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Schiffmann. Rare Dis Orphan Drugs J 2024;3:4 Rare Disease and
DOI: 10.20517/rdodj.2023.50
Orphan Drugs Journal

Review Open Access

Investigating Fabry disease - some lessons learned

Raphael Schiffmann
Department of Internal Medicine, Texas Christian University, Fort Worth, TX 76129, USA.
Correspondence to: Prof. Raphael Schiffmann, Department of Internal Medicine, Texas Christian University, TCU Box 297085,
Fort Worth, TX 76129, USA. E-mail: rschiffmann@gmail.com

How to cite this article: Schiffmann R. Investigating Fabry disease - some lessons learned. Rare Dis Orphan Drugs J 2024;3:4.
https://dx.doi.org/10.20517/rdodj.2023.50

Received: 11 Nov 2023 First Decision: 19 Dec 2023 Revised: 24 Dec 2023 Accepted: 15 Jan 2024 Published: 23 Jan 2024

Academic Editor: Guillem Pintos-Morell Copy Editor: Dan Zhang Production Editor: Dan Zhang

Abstract
Despite recent advances, there is still much to be learned about the pathogenesis of Fabry disease. The
categorization of GLA gene missense mutations has been complicated by the fact that some missense variants may
fall into more than one category. For instance, the A143T variant may cause late-onset Fabry disease in some
subjects and not result in Fabry disease in others (pseudo-deficient). Efforts to mitigate the pathobiology of
α-galactosidase A deficiency should differentiate between damaging (maladaptive) consequences and
compensatory (adaptive) changes. Current therapy leaves a significant unmet need, especially concerning
cardiovascular complications and cardiological clinical outcomes. Non-Fabry-specific therapy is necessary and
quite beneficial and must be utilized. Its contribution should be considered when trying to assess the net effect of
Fabry-specific therapy. Enzyme replacement therapy (ERT) can be administered to patients independently of their
GLA genotype, as it slows the decline of kidney function in most patients if initiated sufficiently early in the disease
course. Migalastat has better tissue penetration than ERT, but its usefulness is restricted to patients with amenable
missense GLA variants. However, it is important to realize that in a substantial proportion of common amenable
mutations, migalastat increases α-galactosidase A activity level beyond the disease threshold and thus eliminates
the metabolic disturbance that is at the center of Fabry disease. Substrate reduction therapy and gene therapy
approaches are being developed, but these therapeutic modalities have their own limitations and difficulties.
Keywords: Pathogenesis, lysosomal disease, ERT, pharmacological chaperone, gene therapy, GLA variant

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