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

Figure 1.

Graphic of the α subunit of the BK channel, annotated with all known patient mutations. The S0-S6 transmembrane domains represent the pore-forming portion of the subunit, while S7-S8 and S9-S10 comprise the Ca²⁺-sensitive RCK1 and RCK2 domains respectively. The + symbols in domains S2-S4 mark the location of residues conferring voltage-sensitivity. Mutation types are denoted by color. C413Y/N449fs is a double mutation in a single patient

Figure 2.

Schematic illustrating the observed spectrum of clinical courses and diagnostic outcomes following molecular diagnosis of KCNMA1-linked channelopathy. If there is more than one clinical phenotype for episodic or paroxysmal symptoms, each symptom or episode should be evaluated independently on EEG, given the co-occurrence of epilepsy and other non-epileptic paroxysms. Long-term EEG is often helpful. PNKD3 denotes PNKD associated with a confirmed KCNMA1 mutation. GTC-Generalized Tonic-Clonic, EEG-electroencephalogram, PNKD- paroxysmal nonkinesigenic dyskinesia, PED- paroxysmal exertion-induced dyskinesia, PKD- paroxysmal kinesigenic dyskinesia