Sex Differences in Anderson-Fabry Cardiomyopathy: Clinical, Genetic, and Imaging Analysis in Women

Abstract: Anderson-Fabry Disease (AFD) is a rare, systemic lysosomal storage disease triggeredby mutations in the GLA gene, leading to -galactosidase A (-Gal A) deficiency. The disease'sX-linked inheritance leads to more severe, early-onset presentations in males, while females exhibitvariable, often insidious, manifestations, notably impacting cardiac health. This study aims toexamine gender-based AFD cardiac manifestations in correlation with the variant type: classical(CL), late-onset (LO), or variants of uncertain significance (VUS). We analyzed data from 72 AFDpatients (53 females, 19 males) referred to the "G. Rodolico" University Hospital, employing enzymeactivity measurements, genetic analysis, periodic lyso-Gb3 monitoring, comprehensive medicalhistories, and advanced cardiac imaging techniques. Statistical analysis was performed using SPSSversion 26. Our AFD cohort, with an average age of 45 16.1 years, comprised 12 individualswith hypertrophy (AFD-LVH) and 60 without (AFD-N). Women, representing about 75% of thesubjects, were generally older than men (47.2 16.2 vs. 38.8 14.6, p = 0.046). In the female group,17% had CL variants, 43.3% LO, and 39.6% had VUS, compared to 21.1%, 36.8%, and 31.6% in themale group, respectively. Females exhibited significantly higher -Gal A values (median 7.9 vs.1.8 nmol/mL/h, p < 0.001) and lower lyso-Gb3 levels (1.5 [IQR 1.1-1.7] vs. 1.9 [1.5-17.3] nmol/L,p = 0.02). Regarding the NYHA class distribution, 70% of women were in class I and 28% in classII, compared to 84% and 16% of men, respectively. Among women, 7.5% exhibited ventriculararrhythmias (10.5% in men), and 9.4% had atrial fibrillation (10.5% in men). Cardiac MRIs revealedfibrosis in 57% of examined women, compared to 87% of men. Even among patients without LVH,significant differences persisted in -Gal A and lyso-Gb3 levels (p = 0.003 and 0.04), as well as LVMi(61.5 vs. 77.5 g/sqm, p = 0.008) and GLS values (?20% vs. ?17%, p = 0.01). The analysis underscoredolder age, decreased lyso-Gb3 deposition, reduced hypertrophy, and lesser GLS compromise infemales, suggesting later disease onset. Severe cardiac patterns were associated with classic variants,while more nuanced manifestations were noted in those with VUS. Early GLS impairment in males,irrespective of hypertrophy, emphasized the role of subclinical damage in AFD.