Genotype-Phenotype Correlations, Dystonia and Disease Progression in Spinocerebellar Ataxia Type 14
Genotype-Phenotype Correlations, Dystonia and Disease Progression in Spinocerebellar Ataxia Type 14
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DOI：
10.1002/mds.27334
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发表时间：
2018-07-01
影响因子：
8.6
通讯作者：
Houlden, Henry
中科院分区：
文献类型：
--
作者：
Chelban, Viorica;Wiethoff, Sarah;Houlden, Henry
背景：脊髓小脑性共济失调14型是一种罕见的常染色体显性小脑性共济失调，由蛋白激酶C γ基因突变引起。临床表现为缓慢进展，以单纯小脑性共济失调为主。方法采用下一代测序技术，筛选194个常染色体显性小脑性共济失调和正常多聚谷氨酰胺重复序列的家族。使用有效的临床评分量表、神经影像学和电生理调查进行深入的表型分析。结果：我们从13个家族中鉴定出25个携带蛋白激酶C γ基因致病性突变的个体。共有10个独特的蛋白激酶C γ基因突变已被证实，其中5个是新的，5个以前被描述过。我们的数据表明，发病年龄是高度可变的；病程进展缓慢，很少伴有严重残疾。然而，三分之一的患者表现为复杂的共济失调，包括严重的局灶性和/或任务性肌张力障碍、周围神经病变、帕金森病、肌阵挛和锥体综合征。最复杂的表型与外显子11催化结构域的错义突变有关。结论：我们提出了一个最大的基因确认脊髓小脑共济失调14型队列贡献新的变异和临床特征。我们发现，虽然蛋白激酶C γ基因突变主要表现为缓慢进展的纯共济失调，但超过三分之一的病例具有复杂的表型。总的来说，我们的病例系列扩展了表型，并表明在缓慢进展的常染色体显性小脑性共济失调患者中，特别是当肌阵挛、肌张力障碍或轻度认知障碍存在时，应考虑蛋白激酶C γ基因突变，而没有多聚谷氨酰胺扩增。(C) 2018年作者。Wiley期刊公司代表国际帕金森和运动障碍学会出版的《运动障碍》。
Background: Spinocerebellar ataxia type 14 is a rare form of autosomal dominant cerebellar ataxia caused by mutations in protein kinase C gamma gene. Clinically, it presents with a slowly progressive, mainly pure cerebellar ataxia.Methods: Using next generation sequencing, we screened 194 families with autosomal dominant cerebellar ataxia and normal polyglutamine repeats. In-depth phenotyping was performed using validated clinical rating scales neuroimaging and electrophysiological investigations.Results: We identified 25 individuals from 13 families carrying pathogenic mutations in protein kinase C gamma gene. A total of 10 unique protein kinase C gamma gene mutations have been confirmed of which 5 are novel and 5 were previously described. Our data suggest that the age at onset is highly variable; disease course is slowly progressive and rarely associated with severe disability. However, one third of patients presented with a complex ataxia comprising severe focal and/or task-induced dystonia, peripheral neuropathy, parkinsonism, myoclonus, and pyramidal syndrome. The most complex phenotype is related to a missense mutation in the catalytic domain in exon 11.Conclusion: We present one of the largest genetically confirmed spinocerebellar ataxia type 14 cohorts contributing novel variants and clinical characterisation. We show that although protein kinase C gamma gene mutations present mainly as slowly progressive pure ataxia, more than a third of cases had a complex phenotype. Overall, our case series extends the phenotype and suggests that protein kinase C gamma gene mutations should be considered in patients with slowly progressive autosomal dominant cerebellar ataxia, particularly when myoclonus, dystonia, or mild cognitive impairment are present in the absence of polyglutamine expansion. (C) 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.