate-to-severe developmental delay / intellectual disability, structural brain abnormalities, and often infantile hypotonia and seizures. Other less common findings include dystonia, reduced vision, behavior issues, growth delay, gastrointestinal (GI) problems, genitourinary (GU) abnormalities in males, and cutaneous mastocytosis.

Distal chromosome 19q13.11 deletion syndrome is an autosomal dominant neurodevelopmental disorder characterized by poor overall growth, slender habitus, microcephaly, delayed development, intellectual disability with poor or absent speech, and feeding difficulties. Additional features include dysmorphic facies, signs of ectodermal dysplasia, hand and foot anomalies, and genitourinary anomalies, particularly in males (summary by Chowdhury et al., 2014).

Developmental and epileptic encephalopathy-52 (DEE52) is a severe autosomal recessive seizure disorder characterized by infantile onset of refractory seizures with resultant delayed global neurologic development. Affected individuals have impaired intellectual development and may have other persistent neurologic abnormalities, including axial hypotonia and spasticity; death in childhood may occur (summary by Patino et al., 2009 and Ramadan et al., 2017). Some patients with DEE52 may have a clinical diagnosis of Dravet syndrome (607208), which is characterized by the onset of seizures in the first year or 2 of life after normal early development. Developmental delay, impaired intellectual development, and behavioral abnormalities usually become apparent later between 1 and 4 years of age. Dravet syndrome may also include 'severe myoclonic epilepsy in infancy' (SMEI) (summary by Patino et al., 2009). For a discussion of genetic heterogeneity of DEE, see 308350.

The Houge type of X-linked syndromic intellectual developmental disorder (MRXSHG) is characterized by delayed development, intellectual disability, speech and language delay, and early-onset seizures. EEG tends to show continuous spike-wave activity or centrotemporal spikes. Some patients may have remission of seizures by adolescence. Carrier females may be mildly affected (summary by Damiano et al., 2017).

Combined oxidative phosphorylation deficiency-35 (COXPD35) is an autosomal recessive disorder characterized mainly by global developmental delay with intellectual disability, microcephaly, and early-onset myoclonic and other types of seizures. Affected individuals have variable deficiencies of mitochondrial respiratory enzyme complexes resulting from a defect in mitochondrial metabolism (summary by Kernohan et al., 2017). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Juvenile myoclonic epilepsy-10 is an autosomal dominant seizure disorder with variable manifestations, even within families. Affected individuals have febrile, myoclonic, tonic-clonic, or absence seizures, although several seizure types can occur in the same individual. The age of onset also shows great variability: some patients present in the first years of life, whereas other have onset of seizures in teenage years. EEG typically shows 3.5 to 5 Hz polyspike wave discharges. There is evidence of incomplete penetrance (summary by Bailey et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of juvenile myoclonic epilepsy, see 254770.

Developmental and epileptic encephalopathy (DEE93) is an autosomal dominant neurologic disorder characterized by delayed psychomotor development, early-onset refractory seizures, and impaired intellectual development. The severity of the phenotype is highly variable: some patients may be nonverbal and nonambulatory with spastic quadriparesis and poor eye contact, whereas others have moderate intellectual disability (summary by Fassio et al., 2018). For a discussion of genetic heterogeneity of DEE, see 308350.

Glycosylphosphatidylinositol biosynthesis defect-17 (GPIBD17) is an autosomal recessive disorder characterized by variable neurologic deficits that become apparent in infancy or early childhood. Patients may present with early-onset febrile or afebrile seizures that tend to be mild or controllable. Other features may include learning disabilities, autism, behavioral abnormalities, hypotonia, and motor deficits. The phenotype is relatively mild compared to that of other GPIBDs (summary by Nguyen et al., 2018). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

Familial temporal lobe epilepsy (FTLE, ETL) is a genetically heterogeneous syndrome characterized by relatively benign simple or complex partial seizures with intense psychic or autonomic auras (Berkovic et al., 1996). For a discussion of genetic heterogeneity of temporal lobe epilepsy, see ETL1 (600512).

Paganini-Miozzo syndrome (MRXSPM) is a neurodevelopmental disorder characterized by global developmental delay, impaired intellectual development, high myopia, and mild dysmorphic facial features (summary by Paganini et al., 2019)

Acute reversible leukoencephalopathy with increased urinary alpha-ketoglutarate (ARLIAK) is an autosomal recessive disorder characterized by acute reversible neurologic deterioration in the context of a febrile illness. The disorder is associated with transient leukoencephalopathy on brain imaging concurrent with the acute episode, as well as persistently increased excretion of dicarboxylic acids, particularly alpha-ketoglutarate (summary by Dewulf et al., 2019).

