MedGen

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]

Gaucher disease (GD) encompasses a continuum of clinical findings from a perinatal lethal disorder to an asymptomatic type. The identification of three major clinical types (1, 2, and 3) and two other subtypes (perinatal-lethal and cardiovascular) is useful in determining prognosis and management. GD type 1 is characterized by the presence of clinical or radiographic evidence of bone disease (osteopenia, focal lytic or sclerotic lesions, and osteonecrosis), hepatosplenomegaly, anemia and thrombocytopenia, lung disease, and the absence of primary central nervous system disease. GD types 2 and 3 are characterized by the presence of primary neurologic disease; in the past, they were distinguished by age of onset and rate of disease progression, but these distinctions are not absolute. Disease with onset before age two years, limited psychomotor development, and a rapidly progressive course with death by age two to four years is classified as GD type 2. Individuals with GD type 3 may have onset before age two years, but often have a more slowly progressive course, with survival into the third or fourth decade. The perinatal-lethal form is associated with ichthyosiform or collodion skin abnormalities or with nonimmune hydrops fetalis. The cardiovascular form is characterized by calcification of the aortic and mitral valves, mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia. Cardiopulmonary complications have been described with all the clinical subtypes, although varying in frequency and severity. [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]

Pyridoxine-dependent epilepsy – ALDH7A1 (PDE-ALDH7A1) is characterized by seizures not well controlled with anti-seizure medication that are responsive clinically and electrographically to large daily supplements of pyridoxine (vitamin B6). This is true across a phenotypic spectrum that ranges from classic to atypical PDE-ALDH7A1. Intellectual disability is common, particularly in classic PDE-ALDH7A1. Classic PDE-ALDH7A1. Untreated seizures begin within the first weeks to months of life. Dramatic presentations of prolonged seizures and recurrent episodes of status epilepticus are typical; recurrent self-limited events including partial seizures, generalized seizures, atonic seizures, myoclonic events, and infantile spasms also occur. Electrographic seizures can occur without clinical correlates. Atypical PDE-ALDH7A1. Findings in untreated individuals can include late-onset seizures beginning between late infancy and age three years, seizures that initially respond to anti-seizure medication and then become intractable, seizures during early life that do not respond to pyridoxine but are subsequently controlled with pyridoxine several months later, and prolonged seizure-free intervals (=5 months) that occur after discontinuation of pyridoxine. [from GeneReviews]

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a disorder of the urea cycle and ornithine degradation pathway. Clinical manifestations and age of onset vary among individuals even in the same family. Neonatal onset (~8% of affected individuals). Manifestations of hyperammonemia usually begin 24-48 hours after feeding begins and can include lethargy, somnolence, refusal to feed, vomiting, tachypnea with respiratory alkalosis, and/or seizures. Infantile, childhood, and adult onset (~92%). Affected individuals may present with: Chronic neurocognitive deficits (including developmental delay, ataxia, spasticity, learning disabilities, cognitive deficits, and/or unexplained seizures); Acute encephalopathy secondary to hyperammonemic crisis precipitated by a variety of factors; and Chronic liver dysfunction (unexplained elevation of liver transaminases with or without mild coagulopathy, with or without mild hyperammonemia and protein intolerance). Neurologic findings and cognitive abilities can continue to deteriorate despite early metabolic control that prevents hyperammonemia. [from GeneReviews]

GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB). The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late-infantile and juvenile) to mild (chronic/adult). Type I (infantile) GM1 gangliosidosis begins before age 12 months. Prenatal manifestations may include nonimmune hydrops fetalis, intrauterine growth restriction, and placental vacuolization; congenital dermal melanocytosis (Mongolian spots) may be observed. Macular cherry-red spot is detected on eye exam. Progressive central nervous system dysfunction leads to spasticity and rapid regression; blindness, deafness, decerebrate rigidity, seizures, feeding difficulties, and oral secretions are observed. Life expectancy is two to three years. Type II can be subdivided into the late-infantile (onset age 1-3 years) and juvenile (onset age 3-10 years) phenotypes. Central nervous system dysfunction manifests as progressive cognitive, motor, and speech decline as measured by psychometric testing. There may be mild corneal clouding, hepatosplenomegaly, and/or cardiomyopathy; the typical course is characterized by progressive neurologic decline, progressive skeletal disease in some individuals (including kyphosis and avascular necrosis of the femoral heads), and progressive feeding difficulties leading to aspiration risk. Type III begins in late childhood to the third decade with generalized dystonia leading to unsteady gait and speech disturbance followed by extrapyramidal signs including akinetic-rigid parkinsonism. Cardiomyopathy develops in some and skeletal involvement occurs in most. Intellectual impairment is common late in the disease with prognosis directly related to the degree of neurologic impairment. MPS IVB is characterized by skeletal dysplasia with specific findings of axial and appendicular dysostosis multiplex, short stature (below 15th centile in adults), kyphoscoliosis, coxa/genu valga, joint laxity, platyspondyly, and odontoid hypoplasia. First signs and symptoms may be apparent at birth. Bony involvement is progressive, with more than 84% of adults requiring ambulation aids; life span does not appear to be limited. Corneal clouding is detected in some individuals and cardiac valvular disease may develop. [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]

