Front Med (Lausanne). 2026 Jun 23;13:1867822. doi: 10.3389/fmed.2026.1867822. eCollection 2026.
ABSTRACT
Anderson-Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by deficient activity of the enzyme α-galactosidase A, resulting in progressive accumulation of glycosphingolipids, particularly globotriaosylceramide (Gb3), across multiple organs. FD exhibits marked phenotypic variability influenced by residual enzyme activity, mutation type, and X-chromosome inactivation. Pathogenic mechanisms involve genetic, enzymatic, and metabolic dysregulation, leading to lysosomal dysfunction, inflammation, oxidative stress, mitochondrial impairment, and autophagic defects. Multi-system involvement includes vasculopathy, cardiovascular abnormalities such as left ventricular hypertrophy and arrhythmias, progressive renal injury, central nervous system lesions with cognitive and psychiatric manifestations, and peripheral neuropathy characterized by pain and autonomic dysfunction. Accumulation of Gb3 and its derivative globotriaosylsphingosine (lyso-Gb3) underlies both direct cellular toxicity and secondary pathological processes, including inflammatory activation, oxidative damage, and ion-channel dysregulation. This review synthesizes current understanding of the molecular and cellular pathogenesis of FD, highlights mechanisms underlying phenotypic variability, and integrates organ-specific manifestations.
PMID:42415779 | PMC:PMC13337472 | DOI:10.3389/fmed.2026.1867822