Prevalence of CADASIL and Fabry Disease in a Cohort of MRI Defined Younger Onset Lacunar Stroke.
Prevalence of CADASIL and Fabry Disease in a Cohort of MRI Defined Younger Onset Lacunar Stroke.
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DOI：
10.1371/journal.pone.0136352
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
UK Young Lacunar Stroke DNA Study
中科院分区：
文献类型：
--
作者：
Kilarski LL;Rutten-Jacobs LC;Bevan S;Baker R;Hassan A;Hughes DA;Markus HS;UK Young Lacunar Stroke DNA Study
脑常染色体显性动脉病变伴皮层下梗死和脑白质病（CADASIL）是由NOTCH3基因突变引起的最常见的单基因疾病，可导致腔隙性卒中和脑血管病（SVD）。由于GLA基因突变引起的法布里病（FD）被认为是一种未被诊断的中风病因，其中一个特征是SVD。先前的研究报告了CADASIL和FD在卒中中的患病率不同，可能是由于研究的亚型不同；没有一项研究对年轻发病的室性心动障碍进行了大规模研究。我们在一个明确的、mri验证的明显散发性腔隙性梗死患者队列中确定了患病率。年龄≤70岁（平均年龄56.7岁（SD8.6））的腔隙性梗死白人患者从全英国72个专科卒中中心招募，作为年轻腔隙性卒中DNA资源的一部分。先前确认的单基因性卒中患者被排除在外。所有MRI和临床病史集中回顾。筛选NOTCH3和GLA突变。在994名受试者中，有5名具有致病性NOTCH3突变（R169C、R207C、R587C、C1222G和C323S），所有这些突变都导致NOTCH3蛋白中半胱氨酸的缺失或增加。5例患者均为合流性白质病变（Fazekas分级≥2级）。CADASIL的总体患病率为0.5% (95% CI 0.2%-1.1%)，合流性白质病变的患病率为1.5% （95% CI 0.6%-3.3%）。未发现典型致病性FD突变；1例患者有错义突变（R118C），与迟发性FD相关。CADASIL病例很少见，仅在SVD合并合并白质变的患者中检测到。未发现明确的FD病例。
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by mutations in the NOTCH3 gene, is the most common monogenic disorder causing lacunar stroke and cerebral small vessel disease (SVD). Fabry disease (FD) due to mutations in the GLA gene has been suggested as an underdiagnosed cause of stroke, and one feature is SVD. Previous studies reported varying prevalence of CADASIL and FD in stroke, likely due to varying subtypes studied; no studies have looked at a large cohort of younger onset SVD. We determined the prevalence in a well-defined, MRI-verified cohort of apparently sporadic patients with lacunar infarct. Caucasian patients with lacunar infarction, aged ≤70 years (mean age 56.7 (SD8.6)), were recruited from 72 specialist stroke centres throughout the UK as part of the Young Lacunar Stroke DNA Resource. Patients with a previously confirmed monogenic cause of stroke were excluded. All MRI’s and clinical histories were reviewed centrally. Screening was performed for NOTCH3 and GLA mutations. Of 994 subjects five had pathogenic NOTCH3 mutations (R169C, R207C, R587C, C1222G and C323S) all resulting in loss or gain of a cysteine in the NOTCH3 protein. All five patients had confluent leukoaraiosis (Fazekas grade ≥2). CADASIL prevalence overall was 0.5% (95% CI 0.2%-1.1%) and among cases with confluent leukoaraiosis 1.5% (95% CI 0.6%-3.3%). No classic pathogenic FD mutations were found; one patient had a missense mutation (R118C), associated with late-onset FD. CADASIL cases are rare and only detected in SVD patients with confluent leukoaraiosis. No definite FD cases were detected.