Case Report: Fabry cardiomyopathy associated with a novel truncating GLA variant, c.837_838delinsAT, p.(Gln280Ter)

Abstract

We report the comprehensive clinical characterization of a woman with Fabry disease (FD) carrying a previously unreported truncating GLA variant, c.837_838delinsAT, p.(Gln280Ter). The patient, a 52-year-old woman with longstanding hypertrophic cardiomyopathy, was referred to a specialized Fabry Disease Program to investigate FD as the underlying etiology of her cardiomyopathy. Cardiac magnetic resonance imaging demonstrated diffuse left ventricular hypertrophy with extensive late gadolinium enhancement, indicating advanced replacement fibrosis and an increased arrhythmic risk. Biochemical evaluation revealed reduced α -galactosidase A activity and markedly elevated Lyso-Gb3 levels. Comprehensive systemic assessment identified bilateral cornea verticillata and nonspecific periventricular white matter hyperintensities on brain magnetic resonance imaging, while renal function remained preserved without clinically significant renal involvement. Molecular analysis identified the heterozygous truncating GLA variant c.837_838delinsAT, p.(Gln280Ter), which had not previously been reported. The patient received an implantable cardioverter-defibrillator following cardiovascular risk assessment and subsequently initiated enzyme replacement therapy with agalsidase beta. This case expands the known mutational spectrum of the GLA gene and illustrates the value of integrating molecular genetic analysis with multimodality cardiac imaging and comprehensive phenotyping in patients with unexplained hypertrophic cardiomyopathy. This integrated approach not only supports the interpretation of previously unreported GLA variants but may also refine etiologic diagnosis, cardiovascular risk assessment, and individualized clinical management in FD.