MedGen

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]

Infantile-onset spinocerebellar ataxia (IOSCA) is a severe, progressive neurodegenerative disorder characterized by normal development until age one year, followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, and athetosis. Ophthalmoplegia and sensorineural deafness develop by age seven years. By adolescence, affected individuals are profoundly deaf and no longer ambulatory; sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotropic hypogonadism in females become evident. Epilepsy can develop into a serious and often fatal encephalopathy: myoclonic jerks or focal clonic seizures that progress to epilepsia partialis continua followed by status epilepticus with loss of consciousness. [from GeneReviews]

Developmental and epileptic encephalopathy-2 (DEE2) is an X-linked dominant severe neurologic disorder characterized by onset of seizures in the first months of life and severe global developmental delay resulting in impaired intellectual development and poor motor control. Other features include lack of speech development, subtle dysmorphic facial features, sleep disturbances, gastrointestinal problems, and stereotypic hand movements. There is some phenotypic overlap with Rett syndrome (312750), but DEE2 is considered to be a distinct entity (summary by Fehr et al., 2013). For a discussion of genetic heterogeneity of DEE, see 308350. [from OMIM]

Developmental and epileptic encephalopathy-8 (DEE8) is an X-linked disorder characterized by seizure onset before 2 years of age and severe developmental delay. Some patients have hyperekplexia (summary by Shimojima et al., 2011). For general phenotypic descriptions and discussions of genetic heterogeneity of developmental and epileptic encephalopathy and hyperekplexia, see DEE1 (308350) and HKPX1 (149400), respectively. [from OMIM]

