Precision Medicine in Fabry Disease

Nephrol Dial Transplant 2021 Jun 22;36(Supplement_2):14-23. doi: 10.1093/ndt/gfab038.

PMID: 34153986

Malte Lenders, Eva Brand

Highlights: In Fabry disease, precision medicine practices can enable physicians to predict more accurately which prevention and treatment strategy is best for which patient.

Abstract

Background: Fabry disease (FD) is an X-linked lysosomal storage disease caused by mutations in the α-galactosidase A (GLA) gene, which results in a deficiency in α-galactosidase A. The lysosomal accumulation of glycosphingolipids, primarily globotriaosylceramide (Gb3) and its deacylated form, globotriaosylsphingosine (lyso-Gb3), causes progressive renal failure, cardiomyopathy with cardiac arrhythmia, and recurrent cerebrovascular events, severely limiting the life expectancy of affected patients. A GLA deficiency in leucocytes is required for a definitive diagnosis of FD in male patients. Because of the possibility for substantial residual enzymatic activity in females, molecular genetic tests are the gold standard for diagnosis. Recombinant enzyme replacement therapies (ERTs) with intravenous agalsidase-α (0.2 mg/kg body weight) or agalsidase-β (1 mg/kg body weight) every 2 weeks, as well as an oral pharmacological chaperone (migalastat 123 mg every other day) that selectively and reversibly binds to the active sites of amenable mutant forms of the GLA enzyme, are the current treatment options for FD. These treatments help with cellular Gb3 clearance and overall disease burden reduction. ERT, on the other hand, can cause infusion-related reactions as well as the production of neutralizing anti-drug antibodies in up to 40% of ERT-treated males, resulting in a reduction in therapy efficacy.

Objective: This article discusses the clinical presentation, diagnosis, and interdisciplinary clinical management of FD, as well as therapeutic options, with a special focus on precision medicine, which accounts for individual variability in genetic mutations, Gb3 and lyso-Gb3 levels, allowing physicians to predict which prevention and treatment strategy is best for which patient.

Keywords: Fabry disease, chaperone therapy,  precision medicine, renal replacement therapy, α-galactosidase A.