Epileptic Encephalopathy, Early Infantile, 19

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Retrieved

2019-09-22

Source

Omim

Trials

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Genes

SCN1A, SCN9A, STXBP1, SCN2A, SCN1B, PCDH19, GABRG2, GABRA1, TNRC6A, POMC, PMP22, RAPGEF2, SAMD12, KCNQ2, SCN8A, ADRA1D, PVALB, POLG, SCN2B, KCNQ3, SST, GABRB3, GPR55, PRRT2, TLR1, VIP, LINC01672, CPLX1, EPM2A, B3GNT2, OPN1MW2, SLC12A5, LOH19CR1, GPHN, ARX, EJM2, B3GNTL1, CACNA1G, TSPYL4, ACHE, CDKL5, FOXM1, ALDH7A1, CACNA1A, CACNB4, CHD2, CSTB, CYP2C19, E2F1, EPHA5, FOXG1, MTOR, SLC12A2, GABRA2, GABRD, GAPDH, OPN1MW, IGF1, MECP2, RPS19, SCN7A, SLC2A1, OPN1MW3

Drugs

26 base synthetic single-stranded fully phosphorothioated 2'-O-methyl-RNA and DNA mixmer oligonucleotide-based compound, Cannabidiol ( EPIDIOLEX, EPIDYOLEX ), Fenfluramine hydrochloride

26 base synthetic single-stranded fully phosphorothioated 2'-O-methyl-RNA and DNA mixmer oligonucleotide-based compound, Cannabidiol ( EPIDIOLEX, EPIDYOLEX ), Fenfluramine hydrochloride, Stiripentol ( DIACOMIT )

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A number sign (#) is used with this entry because early infantile epileptic encephalopathy-19 (EIEE19) is caused by heterozygous mutation in the GABRA1 gene (137160) on chromosome 5q34.

For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see 308350.

Clinical Features

Carvill et al. (2014) reported 4 unrelated patients with onset of seizures between ages 8 and 11 months. Seizure types included hemiclonic, tonic-clonic, focal dyscognitive, myoclonic, absence, and atonic. Three patients had status epilepticus. Febrile sensitivity to seizures was present in all patients. Two patients had moderate intellectual disability at ages 7 and 18 years, and 2 had mild intellectual disability at ages 2 and 18 years. The features were consistent with a clinical diagnosis of Dravet syndrome. Three patients had abnormal EEG with generalized spike-wave discharges or focal discharges. Brain MRI of 1 patient showed a calcified ependymal nodule in the left lateral ventricle. None had a family history of the disorder.

Molecular Genetics

In a 2-year-old girl with early infantile epileptic encephalopathy who was negative for mutations in the SCN1A gene (182389), Carvill et al. (2014) identified a de novo heterozygous missense mutation in the GABRA1 gene (G251S; 137160.0003). The mutation was found by whole-exome sequencing. Targeted resequencing of the GABRA1 gene in 67 additional patients with a similar phenotype revealed heterozygous missense mutations in 3 other unrelated patients (R112Q, 137160.0004 and K306T, 137160.0005). Two of the mutations were shown to occur de novo; parental samples from the third patient were not available. In vitro functional expression studies of the G251S mutation showed that it caused a 2.6-fold reduction in the amplitude of GABA-induced currents, as well as a 5-fold decrease in GABA sensitivity. Functional studies of the other variants were not performed. Carvill et al. (2014) suggested that the seizures in these patients resulted from impaired functioning of GABA inhibition in the brain.