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.

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ObjectiveTo present phenotypic characteristics and biomarkers of a family with the rare mutation Thr410Ala of theα-galactosidase Agene (T410A/GLA) causing Fabry disease (FD).Methods and resultsIn a woman in her 60s with hypertrophic cardiomyopathy, T410A/GLAwas 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/GLAhad no active α-Gal A, high lyso-Gb3levels 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/GLAhad α-Gal A activities of 8–18 and 10% of normal. The older granddaughter in her 30s was diagnosed with incipient FC. Plasma lyso-Gb3analogues were elevated, markedly in the elder male with FC and moderately in the elder granddaughter. In young males with classic phenotype, plasma lyso-Gb3analogues were only slightly elevated.ConclusionsThe T410A/GLAmutation 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-Gb3analogues reflected variable phenotype of FD in the family.

Background/Introduction Fabry disease (FD) is a lysosomal storage disorder caused by mutations in the α- galactosidase A gene (GLA) leading to lack of an active GLA enzyme and accumulation of glycosphingolipids in different organs, including heart. Because of X-linked inheritance, the phenotype is usually more severe in males than in females. Purpose There are very few national studies on FD. Our aim was to investigate the genetics, phenotype, treatment and prognosis of Finnish Fabry patients by gender. Methods Finnish Fabry Registry includes 98 patients, approximately 90% of all Finnish patients with FD, diagnosed from 1972 to 2018. Cardiovascular, neurological and renal events, and cardiac imaging data were recorded from medical charts until 2020. Cardiac ultrasound and MRI (CMR) were performed in 86% and 77% of females and 88% and 78% of males, respectively. Results Altogether, 24 different pathogenic GLA mutations were found in 66 females and 32 males from 27 Finnish families. FD, or the causative mutation, was diagnosed at an average age of 41 years in females, and at 29 years in males. During the mean 17 years of follow-up, either ERT or migalastat was started for 58% of females and 88% of males. At the end of the follow-up, Fabry cardiomyopathy (FCM; maximal left ventricular wall thickness (LVMWT) 13 mm or more in cardiac imagining) had been diagnosed in 47% of females and 66% of males at the mean age of 55 years and 41 years, respectively. Atrial fibrillation (AF) was diagnosed in 21% of females and 9% of males. Heart failure (HF) due to FCM was diagnosed in 20% of females and in 12% of males at the mean age of 62 and 54 years, respectively. A bradycardia pacemaker was required for 9 females and for 2 males and one female and one male had also implantable cardioverter defibrillator. Over 20% of both female and male FD patients suffered a stroke during the follow-up. End-stage kidney disease was not found in females, but 9% of males received a renal transplantation. During the follow-up 5 females and 3 males died. The mean age at death was 77 years in females, and 48 years in males. All deceased males and 40% of females had been treated with ERT from an average age of 40 and 66 years, respectively. All deceased subjects had FCM. All females and one male died of FD. Two females died of a stroke and three of HF. All deceased males had severe classical FD phenotype. One male suffering from severe HF died of a stroke. One male with an ICD and renal transplant, died of malignancy. The third male withdrew from follow-up and died of gastrointestinal bleeding. Conclusions In Finnish patients with FD, cardiomyopathy, related arrhythmias and heart failure were common in both genders. All eight deceased subjects had Fabry cardiomyopathy, and the immediate cause of death was most often heart failure or stroke. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Finnish Heart Research Foundationand Sanofi Genzyme

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