Review Provides Overview of Clinical Picture, Diagnostic Confirmation of Fabry Disease

Investigators discuss the humoral response to enzyme-replacement therapy in their review of the clinical picture and diagnostic confirmation of Fabry disease.

A new review provides an overview of the clinical picture of Fabry disease (FD) and its diagnostic confirmation, as well as the biochemical and clinical significance of neutralizing anti-drug antibodies (ADAs) as a humoral response to enzyme-replacement therapy (ERT).

The review, published in Drugs, also discusses different methods for ADA measurement and characterization, as well as potential therapeutic approaches to mitigate ADAs in affected patients.

ERT was approved as the first causal treatment for FD in 2001. It works to stabilize kidney function (ie, estimated glomerular filtration rate, proteinuria) or delay progression to terminal kidney failure, stabilize cardiac mass and function and reduction of left ventricular hypertrophy, ameliorate FD-specific pain and gastrointestinal symptoms, and improve hypohidrosis.

Although ERT has been used to treat FD for years, but male patients have a high risk for the formation of neutralizing ADAs, which reduces the efficacy of ERT and leads to worse clinical outcomes. In men, a diagnosis of FD is confirmed by the determination of pathological low α-galactosidase A (AGAL) activity in leukocytes or in dried blood spots. In women, FD is confirmed by the detection of a disease-causing mutation in the GLA gene. Pathologically elevated globotriaosylsphingosine, the deacylated form of globotriaosylceramide, can be used as a biomarker for disease burden and contribute to diagnosis and therapy monitoring.

Once individuals receive a diagnosis of FD, experts suggest that therapeutic interventions should target pain reduction; preventing and/or delaying progressive organ manifestations, with a special focus on the kidney, heart, and central nervous system; improving quality of life; and normalizing life expectancy. Recommendations for FD-specific therapeutic approaches in adult patients with a classic or milder late-onset clinical phenotype should be personalized, because male patients with FD typically present with worse disease progression than females.

Past research has shown that patients who are cross-reactive immunologic material (CRIM) negative are more likely to develop an immune response after ERT initiation, since the therapeutic approach involves the intravenous infusion of a foreign recombinant protein that may cause the formation of specific antibodies. Infusion-associated reactions often occur in ERT-naive patients, predominantly CRIM-negative males with zero endogenous AGAL activity, after ERT initiation.

Although specific protocols to mitigate preexisting neutralizing ADAs in patients with FD have not been reported in detail, the investigators believe their findings show that an immunosuppressive therapy in transplanted male patients with FD might prevent ADA formation in ERT-naive patients and reduce ADA titers in patients undergoing ERT.

Existing protocols for immune tolerance induction to prevent or reduce ADAs can be transferred from other ERT-treated diseases to improve therapeutic efficacy in FD and other lysosomal storage diseases, the authors concluded.


Lenders M, Brand E. Mechanisms of neutralizing anti-drug antibody formation and clinical relevance on therapeutic efficacy of enzyme replacement therapies in Fabry disease. Drugs. 2021;81(17):1969-1981. doi:10.1007/s40265-021-01621-y

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