A Meta-Analysis to Unveil the Diagnostic Gaps in Anderson-Fabry Disease in Women

Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to deficient α-galactosidase A activity. Although historically considered a male disease, it is now recognized that heterozygous women can present with a wide range of symptoms. However, diagnosis in women remains challenging, as enzymatic activity may be normal. A meta-analysis of 67 studies was conducted to evaluate the prevalence of AFD in female populations referred for cardiac, renal, or cerebrovascular events of unknown etiology, focusing on current diagnostic methodologies. Out of 28 878 high-risk women screened, 114 were diagnosed with AFD, yielding a pooled prevalence of 0.007 (95% CI 0.005-0.009). When considering the prevalence in the three main groups of indication for AFD testing (patients referred for cardiac, renal or cerebrovascular events of unknown etiology), the highest prevalence was found after a stroke (23 studies: 0.014, 95% CI 0.011-0.019), followed by cardiac event (19 studies: 0.010, 95% CI 0.007-0.015) and renal event (25 studies: 0.004, 95% CI 0.003-0.006). Genetic testing was significantly more effective in identifying cases (prevalence of AFD from 34 studies: 0.012, 95% CI 0.010-0.015) compared to enzymatic protocols (prevalence of AFD from 33 studies: 0.003, 95% CI 0.002-0.005). However, the reliance on enzymatic testing in some regions is still preferred. These findings underscore the limitations of relying solely on enzymatic assays in women and highlight the critical role of genetic testing in achieving accurate diagnosis. Early identification allows for timely treatment and enables family cascade screening, preventing further missed diagnoses.