Key result
The NaV1.4 R222Q mutation caused enhanced channel activation and gating pore currents, which, alongside a concomitant CLCN1 variant, resulted in severe myotonia and episodic weakness.
Why the study?
Mutations affecting arginine residues in the S4 helix of Na V 1.4 VSDs cause hypokalemic periodic paralysis via leak current but had not hitherto been associated with myotonia.
Case Report (n=1)
The Nav1.4 R222Q mutation can present with severe myotonia rather than hypokalemic periodic paralysis, highlighting phenotypic variability at this residue.
R222Q may cause myotonia with leak current rather than paralysis; this case report leaves open systematic phenotype mapping for Nav1.4 S4 mutations.
The sarcolemmal voltage gated sodium channel Na V 1.4 conducts the key depolarizing current that drives the upstroke of the skeletal muscle action potential. It contains four voltage-sensing domains (VSDs) that regulate the opening of the pore domain and ensuing permeation of sodium ions. Mutations that lead to increased Na V 1.4 currents are found in patients with myotonia or hyperkalaemic periodic paralysis (HyperPP). Myotonia is also caused by mutations in the CLCN1 gene that result in loss-of-function of the skeletal muscle chloride channel ClC-1. Mutations affecting arginine residues in the fourth transmembrane helix (S4) of the Na V 1.4 VSDs can result in a leak current through the VSD and hypokalemic periodic paralysis (HypoPP), but these have hitherto not been associated with myotonia. We report a patient with an Nav1.4 S4 arginine mutation, R222Q, presenting with severe myotonia without fulminant paralytic episodes. Other mutations affecting the same residue, R222W and R222G, have been found in patients with HypoPP. We show that R222Q channels have enhanced activation, consistent with myotonia, but also conduct a leak current. The patient carries a concomitant synonymous CLCN1 variant that likely worsens the myotonia and potentially contributes to the amelioration of muscle paralysis. Our data show phenotypic variability for different mutations affecting the same S4 arginine that have implications for clinical therapy.
No takes yet. Share an insight, caveat, or question.
Thor et al. (2019) conducted a case report in Myotonia and episodic weakness (n=1). NaV1.4 R222Q mutation and CLCN1 c.1650G>A variant vs. Wild-type channels and healthy controls was evaluated. The NaV1.4 R222Q mutation caused enhanced channel activation and gating pore currents, which, alongside a concomitant CLCN1 variant, resulted in severe myotonia and episodic weakness.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: