An emerging spectrum of variants and clinical features in KCNMA1-linked channelopathy

ABSTRACT

KCNMA1-linked channelopathy is an emerging neurological disorder characterized by heterogeneous and overlapping combinations of movement disorder, seizure, developmental delay, and intellectual disability. KCNMA1 encodes the BK K⁺ channel, which contributes to both excitatory and inhibitory neuronal and muscle activity. Understanding the basis of the disorder is an important area of active investigation; however, the rare prevalence has hampered the development of large patient cohorts necessary to establish genotype-phenotype correlations. In this review, we summarize 37 KCNMA1 alleles from 69 patients currently defining the channelopathy and assess key diagnostic and clinical hallmarks. At present, 3 variants are classified as gain-of-function with respect to BK channel activity, 14 loss-of-function, 15 variants of uncertain significance, and putative benign/VUS. Symptoms associated with these variants were curated from patient-provided information and prior publications to define the spectrum of clinical phenotypes. In this newly expanded cohort, seizures showed no differential distribution between patients harboring GOF and LOF variants, while movement disorders segregated by mutation type. Paroxysmal non-kinesigenic dyskinesia was predominantly observed among patients with GOF alleles of the BK channel, although not exclusively so, while additional movement disorders were observed in patients with LOF variants. Neurodevelopmental and structural brain abnormalities were prevalent in patients with LOF mutations. In contrast to mutations, disease-associated KCNMA1 single nucleotide polymorphisms were not predominantly related to neurological phenotypes but covered a wider set of peripheral physiological functions. Together, this review provides additional evidence exploring the genetic and biochemical basis for KCNMA1-linked channelopathy and summarizes the clinical repository of patient symptoms across multiple types of KCNMA1 gene variants.

KEYWORDS:

• BK channel
• KCa1.1
• calcium-activated potassium channel
• KCNMA1
• potassium channel
• MaxiK
• Slo
• slowpoke
• channelopathy
• epilepsy
• seizure
• paroxysmal non-kinesigenic dyskinesia
• PNKD3
• GEPD
• movement disorder
• developmental delay
• intellectual disability

Acknowledgments

We gratefully acknowledge patients, families, and physicians for their participation in the KCNMA1 Channelopathy International Advocacy Foundation (KCIAF) registry questionnaire or providing direct submission information, and Alyssa Mendel and the Coordination of Rare Diseases at Sanford (CoRDS) program for providing patient registry data collation and access.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by grants from the National Heart, Lung, and Blood Institute [R01-HL102758], the National Institute of General Medical Sciences Training Program in Integrative Membrane Biology [T32-GM008181], and the American Physiological Society’s Ryuji Ueno award, sponsored by the S & R Foundation (to A.L. Meredith), and a University of Maryland School of Medicine Proposed Research Initiated by Students and Mentors (PRISM) Program Merit Award (to J.P. Miller). Statistical consultation was provided by the University of Maryland School of Medicine Institute for Clinical and Translational Research (ICTR) Biostatistics Core, with the help of Soren Bentzen and Kai Sun.