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Hum Mutat. 2018 Jul;39(7):965-969. doi: 10.1002/humu.23547. Epub 2018 May 17.

Partial loss-of-function of sodium channel SCN8A in familial isolated myoclonus.

Author information

1
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan.
2
Department of Neurology, Northwestern University, Chicago, Illinois.
3
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
4
Department of Anesthesiology, University of Virginia, Charlottesville, Virginia.
5
Neuroscience Graduate Program, University of Virginia, Charlottesville, Virginia.
6
Sobell Department, Institute of Neurology, University College of London, London, UK.
7
Molecular Neurogenetics Unit, IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy.
8
Department of Pediatric Neurology, IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy.
9
Department of Medicine and Surgery, PhD Programme in Molecular and Translational Medicine, Milan Bicocca University, Monza, Italy.
10
Department of Neurology, University of Michigan, Ann Arbor, Michigan.

Abstract

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 Nav 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.

KEYWORDS:

Nav1.6; movement disorder; myoclonus; sodium channel

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