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

• Published in: International journal of cardiology Vol. 177; no. 2; pp. 400 - 408
• Main Authors: Smid, B.E., van der Tol, L., Cecchi, F., Elliott, P.M., Hughes, D.A., Linthorst, G.E., Timmermans, J., Weidemann, F., West, M.L., Biegstraaten, M., Lekanne Deprez, R.H., Florquin, S., Postema, P.G., Tomberli, B., van der Wal, A.C., van den Bergh Weerman, M.A., Hollak, C.E.
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 15.12.2014; Elsevier
• Subjects: Adult; Biological and medical sciences; Cardiology. Vascular system; Cardiovascular; Consensus; Delphi Technique; Diagnosis; Diagnosis, Differential; Errors of metabolism; Fabry disease; Fabry Disease - diagnosis; Fabry Disease - genetics; Genetic Variation - genetics; Heart; Humans; Hypertrophic cardiomyopathy; Hypertrophy, Left Ventricular - diagnosis; Hypertrophy, Left Ventricular - genetics; Left ventricular hypertrophy; Lipids (lysosomal enzyme disorders, storage diseases); Male; Medical sciences; Metabolic diseases; Myocarditis. Cardiomyopathies; ERT; Fabry disease; MWT; GVUS; lysoGb3; Consensus; HCM; AGAL-A; Left ventricular hypertrophy; Hypertrophic cardiomyopathy; Diagnosis; GLA; FD; LVH; alpha-galactosidase A gene; enzyme replacement therapy; maximal wall thickness; globotriaosylsphingosine; left ventricular hypertrophy; alpha-galactosidase A; hypertrophic cardiomyopathy; genetic variant of unknown significance; Human; Nervous system diseases; Genetic variant; Metabolic diseases; Lipids; Cardiovascular disease; Enzymopathy; Myocardial disease; Recommendation; Left ventricle; Genetic disease; Vascular disease; Heart disease; Adult; Cardiology; Lipoidosis; Hypertrophy
• ISSN: 0167-5273; 1874-1754; 1874-1754
• DOI: 10.1016/j.ijcard.2014.09.001

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 >12mm), GLA GVUS and an uncertain diagnosis of FD. 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. 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>15mm) <20years exclude FD. Other criteria were rejected due to insufficient evidence. 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.