Central nervous system biomarkers in Fabry disease: Mechanisms, clinical evidence, and translational integration

Fabry disease is an X-linked lysosomal disorder caused by deficient α-galactosidase A activity, leading to progressive tissue accumulation of globotriaosylceramide (Gb₃) and globotriaosylsphingosine (lyso-Gb₃) throughout the body, with vascular, renal, cardiac, and neural tissues considered the most prominently affected. Although renal and cardiac endpoints currently dominate therapeutic monitoring and regulatory assessment, accumulating evidence demonstrates that central nervous system (CNS) involvement begins early, evolves sub-clinically, and contributes significantly to long-term morbidity. CNS injury in Fabry disease reflects a convergence of multi-system consequences of substrate accumulation, manifesting into endothelial dysfunction, microvascular ischemia, neuroinflammation, oxidative stress, and impaired autophagy–lysosome homeostasis. This review synthesizes advances in fluid and imaging biomarkers that are directly or indirectly associated with mechanistic pathways, including lyso-Gb₃ analogues, inflammatory and oxidative stress mediators, and neurofilament light chain (NfL) as a dynamic marker of neuroaxonal injury. We further examine emerging neuroimaging modalities, e.g., diffusion tensor imaging (DTI), quantitative susceptibility mapping, perfusion magnetic resonance imaging (MRI), and volumetric analyses, that quantify microstructural white matter injury, thalamic vulnerability, and cerebrovascular dysfunction. The strengths, limitations, and translational readiness of these biomarker classes are evaluated in the context of therapeutic monitoring, clinical trial design, and biomarker qualification pathways. Taken together, a multidomain biomarker strategy integrating advanced MRI metrics, NfL, and substrate- or inflammation-linked markers provides a more complete assessment of CNS involvement and offers a promising direction for earlier detection, improved disease monitoring, and future development of surrogate endpoints relevant to neurologic outcomes in Fabry disease.