Developmental and epileptic encephalopathy-1 (DEE1) is a severe form of epilepsy characterized by frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst patterns, characterized by high-voltage bursts alternating with almost flat suppression phases. Approximately 75% of DEE1 patients progress to tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG (Kato et al., 2007). DEE1 is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from lissencephaly (LISX2; 300215) to Proud syndrome (300004) to infantile spasms without brain malformations (DEE) to syndromic (309510) and nonsyndromic (300419) mental retardation. Although males with ARX mutations are often more severely affected, female mutation carriers may also be affected (Kato et al., 2004; Wallerstein et al., 2008). Reviews Deprez et al. (2009) reviewed the genetics of epilepsy syndromes starting in the first year of life and included a diagnostic algorithm. Genetic Heterogeneity of Developmental and Epileptic Encephalopathy Also see DEE2 (300672), caused by mutation in the CDKL5 gene (300203); DEE3 (609304), caused by mutation in the SLC25A22 gene (609302); DEE4 (612164), caused by mutation in the STXBP1 gene (602926); DEE5 (613477), caused by mutation in the SPTAN1 gene (182810); DEE6A (607208), also known as Dravet syndrome, caused by mutation in the SCN1A gene (182389); DEE6B (619317), also caused by mutation in the SCN1A gene; DEE7 (613720), caused by mutation in the KCNQ2 gene (602235); DEE8 (300607), caused by mutation in the ARHGEF9 gene (300429); DEE9 (300088), caused by mutation in the PCDH19 gene (300460); DEE10 (613402), caused by mutation in the PNKP gene (605610); DEE11 (613721), caused by mutation in the SCN2A gene (182390); DEE12 (613722), caused by mutation in the PLCB1 gene (607120); DEE13 (614558), caused by mutation in the SCN8A gene (600702); DEE14 (614959), caused by mutation in the KCNT1 gene (608167); DEE15 (615006), caused by mutation in the ST3GAL3 gene (606494); DEE16 (615338), caused by mutation in the TBC1D24 gene (613577); DEE17 (615473), caused by mutation in the GNAO1 gene (139311); DEE18 (615476), caused by mutation in the SZT2 gene (615463); DEE19 (615744), caused by mutation in the GABRA1 gene (137160); DEE20 (300868), caused by mutation in the PIGA gene (311770); DEE21 (615833), caused by mutation in the NECAP1 gene (611623); DEE22 (300896), caused by mutation in the SLC35A2 gene (314375); DEE23 (615859), caused by mutation in the DOCK7 gene (615730); DEE24 (615871), caused by mutation in the HCN1 gene (602780); DEE25 (615905), caused by mutation in the SLC13A5 gene (608305); DEE26 (616056), caused by mutation in the KCNB1 gene (600397); DEE27 (616139), caused by mutation in the GRIN2B gene (138252); DEE28 (616211), caused by mutation in the WWOX gene (605131); DEE29 (616339), caused by mutation in the AARS gene (601065); DEE30 (616341), caused by mutation in the SIK1 gene (605705); DEE31A (616346) and DEE31B (620352), caused by mutation in the DNM1 gene (602377); DEE32 (616366), caused by mutation in the KCNA2 gene (176262); DEE33 (616409), caused by mutation in the EEF1A2 gene (602959); DEE34 (616645), caused by mutation in the SLC12A5 gene (606726); DEE35 (616647), caused by mutation in the ITPA gene (147520); DEE36 (300884), caused by mutation in the ALG13 gene (300776); DEE37 (616981), caused by mutation in the FRRS1L gene (604574); DEE38 (617020), caused by mutation in the ARV1 gene (611647); DEE39 (612949), caused by mutation in the SLC25A12 gene (603667); DEE40 (617065), caused by mutation in the GUF1 gene (617064); DEE41 (617105), caused by mutation in the SLC1A2 gene (600300); DEE42 (617106), caused by mutation in the CACNA1A gene (601011); DEE43 (617113), caused by mutation in the GABRB3 gene (137192); DEE44 (617132), caused by mutation in the UBA5 gene (610552); DEE45 (617153), caused by mutation in the GABRB1 gene (137190); DEE46 (617162), caused by mutation in the GRIN2D gene (602717); DEE47 (617166), caused by mutation in the FGF12 gene (601513); DEE48 (617276), caused by mutation in the AP3B2 gene (602166); DEE49 (617281), caused by mutation in the DENND5A gene (617278); DEE50 (616457) caused by mutation in the CAD gene (114010); DEE51 (617339), caused by mutation in the MDH2 gene (154100); DEE52 (617350), caused by mutation in the SCN1B gene (600235); DEE53 (617389), caused by mutation in the SYNJ1 gene (604297); DEE54 (617391), caused by mutation in the HNRNPU gene (602869); DEE55 (617599), caused by mutation in the PIGP gene (605938); DEE56 (617665), caused by mutation in the YWHAG gene (605356); DEE57 (617771), caused by mutation in the KCNT2 gene (610044); DEE58 (617830), caused by mutation in the NTRK2 gene (600456); DEE59 (617904), caused by mutation in the GABBR2 gene (607340); DEE60 (617929), caused by mutation in the CNPY3 gene (610774); DEE61 (617933), caused by mutation in the ADAM22 gene (603709); DEE62 (617938), caused by mutation in the SCN3A gene (182391); DEE63 (617976), caused by mutation in the CPLX1 gene (605032); DEE64 (618004), caused by mutation in the RHOBTB2 gene (607352); DEE65 (618008), caused by mutation in the CYFIP2 gene (606323); DEE66 (618067), caused by mutation in the PACS2 gene (610423); DEE67 (618141), caused by mutation in the CUX2 gene (610648); DEE68 (618201), caused by mutation in the TRAK1 gene (608112); DEE69 (618285), caused by mutation in the CACNA1E gene (601013); DEE70 (618298) caused by mutation in the PHACTR1 gene (608723); DEE71 (618328), caused by mutation in the GLS gene (138280); DEE72 (618374), caused by mutation in the NEUROD2 gene (601725); DEE73 (618379), caused by mutation in the RNF13 gene (609247); DEE74 (618396), caused by mutation in the GABRG2 gene (137164); DEE75 (618437), caused by mutation in the PARS2 gene (612036); DEE76 (618468), caused by mutation in the ACTL6B gene (612458); DEE77 (618548), caused by mutation in the PIGQ gene (605754); DEE78 (618557), caused by mutation in the GABRA2 gene (137140); DEE79 (618559), caused by mutation in the GABRA5 gene (137142); DEE80 (618580), caused by mutation in the PIGB gene (604122); DEE81 (618663), caused by mutation in the DMXL2 gene (612186); DEE82 (618721), caused by mutation in the GOT2 gene (138150); DEE83 (618744), caused by mutation in the UGP2 gene (191760); DEE84 (618792), caused by mutation in the UGDH gene (603370); DEE85 (301044), caused by mutation in the SMC1A gene (300040); DEE86 (618910), caused by mutation in the DALRD3 gene (618904); DEE87 (618916), caused by mutation in the CDK19 gene (614720); DEE88 (618959), caused by mutation in the MDH1 gene (152400); DEE89 (619124), caused by mutation in the GAD1 gene (605363); DEE90 (301058), caused by mutation in the FGF13 gene (300070); DEE91 (617711), caused by mutation in the PPP3CA gene (114105); DEE92 (617829), caused by mutation in the GABRB2 gene (600232); DEE93 (618012), caused by mutation in the ATP6V1A gene (607027); DEE94 (615369), caused by mutation in the CHD2 gene (602119); DEE95 (618143), caused by mutation in the PIGS gene (610271); DEE96 (619340), caused by mutation in the NSF gene (601633); DEE97 (619561), caused by mutation in the iCELF2 gene (602538); DEE98 (619605), caused by mutation in the ATP1A2 gene (182340); DEE99 (619606), caused by mutation in the ATP1A3 gene (182350); DEE100 (619777), caused by mutation in the FBXO28 gene (609100); DEE101 (619814), caused by mutation in the GRIN1 gene (138249); DEE102 (619881), caused by mutation in the SLC38A3 gene (604437); DEE103 (619913), caused by mutation in the KCNC2 gene (176256); DEE104 (619970), caused by mutation in the ATP6V0A1 gene (192130); DEE105 (619983), caused by mutation in the HID1 gene (605752); DEE106 (620028), caused by mutation in the UFSP2 gene (611482); DEE107 (620033), caused by mutation in the NAPB gene ( [from OMIM]

