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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相关的信道病是一种新兴的神经系统疾病，其特征是运动障碍的异质性和重叠组合，癫痫发作,发育迟缓,智力残疾。KCNMA1编码BK+通道，这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重要领域；然而，罕见的患病率阻碍了建立基因型-表型相关性所需的大型患者队列的发展.在这次审查中,我们总结了目前69例患者的37个KCNMA1等位基因,并评估了关键的诊断和临床标志.目前,3个变体被分类为关于BK通道活动的功能增益，14功能丧失，15个不确定意义的变体，和假定的良性/VUS。与这些变异相关的症状从患者提供的信息和先前的出版物中进行策划，以定义临床表型的谱。在这个新扩展的队列中，癫痫发作在携带GOF和LOF变异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具有BK通道的GOF等位基因的患者中观察到，虽然不完全如此，而在LOF变异的患者中观察到其他运动障碍。神经发育和脑结构异常在LOF突变患者中普遍存在。与突变相反,疾病相关的KCNMA1单核苷酸多态性并不主要与神经系统表型相关,但涵盖了更广泛的外周生理功能.一起,这篇综述提供了探索KCNMA1相关信道病的遗传和生化基础的更多证据,并总结了多种KCNMA1基因变异类型的患者症状的临床储存库.
