A Meta-Analysis of α-Synuclein Multiplication in Familial Parkinsonism
A Meta-Analysis of α-Synuclein Multiplication in Familial Parkinsonism
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DOI：
10.3389/fneur.2018.01021
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发表时间：
2018-12-11
影响因子：
3.4
通讯作者：
Farrer, Matthew J.
中科院分区：
文献类型：
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作者：
Book, Adam;Guella, Ilaria;Farrer, Matthew J.
慢性α-突触核蛋白（SNCA）过度表达是帕金森综合征和痴呆的一个相对同质和明确的原因。帕金森病（PD）、PD伴痴呆、路易体痴呆和多系统萎缩都在SNCA倍增家族中表现出来。在此，我们总结了来自59个家族（25个以前未发表）的家系，临床和遗传数据与SNCA倍增引起的帕金森症。记录所有家庭成员的纵向临床评估和系谱关系。使用Illumine MEGA高密度基因分型阵列对所有先证者进行基因分型，以鉴定拷贝数变异（CNV）并确定SNCA增殖断点。三SNCA短串联重复序列（STR）标记的基因分型在所有可用的样本，以验证基因组剂量和遗传。建立了一个网络应用程序，作为未来数据共享的论坛。CNV分析确定了49例杂合SNCA重复（CNV 3），2例纯合重复（CNV 4）和7例三重突变（CNV 4）。整个队列的临床表现差异很大。SNCA剂量与疾病发作相关（CNV 3的平均发病年龄：46.9 ± 10.5岁vs. 34.5 ± 7.4 CNV 4，p = 0.003）。在一些患者中描述了非典型或更严重的临床病程，在50.9%的先证者中注意到痴呆。倍增大小（平均2.05 +/- 2.45 Mb）和包含的基因数量（范围1-50）都与运动症状发作或痴呆无关。具有SNCA倍增的家族是罕见的并且全球分布。然而，他们可能会告知并受益于SNCA靶向治疗策略的发展，这些策略与所有α-突触核蛋白病的治疗相关。
Chronic alpha-synuclein (SNCA) overexpression is a relatively homogenous and well-defined cause of parkinsonism and dementia. Parkinson's disease (PD), PD with dementia, dementia with Lewy bodies and multiple system atrophy all manifest in SNCA multiplication families. Herein we summarize genealogic, clinical and genetic data from 59 families (25 not previously published) with parkinsonism caused by SNCA multiplications. Longitudinal clinical assessments and genealogic relationships were documented for all family members. All probands were genotyped with an Illumine MEGA high-density genotyping array to identify copy number variants (CNV) and enable SNCA multiplication breakpoints to be defined. Three SNCA short tandem repeat (STR) markers were genotyped in all available samples to validate genomic dosage and inheritance. A web-application was built as a forum for future data sharing. CNV analysis identified 49 subjects with heterozygous SNCA duplication (CNV3), 2 with homozygous duplication (CNV4) and 7 with a triplication mutation (CNV4). Clinical presentations varied greatly throughout the cohort. SNCA dosage correlates with disease onset (mean age of onset CNV3: 46.9 +/- 10.5 years vs. 34.5 +/- 7.4 CNV4, p = 0.003). Atypical or more severe clinical courses were described in several patients and dementia was noted in 50.9% of the probands. Neither the multiplication size (average 2.05 +/- 2.45 Mb) nor the number of genes included (range 1-50) was associated with motor symptom onset or dementia. Families with SNCA multiplication are rare and globally-distributed. Nevertheless, they may both inform and benefit from the development of SNCA targeted therapeutic strategies relevant to the treatment of all alpha-synucleinopathies.