A novel in-frame mutation at the boundary between exon 21 and intron 21 of SCN4A in a family with paramyotonia congenita

@#Nondystrophic myotonias and periodic paralyses are an important group of genetic skeletal muscle disorders characterized by dysfunction of ion channels that regulate cell membrane excitability. Mutations in the Sodium Voltage-Gated Channel Alpha Subunit 4 (SCN4A) gene are associated with a spectrum of a heterogeneous group of skeletal muscle such as sodium channel myotonia, paramyotonia congenita, hyperkalemic periodic paralysis, congenital myasthenia, and congenital myopathy. Gain of function mutations in SCN4A cause three muscle disorders with overlapping clinical phenotypes: myotonia, paramyotonia congenita, and hyperkalemic periodic paralysis. Here, we describe the clinical and genetic features of a new family with paramyotonia. The proband, an eight-year-old girl, began to experience muscle stiffness in her hands and limbs on exposure to exercise exercise at the age of four and presented with myotonia. She was initially misdiagnosed with myotonic dystrophy because of worsening weakness with significant elevation of serum creatinine kinase levels. Two other affected family members had paradoxical myotonia in the face and hands on exposure to cold muscle stiffness in her face, hands, and limbs on exposure to cold and showed grip myotonia on physical examination. A novel heterozygous in-frame insertion, c.3911_3912+1dupAGA, at the boundary between exon 21 and intron 21 of SCN4A was identified using whole exome sequencing. Our finding enhances our understanding of the genotype and phenotype of patients with paramyotonia congenita, caused by mutations in the SCN4A gene.

A Case of Paramyotonia Congenita

Paramyotonia congenita (PMC), an autosomal dominant non-progressive muscle disorder, is characterised by cold-induced stiffness followed by muscle weakness. The weakness is considered to be caused by a dysfunction of the sodium channel in muscle fiber. We report a 37-year-old male patient with PMC, complaining of episodic myotonia and motor weakness on cold exposure. In this patient, we performed clinical and neurological examination, electrophysiologic examination and muscle biopsy. On electrophysiologic study, needle EMG showed spontaneous myotonic discharges at room temperature but disappeared after cooling. Amplitude of compound action potential in abductor pollicis brevis muscle decreased significantly after cooling the tested extremity. Muscle biopsy showed a minimal variation of muscle fiber diameters, internal nuclei, chained nuclei, occasional atrophic fibers in vastus lateralis muscle. His mother, his son, three of six siblings, and five of eleven nephewes are affected with same symptomes.