[en] 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 GLA 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 GLA mutation) was performed. RESULTS: Genetic family screening revealed 18 additional GLA mutation carriers. Bloodspot alpha-Gal A enzyme activity was normal in all GLA 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 Fabry 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.
Disciplines :
Neurology
Author, co-author :
De Brabander, Isabel
Yperzeele, Laetitia
Ceuterick-De Groote, Chantal
Brouns, Raf
Baker, Robert
Belachew, Shibeshih ; Université de Liège - ULiège > Département des sciences cliniques > Neurologie
Delbecq, Jean
De Keulenaer, Gilles
Dethy, Sophie
Eyskens, Francois
Fumal, Arnaud
Hemelsoet, Dimitri
Hughes, Derralynn
Jeangette, Sandrine
Nuytten, Dirk
Redondo, Patricia
Sadzot, Bernard ; Université de Liège - ULiège > Département des sciences cliniques > Département des sciences cliniques
H. Fabry An historical overview of Fabry disease Journal of Inherited Metabolic Disease 24 Suppl. 2 2001 3 7
J.M. Aerts, J.E. Groener, S. Kuiper, W.E. Donker-Koopman, A. Strijland, R. Ottenhoff, C. van Roomen, M. Mirzaian, F.A. Wijburg, G.E. Linthorst, A.C. Vedder, S.M. Rombach, J. Cox-Brinkman, P. Somerharju, R.G. Boot, C.E. Hollak, R.O. Brady, and B.J. Poorthuis Elevated globotriaosylsphingosine is a hallmark of Fabry disease Proceedings of the National Academy of Sciences of the United States of America 105 2008 2812 2817
T. Togawa, T. Kodama, T. Suzuki, K. Sugawara, T. Tsukimura, T. Ohashi, N. Ishige, K. Suzuki, T. Kitagawa, and H. Sakuraba Plasma globotriaosylsphingosine as a biomarker of Fabry disease Molecular Genetics and Metabolism 100 2010 257 261
R. Brouns, V. Thijs, F. Eyskens, M. Van den Broeck, S. Belachew, B.C. Van, P. Redondo, D. Hemelsoet, A. Fumal, S. Jeangette, W. Verslegers, R. Baker, D. Hughes, and P.P. De Deyn Belgian Fabry study: prevalence of Fabry disease in a cohort of 1000 young patients with cerebrovascular disease Stroke 41 2010 863 868
C. Chimenti, M. Pieroni, E. Morgante, D. Antuzzi, A. Russo, M.A. Russo, A. Maseri, and A. Frustaci Prevalence of Fabry disease in female patients with late-onset hypertrophic cardiomyopathy Circulation 110 2004 1047 1053
M. Ichinose, M. Nakayama, T. Ohashi, Y. Utsunomiya, M. Kobayashi, and Y. Eto Significance of screening for Fabry disease among male dialysis patients Clinical and Experimental Nephrology 9 2005 228 232
S. Nakao, T. Takenaka, M. Maeda, C. Kodama, A. Tanaka, M. Tahara, A. Yoshida, M. Kuriyama, H. Hayashibe, H. Sakuraba, and H. Tanaka An atypical variant of Fabry's disease in men with left ventricular hypertrophy New England Journal of Medicine 333 1995 288 293
S. Nakao, C. Kodama, T. Takenaka, A. Tanaka, Y. Yasumoto, A. Yoshida, T. Kanzaki, A.L. Enriquez, C.M. Eng, H. Tanaka, C. Tei, and R.J. Desnick Fabry disease: detection of undiagnosed hemodialysis patients and identification of a "renal variant" phenotype Kidney International 64 2003 801 807
W. Terryn, B. Poppe, B. Wuyts, K. Claes, B. Maes, D. Verbeelen, R. Vanholder, K. De Boeck, N. Lameire, A. De Paepe, and G. De Schoenmakere Two-tier approach for the detection of alpha-galactosidase A deficiency in a predominantly female haemodialysis population Nephrology, Dialysis, Transplantation 23 2008 294 300
T. Yoshitama, S. Nakao, T. Takenaka, H. Teraguchi, T. Sasaki, C. Kodama, A. Tanaka, A. Kisanuki, and C. Tei Molecular genetic, biochemical, and clinical studies in three families with cardiac Fabry's disease American Journal of Cardiology 87 2001 71 75
R. Brouns, R. Sheorajpanday, E. Braxel, F. Eyskens, R. Baker, D. Hughes, A. Mehta, T. Timmerman, M.F. Vincent, and P.P. De Deyn Middelheim Fabry Study (MiFaS): a retrospective Belgian study on the prevalence of Fabry disease in young patients with cryptogenic stroke Clinical Neurology and Neurosurgery 109 2007 479 484
