MedGen

GRIN2A-related speech disorders and epilepsy are characterized by speech disorders in all affected individuals and a range of epilepsy syndromes present in about 90%. Severe speech disorders observed can include dysarthria and speech dyspraxia, and both receptive and expressive language delay/regression; more mildly affected individuals may display subtly impaired intelligibility of conversational speech. Epilepsy features include seizure onset usually between ages three and six years, focal epilepsy with language and/or global developmental regression, and electroencephalogram (EEG) showing continuous spike-and-wave discharges in sleep or very active centrotemporal discharges. Seizure types include seizures associated with aura of perioral paresthesia, focal or focal motor seizures (often evolving to generalized tonic-clonic), and atypical absence seizures. Epilepsy syndromes can include: Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), childhood epilepsy with centrotemporal spikes (CECTS), atypical childhood epilepsy with centrotemporal spikes (ACECTS), autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD), and infantile-onset epileptic encephalopathy. [from GeneReviews]

The spectrum of COL4A1-related disorders includes: small-vessel brain disease of varying severity including porencephaly, variably associated with eye defects (retinal arterial tortuosity, Axenfeld-Rieger anomaly, cataract) and systemic findings (kidney involvement, muscle cramps, cerebral aneurysms, Raynaud phenomenon, cardiac arrhythmia, and hemolytic anemia). On imaging studies, small-vessel brain disease is manifest as diffuse periventricular leukoencephalopathy, lacunar infarcts, microhemorrhage, dilated perivascular spaces, and deep intracerebral hemorrhages. Clinically, small-vessel brain disease manifests as infantile hemiparesis, seizures, single or recurrent hemorrhagic stroke, ischemic stroke, and isolated migraine with aura. Porencephaly (fluid-filled cavities in the brain detected by CT or MRI) is typically manifest as infantile hemiparesis, seizures, and intellectual disability; however, on occasion it can be an incidental finding. HANAC (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome usually associates asymptomatic small-vessel brain disease, cerebral large vessel involvement (i.e., aneurysms), and systemic findings involving the kidney, muscle, and small vessels of the eye. Two additional phenotypes include isolated retinal artery tortuosity and nonsyndromic autosomal dominant congenital cataract. [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]

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]

The congenital variant of Rett syndrome is a severe neurodevelopmental disorder with features of classic Rett syndrome (RTT; 312750), but earlier onset in the first months of life. Classic Rett syndrome shows later onset and is caused by mutation in the MECP2 gene (300005). [from OMIM]

Complex cortical dysplasia with other brain malformations-13 (CDCBM13) is an autosomal dominant neurodevelopmental disorder characterized by global developmental delay with impaired intellectual development. Brain imaging shows variable neuronal migration defects resulting in cortical malformations, including pachygyria. More variable features include early-onset seizures and dysmorphic features. Some patients may also show signs of peripheral neuropathy, such as abnormal gait, hyporeflexia, and foot deformities (summary by Willemsen et al., 2012 and Poirier et al., 2013). For a discussion of genetic heterogeneity of CDCBM, see CDCBM1 (614039). [from OMIM]

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]

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]

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clusters of nocturnal motor seizures, which are often stereotyped and brief (5 seconds to 5 minutes). They vary from simple arousals from sleep to dramatic, often bizarre hyperkinetic events with tonic or dystonic features. Affected individuals may experience aura. Retained awareness during seizures is common. A minority of individuals experience daytime seizures. Onset ranges from infancy to adulthood. About 80% of individuals develop ADNFLE in the first two decades of life; mean age of onset is ten years. Clinical neurologic examination is normal and intellect is usually preserved, but reduced intellect, psychiatric comorbidity, or cognitive deficits may occur. Within a family, the manifestations of the disorder may vary considerably. ADNFLE is lifelong but not progressive. As an individual reaches middle age, attacks may become milder and less frequent. [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]

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]

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clusters of nocturnal motor seizures, which are often stereotyped and brief (5 seconds to 5 minutes). They vary from simple arousals from sleep to dramatic, often bizarre hyperkinetic events with tonic or dystonic features. Affected individuals may experience aura. Retained awareness during seizures is common. A minority of individuals experience daytime seizures. Onset ranges from infancy to adulthood. About 80% of individuals develop ADNFLE in the first two decades of life; mean age of onset is ten years. Clinical neurologic examination is normal and intellect is usually preserved, but reduced intellect, psychiatric comorbidity, or cognitive deficits may occur. Within a family, the manifestations of the disorder may vary considerably. ADNFLE is lifelong but not progressive. As an individual reaches middle age, attacks may become milder and less frequent. [from GeneReviews]

