The impact of cardiovascular risk factors in non-classical Fabry disease

Recent advances in diagnostic and screening technologies have led to increased identification of presumed pathogenic GLA variants associated with non-classical Fabry disease (FD). However, the high number of identified carriers contrasts with the far lower incidence of clinical FD cases, raising questions about the clinical impact of these variants. Identifying drivers of symptom development and clinical heterogeneity is needed for guiding monitoring and intervention.

This study investigated a large cohort of 42 patients carrying the same p.I319T GLA variant to explore prognostic markers and disease-modifying factors in a monogenic context. Functional analysis of the variant in a GLA knockout HEK cell line revealed substantial residual enzyme activity (7%), and patients predominantly exhibited a cardiac phenotype, both consistent with non-classical FD. Among males, plasma lysoGb3 levels were markedly elevated, and all developed cardiac disease from age 50. Females showed variable clinical impact: those with intermediate plasma lysoGb3 levels developed cardiac complications after age 60, while those with low levels (< 2.3 nmol/L) rarely developed disease complications, even at older ages. Notably, 86% of the cohort had cardiovascular disease (CVD) risk factors, which likely contributed to the cardiac manifestations.

These findings suggest that while non-classical GLA variants may confer genetic susceptibility to cardiac disease, clinical expression is likely strongly influenced by CVD risk factors. Patients with elevated lysoGb3 may benefit from FD-specific therapy, but strict CVD risk management remains equally important. This study underscores the importance of integrating lifestyle interventions and CVD risk factor modification in carriers of non-classical FD associated GLA variants.