Middelheim Fabry Study (MiFaS): A retrospective Belgian study on the prevalence of Fabry disease in young patients with cryptogenic stroke

https://doi.org/10.1016/j.clineuro.2007.03.008Get rights and content

Abstract

Objective

To assess the prevalence of Fabry disease in young patients with cryptogenic stroke.

Patients and methods

We retrospectively assessed the prevalence of Fabry disease in patients aged 16–60 years that were admitted to ZNA Middelheim Hospital from January 1, 2000 to December 31, 2004 for cryptogenic stroke.

We screened for Fabry disease by measurement of α-galactosidase A and β-glucuronidase activity on blood spot. In all patients with abnormal enzymatic activity and in all female patients with low normal values, genetic sequencing of the α-GAL-gene was performed.

Results

In a population of 103 young patients with cryptogenic stroke that met the in- and exclusion criteria, we were unable to identify any patient with Fabry disease.

Conclusion

Based on the results of α-galactosidase A and β-glucuronidase activity, genetic sequencing and the low prevalence of clinical signs and symptoms of Fabry disease in this population, we believe that the true prevalence of Fabry disease in patients with cryptogenic stroke may be less than currently accepted in literature.

Introduction

Fabry disease (FD) is a rare X-linked lysosomal storage disorder in which partial or complete deficiency of α-galactosidase A (α-Gal) leads to progressive accumulation of metabolic intermediates, particularly globotriaosylceramide in many tissues.

Male hemizygotes with FD are generally more severely affected than heterozygote females, but disabling clinical features and disease progression often occur in female patients and are thought to be the consequence of unequal X chromosome inactivation [1], [2].

Patients with the classic phenotype of FD usually present in childhood with pain crises, acroparesthesia, hypohidrosis, gastrointestinal symptoms, angiokeratoma and corneal abnormalities. Severe morbidity and mortality follow in adult life due to renal failure, cardiac involvement and stroke [3]. This phenotype is thought to occur in 1 in 50,000 males, but estimates vary from 1 in 40,000 to 1 in 117,000 [4]. Late-onset cardiac and renal variants of FD without the early features as described above have been found in patients with residual α-Gal activity [5], [6] and are probably underdiagnosed [7]. Epidemiologic studies have identified FD in 6.3% of patients with late-onset idiopathic hypertrophic cardiomyopathy [8] and in 0.02–1.2% of patients undergoing chronic renal dialysis [6], [9]. Stroke is the third potentially life-threatening complication of FD and has been described in 13–25% of Fabry patients [10], [11]. Recently, Rolfs et al. diagnosed FD in 4% of young patients with cryptogenic stroke [12].

The incidence of stroke in Belgium is 1 in 18,975 inhabitants per year, of which 4% occurs before the age of 50 years and 10% between 50 and 60 years [13]. If 4% of young stroke patients suffers from FD, as suggested by Rolfs’ study, this would imply that about 50 strokes per year in Belgium could be attributable to FD. This is in strong contrast to the current prevalence of FD in Belgium where only 55 patients are known to have this disease (1 in 180,000) [14]. Therefore, the primary objective of this single-center study is to retrospectively asses the prevalence of FD in patients aged 16–60 years with cryptogenic stroke.

Section snippets

Study population

We retrospectively evaluated medical data from patients who were referred to ZNA Middelheim General Hospital from January 1, 2000 to December 31, 2004 for suspicion of stroke or transient ischemic attack (TIA). Only patients who experienced a cryptogenic TIA or stroke and that were at least 16 years and younger than 60 years at stroke onset were included. Cryptogenic TIA or stroke was diagnosed by physicians with experience in the field and according to the international recommendations on

Clinical data

We identified 401 patients who were referred to ZNA Middelheim General Hospital between January 1, 2000 and December 31, 2004 for suspicion of TIA or stroke and who were aged between 16 and 60 years at stroke onset (Fig. 1). After evaluation of the medical data, 188 patients were excluded. Reasons for exclusion were: no evidence for stroke or TIA (86 patients), onset of stroke before January 1, 2000 (27 patients), TIA or ischemic stroke secondary to carotid or vertebral artery dissection (six

