Research Report

JIMD Reports - Case and Research Reports, 2012/5

Volume 8 of the series JIMD Reports pp 101-108

Open Access This content is freely available online to anyone, anywhere at any time.

Date:

Questioning the Pathogenic Role of the GLA p.Ala143Thr “Mutation” in Fabry Disease: Implications for Screening Studies and ERT

  • W. TerrynAffiliated withDepartment of Internal Medicine, Division of Nephrology, Regional Hospital Jan YpermanDepartment of Internal Medicine, Division of Nephrology, Ghent University Hospital Email author 
  • , R. VanholderAffiliated withDepartment of Internal Medicine, Division of Nephrology, Ghent University Hospital
  • , D. HemelsoetAffiliated withDepartment of Neurology, Ghent University Hospital
  • , B. P. LeroyAffiliated withDepartment of Ophthalmology, Ghent University Hospital & Ghent UniversityCenter for Medical Genetics, Ghent University Hospital
  • , W. Van BiesenAffiliated withDepartment of Internal Medicine, Division of Nephrology, Ghent University Hospital
  • , G. De SchoenmakereAffiliated withDepartment of Internal Medicine, Division of Nephrology, Heilig Hart Ziekenhuis
  • , B. WuytsAffiliated withDepartment of Clinical Biology, Laboratory for Metabolic Diseases, Ghent University Hospital
  • , K. ClaesAffiliated withCenter for Medical Genetics, Ghent University Hospital
  • , J. De BackerAffiliated withDepartment of Cardiology, Ghent University Hospital
    • , G. De PaepeAffiliated withCenter for Medical Genetics, Ghent University Hospital
    • , A. FogoAffiliated withDepartment of Pathology, Vanderbilt University Medical Center
    • , M. PraetAffiliated withDepartment of Pathology, Ghent University Hospital
    • , B. PoppeAffiliated withCenter for Medical Genetics, Ghent University Hospital

Abstract

Fabry disease is an X-linked inborn error of glycosphingolipid metabolism caused by quantitative or qualitative defects in the lysosomal enzyme alfa-Galactosidase A (aGAL A), ultimately resulting in vital organ dysfunction. Mainly the kidneys, the heart, and the central nervous system are involved. While the classical phenotype of Fabry disease is readily recognizable, screening studies have identified clinical variants. Here, we report the phenotype associated with the GLA p.Ala143Thr (c.427G>A) mutation in 12 patients aged 42–83 years. None of the patients had classical Fabry signs or symptoms as angiokeratoma, hypohidrosis, acroparesthesia, or cornea verticillata. Possible Fabry manifestations were renal failure (5/12), stroke (7/12), and left ventricular hypertrophy (5/12), but these were not necessarily attributable to the p.Ala143Thr mutation, as a cardiac biopsy in one female and left ventricular hypertrophy and kidney biopsies in two males with renal failure and microalbuminuria lacked Gb-3 deposits. The literature data on this mutation as well as data collected in the Fabry Outcome Survey (FOS) database confirm these findings. The association of renal failure, stroke, and left ventricular hypertrophy with this mutation could be the result of selection bias, as most patients were detected in screening studies.

We conclude that care should be taken with attribution of vital organ dysfunction to GLA sequence alterations. In case of the p.Ala143Thr mutation, and possibly also other mutations associated with an attenuated phenotype, diagnostic tools such as biopsy and imaging should critically evaluate the relation of end-organ failure with Fabry disease, as this has important consequences for enzyme replacement therapy.