INTRODUCING
DIAGNOSIS OF FABRY DISEASE
Fabry disease is a multisystemic disorder with a range of signs and symptoms, and should be considered in the differential diagnosis of many systemic diseases.
Fabry disease is a complex, multisystemic disorder with a wide range of signs and symptoms.1 Variants in the GLA gene encoding alpha-galactosidase A (α-Gal A) lead to alterations in lysosomal enzyme activity.2 Enzyme activity levels of <1% for α-Gal A are suggestive of classical Fabry disease.2,3 Patients with residual enzyme activity of levels of α-Gal A >3‒30% typically have late-onset Fabry disease.4 The α-Gal A enzyme assay, in addition to genetic testing, 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.6-8 A diagnostic algorithm for Fabry disease in males and females is presented in Figure 1.
Figure 1.
Proposed diagnostic algorithm for Fabry disease in males and females. Reproduced with permission from Michaud M et al. Am J Med Sci 2020; 360: 641-649.4
In patients with lysosomal storage disorders, biomarkers can be used to support a diagnosis.9 In Fabry disease, deficient enzymatic 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.2,10-12 Therefore, lyso-Gb3 is a useful diagnostic biomarker, because levels are markedly elevated in some patients with Fabry disease, particularly males.2,13,14 The extent of organ involvement in Fabry disease can also be assessed via a number of clinical indicators.15
Following a diagnosis of Fabry disease, a thorough pedigree analysis should be performed for each patient to identify any family members at risk of Fabry disease.16,17 One of the advantages of family screening is the identification of family members early in the disease course.18 In addition, family screening for Fabry disease may also identify patients who are at risk of having children with the disease (see prenatal and newborn screening).19
C-ANPROM/INT/FAB/0016; Date of preparation: March 2021
- Kiykim E, Zeybek CAA, Zubarioglu T, et al. Lessons from two cases: is Fabry disease the correct diagnosis? BMJ Case Rep 2015; 2015: bcr2014208150.
- Vardarli I, Rischpler C, Herrmann K, et al. Diagnosis and screening of patients with Fabry disease. Ther Clin Risk Manag 2020; 16: 551-558.
- Clarke JT. Narrative review: Fabry disease. Ann Intern Med 2007; 146: 425-433.
- Michaud M, Mauhin W, Belmatoug N, et al. When and how to diagnose Fabry disease in clinical pratice. Am J Med Sci 2020; 360: 641-649.
- 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.
- Simonetta I, Tuttolomondo A, Daidone M, et al. Biomarkers in Anderson-Fabry Disease. Int J Mol Sci 2020; 21.
- 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.
- Aerts JM, Groener JE, Kuiper S, et al. Elevated globotriaosylsphingosine is a hallmark of Fabry disease. Proc Natl Acad Sci U S A 2008; 105: 2812-2817.
- Rombach SM, Dekker N, Bouwman MG, et al. Plasma globotriaosylsphingosine: diagnostic value and relation to clinical manifestations of Fabry disease. Biochim Biophys Acta 2010; 1802: 741-748.
- Hughes DA, Aguiar P, Deegan PB, et al. Early indicators of disease progression in Fabry disease that may indicate the need for disease-specific treatment initiation: findings from the opinion-based PREDICT-FD modified Delphi consensus initiative. BMJ Open 2020; 10: e035182.
- 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.
- 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.
- Laney DA, Fernhoff PM. Diagnosis of Fabry disease via analysis of family history. J Genet Couns 2008; 17: 79-83.
- Germain DP. General aspects of X-linked diseases. In: Mehta A, Beck M, Sunder-Plassmann G, eds. Fabry Disease: Perspectives from 5 Years of FOS. Oxford, UK: Oxford PharmaGenesis, 2006.