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Int J Cardiol. 2014 Dec 15;177(2):400-8. doi: 10.1016/j.ijcard.2014.09.001. Epub 2014 Sep 20.

Uncertain diagnosis of Fabry disease: consensus recommendation on diagnosis in adults with left ventricular hypertrophy and genetic variants of unknown significance.

Author information

1
Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
2
Department of Clinical and Experimental Medicine, University of Florence, Italy.
3
Department of Cardiology, Heart Hospital, London, UK.
4
Department of Haematology, Royal Free & University College Medical School, London, UK.
5
Department of Cardiology, RadboudUMC, Nijmegen, The Netherlands.
6
Department of Cardiology, Comprehensive Heart Failure Centre, University Hospital Würzburg, Germany.
7
Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
8
Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
9
Department of Pathology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
10
Department of Cardiology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
11
Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: c.e.hollak@amc.uva.nl.

Abstract

BACKGROUND:

Screening 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.

METHODS:

A 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.

RESULTS:

A 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.

CONCLUSIONS:

In 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.

KEYWORDS:

Consensus; Diagnosis; Fabry disease; Hypertrophic cardiomyopathy; Left ventricular hypertrophy

PMID:
25442977
DOI:
10.1016/j.ijcard.2014.09.001
[Indexed for MEDLINE]

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