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

https://doi.org/10.1016/j.clineuro.2012.11.003Get rights and content

Abstract

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 α-galactosidase A (α-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 α-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.

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.

Section snippets

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

References (28)

  • J.M. Aerts et al.

    Elevated globotriaosylsphingosine is a hallmark of Fabry disease

    Proceedings of the National Academy of Sciences of the United States of America

    (2008)
  • R. Brouns et al.

    Belgian Fabry study: prevalence of Fabry disease in a cohort of 1000 young patients with cerebrovascular disease

    Stroke

    (2010)
  • C. Chimenti et al.

    Prevalence of Fabry disease in female patients with late-onset hypertrophic cardiomyopathy

    Circulation

    (2004)
  • M. Ichinose et al.

    Significance of screening for Fabry disease among male dialysis patients

    Clinical and Experimental Nephrology

    (2005)
  • Cited by (0)

    1

    First two authors contributed equally to the study and share first authorship.

    View full text