MedGen

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

Both juvenile myoclonic epilepsy and juvenile absence epilepsy are subtypes of idiopathic generalized epilepsy (EIG). For a general phenotypic description and a discussion of genetic heterogeneity of these disorders, see EIG1 (600669), EJM1 (254770), and EJA1 (607631). [from OMIM]

Progressive myoclonic epilepsy type 1(EPM1) is a neurodegenerative disorder characterized by onset from age six to 15 years, stimulus-sensitive myoclonus, and tonic-clonic epileptic seizures. Some years after the onset, ataxia, incoordination, intentional tremor, and dysarthria develop. Individuals with EPM1 are cognitively mostly within the normal range, but show emotional lability and depression. The epileptic seizures are usually well controlled by anti-seizure medication, but the myoclonic jerks are progressive, action activated, and treatment resistant, and can be severely disabling. [from GeneReviews]

Smith-Magenis syndrome (SMS) is characterized by distinctive physical features (particularly coarse facial features that progress with age), developmental delay, cognitive impairment, behavioral abnormalities, sleep disturbance, and childhood-onset abdominal obesity. Infants have feeding difficulties, failure to thrive, hypotonia, hyporeflexia, prolonged napping or need to be awakened for feeds, and generalized lethargy. The majority of individuals function in the mild-to-moderate range of intellectual disability. The behavioral phenotype, including significant sleep disturbance, stereotypies, and maladaptive and self-injurious behaviors, is generally not recognized until age 18 months or older and continues to change until adulthood. Sensory issues are frequently noted; these may include avoidant behavior, as well as repetitive seeking of textures, sounds, and experiences. Toileting difficulties are common. Significant anxiety is common as are problems with executive functioning, including inattention, distractibility, hyperactivity, and impulsivity. Maladaptive behaviors include frequent outbursts / temper tantrums, attention-seeking behaviors, opposition, aggression, and self-injurious behaviors including self-hitting, self-biting, skin picking, inserting foreign objects into body orifices (polyembolokoilamania), and yanking fingernails and/or toenails (onychotillomania). Among the stereotypic behaviors described, the spasmodic upper-body squeeze or "self-hug" seems to be highly associated with SMS. An underlying developmental asynchrony, specifically emotional maturity delayed beyond intellectual functioning, may also contribute to maladaptive behaviors in people with SMS. [from GeneReviews]

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]

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]

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. [from GeneReviews]

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. [from GeneReviews]

MECP2 duplication syndrome is a severe neurodevelopmental disorder characterized by early-onset hypotonia, feeding difficulty, gastrointestinal manifestations including gastroesophageal reflux and constipation, delayed psychomotor development leading to severe intellectual disability, poor speech development, progressive spasticity, recurrent respiratory infections (in ~75% of affected individuals), and seizures (in ~50%). MECP2 duplication syndrome is 100% penetrant in males. Occasionally females have been described with a MECP2 duplication and a range of findings from mild intellectual disability to a phenotype similar to that seen in males. In addition to the core features, autistic behaviors, nonspecific neuroradiologic findings on brain MRI, mottled skin, and urogenital anomalies have been observed in several affected boys. [from GeneReviews]

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]

Some affected individuals have febrile seizures before they develop childhood absence epilepsy. Febrile seizures are involuntary muscle contractions (convulsions) brought on by a high body temperature (fever).

In most people with childhood absence epilepsy, the absence seizures disappear in adolescence. However, some affected individuals continue to have absence seizures into adulthood, or they may develop generalized tonic-clonic seizures, which cause muscle rigidity, convulsions, and loss of consciousness, or myoclonic seizures, which are characterized by rapid, uncontrolled muscle jerks.

Childhood absence epilepsy is a condition characterized by recurrent seizures (epilepsy). This condition begins in childhood, usually between ages 3 and 8. Affected children have absence seizures (also known as petit mal seizures), which are brief episodes of impaired consciousness that look like staring spells. During seizures, children are not aware of and do not respond to people or activities around them. The seizures usually last several seconds and they occur often, up to 200 times each day. [from MedlinePlus Genetics]

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]

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]

Developmental and epileptic encephalopathy-9 (DEE9) is an X-linked disorder characterized by seizure onset in infancy and mild to severe intellectual impairment. Autistic and psychiatric features have been reported in some individuals. The disorder affects heterozygous females only; transmitting males are unaffected (summary by Jamal et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of developmental and epileptic encephalopathy, see 308350. [from OMIM]

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]

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]

Any Lafora disease in which the cause of the disease is a variation in the EPM2A gene. [from MONDO]

The 1q21.1 recurrent microdeletion itself does not appear to lead to a clinically recognizable syndrome as some persons with the deletion have no obvious clinical findings and others have variable findings that most commonly include microcephaly (50%), mild intellectual disability (30%), mildly dysmorphic facial features, and eye abnormalities (26%). Other findings can include cardiac defects, genitourinary anomalies, skeletal malformations, and seizures (~15%). Psychiatric and behavioral abnormalities can include autism spectrum disorders, attention deficit hyperactivity disorder, autistic features, and sleep disturbances. [from GeneReviews]