MedGen

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]

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]

STXBP1 encephalopathy with epilepsy is characterized by early-onset developmental delay, intellectual disability or cognitive dysfunction, and epilepsy. 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, atonic, absence, and focal seizures. EEG abnormalities can include focal epileptic activity, burst suppression, hypsarrhythmia, or generalized spike-and-slow waves. Other neurologic findings include abnormal tone, movement disorders (especially ataxia and dystonia), and behavioral issues and autism spectrum disorder. Feeding difficulties are common. [from GeneReviews]

A congenital cortical development anomaly due to abnormal neuronal migration involving neocortical and hippocampal lamination, corpus callosum, cerebellum and brainstem. A large clinical spectrum can be observed, from children with severe epilepsy and intellectual and motor deficit to cases with severe cerebral dysgenesis in the antenatal period leading to pregnancy termination due to the severity of the prognosis. [from SNOMEDCT_US]

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]

Primary coenzyme Q10 deficiency-4 (COQ10D4) is an autosomal recessive disorder characterized by childhood-onset of cerebellar ataxia and exercise intolerance. Some affected individuals develop seizures and have mild mental impairment, indicating variable severity. Oral coenzyme Q10 supplementation does not result in significant improvement of neurologic symptoms (summary by Mollet et al., 2008 and Lagier-Tourenne et al., 2008). For a general phenotypic description and a discussion of genetic heterogeneity of primary coenzyme Q10 deficiency, see COQ10D1 (607426). [from OMIM]

Hartnup disorder (HND) is characterized by transient manifestations of pellagra, cerebellar ataxia, and psychosis. It is caused by impaired transport of neutral amino acids across epithelial cells in renal proximal tubules and intestinal mucosa (summary by Kleta et al., 2004). [from OMIM]

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. [from GeneReviews]

GNAO1-related disorder encompasses a broad phenotypic continuum that includes hyperkinetic movement disorders and/or epilepsy and is typically associated with developmental delay and intellectual disability. Viewed by age of onset, three clusters in this continuum can be observed: (1) infantile-onset developmental and epileptic encephalopathy (DEE) with or without prominent movement disorder; (2) infantile- or early childhood-onset prominent movement disorder and neurodevelopmental disorder with or without childhood-onset epilepsy with varying seizure types; (3) later childhood- or adult-onset movement disorder with variable developmental delay and intellectual disability. Epilepsy can be either DEE (onset typically within the first year of life of drug-resistant epilepsy in which developmental delays are attributed to the underlying diagnosis as well as the impact of uncontrolled seizures) or varying seizure types (onset typically between ages three and ten years of focal or generalized tonic-clonic seizures that may be infrequent or well controlled with anti-seizure medications). Movement disorders are characterized by dystonia and choreoathetosis, most commonly a mixed pattern of persistent or paroxysmal dyskinesia that affects the whole body. Exacerbations of the hyperkinetic movement disorder, which can be spontaneous or triggered (e.g., by intercurrent illness, emotional stress, voluntary movements), can last minutes to weeks. Hyperkinetic crises (including status dystonicus) are characterized by temporarily increased and nearly continuous involuntary movements or dystonic posturing that can be life-threatening. Deaths in early childhood have been reported due to medically refractory epilepsy or hyperkinetic crises, but the phenotypic spectrum includes milder presentations, including in adults. As many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with GNAO1-related disorder are underrecognized and underreported. [from GeneReviews]

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

CODAS is an acronym for cerebral, ocular, dental, auricular, and skeletal anomalies. CODAS syndrome is a rare disorder characterized by a distinctive constellation of features that includes developmental delay, craniofacial anomalies, cataracts, ptosis, median nasal groove, delayed tooth eruption, hearing loss, short stature, delayed epiphyseal ossification, metaphyseal hip dysplasia, and vertebral coronal clefts (summary by Strauss et al., 2015). [from OMIM]

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. [from GeneReviews]

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. [from OMIM]

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. [from OMIM]

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. [from OMIM]

CTCF-related disorder is characterized by developmental delay / intellectual disability (ranging from mild to severe), with both speech and motor delays being common; feeding difficulties, including dysphagia, and other gastrointestinal issues (gastroesophageal reflux disease and/or irritable bowel syndrome) that can lead to growth deficiency; hypotonia; eye anomalies (strabismus and/or refractive errors); scoliosis; nonspecific dysmorphic features; sleep disturbance; tooth anomalies (crowded teeth and/or abnormal decay); and, less commonly, other congenital anomalies (cleft palate, gastrointestinal malrotation, genitourinary anomalies, and congenital heart defects, including aortic ectasia). Short stature, seizures, hearing loss, recurrent infections, microcephaly, and autistic features have also been described in a minority of affected individuals. At least four reported individuals with CTCF-related disorder developed Wilms tumor, one of whom had bilateral Wilms tumor. However, there is no clear evidence of a significant predisposition for the development of cancer in individuals with CTCF-related disorder at this time. [from GeneReviews]

Developmental and epileptic encephalopathy-21 (DEE21) is an autosomal recessive neurologic disorder characterized by the onset of intractable seizures in the first months of life. Affected individuals have severely impaired psychomotor development with poor head control and inability to fix and follow visually. Other features may include axial hypotonia, peripheral hypertonia, and cerebral atrophy or delayed myelination on brain imaging (summary by Alazami et al., 2014 and Alsahli et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. [from OMIM]

Infantile-onset progressive leukoencephalopathy with or without deafness (LEPID) is an autosomal recessive complex neurodegenerative disorder with onset of symptoms in infancy or early childhood. Most patients present with sensorineural deafness or hypoacousia and global developmental delay. Affected individuals show episodic regression with progressive motor deterioration resulting in spastic tetraplegia and loss of ambulation, as well as impaired intellectual development with poor or absent speech. Additional more variable features may include poor overall growth with microcephaly, seizures, visual loss, microcytic anemia, and hepatic enlargement or abnormal liver enzymes. Brain imaging shows deep white matter abnormalities consistent with a progressive leukoencephalopathy. The brain and spinal cord are usually both involved; calcifications of these regions are often observed. Laboratory studies show increased serum lactate and deficiencies of mitochondrial respiratory chain complexes, consistent with global mitochondrial dysfunction. Early death often occurs (summary by Itoh et al., 2019). [from OMIM]

PEBAT is an autosomal recessive neurodevelopmental disorder characterized by severely delayed psychomotor development apparent soon after birth or in infancy, profound intellectual disability, poor or absent speech, and seizures. Most patients are never able to walk due to hypotonia or spasticity. Brain imaging shows cerebral and cerebellar atrophy, thin corpus callosum, and secondary hypomyelination. The disorder shows progressive features, including microcephaly, consistent with a neurodegenerative process (summary by Miyake et al., 2016; Flex et al., 2016). [from OMIM]

Developmental and epileptic encephalopathy-66 (DEE66) is a neurologic disorder characterized by the onset of various types of seizures in the first days or weeks of life. Most seizures have focal origins; secondary generalization is common. Seizure control is difficult at first, but may become easier with time. Affected individuals show global developmental delay with hypotonia, behavioral abnormalities, and dysmorphic features or ophthalmologic defects. Brain imaging often shows cerebellar dysgenesis. A subset of patients have extraneurologic manifestations, including hematologic and distal limb abnormalities (summary by Olson et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. [from OMIM]