Preventing misdiagnosis of Fabry disease: a consensus recommendation for improved diagnosis in adults presenting with kidney disease or left ventricular hypertrophy and mutations of unknown clinical significance
Smid, B.E., Tol, L. van der, Biegstraaten, M., Cecchi, F., Lekanne Dit Deprez, R.H., Elliott, P.M., Florquin, S., Hughes, D.A., Lachmann, R.A., Oliveira, J.P., Ortiz, A., Postema, P.G., Svarstad, E., Terryn, W., Timmermans, J., Tøndel, C., Vogt, L., Waldek, S., Wanner, C., Wal, A.C. van der, Weidemann, F., West, M.L., Bergh Weerman, M.A. van den, Linthorst, G.E., Hollak, C.E.
Voorzitter(s): prof.dr. J.L.C.M. van Saase, Rotterdam & dr. J.W.J. van Esser, Breda
Locatie(s): Zaal 0.4
Categorie(ën):
Introduction: Genetic screening is increasingly employed, but will impose major diagnostic dilemmas on clinicians. Screening for Fabry disease (FD), an inherited lysosomal storage disorder, in subjects with kidney disease and left ventricular hypertrophy (LVH) reveals an unexpectedly high prevalence of FD. Often, a diagnosis of FD is uncertain because characteristic clinical and biochemical features lack and mutations of unknown clinical significance in the alpha-galactosidase A (GLA) gene are identified. The societal impact of a misdiagnosis is large, as it causes inappropriate counselling and initiation of exorbitantly expensive and burdensome enzyme therapy.
Aim of the study: To develop diagnostic algorithms for adults presenting with chronic kidney disease or LVH, a GLA mutation and an uncertain diagnosis of FD.
Methods: A modified Delphi method was used to reach consensus between FD experts. Criteria for a definite and uncertain diagnosis and the gold standard for FD were defined. We performed a systematic review selecting imaging and laboratory criteria to confirm or exclude FD.
Results: A definite diagnosis of FD was defined as: a GLA mutation with ≤5% GLA enzyme activity (males only) with≥1 characteristic FD symptom (acroparesthesia, cornea verticillata, angiokeratoma following strict definitions) orincreased plasma (lyso) Gb3 (in classical male range) or family members with definite FD. Subjects with a GLA mutation and chronic kidney disease (KDIGO guideline) or LVH (maximal wall thickness >12 mm) failing these criteria have an uncertain diagnosis of FD. The gold standard was defined as characteristic storage on electron microscopy (EM) in a heart or kidney biopsy, in the absence of medication use inducing a similar storage pattern. Microvoltages on ECG and severe LVH (maximal wall thickness >15 mm) before the age of 20 years exclude FD. Other cardiac or nephrological criteria were rejected. A PQ interval <120 ms on ECG, hypertrophied papillary muscles, myocardial late enhancement in infero-postero-lateral regions on cardiac MRI, urinary Maltese Cross sign and high urinary Gb3 were considered useful in daily practice as a red flag to suspect FD.
Conclusion: We propose diagnostic guidelines for adults with chronic kidney disease or LVH and an uncertain diagnosis of FD. When LVH is present, microvoltages and severe LVH at young age can exclude FD. In all remaining instances, a biopsy of the heart or kidney with EM analysis should be performed to confirm or reject FD.
- Over Smid, B.E.
- Over Tol, L. van der
- Over Biegstraaten, M.
- Over Cecchi, F.
- Over Lekanne Dit Deprez, R.H.
- Over Elliott, P.M.
- Over Florquin, S.
- Over Hughes, D.A.
- Over Lachmann, R.A.
- Over Oliveira, J.P.
- Over Ortiz, A.
- Over Postema, P.G.
- Over Svarstad, E.
- Over Terryn, W.
- Over Timmermans, J.
- Over Tøndel, C.
- Over Vogt, L.
- Over Waldek, S.
- Over Wanner, C.
- Over Wal, A.C. van der
- Over Weidemann, F.
- Over West, M.L.
- Over Bergh Weerman, M.A. van den
- Over Linthorst, G.E.
- Over Hollak, C.E.