MRT70 is characterized primarily by impaired intellectual development. Mild facial dysmorphism, febrile seizures, and behavioral abnormalities have been reported in some patients (Maddirevula et al., 2018; Perez et al., 2018).

Patients with global developmental delay, progressive ataxia, and elevated glutamine (GDPAG) present in early childhood with delay of both gross and fine motor skills and delayed speech. Ataxia develops by mid- to late childhood, necessitating use of a walker or wheelchair. Plasma glutamine is persistently elevated by a factor of 2.5 despite normal plasma ammonia levels. Residual glutaminase (GLS) activity can be detected in fibroblasts and lymphocytes. One or both alleles of the GLS gene carry an expanded GCA trinucleotide repeat in the 5-prime untranslated region (UTR); the repeat expansion may be found in compound heterozygosity with another GLS mutation. Three patients have been reported (summary by van Kuilenburg et al., 2019).

Generalized epilepsy with febrile seizures plus-10 (GEFSP10) is a seizure disorder characterized by variable types of seizures, including absence, tonic-clonic, febrile, focal, and eyelid myoclonia. Onset tends to be in the first months or years of life, and the seizure type may evolve or even eventually remit. Some patients may have impaired intellectual development or autistic features. Brain imaging is usually normal (summary by Marini et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of GEFS+, see 604233.

Childhood-onset neurodegeneration with ataxia, tremor, optic atrophy, and cognitive decline (CONATOC) is an autosomal recessive progressive disorder with onset of symptoms in the first decade. Brain imaging may show variable features, including leukoencephalopathy and cerebellar atrophy (summary by Fagerberg et al., 2020).

Lissencephaly-10 (LIS10) is a neurologic disorder characterized by variably delayed development with mildly to moderately impaired intellectual development and language delay, as well as seizures, which are often intractable. There is a spectrum of severity, with some patients having normal early development and only borderline to mild cognitive impairment. Brain imaging shows features consistent with neuronal migration defects, including posterior-predominant lissencephaly, pachygyria, agyria, and subcortical band heterotopia (summary by Tsai et al., 2020). For a general description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (607432).

Neurodevelopmental disorder with speech impairment and behavioral abnormalities (NEDLIB) is characterized by impaired intellectual development or developmental delay, behavioral abnormalities including autistic features, and language impairment. Other features include seizures and developmental regression (Salpietro et al., 2019).

Autosomal dominant primary microcephaly-26 (MCPH26) is characterized by progressive microcephaly beginning at birth and associated with global developmental delay with variably impaired intellectual development. Some patients may have only mild learning difficulties or speech delay, whereas other are more severely affected with the inability to walk or speak. Additional features may include short stature, spasticity, feeding difficulties requiring tube feeding, and nonspecific dysmorphic facial features. Brain imaging in some patients shows a simplified gyral pattern or dysgenesis of the corpus callosum, suggesting abnormal neuronal migration (summary by Cristofoli et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).

Mitochondrial complex II deficiency nuclear type 4 (MC2DN4) is a severe autosomal recessive disorder characterized by early-onset progressive neurodegeneration with leukoencephalopathy. Acute episodes of neurodegeneration are often triggered by catabolic stress such as infection or fasting.

Neurodevelopmental disorder with dysmorphic facies and variable seizures (NEDDFAS) is an autosomal recessive disorder characterized by global developmental delay apparent in early childhood. Patients have mildly impaired intellectual development, often with speech delay or behavioral abnormalities. Some may have seizures. Most have nonspecific dysmorphic facial features. Additional findings may include brain imaging abnormalities, mild skeletal defects, and renal abnormalities, although the renal anomalies may be unrelated (summary by Shao et al., 2021).

Developmental delay, impaired speech, and behavioral abnormalities (DDISBA) is characterized by global developmental delay apparent from early childhood. Intellectual disability can range from mild to severe. Additional variable features may include dysmorphic facial features, seizures, hypotonia, motor abnormalities such as Tourette syndrome or dystonia, and hearing loss (summary by Cousin et al., 2021).

DYRK1A syndrome is characterized by intellectual disability including impaired speech development, autism spectrum disorder including anxious and/or stereotypic behavior problems, and microcephaly. Affected individuals often have a clinically recognizable phenotype including a typical facial gestalt, feeding problems, seizures, hypertonia, gait disturbances, and foot anomalies. The majority of affected individuals function in the moderate-to-severe range of intellectual disability; however, individuals with mild intellectual disability have also been reported. Other medical concerns relate to febrile seizures in infancy; the development of epilepsy with seizures of the atonic, absence, and generalized myoclonic types; short stature; and gastrointestinal problems. Ophthalmologic, urogenital, cardiac, and/or dental anomalies have been reported.

