Fabry Disease: Molecular Basis, Pathophysiology, Diagnostics and Potential Therapeutic Directions

Abstract

Fabry disease (FD) is a lysosomal storage disorder (LSD) characterized by the deficiency of α-galactosidase A (α-GalA) and the consequent accumulation of toxic metabolites such as globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3). Early diagnosis and appropriate timely treatment of FD patients are crucial to prevent tissue damage and organ failure which no treatment can reverse. LSDs might profit from four main therapeutic strategies, but hitherto there is no cure. Among the therapeutic possibilities are intravenous administered enzyme replacement therapy (ERT), oral pharmacological chaperone therapy (PCT) or enzyme stabilizers, substrate reduction therapy (SRT) and the more recent gene/RNA therapy. Unfortunately, FD patients can only benefit from ERT and, since 2016, PCT, both always combined with supportive adjunctive and preventive therapies to clinically manage FD-related chronic renal, cardiac and neurological complications. Gene therapy for FD is currently studied and further strategies such as substrate reduction therapy (SRT) and novel PCTs are under investigation. In this review, we discuss the molecular basis of FD, the pathophysiology and diagnostic procedures, together with the current treatments and potential therapeutic avenues that FD patients could benefit from in the future.

Keywords: A4GALT; Fabry disease; enzyme replacement therapy; globotriaosyl-sphingosine (lysoGb3); globotriaosylceramide (Gb3); lysosomal storage disorders; pharmacological chaperone therapy; substrate reduction therapy; α-galactosidase A.

Figure 1

Enzyme structure and reaction mechanism of α-N-acetylgalactosaminidase (α-GalB) and α-galactosidase A (α-GalA). (A) Active site of α-GalB (gray) with GalNAc (blue) bound in the pocket. (B) Active site of α-GalA (blue) with galactose (black). Larger C-2 substituents cannot be accommodated in α-GalA due to the presence of residues L206 and E203. Structures were obtained from the Protein Data Bank (PDB) IDs 3H55, 3H54 or 3GXP and visualized using CCP4MG. (C) Koshland double displacement mechanism of retaining α-GalA.

Figure 2

α-GalA inhibitors and activity-based probes (ABPs). (A) Irreversible inhibitors: 2-deoxy-2-fluoro-D-galactosyl fluoride 1, conduritol C 2, cyclophellitol epoxide 3, cyclophellitol aziridine 4 and cyclosulfate 5. (B) Reversible inhibitors: Gal-DNJ 6; cyclosulfamidate 7. (C) ABPs: Cy5 probe 8 (blue), Bodipy-green probe 9 (green) and biotinylated probe 10 (black).

Figure 3

Therapeutic strategies for treatment of Fabry disease. (A) Enzyme replacement therapy (ERT). (B) Pharmacological chaperone therapy (PCT). (C) Substrate reduction therapy (SRT). (D) Gene therapy.

Figure 4

Active site of bacterial A4GALT homologue LgtC. Enzyme active site containing donor analogue UDP-2FGal (black) and acceptor analogue 4′-deoxylactose (green) bound in the pocket. The Mn²⁺ cation (pink) coordinates with the diphosphate group of UDP-Gal and the DXD motif (yellow) to assist in catalysis. Residue D190 (purple) is positioned 8.9 Å away from the UDP-Gal donor and is visualized for clarity. Structure was obtained from the Protein Data Bank (PDB) ID 1GA8 and visualized using CCP4MG.

Figure 5

Proposed A4GALT mechanisms. (A) Koshland double displacement mechanism of retaining glycosyltransferases (GTs). (B) Front-face (S_Ni-like) mechanism of retaining GTs.

Figure 6

A4GALT glycosphingolipid (GSL) products and Gb3 modulators. (A) Structures of glycosphingolipids produced by A4GALT. (B) AdaGalCer 11 and AdaGlcCer 12 and their effect on GSL production.