Objective: The objectives of this study are to delineate the distinct genotype-phenotype correlations between gain-of-function and loss-of-function KCNMA1 variants by analyzing a novel clinical cohort alongside an extensive literature review. Furthermore, we aim to refine the clinical framework for this evolving channelopathy by characterizing progressive neuroimaging findings, typical paroxysmal sequences, and multi-systemic manifestations.

Background: Pathogenic variants in the KCNMA1 gene, encoding the large-conductance calcium-activated potassium (BK) channel, cause a spectrum of neurological disorders. We aimed to delineate the genotype-phenotype correlations by comparing gain-of-function and loss-of-function variants.

Method: We analyzed an institutional cohort of 8 patients and conducted a literature review of 76 previously reported cases (total n=84). Variants were stratified by functional status, and clinical features including paroxysmal events, neurodevelopment, neuroimaging, and treatment outcomes were compared.

Results: Gain-of-function variants (n=37) were predominantly associated with paroxysmal nonkinesigenic dyskinesia (82.4%), often mimicking absence seizures or cataplexy. Conversely, loss-of-function variants (n=26) more frequently exhibited with structural brain abnormalities (54.5% vs. 22.2% in gain-of-function), such as cerebellar atrophy and a hypoplastic corpus callosum. Longitudinal imaging in our cohort demonstrated the progressive nature of cerebellar atrophy. Notably, methylphenidate was consistently effective in reducing the frequency and severity of hyperkinetic movements as well as cognitive and behavior features in gain-of-function patients. Beyond neurological symptoms, systemic comorbidities such as intestinal malrotation and arterial dilatation were identified.

Conclusion: Our study confirms a distinct dichotomy: gain-of-function variants drive functional paroxysmal disturbances, while loss-of-function variants lead to structural abnormalities. Recognizing these functional subtypes and the potential for multisystem involvement is crucial for avoiding inappropriate anti-seizure medications and implementing targeted therapies such as stimulants for symptom management.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genotype-phenotype-correlations-in-kcnma1-channelopathy-a-comparative-analysis-of-gain-of-function-and-loss-of-function-variants-in-a-korean-cohort-and-literature-review/