Discussion

In Fabry disease, ischemic stroke occurs more frequently than hemorrhagic stroke and can be the consequence of cardiac embolism or cerebral vasculopathy. FD affects both the small and large vasculature in the brain directly with a predilection for the vertebrobasilar system [20]. Deposition of glycosphingolipids in vascular endothelial and smooth muscle cells may result in progressive stenosis and occlusion of small arteries and arterioles [21]. In larger vessels, lipid deposition is thought to

Conclusion

We were unable to identify any patient with FD in a population of 103 young stroke patients that suffered from cryptogenic stroke. Initial screening was performed by measurement of α-Gal activity on blood spot. This technique has proven to be reliable in hemizygous males, but only diagnoses 63–75% of the heterozygous women. In order to reduce false negative results, female patients with α-Gal activity in the lower 30% of the normal range were also regarded as abnormal and additional measurement

Conflicts of interest statement

We declare that we have no conflict of interest.

Acknowledgements

We thank the participating patients and colleagues for their commitment to the study and Shire Belgium for funding the infrastructure of the analytical part of the study. We are indebted to P. Hilbert and C. Verellen-Dumoulin, Institut de Pathologie et de Génétique, Loverval for the genetic analyses.

References (34)

  • R. Dobrovolny et al.

    Relation between X-inactivation and clinical involvement in Fabry heterozygotes. Eleven novel mutations in the alpha-galactosidase A gene in the Czech and Slovak population

    J Mol Med

    (2005)
  • R.O. Brady et al.

    Clinical features of and recent advances in therapy for Fabry disease

    JAMA

    (2000)
  • P.J. Meikle et al.

    Prevalence of lysosomal disorders

    JAMA

    (1999)
  • B. Sachdev et al.

    Prevalence of Anderson–Fabry disease in male patients with late onset hypertrophic cardiomyopathy

    Circulation

    (2002)
  • Tsakiris D, Simpson HK, Jones EH, Briggs JD, Elinder CG, Mendel S, et al. Report on management of renal failure in...
  • K.D. MacDermot et al.

    Anderson–Fabry disease: clinical manifestations and impact of diseases in a cohort of 98 hemizygous males

    J Med Genet

    (2001)
  • D. Devroey et al.

    Registration of stroke through the Belgian sentinel network and factors influencing stroke mortality

    Cerebrovasc Dis

    (2003)
  • Cited by (60)

    • Genetic Basis of Stroke Occurrence, Prevention, and Outcome

      2021, Stroke: Pathophysiology, Diagnosis, and Management
    • Fabry Disease in Young Ischemic Stroke Patients in Northern Israel

      2020, Journal of Stroke and Cerebrovascular Diseases
      Citation Excerpt :

      The available data regarding the prevalence of FD among young stroke patients are controversial. Brouns et al.13 retrospectively assessed the prevalence of FD in Belgian patients aged 16-60 with cryptogenic stroke and were not able to identify any patient with FD. Sims and colleagues14 explored data from 2446 patients with FD aiming to identify patients with stroke.

    • Prevalence of Fabry Disease in Young Patients with Stroke in Argentina

      2018, Journal of Stroke and Cerebrovascular Diseases
      Citation Excerpt :

      No mutation was identified in the third patient.43 The prevalence we identified in our study is similar to the low prevalence of FD reported by the SIFAP20, the largest study on the subject and is within the range of 0% to .5% reported by most studies evaluating FD in young patients with strokes.14,17-22 Although the frequency of FD among young adults with stroke is low, the prevalence is higher when patients with cryptogenic cerebrovascular accident are evaluated.

    • The Frequency of Fabry Disease among Young Cryptogenic Stroke Patients in the City of Sakarya

      2017, Journal of Stroke and Cerebrovascular Diseases
      Citation Excerpt :

      Rolfs et al reported the FD prevalence as 1.2% among the young cryptogenic ischemic stroke patients in 2005.2 However, Brouns et al did not detect any FD patients in their series with 103 young cryptogenic stroke patients.13 They also reported FD prevalence as 1% (10 FD out of 1000 stroke patients) in a general stroke population in 2010.17

    • Genetic Basis of Stroke Occurrence, Prevention and Outcome

      2016, Stroke: Pathophysiology, Diagnosis, and Management
    View all citing articles on Scopus
    View full text