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Fabry disease is an X-linked recessive lysosomal storage disorder caused by pathogenic variants in the GLA gene (alpha-galactosidase A) leading to systemic accumulation of globotriaosylceramide. Heterozygous females exhibit highly variable expressivity due to skewed X inactivation, while hemizygous males typically present early with neuropathic pain, angiokeratoma, and progressive renal and cardiac involvement (PMID:8863162).
Over 600 unique GLA variants have been reported in more than 200 unrelated probands and over 100 families worldwide, including well-characterized missense, nonsense, frameshift, splice, and deep-intronic changes. A de novo point mutation c.691G>A (p.Asp231Asn) was identified in discordant monozygotic female twins, with segregation in a nephew hemizygous for the same allele, illustrating both novel mutational events and familial transmission (PMID:8863162). Founder screening in Taiwan uncovered a later-onset cryptic splice variant c.936+919G>A (IVS4+919G>A) in 86% of male carriers, demonstrating population-specific alleles with cardiac-predominant phenotypes (PMID:19621417).
The GLA variant spectrum is dominated by missense mutations affecting enzyme active or structural residues, with recurrent pathogenic alleles such as c.644A>G (p.Asn215Ser) and c.902G>C (p.Arg301Pro). Loss-of-function alleles include frameshifts (e.g., c.421del (p.Thr141ProfsTer24)) and nonsense changes (e.g., c.658C>T (p.Cys52Ter)). Carrier frequencies range up to 0.08% in dialysis and hypertrophic cardiomyopathy cohorts, underlining the need for targeted genetic testing in unexplained renal, cardiac, or cerebrovascular disease (PMID:8739292).
Mechanistic studies confirm that pathogenic GLA variants reduce alpha-Gal A activity and stability, with in vitro expression in HEK-293 or COS-7 cells showing retention of mutant protein in the ER or impaired lysosomal targeting. Patient-derived iPSC-cardiomyocytes recapitulate glycosphingolipid accumulation, impaired contractility, and a metabolic shift toward glycolysis, all partially reversible by enzyme rescue or pharmacological chaperones (PMID:28082092; PMID:20031620).
Variants of uncertain significance such as p.Ala143Thr and p.Asp313Tyr exhibit near-normal lyso-Gb3 levels, absent tissue Gb3 deposits, and no consistent clinical features, underscoring the importance of integrating biochemical, histopathological, and family data to distinguish benign polymorphisms from true disease-causing mutations (PMID:27142856).
In conclusion, the GLA–Fabry disease association is Definitive based on extensive genetic and functional data spanning decades. Early molecular screening in high-risk populations, combined with enzyme and biomarker assays, enables timely initiation of enzyme replacement or chaperone therapy to prevent irreversible organ damage. Key Take-home: Genetic testing for GLA variants should be standard in unexplained renal, cardiac or stroke presentations to guide early intervention.
Gene–Disease AssociationDefinitiveMultiple large cohorts with >200 unrelated probands, multi-family segregation, consistent functional concordance Genetic EvidenceStrongOver 600 unique GLA variants reported in >100 families and >200 probands; variant segregation across three-generation pedigrees Functional EvidenceStrongBiochemical assays, in vitro expression, iPSC-CM models and chaperone rescue demonstrate enzyme deficiency and therapeutic reversal |