Expanding the Phenotype of Homozygous KCNMA1 Mutations; Dyskinesia, Epilepsy, Intellectual Disability, Cerebellar and Corticospinal Tract Atrophy

Abstract

Background: The KCNMA1 gene encodes the α-subunit of the large conductance, voltage, and calcium-sensitive potassium channel (BK channels) that plays a critical role in neuronal excitability. Heterozygous mutations in KCNMA1 were first illustrated in a large family with generalized epilepsy and paroxysmal nonkinesigenic dyskinesia. Recent research has established homozygous KCNMA1 mutations accountable for the phenotype of cerebellar atrophy, developmental delay, and seizures.

Case report: Here, we report the case of a patient with a novel homozygous truncating mutation in KCNMA1 (p.Arg458Ter) presenting with both the loss- and gain-of-function phenotype with paroxysmal dyskinesia, epilepsy, intellectual delay, and corticospinal–cerebellar tract atrophy.

Conclusion: This report extends the KNCMA1 mutation phenotype with a patient who carries a novel frameshift variant, presenting with both the gain- and loss-of-function phenotypes along with spinal tract involvement as a novel characteristic.

Keywords: Cerebellar atrophy, dyskinesia, epilepsy, KCNMA1, spinal tract atrophy.

Figure 1. Sagittal and coronal brain magnetic resonance images of a 14-year-old boy revealed cerebellar vermian volume loss with normal pons and spinal canal (a). Diffusion tensor imaging images displayed thinning of the tegmental extending through corticospinal tracts (b).

Figure 2. Compared to previous magnetic resonance imaging, the atrophy of the cerebellum progressed; (a) performed when he was of 3 years and (b) performed 12 years after the initial magnetic resonance imaging.