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Implementing evolving Fabry disease management recommendations in resource-constrained settings: lessons from South Africa
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DOI：10.1186/s13023-026-04542-9.png)
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Abstract
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Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by deficient activity of the enzyme α-galactosidase A, resulting in glycosphingolipid accumulation and progressive involvement of multiple organ systems, particularly the kidneys, heart and cerebrovascular system. Clinical manifestations are highly heterogeneous, with disease onset ranging from early childhood to late adulthood depending on sex, genotype and phenotype. Although rare, FD can result in substantial morbidity and premature mortality when diagnosis is delayed or management is suboptimal. International registry data suggest that diagnostic delays of more than a decade are common, with many patients presenting with advanced organ involvement before treatment is initiated. Delayed diagnosis and late initiation of therapy may be associated with irreversible organ damage and substantial downstream healthcare use related to dialysis, cardiac complications and stroke. Earlier recognition may improve the opportunity for clinically beneficial intervention; however, whether earlier initiation of high-cost disease-specific therapy represents a cost-effective use of resources depends on phenotype, disease stage, expected treatment effect, treatment cost and the opportunity costs within the relevant healthcare system. Over the past decade, the international evidence base guiding FD management has evolved substantially. Contemporary consensus recommendations increasingly emphasise earlier initiation of disease-specific therapy, improved recognition of clinically significant disease in females, genotype-informed treatment strategies, and risk-stratified approaches to monitoring and longitudinal care. Advances in biomarkers, molecular diagnostics and cardiac imaging have further refined approaches to disease assessment and treatment decision-making. This commentary highlights key developments in the international management of FD since the publication of South African recommendations in 2015 and considers their implications for rare disease care in resource-constrained health systems. It proposes an adaptive, resource-stratified implementation framework that integrates evolving international recommendations with transparent treatment prioritisation, longitudinal monitoring, local real-world evidence generation and periodic reassessment. The framework recognises that treatment effects differ by phenotype, sex, organ involvement and disease stage, and that decisions concerning high-cost disease-specific therapies must consider expected benefit, uncertainty, equity, affordability and opportunity cost.
Keywords:
Fabry disease
Lysosomal storage disorder
Rare diseases
Enzyme replacement therapy
Early diagnosis
Risk stratification
Disease monitoring
South Africa
Real-world evidence
Resource-constrained settings
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