Front Mol Biosci. 2026 Aug 20;13:1828669. doi: 10.3389/fmolb.2026.1828669. eCollection 2026.
ABSTRACT
BACKGROUND: Fabry disease (Anderson-Fabry disease,FD) is an X-linked lysosomal storage disorder caused by variants in GLA, resulting in α-galactosidase A (α-Gal A) deficiency and accumulation of globotriaosylsphingosine (lyso-Gb3), with frequent cardiac involvement.
CASE SUMMARY: A 53-year-old man presented with exertional chest tightness and dyspnea. Electrocardiography and echocardiography demonstrated marked left ventricular hypertrophy. Cardiac magnetic resonance revealed diffuse hypertrophy with extensive subendocardial late gadolinium enhancement. ^99mTc-pyrophosphate scintigraphy showed minimal myocardial uptake, arguing against transthyretin cardiac amyloidosis. Biochemical testing showed markedly reduced α-Gal A activity and elevated lyso-Gb3 levels. Whole-exome sequencing identified a previously unreported GLA variant (NM_000169.3:c.752A>C; p.Glu251Ala), which was confirmed by Sanger sequencing and detected in multiple family members. The variant is currently classified as a variant of uncertain significance (VUS). Familial analysis demonstrated a segregation pattern consistent with X-linked inheritance.
CONCLUSION: We report a novel GLA variant associated with biochemical abnormalities and familial segregation consistent with FD. These findings support a potential role of this variant in Fabry cardiomyopathy and expand the mutational spectrum of GLA, although its pathogenicity requires further validation.
PMID:42694033 | PMC:PMC13537968 | DOI:10.3389/fmolb.2026.1828669