title: Uncertain diagnosis of Fabry disease: consensus recommendation on diagnosis in adults with left ventricular hypertrophy and genetic variants of unknown significance.
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.
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: B E
authors.initials: BE
authors.lastname: Smid
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: van der Tol
authors.affiliation: Department of Clinical and Experimental Medicine, University of Florence, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Cecchi
authors.affiliation: Department of Cardiology, Heart Hospital, London, UK.
authors.forename: P M
authors.initials: PM
authors.lastname: Elliott
authors.affiliation: Department of Haematology, Royal Free & University College Medical School, London, UK.
authors.forename: D A
authors.initials: DA
authors.lastname: Hughes
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: G E
authors.initials: GE
authors.lastname: Linthorst
authors.affiliation: Department of Cardiology, RadboudUMC, Nijmegen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Timmermans
authors.affiliation: Department of Cardiology, Comprehensive Heart Failure Centre, University Hospital Würzburg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Weidemann
authors.affiliation: Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: M L
authors.initials: ML
authors.lastname: West
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Biegstraaten
authors.affiliation: Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: R H
authors.initials: RH
authors.lastname: Lekanne Deprez
authors.affiliation: Department of Pathology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Florquin
authors.affiliation: Department of Cardiology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: P G
authors.initials: PG
authors.lastname: Postema
authors.affiliation: Department of Clinical and Experimental Medicine, University of Florence, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Tomberli
authors.affiliation: Department of Pathology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: A C
authors.initials: AC
authors.lastname: van der Wal
authors.affiliation: Department of Pathology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: M A
authors.initials: MA
authors.lastname: van den Bergh Weerman
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: c.e.hollak@amc.uva.nl.
authors.forename: C E
authors.initials: CE
authors.lastname: Hollak
mesh_terms: D000328:Adult; D003697:Delphi Technique; D003937:Diagnosis, Differential; D000795:Fabry Disease / Q000175:diagnosis* / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000175:diagnosis* / Q000235:genetics*; D008297:Male
keywords: Consensus; Diagnosis; Fabry disease; Hypertrophic cardiomyopathy; Left ventricular hypertrophy