Gene Mutations Versus Clinically Relevant Phenotypes-Lyso-Gb3 Defines Fabry Disease
Background—Currently, no method is available to identify alpha-galactosidase A (agalA) mutations determining clinically relevant Fabry disease. In our European largest Fabry cohort we investigated whether a biomarker, specific for the defect, could stratify persons at risk.
Methods and Results—124 individuals with agalA mutations were investigated with a comprehensive clinical work-up, 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 work-up of relatives was done. The patient population was divided in two samples: previously described mutations (n=72) and novel mutations (n=52). The patients with previously described mutations were subdivided into two 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 three main organs (heart, kidney, 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 cut-off value of 2.7 ng/ml separated the two groups. 6 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.
- Received January 26, 2013.
- Revision received October 29, 2013.
- Accepted December 11, 2013.