A <scp>Gain‐of‐Function</scp> Mutation in <scp><i>KCNMA1</i></scp> Causes Dystonia Spells Controlled With Stimulant Therapy
Guohui Zhang, Rebecca A. Gibson, Marie McDonald, Pengfei Liang, Po Wei Kang, Jingyi Shi, Huanghe Yang, Jianmin Cui, Mohamad A. Mikati
Abstract
BACKGROUND: channel have been identified in patients with various movement disorders. The underlying pathophysiology and corresponding therapeutics are lacking. OBJECTIVES: To report our clinical and biophysical characterizations of a novel de novo KCNMA1 variant, as well as an effective therapy for the patient's dystonia-atonia spells. METHODS: Combination of phenotypic characterization, therapy, and biophysical characterization of the patient and her mutation. RESULTS: The patient had >100 dystonia-atonia spells per day with mild cerebellar atrophy. She also had autism spectrum disorder, intellectual disability, and attention deficit hyperactivity disorder. Whole-exome sequencing identified a heterozygous de novo BK N536H mutation. Our biophysical characterization demonstrates that N536H is a gain-of-function mutation with markedly enhanced voltage-dependent activation. Remarkably, administration of dextroamphetamine completely suppressed the dystonia-atonia spells. CONCLUSIONS: BK N536H is a gain-of-function that causes dystonia and other neurological symptoms. Our stimulant therapy opens a new avenue to mitigate KCNMA1-linked movement disorders. © 2020 International Parkinson and Movement Disorder Society.