Phenotypical characterization of α-galactosidase A gene mutations identified in a large Fabry disease screening program in stroke in the young
Introduction
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the α-Galactosidase A gene (GLA), leading to α-Galactosidase A (α-Gal A) enzyme deficiency [1]. This results in the lysosomal accumulation of its substrates, globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) [2], [3]. In patients with the classic clinical Fabryphenotype the early clinical manifestations include pain crises, acroparesthesia, angiokeratoma, gastrointestinal complaints, corneal abnormalities and hypohidrosis. Later there is a progression to renal, cerebrovascular and cardiovascular disease, leading to early demise in the 4th or 5th decade of life. Atypical variants of Fabry disease with low levels of residual enzyme activity have been described as well. These variants have late-onset manifestations in the cardiac, neurological or renal system [4], [5], [6], [7], [8], [9], [10].
The Belgian Fabry Study (BeFaS) study examined the frequency of Fabry disease in 1000 young Belgian patients with stroke (ischemic stroke in 57.3%, Transient Ischemic Attack in 22.0%, intracranial hemorrhage in 4.9%), unexplained white matter lesions and vertebrobasilar dolichoectasia [4]. GLA mutations (p.A143T, p.D313Y, and p.S126G) were identified in 8 female patients. Two male patients had α-Gal A enzyme deficiency in repeated bloodspot analysis, but a GLA mutation could not be identified. The results of the BeFaS suggested that Fabry disease may play a role in up to 1% of young patients with stroke, unexplained white matter lesions or vertebrobasilar dolichoectasia. The aim of this study was to perform detailed phenotypic characterization in these 10 patients with α-Gal A enzyme deficiency or GLA mutations identified in BeFaS. In a second phase the relatives of these index patients were subjected to GLA mutation screening and α-Gal A enzyme analysis. Relatives carrying a GLA mutation were also subjected to phenotypic characterization.
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Subjects
Ten index patients from the BeFaS were included, as well as 32 relatives of 5 index patients. These relatives were subjected to GLA mutation screening by genomic DNA sequencing and α-Gal A enzyme analysis as described in detail by Brouns et al. [11]. The relatives of the other 5 index patients did not provide informed consent for inclusion in this study. Eighteen relatives, who were carrying a GLA mutation, were subjected to phenotypic characterization.
The study was conducted in agreement with
Family screening
Twelve relatives of index patient 1 (p.A143T) were tested and 8 were found to be mutation carriers .Among the 4 relatives of index patient 2 (p.D313Y) only the eldest son was found to be a mutation carrier.
Twelve relatives of index patient 3 (p.S126G) were screened and 6 were found to have the mutation. The son, daughter and sister of index patient 9 were screened for the p.D313Y mutation and were all shown to carry the mutation. The brother of index patient 10 (p.A143T) did not carry the
Discussion
To our knowledge this is the first study to report both on clinical and biochemical phenotyping in subjects identified in a large screening program for Fabry disease in stroke in the young (BeFaS) and with focus on family screening in these subjects.
Our findings suggest that screening for Fabry disease through bloodspot α-Gal A enzyme activity analysis may lead to false positive and false negative results. In two male index patients with α-Gal A enzyme deficiency in bloodspots, no GLA mutation
Conclusion
We could not identify mutations causing the classical clinical Fabry disease phenotype in our cerebrovascular disease population. This is consistent with the findings of Baptista et al. [26] and Wozniak et al. [27]. Nonetheless, the identification of patients with atypical, late-onset variants of Fabry disease and their affected family members is important, because they may also develop renal, cardiac and cerebrovascular manifestations. However, there is insufficient data on disease progression
Acknowledgements
We thank the participating patients for their commitment to the study. We thank Dr. B. Rosu for his commitment to the study. We thank Mrs. M. Van den Broeck (VIB Genetic Service Facility), Mrs. L. De Wit and Mrs. I. Bats (Institute Born-Bunge, Belgium) for technical assistance. We thank Dr. K. De Boeck for his advice on renal function in some patients. We thank Prof. Dr. H. Aerts, Dr. Sc. J. Groener and Dr. B. Poorthuis for performing all Gb3 and Lyso-Gb3 measurements.
BeFaS II was funded by an
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First two authors contributed equally to the study and share first authorship.