Fabry disease is a rare, multisystemic, lysosomal storage disorder caused by variants in the GLA gene, which is located on the X chromosome. The GLA gene encodes the enzyme alpha-galactosidase A (α-Gal A).1 More than 1000 variants in the GLA gene have been identified, leading to a deficiency of α-Gal A activity (see genetic inheritance of Fabry disease).2-5 In patients with 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 (Figure 1).4,6 Progressive glycosphingolipid accumulation within cells culminates in the varied disease manifestations of Fabry disease (Figure 2).4,5 Enzymatic activity levels of α-Gal A are somewhat predictive of the classical or late-onset phenotypes of Fabry disease.4 Variants in the GLA gene culminating in little or no enzyme activity (<1%) are associated with classical Fabry disease, whereas patients with residual α-Gal A activity (≥1‒30%) typically develop late-onset Fabry disease.1,7-9 Patients with the classical phenotype usually present with the characteristic symptoms of Fabry disease, whereas for patients with the late-onset phenotype, the disease course may be more variable, and some patients are generally less severely affected; clinical manifestations may also even be limited to a single organ.10,11

Figure 1.
Progression of Fabry disease. Reproduced with permission from Eng CM et al. J Inherit Metab Dis 2007; 30: 184-192.12

Figure 2.
The clinical manifestations of classical Fabry disease are varied.7

The incidence of Fabry disease is estimated to affect approximately 1 in 40,000 males and approximately 1 in 20,000 females.11,13 However, data from newborn screening programmes suggest that the prevalence of Fabry disease is underestimated and is much higher than previously approximated.11,13-19 Fabry disease can affect all ethnic, racial and demographic groups.20

Given that Fabry disease is characterised by severe multisystemic involvement, with a wide range of signs and symptoms, this may ultimately lead to major organ failure and premature death.11,21 The age at onset of disease manifestations in males and females with Fabry disease can also vary.21 Consequently, Fabry disease can have a significant impact on patients with many exhibiting a reduced quality of life.22


C-ANPROM/INT/FAB/0015; Date of preparation: March 2021