STXBP1 encephalopathy with epilepsy is characterized by early-onset encephalopathy with epilepsy (i.e., moderate-to-severe intellectual disability, refractory seizures, and ongoing epileptiform activity). The median age of onset of seizures is six weeks (range 1 day to 13 years). Seizure types can include infantile spasms; generalized tonic-clonic, clonic, or tonic seizures; and myoclonic, focal, atonic, and absence seizures. Epilepsy syndromes can include Ohtahara syndrome, West syndrome, Lennox-Gaustaut syndrome, and Dravet syndrome (not SCN1A-related), classic Rett syndrome (not MECP2-related), and atypical Rett syndrome (not CDKL5-related). The EEG is characterized by focal epileptic activity, burst suppression, hypsarrhythmia, or generalized spike-and-slow waves. Other findings can include abnormal tone, movement disorders (especially ataxia and dystonia), and behavior disorders (including autism spectrum disorder). Feeding difficulties are common. [from GeneReviews]

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]

SYNGAP1-related intellectual disability (SYNGAP1-ID) is characterized by developmental delay (DD) or intellectual disability (ID) (100% of affected individuals), generalized epilepsy (~84%), and autism spectrum disorder (ASD) and other behavioral abnormalities (=50%). To date more than 50 individuals with SYNGAP1-ID have been reported. In the majority DD/ID was moderate to severe; in some it was mild. The epilepsy is generalized; a subset of individuals with epilepsy have myoclonic astatic epilepsy (Doose syndrome) or epilepsy with myoclonic absences. Behavioral abnormalities can include stereotypic behaviors (e.g., hand flapping, obsessions with certain objects) as well as poor social development. Feeding difficulties can be significant in some. [from GeneReviews]

