A Gain-of-Function Mutation in KCNMA1 Causes Dystonia Spells Controlled With Stimulant Therapy

The mutations of KCNMA1 BK-type K⁺ channel have been identified in patients with various movement disorders. The underlying pathophysiology and corresponding therapeutics are lacking.

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.

Combination of phenotypic characterization, therapy, and biophysical characterization of the patient and her mutation.

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.

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.