A novel double GLA gene mutation of W24R and N419D in a patient with cardiac Fabry disease

Mol Genet Metab Rep. 2023 Jun 10:36:100982.

PMID: 37332487

Masanori Hirose, Sho Okada, Yoshio Kobayashi

Highlights: This article reports a rare familial case of inherited cardiac Fabry disease (FD) associated with a novel double mutation in the GLA gene: W24R and N419D.

Abstract:

Background: X-linked lysosomal storage disorder Fabry disease (FD) is brought on by insufficient activity of GLA-encoded α-galactosidase A (α-Gal A). Systemic disorders result from the increasing accumulation of sphingolipids in different body fluids and tissues due to an enzymatic deficiency.

Objective: This study presents a novel double mutation (W24R and N419D) in the GLA gene, which is linked to a rare familial case of inherited cardiac FD.

Results: A young man with severe obesity was admitted for heart failure (HF) with the diagnosis of dilated cardiomyopathy. Following discharge, during HF treatment, left ventricular hypertrophy was suspected; the origin of the hypertrophy was reexamined in light of his mother's family history of cardiac conditions and sudden death. Incredibly low α-Gal A activity confirmed the FD diagnosis. A double mutation—W24R and N419D—was found by GLA gene mutation analysis. His mother had the identical double mutation, according to proband analysis. Despite the absence of any FD symptoms or indicators, a mild accumulation of globotriaosylsphingosine was found. Using HEK293 cells, the experiment confirmed by good laboratory practices revealed that the double mutation could be stabilized by migalastat, a pharmacological chaperone stabilizing α-Gal A.

Conclusion: This instance demonstrates a newly discovered double gene mutation in GLA (W24R and N419D) found in a family suffering from FD. Each mutation's clinical importance is still unknown, however its combination might work synergistically to attain or augment pathogenicity.

Keywords: A double mutation, Fabry disease, N419D, W24R, α-Galactosidase A