Background

This study aimed to determine the role of five new rare SCN4A variants suspected to cause paramyotonia or myotonic disorder.

Methods

Ten patients from seven families underwent clinical, neurophysiological, imaging, and muscle biopsy examinations. Genetic studies were performed with targeted sequencing of all known myopathy genes. Functional changes resulting from these variants were studied with HEK293T cells, by using a whole-cell patch clamp.

Results

Five SCN4A variants were identified: c.662 T > C p.(F221S), c.2143G > A p.(A715T), c.4352G > A p.(R1451H), c.3610 A > G p.(N1204D), and c.4255 T > C, p.(F1419L). Patients had exercise- and/or cold-induced myalgia, muscle stiffness or cramping, and varying degrees of muscle weakness. On examination, some but not all patients had percussion myotonia or findings compatible with paramyotonia. One patient with the A715T variant also had eyelid myotonia. The patient with the F221S variant had ptosis, weakness in hip flexion, and mild muscle hypertrophy in the calves. EMG showed myotonic discharges in all the patients examined except for the patient with N1204D. Electrophysiological exercise tests demonstrated results compatible with the Fournier pattern in six patients. All but the N1204D variant showed gain-of-function features upon functional expression.

Conclusions

The clinical and genetic findings suggested that all five variants were pathogenic, whereas functional data did not confirm association with myotonia for N1204D. Our results expand the mutational spectrum of the SCN4A gene. The reported variants should be considered in patients with paramyotonia, or in patients with exercise-induced myalgia or muscle cramping and who demonstrate myotonia in EMG.