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-offunction 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.

BK channel properties correlate with neurobehavioral severity in three KCNMA1-linked channelopathy mouse models

“…We hypothesized that Kcnma1 N999S/WT and Kcnma1 D434G/WT mice would show increased number, duration, or severity of seizure events compared to WT controls. However, since half of those harboring LOF variants also report seizures (Liang et al ., 2019; Miller et al ., 2021), including the H444Q and individuals with putative truncation alleles, Kcnma1 H444Q/WT and Kcnma1 —/— mice were assessed in parallel. No seizures have been previously reported in two established Kcnma1 —/— mouse models (Bailey et al ., 2019; ALM unpublished data), but spontaneous epilepsy was reported in a CRISPR-exon4 Kcnma1 —/— line (Yao et al ., 2021).…”

“…However, the inactive bouts were longer for Kcnma1 N999S/WT mice (311 ± 126, n= 10, P < 0.0001, Mann Whitney test) and were visually apparent (Video S2). The movement suppression exhibited by Kcnma1 N999S/WT mice under PTZ does not have a correlate in individuals harboring N999S variants, although a few report absence seizures among other types (Miller et al ., 2021). Since no spontaneous EEG + /EMG — events were observed in the baseline EEG recording period of these mice, it remains to be determined whether the PTZ-elicited movement suppression is related to an absence-like seizure manifestation.…”

“…Within the D434G family, there an intermediate penetrance for epilepsy (56%), the most frequent diagnosis being absence (Du et al ., 2005; Miller et al ., 2021). Like N999S, Kcnma1 D434G/WT mice also showed a reduced latency to first seizure (101 ± 27 sec) compared to Kcnma1 WT/WT mice (209 ± 35 sec; Figure 4Aii, C-D).…”

“…KCNMA1 -linked channelopathy encompasses an array of neurological symptoms associated with clinical detection of a KCNMA1 variant. Affected individuals typically present with epilepsy and/or dyskinesia, but also have other types of movement disorder including ataxia, developmental delay, intellectual disability, and brain and structural abnormalities (Bailey et al ., 2019; Liang et al ., 2019; Miller et al ., 2021). The basis for these symptoms is not mechanistically established but is likely similar to other neurological channelopathies involving direct or indirect changes in neuronal excitability leading to excitation-inhibition imbalance (Benatar, 2000; Menezes et al ., 2020).…”

BK Channel Gating Mechanisms: Progresses Toward a Better Understanding of Variants Linked Neurological Diseases

“…With the progress in human genetics, more KCNMA1 variants that link to neurological disorders have been identified. Some of the mutations in BK channels due to these variants have been functionally characterized, and the results show that these mutations alter voltage and Ca 2+ dependent activation to different effects ( Bailey et al, 2019 ; Miller et al, 2021 ). These results demonstrate that the changes in voltage and Ca 2+ dependent activation of BK channels are important factors linking the KCNMA1 variants to neurological disorders.…”