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

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 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.

Keywords: Nav1.6; movement disorder; myoclonus; sodium channel.

Figure 1

Inheritance of the SCN8A variant P1719R in a family with essential myoclonus. A: Pedigree demonstrating coinheritance of myoclonus and the SCN8A variant (c. 5156C > G, P1719R). Filled symbols, isolated myoclonus. B: Four‐domain structure of the voltage‐gated sodium channel alpha subunit. P1719R is located in the pore loop of domain IV. C: Evolutionary conservation of residue P1719R in multiple species. h, human; m, mouse; c, chicken; a, anole; z, zebrafish

Figure 2

The SCN8A variant P1719R results in partial loss of Na_v1.6 function. A: Representative traces of sodium currents recorded from ND7/23 cells that were transfected with Na_v1.6 cDNA. Black, wild‐type (WT); red, P1719R. B: Averaged current–voltage (I–V) relation for WT (black, n = 9) and P1719R (red, n = 9) channels, and nontransfected cells (purple, n = 12). C: Voltage dependence of channel activation. Smooth lines correspond to the least squares fit when average data were fit to a single Boltzmann equation. D: Scatter plot of voltage at half‐maximal activation (V _1/2) for cells expressing WT and P1719R channels. E: Voltage dependence of steady‐state inactivation. Smooth lines correspond to the least squares fit when average data were fit to a single Boltzmann equation. F: Scatter plot of voltage at half‐maximal inactivation (V _1/2) for cells expressing WT and P1719R channels