Cardiomyopathy associated with the Ala143Thr variant of the α-galactosidase A gene

Abstract

ObjectiveTo investigate whether the Ala143Thr variant of the α-galactosidase A gene (A143T/GLA), with conflicting interpretations of pathogenicity, is associated with Fabry cardiomyopathy.MethodsThe index patient, a woman in her 60s with cardiomyopathy, was screened for variants in 59 cardiomyopathy-related genes. A143T/GLA, the only rare variant found, was screened in 10 relatives. GLA activity and lyso-Gb3 levels were measured and echocardiography was performed in 8 of 9 subjects carrying A143T/GLA. Cardiac magnetic resonance (CMR) imaging and 18F-fluorodeoxyglucose (FDG) positron emission tomography/CT (PET/CT) were performed in four adult A143T/GLA carriers. Endomyocardial biopsy was obtained from two adult A143T/GLA carrying sons of the index patient.ResultsThe index patient and her elder son had a pacemaker implantation because of sick sinus syndrome and atrioventricular block. GLA activities were decreased to 25%–40% of normal in both sons and one granddaughter. Lyso-Gb3 levels were elevated in both sons. In CMR, the index patient and her two sons had left ventricular (LV) hypertrophy and/or dilatation. The elder son had late gadolinium enhancement, high CMR-derived T1 time and positive FDG signal in PET/CT in the basal inferolateral LV wall. The younger son had low T1 time and the mother had positive FDG signal in PET/CT in the basal inferolateral LV wall. Endomyocardial biopsy of both sons showed myocardial accumulation compatible with glycolipids in light and electron microscopy, staining with anti-Gb3 antibody available for the younger son. Five female relatives with A143T/GLA had no cardiomyopathy in cardiac imaging.ConclusionsA143T/GLA is likely a late-onset Fabry cardiomyopathy causing variant with incomplete penetrance.

Mono-symptomatic Fabry disease in a population with mild-to-moderate left ventricular hypertrophy

“…Initially believed to be pathogenic, a comprehensive analysis of the expression of this genetic variant then redefined it as benign. However, more recently p.Ala143Thr has been shown to be associated with FD cardiomyopathy with incomplete age- and gender- related penetrance [ 10 ].…”

Fabry cardiomyopathy: missing links from genotype to phenotype

“…Reduced enzyme activity will lead to accumulation of the enzyme’s direct substrate, globotriaosylceramide, which could be quantified in the biopsies as direct proof of substrate storage. Indeed, Valtola et al 1 confirm this correlation in the male family members but not in the females. Intriguingly, increased urinary levels of globotriaosylceramide are reported to occur in patients who die of cardiac disease due to whatever cause, even in the absence of GLA variants, emphasising the importance of these housekeeping enzymes in cardiomyocytes 2…”

“…In their Heart article, Valtola et al 1 study a Finnish family of 11 members of whom eight harboured c.472G>A. Sophisticated cardiac imaging supported by biochemical and histological studies showed that the 65-year-old female index patient and her two hemizygous sons, aged 36 and 24 years, manifested cardiomyopathy.…”

Fabry Disease: A Atypical Presentation

“…However, there seems to be an association of this mutation with late-onset disease. The disease phenotype caused by this mutation involves only one of the main organ systems affected by FD [6,7], particularly the central [7][8][9] and peripheral nervous systems [10]. The p.A143T mutation and its pathological significance must be evaluated case-by-case basis [5].…”