A Novel KCNA1 Variant Manifesting as Persistent Limb Myokymia Without Episodic Ataxia

Abstract

Dear Editor, We read with great interest the article by Lee et al.1 describing the first Korean episodic ataxia (EA) type 1 patient with a novel KCNA1 mutation. We report another novel KCNA1 variant with a rare phenotype: isolated myokymia without either EA or seizure. We also make additional comments on the phenotypic variability in KCNA1 mutations. A 39-year-old female presented with continuous muscle twitches involving both thighs with intermittent right-foot dystonia. The muscle twitching had initially started in the right thigh and spread to the left side 1 year later. Her previous medical history included bronchial asthma and several orthopedic surgeries of both ankles and knees after a traffic collision 7 years previously. The family history was unremarkable. A neurologic examination identified continuous involuntary undulating muscle movements in both thighs that was worse on the right side (Supplementary Video 1 in the online-only Data Supplement). She had difficulty walking due to persistent muscle spasms. Muscle weakness, dysarthria, limb dysmetria, and spasticity were not observed. A nerve conduction study revealed normal sensory and motor responses. Needle electromyography showed myokymic discharges in several muscles (including rectus femoris) bilaterally in the lower extremities (Fig. 1A). Overnight polysomnography confirmed persistent muscle twitching during sleep. Routine laboratory testing showed normal creatine kinase and inflammatory markers. Thyroid-stimulating hormone, thyroxine, magnesium, and vitamin D levels were normal. Serologic studies were negative for human immunodeficiency virus and syphilis. An additional evaluation for the differential diagnosis of peripheral nerve hyperexcitability was performed. Paraneoplastic antibodies, tumor markers, and anti-glutamic-acid decarboxylase antibodies were not detected, nor were autoantibodies to leucine-rich glioma inactivated-1 and contactin-associated protein-2. Chest and abdomen computed tomography was unrevealing. An electroencephalogram (EEG) showed occasional frontally predominant generalized delta slowing, which is usually considered a nonspecific EEG pattern. Brain magnetic resonance imaging findings were normal. Given the unremarkable initial workup, genetic testing was conducted. Diagnostic exome sequencing identified a novel variant, c.724G>A (p.Ala242Thr), in KCNA1 (NM_000217.3) (Fig. 1B). This KCNA1 variant was predicted to be likely pathogenic based on the American College of Medical Genetics and Genomics guidelines (PM1, PM2, PM5, PP2, and PP3).2 KCNA1 mutations are known to be associated with EA1, which is a potassium channelopathy characterized by brief attacks of ataxic gait with interictal myokymia.3 While the broad clinical spectrum includes EA1 with epilepsy and also epilepsy without EA1,3 isolated myokymia without EA1 or epilepsy is extremely rare: only two cases of isolated myokymia have been reported,4,5 and to our knowledge the present case is the first Korean one. Our case illustrates not only the phenotypic variability but also the complex relationship between phenotype and genotype. The KCNA1 mutation in our patient is a novel missense mutation (p.Ala242Thr) that is located in the S2 segment of the Kv1.1 (voltage-gated potasIn Ja Shin Sung-Yeon Sohn Shin Yeop Kim In Soo Joo