An emerging spectrum of variants and clinical features in KCNMA1-linked channelopathy.
An emerging spectrum of variants and clinical features in KCNMA1-linked channelopathy.
复制标题
KCNMA1链接通道病的变体和临床特征的新兴范围。
DOI：
10.1080/19336950.2021.1938852
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Meredith AL
中科院分区：
文献类型：
--
作者：
Miller JP;Moldenhauer HJ;Keros S;Meredith AL
kcnma1相关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、发育迟缓和智力残疾的异质性和重叠组合。KCNMA1编码bkk +通道，该通道参与兴奋性和抑制性神经元和肌肉活动。了解这种障碍的基础是积极调查的一个重要领域；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。在这篇综述中，我们总结了来自69名患者的37个KCNMA1等位基因，并评估了关键的诊断和临床特征。目前，3种变异被归类为BK通道活性方面的功能获得，14种功能丧失，15种意义不确定的变异，以及推定的良性/VUS。从患者提供的信息和先前的出版物中整理出与这些变异相关的症状，以定义临床表型谱。在这个新扩大的队列中，癫痫发作在GOF和LOF变体患者之间没有差异分布，而运动障碍则按突变类型区分。阵发性非运动性运动障碍主要发生在BK通道GOF等位基因的患者中，尽管并非完全如此，但在LOF变异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。与突变相反，疾病相关的KCNMA1单核苷酸多态性并不主要与神经表型相关，而是涵盖了更广泛的外周生理功能。总之，本综述为探索KCNMA1相关通道病变的遗传和生化基础提供了额外的证据，并总结了多种类型KCNMA1基因变异的临床患者症状库。
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.
影响因子：
4.6
作者：
Hou, Panpan;Zeng, Wenping;Gan, Geliang;Lv, Caixia;Guo, Xiying;Zhang, Zheng;Liu, Haowen;Wu, Ying;Yao, Jing;Wei, Aguan D.;Wang, Sheng;Ding, Jiuping
通讯作者：
Ding, Jiuping
影响因子：
3.7
作者：
Savas S;Briollais L;Ibrahim-zada I;Jarjanazi H;Choi YH;Musquera M;Fleshner N;Venkateswaran V;Ozcelik H
通讯作者：
Ozcelik H