Manville Rían W, Sidlow Richard, Abbott Geoffrey W
Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, Irvine, CA, United States.
Department of Medical Genetics and Metabolism, Valley Children's Hospital, Madera, CA, United States.
Front Neurol. 2022 Aug 9;13:975849. doi: 10.3389/fneur.2022.975849. eCollection 2022.
Episodic ataxia is an umbrella term for a group of nervous system disorders that adversely and episodically affect movement. Episodes are recurrent, characterized by loss of balance and coordination and can be accompanied by other symptoms ranging from nausea to hemiplegia. Episodic Ataxia Type 1 (EA1) is an inherited, autosomal dominant disease caused by sequence variants in , which encodes the voltage-gated potassium channel, KCNA1 (Kv1.1). Here we report a novel loss-of-function pathogenic variant [c.464T>C/p.Leu155Phe] causing frequent, sudden onset of clumsiness or staggering gait in the young female proband. The gene variant was maternally inherited and the mother, whose symptoms also began in childhood, has a normal MRI and EEG, slurred speech and dystonic movements involving upper extremities and mouth. Both mother and daughter are responsive to carbamazepine. Cellular electrophysiology studies of KCNA1-L155P potassium channels revealed complete but non-dominant loss of function, with reduced current and altered gating in heterozygous channels. To our knowledge this is the first EA1-associated pathogenic variant located in the KCNA1 cytoplasmic N-terminus, expanding the reported clinically sensitive domains of the channel.
发作性共济失调是一组对运动产生不利且发作性影响的神经系统疾病的统称。发作是反复出现的，其特征为平衡和协调能力丧失，还可能伴有从恶心到偏瘫等一系列其他症状。发作性共济失调1型（EA1）是一种由编码电压门控钾通道KCNA1（Kv1.1）的基因序列变异导致的常染色体显性遗传病。在此，我们报告了一个新的功能丧失性致病变异[c.464T>C/p.Leu155Phe]，该变异导致年轻女性先证者频繁突然出现笨拙或蹒跚步态。该基因变异由母亲遗传而来，母亲的症状也始于童年，其MRI和脑电图正常，但存在言语不清以及涉及上肢和口腔的肌张力障碍性运动。母亲和女儿对卡马西平均有反应。对KCNA1-L155P钾通道的细胞电生理研究显示功能完全丧失但非显性，杂合通道中的电流减少且门控改变。据我们所知，这是首个位于KCNA1细胞质N端的与EA1相关的致病变异，扩展了该通道已报道的临床敏感区域。
