Background Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene and commonly involves the heart. This study aimed to investigate the pathogenicity of a novel missense variant and its amenability to migalastat. Methods A retrospective analysis was conducted on 28 patients with FD collected over the past 10 years. Pathogenicity was assessed within a family carrying a de novo GLA missense variant through myocardial histopathology, bioinformatic predictions, protein structural modelling and in vitro cellular assays. Results In a cohort of 28 patients (15 males, 13 females), cardiac involvement was prevalent. We further reported a family with GLA c.227T>A (p.Met76Lys) variant. Myocardial biopsy showed cardiomyocyte hypertrophy with diffuse vacuolisation, interstitial fibrosis and microvascular dysfunction. Immunohistochemistry demonstrated markedly decreased expression of α-galactosidase A (α-Gal A) in vacuolated cardiomyocytes. Biochemical testing revealed low-to-normal α-Gal A enzymatic activity together with elevated plasma globotriaosylsphingosine (lyso-Gb3). Bioinformatic analyses suggested this variant was probably pathogenic by altering the three-dimensional structure of GLA protein. AC16 cardiomyocytes overexpressing wild-type and mutant GLA were constructed via lentiviral vectors. Immunofluorescence staining revealed that the intracellular localisation of the mutant protein remained unaltered, whereas α-Gal A enzyme activity was significantly reduced. Treatment with migalastat, a pharmacological chaperone for α-Gal A, partially restored the mutant α-Gal A enzymatic activity. Conclusions This study identified GLA c.227T>A (p.Met76Lys) as a novel pathogenic variant that primarily causes cardiac dysfunction. Migalastat may represent a therapeutic option for this variant.
Fan et al. (2026) studied this question.