Late-onset and classic phenotypes of Fabry disease in males with the GLA-Thr410Ala mutation.

OBJECTIVE: To present phenotypic characteristics and biomarkers of a family with the rare mutation Thr410Ala of the α-galactosidase A gene (T410A/GLA) causing Fabry disease (FD). METHODS AND RESULTS: In a woman in her 60s with hypertrophic cardiomyopathy, T410A/GLA was found in screening for variants in 59 cardiomyopathy-related genes. Her son in his 40s, two granddaughters and two great grandsons carried T410A/GLA. The son had a history of hypertension and paroxysmal AF but no microalbuminuria or classic symptoms or signs of FD. Baseline α-galactosidase A enzyme (α-Gal A) activity varied from 0% to 26.5%. Cardiac MRI showed mild Fabry cardiomyopathy (FC). During 11 years of enzyme replacement therapy (ERT), FC progressed and he suffered sudden cardiac death in his 50s. The great grandsons with T410A/GLA had no active α-Gal A, high lyso-Gb3 levels and normal cardiac imaging. They suffered from neuropathic pain and gastrointestinal symptoms and were started with ERT at the age under 10. Granddaughters with T410A/GLA had α-Gal A activities of 8-18 and 10% of normal. The older granddaughter in her 30s was diagnosed with incipient FC. Plasma lyso-Gb3 analogues were elevated, markedly in the elder male with FC and moderately in the elder granddaughter. In young males with classic phenotype, plasma lyso-Gb3 analogues were only slightly elevated. CONCLUSIONS: The T410A/GLA mutation caused late-onset FD with progressive cardiomyopathy in elder male, and classic FD in young males of the same family. Varying levels of α-Gal A and lyso-Gb3 analogues reflected variable phenotype of FD in the family.

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

OBJECTIVE: To investigate whether the Ala143Thr variant of the α-galactosidase A gene (A143T/GLA), with conflicting interpretations of pathogenicity, is associated with Fabry cardiomyopathy. METHODS: The 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. RESULTS: The 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. CONCLUSIONS: A143T/GLA is likely a late-onset Fabry cardiomyopathy causing variant with incomplete penetrance.