Why use genetic testing?
In patients with Fabry disease, variants in the GLA gene encoding the lysosomal enzyme alpha-galactosidase A (α-Gal A) lead to alterations or a reduction in enzyme activity.1 Deficient activity of α-Gal A leads to an accumulation of the glycosphingolipids globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) within almost all cell types and various organs.2-4 Assessing α-Gal A enzyme activity can be used to confirm a diagnosis of Fabry disease in males.5-8 However, the α-Gal A enzyme assay is considered less reliable for diagnosing Fabry disease in females because many patients exhibit enzyme activity levels comparable with those in unaffected individuals without Fabry disease.5,6 Genetic testing is therefore used to confirm a diagnosis of Fabry disease in female patients, and can be used to support a diagnosis in males.5-8
What is genetic testing for Fabry disease?
More than 1000 variants in the GLA gene leading to a deficiency of α-Gal A activity have been identified.9,10 GLA variants may be attributed to classical or late-onset Fabry disease (see genetic inheritance); many variants have also been categorised on fabry-database.org.11,12 The majority of GLA variants are private, occurring in single or a few families.12,13 Although, even in the same families with the same GLA variant, disease manifestations of Fabry disease can vary between patients.14 To identify Fabry disease-related variants, it is considered necessary to sequence the whole GLA gene and flanking regions.15 Genomic DNA can be extracted from peripheral-blood lymphocytes or dried blood spots using standardised protocols.16,17 In some instances, conventional genomic sequencing may not identify familial variants in the gene coding or flanking region, and microarray-based duplication or deletion testing of the GLA gene may be used.15 Moreover, standard GLA sequencing techniques may not detect large deletions, large duplications, some intronic variants, and variants in the promoter region or other regulatory regions. The results of GLA sequencing must therefore be interpreted in the context of a patient’s individual clinical and biochemical profile.15 GLA gene sequencing results should be analysed by an expert and it is recommend that genetic counselling be offered to patients.18 Following a diagnosis of Fabry disease, a thorough pedigree analysis should be performed to identify any at-risk family members (see family screening).15,18
C-ANPROM/INT/FAB/0016; Date of preparation: March 2021
- Vardarli I, Rischpler C, Herrmann K, et al. Diagnosis and screening of patients with Fabry disease. Ther Clin Risk Manag 2020; 16: 551-558.
- Felis A, Whitlow M, Kraus A, et al. Current and investigational therapeutics for Fabry disease. Kidney Int Rep 2019; 5: 407-413.
- Schiffmann R, Hughes DA, Linthorst GE, et al. Screening, diagnosis, and management of patients with Fabry disease: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference. Kidney Int 2017; 91: 284-293.
- Brady RO, Gal AE, Bradley RM, et al. Enzymatic defect in Fabry's disease. Ceramidetrihexosidase deficiency. N Engl J Med 1967; 276: 1163-1167.
- Gupta S, Ries M, Kotsopoulos S, et al. The relationship of vascular glycolipid storage to clinical manifestations of Fabry disease: a cross-sectional study of a large cohort of clinically affected heterozygous women. Medicine (Baltimore) 2005; 84: 261-268.
- Barbey F, Hayoz D, Widmer U, et al. Efficacy of enzyme replacement therapy in Fabry disease. Curr Med Chem Cardiovasc Hematol Agents 2004; 2: 277-286.
- Mehta A. Agalsidase alfa: specific treatment for Fabry disease. Hosp Med 2002; 63: 347-350.
- German Society for Neurology (DGN). Interdisciplinary guidelines for the diagnosis and treatment of Fabry disease. September 2013.
- McCafferty EH, Scott LJ. Migalastat: a review in Fabry disease. Drugs 2019; 79: 543-554.
- Tuttolomondo A, Simonetta I, Duro G, et al. Inter-familial and intra-familial phenotypic variability in three Sicilian families with Anderson-Fabry disease. Oncotarget 2017; 8: 61415-61424.
- Fabry disease mutation database. Available at: http://fabry-database.org/mutants/. Accessed November 2020.
- Ortiz A, Germain DP, Desnick RJ, et al. Fabry disease revisited: management and treatment recommendations for adult patients. Mol Genet Metab 2018; 123: 416-427.
- Wanner C, Oliveira JP, Ortiz A, et al. Prognostic indicators of renal disease progression in adults with Fabry disease: natural history data from the Fabry Registry. Clin J Am Soc Nephrol 2010; 5: 2220-2228.
- Ortiz A, Abiose A, Bichet DG, et al. Time to treatment benefit for adult patients with Fabry disease receiving agalsidase β: data from the Fabry Registry. J Med Genet 2016; 53: 495-502.
- Laney DA, Bennett RL, Clarke V, et al. Fabry disease practice guidelines: recommendations of the National Society of Genetic Counselors. J Genet Couns 2013; 22: 555-564.
- Stiles AR, Zhang H, Dai J, et al. A comprehensive testing algorithm for the diagnosis of Fabry disease in males and females. Mol Genet Metab 2020; 130: 209-214.
- Hagège AA, Caudron E, Damy T, et al. Screening patients with hypertrophic cardiomyopathy for Fabry disease using a filter-paper test: the FOCUS study. Heart 2011; 97: 131-136.
- Gal A, Hughes DA, Winchester B. Toward a consensus in the laboratory diagnostics of Fabry disease – recommendations of a European expert group. J Inherit Metab Dis 2011; 34: 509-514.