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Relationship of electrophysiological dysfunction and clinical severity in SCN2A-related epilepsies.
Hum Mutat ; 39(12): 1942-1956, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30144217
ABSTRACT
Variants in the SCN2A gene cause a broad spectrum of epilepsy syndromes of variable severity including benign neonatal-infantile epilepsy (BFNIE), developmental and epileptic encephalopathies (DEE), and other neuropsychiatric disorders. Here, we studied three newly identified variants, which caused distinct phenotypes observed in nine affected individuals of three families, including BFNIE, and DEE with intractable neonatal seizures. Whole cell patch-clamp recordings of transfected tsA201 cells disclosed an increased current density and an increased subthreshold sodium inward current upon an action potential stimulus (p.(Lys908Glu)), a hyperpolarizing shift of the activation curve (p.(Val208Glu) and p.(Thr773Ile)), and an increased persistent current (p.(Thr773Ile)). To evaluate genotype-phenotype correlations, we next developed scoring systems for both the extent of the electrophysiological dysfunction and the severity of the clinical phenotype and applied those to 21 previously and newly functionally characterized SCN2A variants. All inherited variants were associated with a mild clinical phenotype and a lower electrophysiological score compared to those occurring de novo and causing severe phenotypes. Our results thus reveal a nice correlation between the extent of channel dysfunction and the clinical severity.

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Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Idioma: Inglês Revista: Hum Mutat Assunto da revista: Genética Médica Ano de publicação: 2018 Tipo de documento: Artigo País de afiliação: Alemanha