A Gain-of-Function Mutation in KCNMA1 Causes Dystonia Spells Controlled With Stimulant Therapy.
A Gain-of-Function Mutation in KCNMA1 Causes Dystonia Spells Controlled With Stimulant Therapy.
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DOI：
10.1002/mds.28138
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发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Mikati MA
中科院分区：
文献类型：
--
作者：
Zhang G;Gibson RA;McDonald M;Liang P;Kang PW;Shi J;Yang H;Cui J;Mikati MA
KCNMA1 BK型K+通道突变在各种运动障碍患者中已被发现。缺乏潜在的病理生理学和相应的治疗方法。报告我们的临床和生物物理特征，一种新的从头开始的KCNMA1变体，以及一种治疗患者肌张力障碍的有效方法。患者及其突变的表型特征、治疗和生物物理特征的组合。患者每天有100多次肌张力障碍-张力障碍发作，并伴有轻度小脑萎缩。她还患有自闭症谱系障碍、智力残疾和注意力缺陷多动障碍。外显子全序列测定发现BKN536H杂合子突变。我们的生物物理特征表明，N536H是一个功能增益(GOF)突变，具有显著增强的电压依赖激活。值得注意的是，注射右旋安非他明完全抑制了肌张力障碍。BK N536H是一种导致肌张力障碍和其他神经症状的GOF。我们的刺激疗法为缓解KCNMA1相关的运动障碍开辟了一条新的途径。
The mutations of KCNMA1 BK type K+ channel have been identified in patients with various movement disorders. The underlying pathophysiology and corresponding therapeutics are lacking. To report our clinical and biophysical characterizations a novel de novo KCNMA1 variant, as well as an effective therapy for the patient’s dystonia-atonia spells. Combination of phenotypic characterization, therapy and biophysical characterization of the patient and her mutation. The patient had more than one hundred dystonia-atonia spells per day with mild cerebellar atrophy. She also had autism spectrum disorder, intellectual disability, and attention deficit hyperactivity disorder. Whole exome sequencing identified a heterozygous de novo BK N536H mutation. Our biophysical characterization demonstrates that N536H is a gain-of-function (GOF) mutation with markedly enhanced voltage dependent activation. Remarkably, administration of dextroamphetamine completely suppressed the dystonia-atonia spells. BK N536H is a GOF that causes dystonia and other neurological symptoms. Our stimulant therapy opens a new avenue to mitigate KCNMA1-linked movement disorders.
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