Abstract
Background: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by an α-galactosidase A enzyme deficiency due to pathogenic variants in the α-galactosidase A gene (GLA). An increasing number of individuals with a GLA variant, but without characteristic FD features, are identified. A definite diagnosis of FD has important consequences for treatment and counselling.
Objectives: We assessed the diagnostic value of quantitative sensory testing (QST) and intraepidermal nerve fibre density (IENFD) for patients with an uncertain FD diagnosis.
Methods: All patients with a GLA variant who initially presented at the Academic Medical Center with an uncertain FD diagnosis were included. A biopsy of an affected organ in a patient or family member showing FD characteristic storage is used as a reference standard for a diagnosis of FD. All patients underwent a comprehensive QST protocol and IENFD assessment which was compared to age and gender-matched healthy controls. Sensitivity and specificity were calculated for a combination of ≥1 abnormal QST modality and an abnormal IENFD.
Results: Twenty-six patients participated (nonclassical FD n = 18, 9 males; no FD n = 5, 3 males; uncertain n = 3, 1 male). Of the patients classified as nonclassical FD, 28% had ≥1 abnormal QST modalities, and 83% had an abnormal IENFD. From the patients without FD, 20% had ≥1 abnormal QST modality, and IENFD was abnormal in 25% (1 not available). Sensitivity was 28% and specificity 80%.
Conclusions: In our study cohort, QST and IENFD could not reliably distinguish patients with FD from those without FD.
Competing interests: None declared
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Communicated by: Robin Lachmann, PhD FRCP
Appendices
Synopsis
In a cohort of 26 individuals with a GLA variant, small fibre neuropathy assessments cannot reliably distinguish patients with FD from those without FD in the presence of a nonpathogenic GLA variant.
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Conflicts of Interest
LT has received travel support and reimbursement of expenses from Actelion, Shire HGT or Genzyme.
MB and CH have received travel support, honoraria for consultancies and educational grants from Actelion, Genzyme, Shire HGT, Protalix or Amicus. All financial arrangements are made with the AMC Medical research BV, in accordance with the AMC Research Code.
IS received departmental honoraria for serving on scientific advisory boards and a steering committee for CSL Behring, and in the past (>5 years) he received honoraria for lecturing and consultancy and research support from Actelion Pharmaceuticals Ltd. All consulting fees for IS were donated to the Stichting Klinische Neurologie, a local foundation that supports research in the field of neurological disorders.
CV and AK report no disclosures.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.
Funding and Acknowledgements
This study was performed within the framework of the Dutch Top Institute Pharma (TIPharma, project number T6-504: “Fabry or not Fabry: valorization of clinical and laboratory tools for improved diagnosis of Fabry disease”). TIPharma is a nonprofit organization that catalyzes research by founding partnerships between academia and industry. Partners: Genzyme, a Sanofi company; Academic Medical Center, University of Amsterdam. Subsidizing 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.
We thank Dr. Eleonora Aronica, pathologist, and Robert P. Evers, laboratory analyst, for their assistance with the processing of skin biopsies.
Contributions
LT study design, data acquisition, data analyses, data interpretation, and first draft of manuscript.
AK data acquisition, data interpretation, and revision of manuscript.
CV study design, data interpretation, and revision of manuscript.
IS data interpretation and revision of manuscript.
MB and CH study design, data interpretation, and revision of manuscript.
Appendix
Z-scores for CDT (cold detection threshold), WDT (warm detection threshold), and TSL (thermal sensory limen) for hand and foot. Black dots represent males, and open dots represent females. Dotted lines represent a Z-score of −1.96. Horizontal lines represent the mean for males and females combined
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van der Tol, L., Verhamme, C., van Schaik, I.N., van der Kooi, A.J., Hollak, C.E.M., Biegstraaten, M. (2015). In Patients with an α-Galactosidase A Variant, Small Nerve Fibre Assessment Cannot Confirm a Diagnosis of Fabry Disease. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 28. JIMD Reports, vol 28. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_503
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DOI: https://doi.org/10.1007/8904_2015_503
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