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