BURDEN OF DISEASE

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