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.
Highlights
In 1898, two dermatologists, Johannes Fabry in Dortmund and William Anderson in London, reported similar patients with characteristic skin lesions, so-called angiokeratoma corporis diffusum [1,2]
The molecular basis for lipid abnormalities was firstly elucidated by Brady and coworkers, demonstrating the deficiency of lysosomal acid α-galactosidase activity converting Gb3 to lactosylceramide (LacCer) [5]
Subsequent research revealed that the reduced α-galactosidase activity in Fabry disease (FD) patients stems from the lysosomal enzyme α-galactosidase A (α-GalA) that is encoded by the GLA gene located
Summary
In 1898, two dermatologists, Johannes Fabry in Dortmund and William Anderson in London, reported similar patients with characteristic skin lesions, so-called angiokeratoma corporis diffusum [1,2]. Subsequent research revealed that the reduced α-galactosidase activity in FD patients stems from the lysosomal enzyme α-galactosidase A (α-GalA) that is encoded by the GLA gene located. NAGA ( known as α-Galactosidase B (α-GalB)), locus 22q13.2, evolved into an N-acetylgalactosaminidase cleaving α-N-acetylgalactosamine from glycoconjugates [7,8]. The globoside Gb3 is degraded by α-GalA, a minor α-GalB activity towards this metabolite has been reported [11]. Thanks to the work of many, by Sakuraba and colleagues, the consequences at the enzyme level of several α-GalA mutations are known [13]. -called α-GalA mutations of unknown significance are often not associated with clearly reduced α-galactosidase activity, promoting the debate as to whether they truly are causing FD [15]
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