Anderson-Fabry Disease: From Endothelial Dysfunction to Emerging Therapies

Abstract

The Anderson-Fabry disease is a rare, X-linked, multisystemic, progressive lysosomal storage disease caused by α-galactosidase A total or partial deficiency. The resulting syndrome is mainly characterized by early-onset autonomic neuropathy and life-threatening multiorgan involvement, including renal insufficiency, heart disease, and early stroke. The enzyme deficiency leads to tissue accumulation of the glycosphingolipid globotriaosylceramide and its analogues, but the mechanisms linking such accumulation to organ damage are only partially understood. In contrast, enzyme replacement and chaperone therapies are already fully available to patients and allow substantial amelioration of quality and quantity of life. Substrate reduction, messenger ribonucleic acid (mRNA)-based, and gene therapies are also on the horizon. In this review, the clinical scenario and molecular aspects of Anderson-Fabry disease are described, along with updates on disease mechanisms and emerging therapies.

Figure 1

Pathophysiology and clinical correlates of Anderson–Fabry disease. The ubiquitous accumulation of GL-3 is central to disease onset and progression.

Figure 2

Possible mechanisms of endothelial dysfunction in Anderson–Fabry disease. IMT: intima-media thickness; NADPH: nicotinamide adenine dinucleotide phosphate; eNOS: endothelial nitric oxide synthase; RAS: renin-angiotensin system; RNS: reactive nitrogen species; ROS: reactive oxygen species.

Figure 3

Enzyme replacement therapy and emerging alternatives. ^∗abnormally folded, unstable α-Gal A protein with preserved enzymatic activity; iv: intravenous; ER: endoplasmic reticulum; eGFR: estimated glomerular filtration rate; ESRD: end-stage renal disease; BBB: blood-brain barrier; AAV: adeno-associated viral vector; LNPs: lipid nanoparticles.