MedGen

Any generalized epilepsy in which the cause of the disease is a mutation in the CASR gene. [from MONDO]

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. [from GeneReviews]

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.

In 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).

Affected individuals who show symptoms of 3-methylglutaconyl-CoA hydratase deficiency in childhood often go on to develop leukoencephalopathy and other neurological problems in adulthood.

All 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. [from MedlinePlus Genetics]

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. [from GeneReviews]

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. [from OMIM]

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.

Mevalonate 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).

During 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.

People 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. [from MedlinePlus Genetics]

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. [from GeneReviews]

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. [from OMIM]

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. [from GeneReviews]

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. [from GeneReviews]

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. [from GeneReviews]

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 EIG, 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 GEFS+, see 604233. [from OMIM]

Multiple congenital anomalies-hypotonia-seizures syndrome-2 (MCAHS2) is an X-linked recessive neurodevelopmental disorder characterized by dysmorphic features, neonatal hypotonia, early-onset myoclonic seizures, and variable congenital anomalies involving the central nervous, cardiac, and urinary systems. Some affected individuals die in infancy (summary by Johnston et al., 2012). The phenotype shows clinical variability with regard to severity and extraneurologic features. However, most patients present in infancy with early-onset epileptic encephalopathy associated with developmental arrest and subsequent severe neurologic disability; these features are consistent with a form of developmental and epileptic encephalopathy (DEE) (summary by Belet et al., 2014, Kato et al., 2014). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of MCAHS, see MCAHS1 (614080). For a discussion of nomenclature and genetic heterogeneity of DEE, see 308350. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293). [from OMIM]

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. [from GeneReviews]

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%). [from GeneReviews]

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. [from GeneReviews]

Kleefstra syndrome is characterized by intellectual disability, autistic-like features, childhood hypotonia, and distinctive facial features. The majority of individuals function in the moderate-to-severe spectrum of intellectual disability although a few individuals have mild delay and total IQ within low-normal range. While most have severe expressive speech delay with little speech development, general language development is usually at a higher level, making nonverbal communication possible. A complex pattern of other findings can also be observed; these include heart defects, renal/urologic defects, genital defects in males, severe respiratory infections, epilepsy / febrile seizures, psychiatric disorders, and extreme apathy or catatonic-like features after puberty. [from GeneReviews]

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. [from GeneReviews]

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. [from OMIM]