Multifocal white matter lesions associated with the D313Y mutation of the α-galactosidase A gene.
Multifocal white matter lesions associated with the D313Y mutation of the α-galactosidase A gene.
复制标题
DOI：
10.1371/journal.pone.0055565
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Brand E
中科院分区：
文献类型：
--
作者：
Lenders M;Duning T;Schelleckes M;Schmitz B;Stander S;Rolfs A;Brand SM;Brand E
白色病变（WML）具有临床意义，因为它们与卒中、认知能力下降、抑郁症或癫痫相关，但在没有经典危险因素的年轻人中，其潜在病因仍不明确。我们的目的是阐明在α-半乳糖苷酶A（GLA）基因中携带D313 Y突变的患者中导致WML的可能临床诊断和机制，该突变以前被描述为非致病性。致病性GLA突变导致法布里病，一种血管内皮鞘糖脂沉积病，通常表现为肾脏、心脏和脑血管表现的综合症状。我们进行了深入的临床，生化和遗传学检查，以及先进的磁共振成像分析与遗传确定GLA突变D313 Y的家系。我们检测到专属的神经系统表现的中枢神经系统的“假”缺陷D313 Y突变导致明显的WML在7个受影响的成年家庭成员。此外，两个不携带突变的家庭成员没有表现出WML。D313 Y突变导致白细胞中GLA酶活性正常，血浆中GLA酶活性严重降低。总之，我们的研究结果提供了证据表明，GLA D313 Y可能参与神经损伤与显着的WML，证明了评估患者携带D313 Y更彻底的必要性。D313 Y可能会扩大遗传性脑小动脉疾病的范围，这些疾病最好发生在没有经典危险因素的年轻人中。鉴于现有的因果治疗方案，D313 Y应更具体地考虑这些患者。
White matter lesions (WML) are clinically relevant since they are associated with strokes, cognitive decline, depression, or epilepsy, but the underlying etiology in young adults without classical risk factors still remains elusive. Our aim was to elucidate the possible clinical diagnosis and mechanisms leading to WML in patients carrying the D313Y mutation in the α-galactosidase A (GLA) gene, a mutation that was formerly described as nonpathogenic. Pathogenic GLA mutations cause Fabry disease, a vascular endothelial glycosphingolipid storage disease typically presenting with a symptom complex of renal, cardiac, and cerebrovascular manifestations. We performed in-depths clinical, biochemical and genetic examinations as well as advanced magnetic resonance imaging analyses in a pedigree with the genetically determined GLA mutation D313Y. We detected exclusive neurologic manifestations of the central nervous system of the “pseudo”-deficient D313Y mutation leading to manifest WML in 7 affected adult family members. Furthermore, two family members that do not carry the mutation showed no WML. The D313Y mutation resulted in a normal GLA enzyme activity in leukocytes and severely decreased activities in plasma. In conclusion, our results provide evidence that GLA D313Y is potentially involved in neural damage with significant WML, demonstrating the necessity of evaluating patients carrying D313Y more thoroughly. D313Y might broaden the spectrum of hereditary small artery diseases of the brain, which preferably occur in young adults without classical risk factors. In view of the existing causal therapy regime, D313Y should be more specifically taken into account in these patients.
登录
查看更多内容
影响因子：
--
作者：
Gaspar P;Herrera J;Rodrigues D;Cerezo S;Delgado R;Andrade CF;Forascepi R;Macias J;del Pino MD;Prados MD;de Alegria PR;Torres G;Vidau P;Sá-Miranda MC
通讯作者：
Sá-Miranda MC
影响因子：
9.9
作者：
Schiffmann, Raphael;van der Knaap, Marjo S.
通讯作者：
van der Knaap, Marjo S.
影响因子：
0.9
作者：
Froissart, R.;Piraud, M.;Maire, I.
通讯作者：
Maire, I.
影响因子：
5.3
作者：
Matsuzawa, F;Aikawa, S;Sakuraba, H
通讯作者：
Sakuraba, H
影响因子：
--
作者：
Lin, Hsiang-Yu;Chong, Kah-Wai;Niu, Dau-Ming
通讯作者：
Niu, Dau-Ming