**1. Introduction**

Fabry disease (OMIM # 301500), also called Anderson-Fabry disease, is a rare X-linked lysosomal storage disorder due to mutations in the *GLA* gene, causing complete or partial deficiency of the lysosomal enzyme alpha-galactosidase A (α-Gal A) [1, 2]. The incidence of Fabry disease is estimated at 1:50,000 to 1:117,000 in males [3]. It has been found among all demographic, ethnic, and racial groups. Fabry disease has been recognized as a heterogeneous, highly complex, and multisystemic disease associated with a high burden of morbidity and mortality [2].

The α-Gal A enzyme is crucial for glycosphingolipid metabolism. Glycosphingolipids are normal constituents of the plasma membrane as well as the membranes of intracellular organelles. In Fabry disease, the α-Gal A deficiency results in a tissue accumulation of trihexosylceramide causing the disease's systemic manifestations [1]. Early and often asymptomatic cellular damage typically precedes various degrees of organ affection that can lead to progressive organ failure [2]. Males with less than 1% α-Gal A enzyme activity usually present with classic Fabry disease characterized by onset in childhood or adolescence. Symptoms include acroparesthesia, angiokeratomas, hypohidrosis or anhidrosis, characteristic corneal and lenticular opacities, cardiac disease, cerebrovascular manifestations, proteinuria, and gradual deterioration of renal function, as well as gastrointestinal, auditory, pulmonary, vascular, and psychological manifestations [4–12]. Males with greater than 1% α-Gal A activity may have later-onset phenotypes and typically develop renal and/or cardiac disease in their fourth to seventh decades of life [13, 14]. Heterozygous females usually have milder symptoms and a later age of onset than males. However, there is broad phenotypic variability and they may have symptoms as severe as those observed in males with the classic form [15, 16], possibly due to skewed X-chromosome inactivation [1, 17].

To date, more than 1000 mutations in the *GLA* gene have been identified [18], and research on clinically relevant genotype-phenotype relationships is increasingly prioritized [2]. Most of the pathogenic *GLA* mutations are private, occurring in a single or few families; intra-familial phenotypic variability has been observed, complicating the study of genotype-phenotype correlations [19]. Some mutations can be associated with the classic phenotype that includes nonsense, most of the splicing and frameshift mutations resulting in little or no α-Gal A enzyme activity [19]. In contrast, some missense mutations can encode enzymes with residual α-Gal A activity presenting with the later-onset phenotypes [19–21].

Current therapeutic approaches for Fabry disease include the reduction of accumulated glycosphingolipids through enzyme-replacement therapy (ERT) and a pharmacological chaperone for a subset of Fabry patients with amenable mutations, along with symptomatic and palliative treatments when needed [22]. In this chapter, we will focus on ERT in Fabry disease, which has clearly demonstrated a modifying effect on serious organ complications and mortality. Kidney manifestations in Fabry disease and the effect of ERT on clinical nephrological outcomes will be highlighted.
