Severe Adult-Onset Non-Dystrophic Myotonia With Apnea and Laryngospasm Due to Digenic Inheritance of SCN4A and CLCN1 Variants: A Case Report

Abstract

Objectives: To report a case of adult-onset non-dystrophic myotonia complicated by recurrent episodes of laryngospasm.

Methods: The patient is a 35-year-old man who was admitted to our hospital for recurrent episodes of apnea requiring endotracheal intubation with mechanical ventilation. He underwent extensive evaluation, including EMG, laryngoscopy, muscle biopsy, and genetic testing, which revealed a diagnosis of non-dystrophic myotonia.

Results: His myotonic disorder was due to the synergistic effects of a pathogenic CLCN1 variant and a newly reported SCN4A variant. His muscle biopsy demonstrated myofibrillar disorganization with Z-band streaming, which may reflect the severity of his clinical and electrographic myotonia. Treatment with mexiletine resulted in resolution of his episodes of laryngospasm and symptoms of myotonia in the extremities.

Discussion: Our case adds to the literature on the potentiating effects of chloride channelopathies on sodium channel myotonia. This is the first reported case of an adult-onset sodium channelopathy manifesting with respiratory failure due to laryngospasm. In addition, we present muscle biopsy findings that have not been described in the recent literature. This case also highlights that a myotonic disorder should be considered in the differential diagnosis for recurrent episodes of mixed hypoxic and hypercarbic respiratory failure.

Figure 1. Laryngoscopy Findings

(A) Bedside laryngoscopy performed shortly after endotracheal extubation revealed laryngeal edema, likely due to intubation, and normal abduction of the vocal folds. (B) Quiet breathing was interrupted by episodes of inappropriate adduction of the vocal folds. Prolonged laryngospasm, induced and/or perpetuated by myotonia, was believed to be responsible for this patient's apneic episodes and respiratory failure.

Figure 2. Left Deltoid Biopsy Findings

(A and B) H&E-stained cryosections showed moderate fiber size variation (fiber size range, 5–120 µm), mild endomysial fibrosis without fatty infiltration, and moderate increase in internal nucleation without subsarcolemmal nuclear aggregates or nuclear chains. Small clear irregular regions of the sarcoplasm were notable on high magnification (arrowheads in B). (C) The NADH-TR stain demonstrated moderate abnormalities of the myofibrillar matrix, with mini cores/moth-eaten change in type 1 muscle fibers and linearized internal architecture in type 2 muscle fibers. (D) The esterase stain showed scattered esterase-positive sarcolemmal patches (arrowheads). (E) Acid phosphatase stain was unremarkable, with no enlarged lysosomes or sarcoplasmic puncta (F and G). Electron microscopy showed disruption of the myofibrillar architecture with Z-band streaming (F) and occasional spheroid bodies (G), but no autophagic vacuoles, no significant increase in glycogen, no mitochondrial abnormalities, and no tubular aggregates. Scale bars: A, C, D, and E, 50 µm; B, 25 µm; F and G, 1 µm.

Figure 3. Pedigree

The patient inherited a pathogenic variant in the CLCN1 gene from his asymptomatic father and a variant of uncertain significance in the SCN4A gene from his mother, who has milder clinical and electrographic myotonia. The patient's brother, niece, and nephew are unaffected.