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Partial loss‐of‐function of sodium channel SCN8A in familial isolated myoclonus
Author(s) -
Wag Jacy L.,
Mencacci Niccolò E.,
Barker Bryan S.,
Wengert Eric R.,
Bhatia Kailash P.,
Balint Bettina,
Carecchio Miryam,
Wood Nicholas W.,
Patel Manoj K.,
Meisler Miriam H.
Publication year - 2018
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23547
Subject(s) - biology , myoclonus , sodium channel , genetics , sodium , neuroscience , materials science , metallurgy
Variants in the neuronal sodium channel gene SCN8A have been implicated in several neurological disorders. Early infantile epileptic encephalopathy type 13 results from de novo gain‐of‐function mutations that alter the biophysical properties of the channel. Complete loss‐of‐function variants of SCN8A have been identified in cases of isolated intellectual disability. We now report a novel heterozygous SCN8A variant, p.Pro1719Arg, in a small pedigree with five family members affected with autosomal dominant upper limb isolated myoclonus without seizures or cognitive impairment. Functional analysis of the p.Pro1719Arg variant in transfected neuron‐derived cells demonstrated greatly reduced Na v 1.6 channel activity without altered gating properties. Hypomorphic alleles of Scn8a in the mouse are known to result in similar movement disorders. This study expands the phenotypic and functional spectrum of SCN8A variants to include inherited nonepileptic isolated myoclonus. SCN8A can be considered as a candidate gene for isolated movement disorders without seizures.