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Gene Mutations Versus Clinically Relevant Phenotypes: Lyso-Gb3 Defines Fabry Disease

Markus Niemann, MD Prof. Arndt Rolfs, MD Stefan Störk, MD PhD Bart Bijnens, PhD Frank Breunig, MD Prof. Meinrad Beer, MD Georg Ertl, MD Christoph Wanner, MD
January 06, 2014

Circ Cardiovasc Genet. 2014;7:8-16.

Background: Currently, no method is available to identify α-galactosidase A (agalA) mutations determining clinically relevant Fabry disease. In our largest European Fabry cohort, we investigated whether a biomarker, specific for the defect, could stratify persons at risk.

Methods and Results: A total of 124 individuals with agalA mutations were investigated with a comprehensive clinical workup, genetic analysis, and laboratory testing, including measurements of agalA activity and lyso-Gb3 (degradation product of the accumulating Gb3). Additionally, an extensive family screening with a clinical workup of relatives was performed. The patient population was divided into 2 samples: previously described mutations (n=72) and novel mutations (n=52). The patients with previously described mutations were subdivided into 2 groups: classical mutations, which were known to cause the classic type of Fabry disease with specific symptoms and a high risk for major events in all 3 main organs (heart, kidney, and central nervous system), and atypical mutations without the typical presentation. All patients with atypical mutations (n=17) had lower lyso-Gb3 levels than any of the patients with classical Fabry disease (n=55). A cutoff value of 2.7 ng/mL separated the 2 groups. Six out of 52 patients with novel mutations showed a lyso-Gb3 level <2.7 ng/mL. Clinical investigation, blinded to lyso-Gb3 results, revealed no classic organ involvement in these patients or their relatives. In contrast, the characterization of patients with lyso-Gb3≥2.7ng/mL suggested classical Fabry mutations in most of the patients (93%).

Conclusions: Our data show that the biomarker lyso-Gb3 may identify the clinically relevant agalA mutations leading to Fabry disease.