A recessive Nav1.4 mutation underlies congenital myasthenic syndrome with periodic paralysis

Neurology. 2016 Jan 12;86(2):161-9. doi: 10.1212/WNL.0000000000002264. Epub 2015 Dec 11.


Objective: To determine the molecular basis of a complex phenotype of congenital muscle weakness observed in an isolated but consanguineous patient.

Methods: The proband was evaluated clinically and neurophysiologically over a period of 15 years. Genetic testing of candidate genes was performed. Functional characterization of the candidate mutation was done in mammalian cell background using whole cell patch clamp technique.

Results: The proband had fatigable muscle weakness characteristic of congenital myasthenic syndrome with acute and reversible attacks of most severe muscle weakness as observed in periodic paralysis. We identified a novel homozygous SCN4A mutation (p.R1454W) linked to this recessively inherited phenotype. The p.R1454W substitution induced an important enhancement of fast and slow inactivation, a slower recovery for these inactivated states, and a frequency-dependent regulation of Nav1.4 channels in the heterologous expression system.

Conclusion: We identified a novel loss-of-function mutation of Nav1.4 that leads to a recessive phenotype combining clinical symptoms and signs of congenital myasthenic syndrome and periodic paralysis, probably by decreasing channel availability for muscle action potential genesis at the neuromuscular junction and propagation along the sarcolemma.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Female
  • Genetic Predisposition to Disease*
  • Humans
  • Muscle Weakness / genetics
  • Mutation / genetics*
  • Myasthenic Syndromes, Congenital / diagnosis
  • Myasthenic Syndromes, Congenital / genetics*
  • NAV1.4 Voltage-Gated Sodium Channel / genetics*
  • Neuromuscular Junction / genetics
  • Paralyses, Familial Periodic / diagnosis
  • Paralyses, Familial Periodic / genetics*
  • Patch-Clamp Techniques / methods


  • NAV1.4 Voltage-Gated Sodium Channel
  • SCN4A protein, human