Genes in infantile epileptic encephalopathies

Excerpt

Infantile epileptic encephalopathies, such as Dravet syndrome, Ohtahara syndrome, West syndrome, Lennox-Gastaut syndrome, myoclonic-astatic epilepsy, and Landau-Kleffner syndrome, are devastating epilepsies. Cases are often sporadic or patients have only a limited family history of epilepsy. Although a complex inheritance has long been suspected in epilepsy, recent data indicate that many sporadic rare epileptic disorders, such as Dravet syndrome, CDKL5/STK9 Rett-like epileptic encephalopathy, ARX-related epilepsies, SRPX2-related rolandic epilepsy associated with oral and speech dyspraxia and mental retardation, and STXBP1-related West/Ohtahara syndromes, are due to a mutation in a unique gene. Dravet syndrome, for example, is mainly due to de novo mutations in SCN1A, the gene encoding the voltage-gated neuronal sodium channel alpha 1 subunit, which explains why most patients are isolated cases. All types of mutations are observed: missense mutations, premature termination codon and intragenic rearrangements. This large mutation spectrum contrasts with that of generalized epilepsy with febrile seizures plus (GEFS+), an autosomal dominant condition also characterized by febrile and afebrile seizures but with a usually benign outcome, in which only missense mutations are found. Recently, mutations in PCDH19, encoding protocadherin 19 on chromosome X, were identified in females with an EFMR or Dravet-like phenotype. Heterozygous females are affected while hemizygous males are spared, this unusual inheritance probably being due to a mechanism called cellular interference. The genetic data accumulated for Dravet syndrome and other related disorders have to be kept in mind when studying epileptic encephalopathies.