Pain in Fabry disease: do experimental models reveal novel therapeutic targets?

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to α-galactosidase A deficiency and progressive accumulation of globotriaosylceramide (Gb3). Although FD is a multisystemic disorder affecting the heart, kidneys, skin, and nervous system, pain is one of its earliest, most prevalent, and disabling manifestations. While several review articles have already addressed the clinical features and management of FD-associated pain, this review specifically focuses on the mechanisms underlying pain as revealed by experimental and preclinical models of the disease. By integrating findings from cellular and animal studies, we provide an updated overview of the molecular and neurobiological pathways implicated in FD-related pain, including dorsal root ganglia dysfunction, ion channel dysregulation, neuroimmune interactions, vascular abnormalities, and central sensitization processes. We further discuss how preclinical studies have identified novel therapeutic targets for pain, such as acid-sensing ion channels (ASIC), transient receptor potential (TRP) receptors, the prokineticin system, glial activation, and glutamatergic signaling, which may complement current disease-modifying therapies. By highlighting the translational relevance of these mechanistic insights, this review aims to bridge the gap between experimental research and the development of more effective pain-focused interventions. A better understanding of the pathophysiology of FD-associated pain may ultimately contribute to improving management strategies with a significant impact on the quality of life for affected individuals.