Fabry disease beyond the classical model: clinical presentation and diagnostic challenges in women

The prevailing concept of Fabry disease as a condition affecting only males, being females considered merely carriers has been superseded by a more nuanced understanding of the condition as a highly complex multisystemic disorder. Contemporary evidence contradicts the prevailing paradigm that heterozygous women are asymptomatic, thereby underscoring substantial phenotypic heterogeneity and a considerable risk of irreversible organ damage. A high index of clinical suspicion is required for diagnosis, which includes family screening, multisystemic evaluation, determination of enzyme activity, and genetic testing, especially in women, in whom residual α-galactosidase A activity may be normal. The treatment of this condition is based on three fundamental approaches: enzyme replacement therapy, pharmacological chaperones, and emerging therapeutic strategies. The latter includes substrate-depleting therapy, mRNA-based therapies, and gene therapy. It is imperative to initiate treatment at an early stage in order to delay disease progression. This review summarizes the current evidence on the epidemiology, pathophysiology, diagnosis and treatment of Fabry disease, with particular emphasis on clinical variability and the relevance of the disease in women - who have historically been considered asymptomatic carriers - as well as the need for sex-specific studies.