AMACR deficiency is a rare autosomal recessive peroxisomal disorder characterized by adult onset of variable neurodegenerative symptoms affecting the central and peripheral nervous systems. Features may include seizures, visual failure, sensorimotor neuropathy, spasticity, migraine, and white matter hyperintensities on brain imaging. Serum pristanic acid and C27 bile acid intermediates are increased (summary by Smith et al., 2010). [from OMIM]

Infantile cerebellar-retinal degeneration (ICRD) is a severe autosomal recessive neurodegenerative disorder characterized by onset between ages 2 and 6 months of truncal hypotonia, athetosis, seizures, and ophthalmologic abnormalities, particularly optic atrophy and retinal degeneration. Affected individuals show profound psychomotor retardation, with only some achieving rolling, sitting, or recognition of family. Brain MRI shows progressive cerebral and cerebellar degeneration (summary by Spiegel et al., 2012). A subset of patients may have a milder phenotype with variable features, including ataxia, developmental delay, and behavioral abnormalities (Blackburn et al., 2020). Mutation in the ACO2 gene also causes isolated optic atrophy (OPA9; 616289). [from OMIM]

Brain small vessel disease-2 is an autosomal dominant disorder characterized by variable neurologic impairment resulting from disturbed vascular supply that leads to cerebral degeneration. The disorder is often associated with 'porencephaly' on brain imaging. Affected individuals typically have hemiplegia, seizures, and intellectual disability, although the severity is variable (summary by Yoneda et al., 2012). For a discussion of genetic heterogeneity of brain small vessel disease, see BSVD1 (175780). [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]

Multiple mitochondrial dysfunctions syndrome-1 (MMDS1) is a severe autosomal recessive disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, lactic acidosis, and early death (Seyda et al., 2001). Genetic Heterogeneity of Multiple Mitochondrial Dysfunctions Syndrome See also MMDS2 (614299), caused by mutation in the BOLA3 gene (613183) on chromosome 2p13; MMDS3 (615330), caused by mutation in the IBA57 gene (615316) on chromosome 1q42; MMDS4 (616370), caused by mutation in the ISCA2 gene (615317) on chromosome 14q24; MMDS5 (617613), caused by mutation in the ISCA1 gene (611006) on chromosome 9q21; MMDS6 (617954), caused by mutation in the PMPCB gene (603131) on chromosome 7q22; MMDS7 (620423), caused by mutation in the GCSH gene (238330) on chromosome 16q23; MMDS8 (251900), caused by mutation in the FDX2 gene (614585) on chromosome 19p13; MMDS9A (617717) and MMDS9B (620887), both caused by mutation in the FDXR gene (103270) on chromosome 17q25. [from OMIM]

X-linked epilepsy-1 with variable learning disabilities and behavior disorders (EPILX1) is an X-linked neurologic disorder characterized by the onset of complex partial seizures in the first or second decades. The seizures are often triggered by showering or water-related hygiene activities, consistent with reflex bathing epilepsy. Additional spontaneous seizures and secondary generalization may also occur. Most patients have associated developmental defects, including learning disabilities, behavioral problems, or autistic features. The pathophysiology of the reflex seizures is thought to be hyperexcitability of the cortical or subcortical neuronal areas that respond to physiologic stimulus in an exaggerated manner, possibly due to aberrant synaptic maturation (summary by Nguyen et al., 2015; Sirsi et al., 2017; Accogli et al., 2021). [from OMIM]

Neuronal ceroid lipofuscinosis-6B (CLN6B) is an autosomal recessive form of 'Kufs disease,' which refers in general to adult-onset neuronal ceroid lipofuscinosis without retinal involvement. CLN6B is a neurodegenerative disorder with a mean onset of symptoms at around age 28 years, although onset in the teens and later adulthood may also occur. Patients typically present with progressive myoclonus epilepsy, ataxia, loss of motor function, dysarthria, progressive dementia, and progressive cerebral and cerebellar atrophy on brain imaging. Ultrastructural examination typically shows fingerprint profiles and granular osmiophilic deposits in some tissues, including brain samples (summary by Arsov et al., 2011 and Berkovic et al., 2019). However, pathologic findings in peripheral tissues in adults is not as accurate for diagnosis as it is in children with the disease (Cherian et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (256730). [from OMIM]

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. [from OMIM]