L.O. Wahlund, F. Barkhof, F. Fazekas, L. Bronge, M. Augustin, M. Sjogren, A. Wallin, H. Ader, D. Leys, L. Pantoni, F. Pasquier, T. Erkinjuntti, and P. Scheltens A new rating scale for age-related white matter changes applicable to MRI and CT Stroke 32 2001 1318 1322
J.S. Mayes, J.B. Scheerer, R.N. Sifers, and M.L. Donaldson Differential assay for lysosomal alpha-galactosidases in human tissues and its application to Fabry's disease Clinica Chimica Acta 112 1981 247 251
J.E. Groener, B.J. Poorthuis, S. Kuiper, M.T. Helmond, C.E. Hollak, and J.M. Aerts HPLC for simultaneous quantification of total ceramide, glucosylceramide, and ceramide trihexoside concentrations in plasma Clinical Chemistry 53 2007 742 747
E.G. Bligh, and W.J. Dyer A rapid method of total lipid extraction and purification Canadian Journal of Biochemistry and Physiology 37 1959 911 917
C. Ceuterick, and J.J. Martin Electron microscopic features of skin in neurometabolic disorders Journal of the Neurological Sciences 112 1992 15 29
M. Merta, J. Reiterova, J. Ledvinova, H. Poupetova, R. Dobrovolny, R. Rysava, D. Maixnerova, J. Bultas, J. Motan, J. Slivkova, D. Sobotova, J. Smrzova, and V. Tesar A nationwide blood spot screening study for Fabry disease in the Czech Republic haemodialysis patient population Nephrology, Dialysis, Transplantation 22 2007 179 186
M. Spada, S. Pagliardini, M. Yasuda, T. Tukel, G. Thiagarajan, H. Sakuraba, A. Ponzone, and R.J. Desnick High incidence of later-onset fabry disease revealed by newborn screening American Journal of Human Genetics 79 2006 31 40
T. Kitagawa, N. Ishige, K. Suzuki, M. Owada, T. Ohashi, M. Kobayashi, Y. Eto, A. Tanaka, K. Mills, B. Winchester, and J. Keutzer Non-invasive screening method for Fabry disease by measuring globotriaosylceramide in whole urine samples using tandem mass spectrometry Molecular Genetics and Metabolism 85 2005 196 202
E. Young, K. Mills, P. Morris, A. Vellodi, P. Lee, S. Waldek, and B. Winchester Is globotriaosylceramide a useful biomarker in Fabry disease? Acta Paediatrica: Supplement 94 2005 51 54
C.M. Eng, L.A. Resnick-Silverman, D.J. Niehaus, K.H. Astrin, and R.J. Desnick Nature and frequency of mutations in the alpha-galactosidase A gene that cause Fabry disease American Journal of Human Genetics 53 1993 1186 1197
N. Guffon, R. Froissart, F. Chevalier-Porst, and I. Maire Mutation analysis in 11 French patients with Fabry disease Human Mutation Suppl. 1 1998 S288 S290
R. Froissart, N. Guffon, M.T. Vanier, R.J. Desnick, and I. Maire Fabry disease: D313Y is an alpha-galactosidase A sequence variant that causes pseudodeficient activity in plasma Molecular Genetics and Metabolism 80 2003 307 314
M. Yasuda, J. Shabbeer, S.D. Benson, I. Maire, R.M. Burnett, and R.J. Desnick Fabry disease: characterization of alpha-galactosidase A double mutations and the D313Y plasma enzyme pseudodeficiency allele Human Mutation 22 2003 486 492
R.R. Townsend, R.M. Orth, C.M. Clawson, S.C. Li, and Y.T. Li Increased glycosphingolipid excretion associated with proteinuria Journal of Clinical Investigation 62 1978 119 123
M.V. Baptista, S. Ferreira, Pinho-E-Melo, M. Carvalho, V.T. Cruz, C. Carmona, F.A. Silva, A. Tuna, M. Rodrigues, C. Ferreira, A.A. Pinto, A. Leitao, J.P. Gabriel, S. Calado, J.P. Oliveira, and J.M. Ferro Mutations of the GLA gene in young patients with stroke: the Portystroke study-screening genetic conditions in Portuguese young stroke patients Stroke 41 2010 431 436
M.A. Wozniak, S.J. Kittner, S. Tuhrim, J.W. Cole, B. Stern, M. Dobbins, M.E. Grace, I. Nazarenko, R. Dobrovolny, E. McDade, and R.J. Desnick Frequency of unrecognized Fabry disease among young European-American and African-American men with first ischemic stroke Stroke 41 2010 78 81
A. Rolfs, P. Martus, P.U. Heuschmann, U. Grittner, M. Holzhausen, T. Tatlisumak, T. Bottcher, F. Fazekas, C. Enzinger, S. Ropele, R. Schmidt, O. Riess, and B. Norrving Protocol and methodology of the Stroke in Young Fabry Patients (sifap1) study: a prospective multicenter European study of 5024 young stroke patients aged 18-55 years Cerebrovascular Diseases 31 2011 253 262