Uncertain diagnosis of Fabry disease: Consensus recommendation on diagnosis in adults with left ventricular hypertrophy and genetic variants of unknown significance |
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Authors: | BE Smid L van der Tol F Cecchi PM Elliott DA Hughes GE Linthorst J Timmermans F Weidemann ML West M Biegstraaten RH Lekanne Deprez S Florquin PG Postema B Tomberli AC van der Wal MA van den Bergh Weerman CE Hollak |
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Institution: | 1. Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands;2. Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands;3. Department of Pathology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands;4. Department of Cardiology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands;5. Department of Clinical and Experimental Medicine, University of Florence, Italy;6. Department of Cardiology, Heart Hospital, London, UK;g Department of Haematology, Royal Free & University College Medical School, London, UK;h Department of Cardiology, RadboudUMC, Nijmegen, The Netherlands;i Department of Cardiology, Comprehensive Heart Failure Centre, University Hospital Würzburg, Germany;j Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada |
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Abstract: | BackgroundScreening in subjects with left ventricular hypertrophy (LVH) reveals a high prevalence of Fabry disease (FD). Often, a diagnosis is uncertain because characteristic clinical features are absent and genetic variants of unknown significance (GVUS) in the α-galactosidase A (GLA) gene are identified. This carries a risk of misdiagnosis, inappropriate counselling and extremely expensive treatment. We developed a diagnostic algorithm for adults with LVH (maximal wall thickness (MWT) of > 12 mm), GLA GVUS and an uncertain diagnosis of FD.MethodsA Delphi method was used to reach a consensus between FD experts. We performed a systematic review selecting criteria on electrocardiogram, MRI and echocardiography to confirm or exclude FD. Criteria for a definite or uncertain diagnosis and a gold standard were defined.ResultsA definite diagnosis of FD was defined as follows: a GLA mutation with ≤ 5% GLA activity (leucocytes, mean of reference value, males only) with ≥ 1 characteristic FD symptom or sign (neuropathic pain, cornea verticillata, angiokeratoma) or increased plasma (lyso)Gb3 (classical male range) or family members with definite FD. Subjects with LVH failing these criteria have a GVUS and an uncertain diagnosis. The gold standard was defined as characteristic storage in an endomyocardial biopsy on electron microscopy. Abnormally low voltages on ECG and severe LVH (MWT > 15 mm) < 20 years exclude FD. Other criteria were rejected due to insufficient evidence.ConclusionsIn adults with unexplained LVH and a GLA GVUS, severe LVH at young age and low voltages on ECG exclude FD. If absent, an endomyocardial biopsy with electron microscopy should be performed. |
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Keywords: | FD Fabry disease LVH left ventricular hypertrophy HCM hypertrophic cardiomyopathy AGAL-A alpha-galactosidase A GLA alpha-galactosidase A gene MWT maximal wall thickness GVUS genetic variant of unknown significance ERT enzyme replacement therapy lysoGb3 globotriaosylsphingosine |
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