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.

摘要

KCNMA1 相关的通道病是一种新兴的神经系统疾病，其特征是运动障碍、癫痫发作、发育迟缓和智力障碍的异质和重叠组合。KCNMA1编码 BK K ⁺通道，它有助于兴奋性和抑制性神经元和肌肉活动。了解疾病的基础是积极调查的一个重要领域；然而，罕见的流行阻碍了建立基因型-表型相关性所必需的大型患者队列的发展。在这篇综述中，我们总结了 37 KCNMA169 名患者的等位基因目前定义了离子通道病并评估了关键的诊断和临床标志。目前，3 种变异被归类为 BK 通道活动的功能获得型、14 种功能丧失型、15 种意义不确定的变异型和推定的良性/VUS。与这些变异相关的症状是从患者提供的信息和先前的出版物中挑选出来的，以定义临床表型的范围。在这个新扩展的队列中，癫痫发作在携带 GOF 和 LOF 变体的患者之间没有差异分布，而运动障碍按突变类型分开。阵发性非运动源性运动障碍主要在 BK 通道的 GOF 等位基因患者中观察到，尽管不完全如此，而在 LOF 变体患者中观察到额外的运动障碍。LOF 突变患者普遍存在神经发育和脑结构异常。与突变相比，疾病相关KCNMA1单核苷酸多态性并不主要与神经表型相关，但涵盖了更广泛的外周生理功能。总之，本综述提供了探索KCNMA1相关通道病的遗传和生化基础的额外证据，并总结了多种类型的KCNMA1基因变异患者症状的临床资料库。