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

Isabel De Brabander1, Laetitia Yperzeele, Chantal Ceuterick-De Groote

  • 1Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.

Clinical Neurology and Neurosurgery
|December 11, 2012
PubMed

Insights

Fabry disease screening in young stroke patients found GLA mutations but lacked classic signs. Enzyme tests may miss late-onset variants, suggesting genetic testing for suspected atypical cases.

Area of Science:

  • Genetics
  • Neurology
  • Rare Diseases

Background:

  • Fabry disease is a rare genetic disorder affecting multiple organs.
  • Cerebrovascular disease in young patients may be linked to Fabry disease.
  • The Belgian Fabry Study (BeFaS) investigated Fabry disease prevalence in young stroke patients.

Purpose of the Study:

  • To perform detailed phenotyping of individuals with alpha-galactosidase A (α-Gal A) enzyme deficiency or GLA mutations identified in the BeFaS.
  • To conduct family screening to identify additional mutation carriers and assess their clinical relevance.
  • To evaluate the diagnostic utility of enzyme activity tests and genetic testing in cerebrovascular disease patients.

Main Methods:

  • Genetic family screening was conducted to identify mutation carriers.
  • Biochemical evaluation included bloodspot and plasma α-Gal A enzyme activity, plasma Gb3 and lyso-Gb3 levels, and urine Gb3.
  • Clinical evaluation focused on identifying classic Fabry disease signs and cerebrovascular disease manifestations.

Main Results:

  • Eighteen additional GLA mutation carriers were identified through family screening.
  • Bloodspot α-Gal A enzyme activity was normal in all carriers, including those with the p.A143T mutation.
  • Classic Fabry disease signs were absent; cardiac symptoms were present in 6/10 p.A143T carriers, but no cerebrovascular disease was found in relatives.

Conclusions:

  • Classical Fabry disease phenotype mutations were not identified in this cerebrovascular disease population.
  • Enzyme activity analysis in bloodspots and plasma may not detect late-onset Fabry disease variants.
  • Genetic testing is recommended for suspected atypical, late-onset Fabry disease in male cerebrovascular patients, acknowledging potential identification of controversial variants.
Abstract

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