How did we move from the initial concept 24 years ago to the current understanding of treating patients with Fabry Disease? A narrative review and personal perspective

Abstract

Fabry disease is a complex, devastating, progressive, hereditary X-linked lysosomal storage disorder. Females were once thought to be only carriers, but 25 years ago it became clear that heterozygous females can be as symptomatic as males, depending on their X-chromosome inactivation pattern and other factors. Although females are generally less affected, some are as severely ill as males. Patients with classical mutations show different disease progression from those with later-onset mutations. In most cases, Fabry disease progresses slowly, which limits the ability to demonstrate strong evidence for the efficacy of approved treatments. The best current evidence for treatment effects comes from registries and real-world data, since controlled clinical trials are no longer feasible after drug approval. Patients with classical mutations, especially males, should start treatment early to prevent disease progression. Clinicians should avoid overtreatment in patients with late-onset mutations, where general organ-protective rather than Fabry-specific treatment may be sufficient. Attention to each patient’s psychological response to the disease is essential, and patient involvement in decisions is paramount for adherence. Regional and international collaborations are crucial to advancing individualized management of Fabry disease.

Keywords

Fabry disease / lysosomal storage / enzyme replacement / hereditary / X-linked / phenotype variability / rare disease

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