Late-onset and classic phenotypes of Fabry disease in males with theGLA-Thr410Ala mutation

Author:

Valtola Kati,Hedman Marja,Kantola Ilkka,Walls Susanne,Helisalmi Seppo,Maria Maleeha,Raivo Joose,Auray-Blais Christiane,Kuusisto JohannaORCID

Abstract

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.

Funder

Academy of Finland

Kuopion Yliopistollinen Sairaala

Sanofi

Sydäntutkimussäätiö

Publisher

BMJ

Subject

Cardiology and Cardiovascular Medicine

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