Phenotypical characterization of α-galactosidase A gene mutations identified in a large Fabry disease screening program in stroke in the young

被引：32

作者：

De Brabander, Isabel ^{[1
,2
,3
,4
]}

Yperzeele, Laetitia ^{[5
]}

Ceuterick-De Groote, Chantal ^{[4
,6
]}

Brouns, Raf ^{[7
]}

Baker, Robert ^{[8
]}

Belachew, Shibeshih ^{[9
]}

Delbecq, Jean ^{[10
]}

De Keulenaer, Gilles ^{[11
,12
]}

Dethy, Sophie ^{[13
]}

Eyskens, Francois ^{[14
,15
]}

Fumal, Arnaud ^{[16
]}

Hemelsoet, Dimitri ^{[17
]}

Hughes, Derralynn ^{[8
]}

Jeangette, Sandrine ^{[18
]}

Nuytten, Dirk ^{[19
]}

Redondo, Patricia ^{[13
]}

Sadzot, Bernard ^{[9
]}

Sindic, Christian ^{[20
]}

Sheorajpanday, Rishi ^{[2
,3
]}

Thijs, Vincent ^{[21
,22
]}

Van Broeckhoven, Christine ^{[23
,24
]}

De Deyn, Peter P. ^{[1
,2
,3
,4
]}

机构：

[1] Univ Antwerp, Inst Born Bunge, Lab Neurochem & Behav, B-2610 Antwerp, Belgium

[2] Hosp Network Antwerp ZNA Middelheim & Hoge Beuken, Dept Neurol, B-2020 Antwerp, Belgium

[3] Hosp Network Antwerp ZNA Middelheim & Hoge Beuken, Memory Clin, B-2020 Antwerp, Belgium

[4] Univ Antwerp, Inst Born Bunge, Biobank, B-2610 Antwerp, Belgium

[5] Univ Antwerp Hosp, Dept Neurol, B-2650 Edegem, Belgium

[6] Univ Antwerp, Inst Born Bunge, Lab Ultrastruct Neuropathol, B-2610 Antwerp, Belgium

[7] Vrije Univ Brussel, Ctr Neurosci C4N, Univ Ziekenhuis Brussel, Dept Neurol, B-1090 Brussels, Belgium

[8] Royal Free Hampstead NHS Trust, Lysosomal Storage Disorders Unit, London NW3 2QG, England

[9] Domains Univ Sart Tilman, Ctr Hosp Univ Liege, Dept Neurol, B-4000 Liege, Belgium

[10] Reg Hosp, Dept Neurol, B-1500 Halle, Belgium

[11] Hosp Network Antwerp ZNA Middelheim, Ctr Heart Failure & Cardiac Rehabil, B-2020 Antwerp, Belgium

[12] Univ Antwerp, Dept Pharmaceut Sci, B-2610 Antwerp, Belgium

[13] Ctr Hosp Univ Tivoli, Dept Neurol, B-7100 La Louviere, Belgium

[14] Univ Antwerp, Prov Ctr Metab Disorders, B-2610 Antwerp, Belgium

[15] Univ Antwerp Hosp, Dept Pediat, B-2650 Edegem, Belgium

[16] Univ Liege, CHR Citadelle, Headache Res Unit, Dept Neurol & Funct Neuroanat, B-4000 Liege, Belgium

[17] Univ Hosp Ghent, Dept Neurol, B-9000 Ghent, Belgium

[18] Ctr Hosp Univ Charleroi, Dept Neurol, B-6000 Charleroi, Belgium

[19] ZNA Stuivenberg Gen Hosp, Dept Neurol, B-2060 Antwerp, Belgium

[20] Clin Univ St Luc, Dept Neurol, B-1200 Brussels, Belgium

[21] Univ Hosp Gasthuisberg, Dept Neurol, B-3000 Louvain, Belgium

[22] VIB, Vesalius Res Ctr, B-3000 Louvain, Belgium

[23] Univ Antwerp VIB, Dept Mol Genet, Neurodegenerat Brain Dis Grp, B-2610 Antwerp, Belgium

[24] Univ Antwerp, Inst Born Bunge, Neurogenet Lab, B-2610 Antwerp, Belgium

来源：

CLINICAL NEUROLOGY AND NEUROSURGERY | 2013年 / 115卷 / 07期

关键词：

Fabry disease; Cerebrovascular disease; Family screening; Phenotyping; Genetics of stroke; Risk factors for stroke; Stroke in young; PLASMA; PREVALENCE; VARIANT; GLOBOTRIAOSYLSPHINGOSINE; GLOBOTRIAOSYLCERAMIDE; POPULATION; BIOMARKER; D313Y;

D O I：

10.1016/j.clineuro.2012.11.003

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Objective: In the Belgian Fabry Study (BeFaS), the prevalence of Fabry disease was assessed in 1000 young patients presenting with stroke, unexplained white matter lesions or vertebrobasilar dolichoectasia. The results of the BeFaS suggested that Fabry disease may play a role in up to 1% of young patients presenting with cerebrovascular disease. However, the clinical relevance was unclear in all cases. We report on detailed phenotyping in subjects identified with alpha-galactosidase A (alpha-Gal A) enzyme deficiency or GM mutations identified in the BeFaS (n=10), and on the results of family screening in this population. Methods: Family screening was performed to identify additional mutation carriers. Biochemical and/or clinical evaluation of all subjects (BeFaS index patients and relatives carrying a GM mutation) was performed. Results: Genetic family screening revealed 18 additional GM mutation carriers. Bloodspot alpha-Gal A enzyme activity was normal in all GM mutation carriers, even in 2 males with the p.A143T mutation. Plasma Gb3 and lyso-Gb3 levels were normal in all subjects. Elevated Gb3 in urine was detected in 2 subjects. Some classic clinical signs of Fabry disease, like angiokeratoma or cornea verticillata, could not be detected in our population. Cardiac symptoms of Fabry disease were found in 6 out of 10 p.A143T carriers. No signs of cerebrovascular disease were found in the relatives with a GLA mutation. Conclusions: We could not identify mutations causing the classical clinical phenotype of Fably disease in our cerebrovascular disease population. Enzyme activity analysis in bloodspots and plasma may fail to identify late-onset variants of Fabry disease. We recommend genetic testing when an atypical, late-onset variant of Fabry disease is suspected in a male cerebrovascular disease patient. However, this may lead to the identification of non-disease causing or controversial genetic variants. (C) 2012 Elsevier B.V. All rights reserved.

引用

页码：1088 / 1093

页数：6

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