Abstract
Introduction: Individuals with neuropathic pain, angiokeratoma (AK) and/or cornea verticillata (CV) may be tested for Fabry disease (FD). Classical FD is characterised by a specific pattern of these features. When a patient presents with a non-specific pattern, the pathogenicity of a variant in the α-galactosidase A (GLA) gene may be unclear. This uncertainty often leads to considerable distress and inappropriate counselling and treatment. We developed a clinical approach for these individuals with an uncertain diagnosis of FD.
Materials and Methods: A document was presented to an FD expert panel with background information based on clinical experience and the literature, followed by an online survey and a written recommendation.
Results: The 13 experts agreed that the recommendation is intended for individuals with neuropathic pain, AK and/or CV only, i.e. without kidney, heart or brain disease, with an uncertain diagnosis of FD. Only in the presence of FD-specific neuropathic pain (small fibre neuropathy with FD-specific pattern), AK (FD-specific localisations) or CV (without CV inducing medication), FD is confirmed. When these features have a non-specific pattern, there is insufficient evidence for FD. If no alternative diagnosis is found, follow-up is recommended.
Conclusions: In individuals with an uncertain diagnosis of FD, the presence of an FD-specific pattern of CV, AK or neuropathic pain is sufficient to confirm the diagnosis of FD. When these features are non-specific, a definite diagnosis cannot (yet) be established and follow-up is indicated. ERT should be considered only in those patients with a confirmed diagnosis of FD.
Competing interests: None declared
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Acknowledgements
This study was performed within the framework of the Dutch Top Institute Pharma (TI Pharma, project number T6-504, “Fabry or not Fabry: valorization of clinical and laboratory tools for improved diagnosis of Fabry disease”). TI Pharma is a non-profit organisation that catalyses research by founding partnerships between academia and industry. Partners: Genzyme, a Sanofi company; Academic Medical Center, University of Amsterdam; subsidising party: Shire HGT. http://www.tipharma.com/pharmaceutical-research-projects/drug-discovery-development-and-utilisation/hamlet-study.html. The industry partners had no role in the content of this manuscript or selection of panel members. The authors confirm independence from the sponsors; the sponsors have not influenced the content of the article.
RHL is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.
We would like to thank Dr. Anette Møller from the Danish Pain Research Center, University Hospital of Aarhus, Denmark, for her participation in the expert panel.
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Communicated by: Francois Feillet, MD, PhD
Appendices
Synopsis
In patients with an α-galactosidase A gene variant and neuropathic pain, cornea verticillata or angiokeratoma, who have an uncertain diagnosis of Fabry disease, detailed characterisation of these features is essential before the diagnosis of Fabry disease can be confirmed.
Guarantor Marieke Biegstraaten
Ethics approval was not required for this study.
Key words: Fabry disease; Diagnosis; Genetic variant; Consensus
Contributions
L van der Tol, CE Hollak and M Biegstraaten were involved in the design of the study, development of the consensus document, the survey rounds and analyses.
D Cassiman, G Houge, M Janssen, RH Lachmann, GE Linthorst, U Ramaswami, C Sommer, C Tøndel, ML West, F Weidemann, FA Wijburg and E Svarstad and AT Møller took part in the survey rounds as expert panellists.
All authors took part in writing and revising the manuscript.
Conflict of Interest
Linda van der Tol has received travel support and reimbursement of expenses from Actelion, Shire HGT or Genzyme.
Marieke Biegstraaten, Gabor E Linthorst and Carla EM Hollak have received travel support, honoraria for consultancies and speaker fee from Actelion, Genzyme, Shire HGT, Protalix or Amicus. All fees are donated to the Gaucher Stichting or the AMC Medical Research for research support.
Gunnar Houge has received travel support from Genzyme and Shire.
Robin Lachmann has received honoraria and consultancy fees from Genzyme, Shire and Actelion.
Einar Svarstad has received speaker fee and travel support from Genzyme and Shire.
Camilla Tøndel has received travel support and speakers fee from Shire and Genzyme.
Michael L West received research funds, honoraria and consultant fees from Actelion Pharmaceuticals, Amicus Therapeutics, Genzyme a Sanofi company, GlaxoSmithKline, Shire Human Genetic Therapies and Sumitomo Pharma.
Frank Weidemann received reimbursement of expenses and honoraria for lectures on the management of lysosomal storage diseases from Genzyme a Sanofi company and Shire HGT.
Frits Wijburg has received honoraria, travel grants or research grants from Shire Human Genetic Therapies, Inc., Genzyme and Actelion Pharmaceuticals.
David Cassiman received travel support, speaker fees and research funding from Genzyme-Sanofi, Shire and Actelion, via the University of Leuven and Leuven University Hospitals financial services.
Claudia Sommer has received honoraria and consultancy fees from Baxter, CSL Behring, Genzyme and Pfizer.
Uma Ramaswami and Mirian Janssen have no disclosures to report.
This article does not contain any studies with human or animal subjects performed by any of the authors.
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van der Tol, L. et al. (2014). Uncertain Diagnosis of Fabry Disease in Patients with Neuropathic Pain, Angiokeratoma or Cornea Verticillata: Consensus on the Approach to Diagnosis and Follow-Up. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports, Volume 17. JIMD Reports, vol 17. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_342
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DOI: https://doi.org/10.1007/8904_2014_342
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