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-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]

Progressive myoclonus epilepsy, Lafora type (also known as Lafora disease [LD]) is characterized by focal occipital seizures presenting as transient blindness or visual hallucinations and fragmentary, symmetric, or generalized myoclonus beginning in previously healthy individuals at age eight to 19 years (peak 14-16 years). Generalized tonic-clonic seizures, atypical absence seizures, atonic seizures, and focal seizures with impaired awareness may occur. The course of the disease is characterized by increasing frequency and intractability of seizures. Status epilepticus with any of the seizure types is common. Cognitive decline becomes apparent at or soon after the onset of seizures. Dysarthria and ataxia appear early while spasticity appears late. Emotional disturbance and confusion are common in the early stages of the disease and are followed by dementia. Most affected individuals die within ten years of onset, usually from status epilepticus or from complications related to nervous system degeneration. [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]

The neuronal ceroid lipofuscinoses (NCL, or CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally (summary by Mole et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (256730). [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]

Molybdenum cofactor deficiency (MoCD) represents a spectrum, with some individuals experiencing significant signs and symptoms in the neonatal period and early infancy (termed early-onset or severe MoCD) and others developing signs and symptoms in childhood or adulthood (termed late-onset or mild MoCD). Individuals with early-onset MoCD typically present in the first days of life with severe encephalopathy, including refractory seizures, opisthotonos, axial and appendicular hypotonia, feeding difficulties, and apnea. Head imaging may demonstrate loss of gray and white matter differentiation, gyral swelling, sulci injury (typically assessed by evaluating the depth of focal lesional injury within the sulci), diffusely elevated T2-weighted signal, and panlobar diffusion restriction throughout the forebrain and midbrain with relative sparring of the brain stem. Prognosis for early-onset MoCD is poor, with about 75% succumbing in infancy to secondary complications of their neurologic disability (i.e., pneumonia). Late-onset MoCD is typically characterized by milder symptoms, such as acute neurologic decompensation in the setting of infection. Episodes vary in nature but commonly consist of altered mental status, dystonia, choreoathetosis, ataxia, nystagmus, and fluctuating hypotonia and hypertonia. These features may improve after resolution of the inciting infection or progress in a gradual or stochastic manner over the lifetime. Brain imaging may be normal or may demonstrate T2-weighted hyperintense or cystic lesions in the globus pallidus, thinning of the corpus callosum, and cerebellar atrophy. [from GeneReviews]

MERRF (myoclonic epilepsy with ragged red fibers) is a multisystem disorder characterized by myoclonus (often the first symptom) followed by generalized epilepsy, ataxia, weakness, exercise intolerance, and dementia. Onset can occur from childhood to adulthood, occurring after normal early development. Common findings are ptosis, hearing loss, short stature, optic atrophy, cardiomyopathy, cardiac dysrhythmias such as Wolff-Parkinson-White syndrome, and peripheral neuropathy. Pigmentary retinopathy, optic neuropathy, diabetes mellitus, and lipomatosis have been observed. [from GeneReviews]

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]

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]

Individuals with biallelic PRICKLE1-related disorders typically present with progressive myoclonus epilepsy (PME) with ataxia characterized by myoclonic seizures (lightning-like jerks), generalized convulsive seizures, varying degrees of neurologic regression mainly presenting with ataxia, and mild cognitive impairment or normal cognition. Onset of symptoms is between ages five and ten years. Action myoclonus may affect the limbs or bulbar muscles, while spontaneous myoclonus may occasionally involve facial muscles. Dysarthria may also be an early feature of this condition. The main seizure types are myoclonic or tonic-clonic with frequent nocturnal occurrence. Individuals with heterozygous PRICKLE1 pathogenic variants have presented with non-PME seizures (isolated myoclonic seizures, juvenile myoclonic epilepsy), myoclonic epilepsy, developmental delay, intellectual disability, autism spectrum disorder, and/or central nervous system malformations. [from GeneReviews]