Hypokalaemic periodic paralysis and myotonia in a patient with homozygous mutation p.R1451L in Na(V)1.4

Dominantly inherited channelopathies of the skeletal muscle voltage-gated sodium channel Na(V)1.4 include hypokalaemic and hyperkalaemic periodic paralysis (hypoPP and hyperPP) and myotonia. HyperPP and myotonia are caused by Na(V)1.4 channel overactivity and overlap clinically. Instead, hypoPP is caused by gating pore currents through the voltage sensing domains (VSDs) of Na(V)1.4 and seldom co-exists clinically with myotonia. Recessive loss-of-function Na(V)1.4 mutations have been described in congenital myopathy and myasthenic syndromes. We report two families with the Na(V)1.4 mutation p.R1451L, located in VSD-IV. Heterozygous carriers in both families manifest with myotonia and/or hyperPP. In contrast, a homozygous case presents with both hypoPP and myotonia, but unlike carriers of recessive Na(V)1.4 mutations does not manifest symptoms of myopathy or myasthenia. Functional analysis revealed reduced current density and enhanced closed state inactivation of the mutant channel, but no evidence for gating pore currents. The rate of recovery from inactivation was hastened, explaining the myotonia in p.R1451L carriers and the absence of myasthenic presentations in the homozygous proband. Our data suggest that recessive loss-of-function Na(V)1.4 variants can present with hypoPP without congenital myopathy or myasthenia and that myotonia can present even in carriers of homozygous Na(V)1.4 loss-of-function mutations.