A Patient With Episodic Ataxia and Paramyotonia Congenita Due to Mutations in Kcna1 and Scn4a

Channelopathies are mendelian disorders arising from mutations in genes that encode ion channel subunits.1 Mutations in SCN4A, which encodes the α-subunit of the muscle sodium channel Nav1.4, underlie paramyotonia congenita (PMC),2 while mutations in KCNA1, which encodes the potassium channel subunit Kv1.1, cause episodic ataxia type 1 (EA1) and isolated myokymia.3 We describe the clinical, genetic, and functional expression studies in an unusual patient who harbors mutations in both SCN4A and KCNA1 and report that sodium channel dysfunction dominates the phenotype. ### Case history. A 34-year-old woman had a lifelong history of muscle cramps and weakness affecting upper and lower limbs. Symptoms were exacerbated by exercise and cold weather, which induced both muscle stiffness and difficulty releasing her grip. Her father, paternal uncle, and second son are similarly affected. Examination demonstrated weakness of intrinsic hand muscles (Medical Research Council 4/5) with paradoxical myotonia of hand grip and eye closure. Neurophysiology confirmed a diagnosis of PMC, with a cooling test showing a rapid decrement in amplitude and area, which did not recover with rewarming. A McManis test was positive, showing a >40% decrement in compound muscle action potential (CMAP) during exercise with recovery during the prolonged rest period. Unexpectedly, needle EMG demonstrated sustained doublets, triplets, and multiplets interspersed with the myotonic discharges in the right abductor digiti minimi, biceps, tibialis anterior, and thoracic paraspinals (figure A). Because generalized myokymic discharges are not a recognized feature of PMC, this prompted further direct questioning about her symptoms. She reported that since the age of 16, she had experienced brief attacks of slurred speech and unsteadiness lasting seconds to minutes. …