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]

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]

Congenital disorders of glycosylation (CDGs) that represent defects of dolichol-linked oligosaccharide assembly are classified as CDG type I. For a general description and a discussion of the classification of CDGs, see CDG1A (212065). [from OMIM]

Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL) is characterized by global developmental delay with hypotonia, poor motor development with limited walking, impaired intellectual development with poor or absent speech, and behavioral abnormalities. Almost all affected individuals demonstrate repetitive stereotypic hand movements that can be categorized as hyperkinetic and resembling those of Rett syndrome (RTT; 312750). About 80% of patients develop various types of seizures that may be refractory to treatment. Additional features may include dysmorphic facial features, particularly dysplastic ears, poor eye contact, episodic hyperventilation, tendency to infection, and abnormalities on brain imaging, such as enlarged ventricles, thin corpus callosum, and delayed myelination (summary by Vrecar et al., 2017, Paciorkowski et al., 2013). [from OMIM]

Encephalopathy due to defective mitochondrial and peroxisomal fission-1 (EMPF1) is characterized by delayed psychomotor development and hypotonia that may lead to death in childhood. Many patients develop refractory seizures, consistent with an epileptic encephalopathy, and thereafter show neurologic decline. The age at onset, features, and severity are variable, and some patients may not have clinical evidence of mitochondrial or peroxisomal dysfunction (summary by Sheffer et al., 2016; Fahrner et al., 2016). Genetic Heterogeneity of Encephalopathy Due to Defective Mitochondrial And Peroxisomal Fission See also EMPF2 (617086), caused by mutation in the MFF gene (614785) on chromosome 2q36. [from OMIM]

Developmental and epileptic encephalopathy-11 (DEE11) is a neurologic disorder characterized by onset of seizures in the first days, weeks, or months of life. Some patients may have later onset. Seizures comprise multiple types, including tonic, generalized, and myoclonic, and tend to be refractory to medication. However, some patients with onset of seizures before 3 months of age may respond to sodium channel blockers, particularly phenytoin. About half of patients become seizure-free in childhood. Affected individuals have global developmental delay, usually with severely impaired intellectual development, although some may be less severely affected and show autism spectrum disorder. Additional common features include microcephaly, hypotonia, and abnormal movements, such as dystonia, dyskinesias, and choreoathetotic movements. Brain imaging may show white matter defects. The phenotype is highly variable, even in patients with the same mutation (summary by Ogiwara et al., 2009; Howell et al., 2015; Wolff et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. [from OMIM]

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. [from GeneReviews]

Developmental and epileptic encephalopathy-5 (DEE5) is a neurologic disorder characterized by global developmental delay and the onset of tonic seizures or infantile spasms in the first months of life. The seizures tend to be refractory to treatment, and EEG shows hypsarrhythmia, consistent with a clinical diagnosis of West syndrome. Affected individuals have severely impaired psychomotor development with lack of visual attention, poor head control, feeding difficulties, microcephaly, and spastic quadriplegia. Brain imaging may show cerebral atrophy and hypomyelination (summary by Saitsu et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of developmental and epileptic encephalopathy, see 308350. [from OMIM]

GRIN2B-related neurodevelopmental disorder is characterized by mild to profound developmental delay / intellectual disability (DD/ID) in all affected individuals. Muscle tone abnormalities (spasticity and/or hypotonia, occasionally associated with feeding difficulties), as well as epilepsy and autism spectrum disorder (ASD) / behavioral issues, are common. Other infantile- or childhood-onset findings include microcephaly; dystonic, dyskinetic, or choreiform movement disorder; and/or cortical visual impairment. Brain MRI reveals a malformation of cortical development in a minority of affected individuals. To date, fewer than 100 individuals with GRIN2B-related neurodevelopmental disorder have been reported. [from GeneReviews]

Any Pitt-Hopkins-like syndrome in which the cause of the disease is a mutation in the NRXN1 gene. [from MONDO]

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]