Autosomal recessive spastic paraplegia-86 (SPG86) is a complex neurologic disorder characterized by global developmental delay apparent from early childhood combined with early-onset progressive spasticity mainly affecting the lower limbs, but also affecting the upper limbs. Affected individuals have hyperreflexia, extensor plantar responses, pyramidal signs, and difficulty walking or inability to walk. Some may have joint contractures and foot or ankle deformities. Patients with SPG86 have impaired intellectual development with poor or absent speech, often with behavioral abnormalities. Brain imaging shows thin corpus callosum and white matter abnormalities. Rare patients may have seizures. The disorder is thus a complicated form of SPG (summary by Yahia et al., 2021, Miyake et al., 2022). For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).

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.

Childhood-onset neurodegeneration with progressive microcephaly (CONPM) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay apparent from infancy. The phenotype is highly variable: the most severely affected individuals have severe and progressive microcephaly, early-onset seizures, lack of visual tracking, and almost no developmental milestones, resulting in early death. Less severely affected individuals have a small head circumference and severely impaired intellectual development with poor speech and motor delay. Additional features may include poor overall growth, axial hypotonia, limb hypertonia with spasticity, undescended testes, and cerebral atrophy with neuronal loss (Lam et al., 2019 and Vanoevelen et al., 2022).

X-linked epilepsy-2 with or without impaired intellectual development and dysmorphic features (EPILX2) is a neurologic disorder characterized by the onset of seizures usually in the first years of life, although later onset may also occur. Most individuals also have developmental delay, speech delay, and intellectual disability or learning difficulties. Some patients have dysmorphic facial features or mild skeletal anomalies. The severity of the disorder and accompanying features are highly variable, even within the same family. In general, males are more severely affected than females, although there is evidence for incomplete penetrance in both sexes (Niturad et al., 2017).

Neurodevelopmental disorder with speech delay and variable ocular anomalies (NEDSOA) is an autosomal recessive disorder characterized by global developmental delay with impaired intellectual development and poor speech acquisition apparent from infancy. Most affected individuals have dysmorphic facial features with notable ocular anomalies, including exotropia, strabismus, hypo- or hypertropia, and refraction problems. Additional features may include febrile seizures, sensorineural hearing loss, and behavioral abnormalities. Brain imaging is usually normal, but abnormalities of the corpus callosum have been reported (Broly et al., 2022).

Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities (NEDDFSB) is a multisystemic developmental disorder characterized by feeding difficulties, poor overall growth, and global developmental delay with moderate to severely impaired intellectual development and poor or absent speech. Affected individuals have dysmorphic facial features and skeletal defects, mainly affecting the distal extremities. More variable additional findings include hypotonia, seizures, and ocular defects. Brain imaging tends to show structural defects of the corpus callosum and cerebellar hypoplasia (Duijkers et al., 2019).

Autosomal recessive spinocerebellar ataxia-33 (SCAR33) is a neurologic disorder characterized by delayed motor development apparent in infancy, unsteady ataxic gait, intention tremor, nystagmus, and speech delay with dysarthria. Some patients have seizures and/or learning difficulties. Brain imaging shows cerebellar hypoplasia (Elsaid et al., 2017).

Autosomal recessive intellectual developmental disorder-78 (MRT78) is a neurodevelopmental disorder characterized by impaired intellectual development that is usually mild, but shows variable severity. Affected individuals have microcephaly and mild short stature. Additional features may include ocular abnormalities and mild skeletal defects (Haag et al., 2021).

Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures (NEDLBAS), is characterized by global developmental delay with variably impaired intellectual development apparent from infancy or early childhood. Affected individuals have significant speech delay, and most demonstrate behavioral abnormalities, including autistic features. About half of patients develop seizures, which may be controlled or refractory. More variable features include hypotonia, feeding difficulties, and subtle facial dysmorphism (Schalk et al., 2022).

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).

Hatipoglu immunodeficiency syndrome (HATIS) is an autosomal recessive immunologic disorder characterized by childhood onset of failure to thrive, skin manifestations, pancytopenia, and susceptibility to recurrent infections (Harapas et al., 2022).

Autosomal recessive spastic paraplegia-89 (SPG89) is characterized by symptom onset in the first years of life. Affected individuals show delayed motor development with abnormal spastic gait and hyperreflexia of the lower limbs. Some patients may have mildly impaired intellectual development or learning difficulties (Deng et al., 2023). For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (270800).