Agalsidase Alfa (Replagal®): A Comprehensive Monograph on an Enzyme Replacement Therapy for Fabry Disease

Section 1: Introduction to Fabry Disease and the Rationale for Enzyme Replacement Therapy

1.1 The Pathophysiology of a Lysosomal Storage Disorder

Fabry disease, also known by a variety of historical names including Anderson-Fabry disease and angiokeratoma corporis diffusum universale, is a rare, progressive, X-linked lysosomal storage disorder.[1] The disease arises from mutations in the

GLA gene, located on the X chromosome (Xq22), which encodes the lysosomal enzyme alpha-galactosidase A (α-Gal A).[2] These mutations, of which over 300 have been described, result in a deficiency or complete absence of functional α-Gal A activity.[5] The evolution of the disease's nomenclature reflects the scientific journey from early clinical observations, such as the dermatological finding of "angiokeratoma corporis diffusum," to the identification of its primary end-organ impact in the "cardiovasorenal syndrome," and finally to the elucidation of its biochemical basis as a "ceramide trihexosidase deficiency".[1] This historical progression underscores the complex, multi-systemic nature of the disorder and highlights the fundamental need for a systemic therapeutic approach.

The X-linked inheritance pattern leads to distinct clinical presentations. Hemizygous males, who inherit the single defective X chromosome, typically experience the most severe form of the disease. Heterozygous females, who have one normal and one mutated GLA gene, can have a highly variable clinical course due to random X-chromosome inactivation (lyonization), ranging from being asymptomatic carriers to having severe manifestations comparable to males.[5] The specific