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Research paper
Yield of peripheral sodium channels gene screening in pure small fibre neuropathy
  1. Ivo Eijkenboom1,2,
  2. Maurice Sopacua2,3,
  3. Janneke G J Hoeijmakers2,3,
  4. Bianca T A de Greef2,3,
  5. Patrick Lindsey1,
  6. Rowida Almomani1,2,4,
  7. Margherita Marchi5,
  8. Jo Vanoevelen1,
  9. Hubertus J M Smeets1,2,
  10. Stephen G Waxman6,7,
  11. Giuseppe Lauria5,8,
  12. Ingemar S J Merkies2,9,
  13. Catharina G Faber2,3,
  14. Monique M Gerrits10
  1. 1 Department of Genetics and Cell Biology, Clinical Genomics Unit, Maastricht University, Maastricht, The Netherlands
  2. 2 MHeNs School of Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
  3. 3 Department of Neurology, Maastricht University Medical Centre+, Maastricht, The Netherlands
  4. 4 Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid, Jordan
  5. 5 Neuroalgology Unit, IRCCS Fondazione Istituto Neurologico "Carlo Besta", Milan, Italy
  6. 6 Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, USA
  7. 7 Centre for Neuroscience and Regeneration Research, Veterans Affairs Medical Center, West Haven, Connecticut, USA
  8. 8 Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Milan, Italy
  9. 9 Department of Neurology, St. Elisabeth Hospital, Willemstad, Curaçao
  10. 10 Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands
  1. Correspondence to Dr Monique M Gerrits, Department of Clinical Genetics, Maastricht University Medical Centre+, P.O. Box 5800, 6202AZ Maastricht, The Netherlands; monique.gerrits{at}mumc.nl

Abstract

Background Neuropathic pain is common in peripheral neuropathy. Recent genetic studies have linked pathogenic voltage-gated sodium channel (VGSC) variants to human pain disorders. Our aims are to determine the frequency of SCN9A, SCN10A and SCN11A variants in patients with pure small fibre neuropathy (SFN), analyse their clinical features and provide a rationale for genetic screening.

Methods Between September 2009 and January 2017, 1139 patients diagnosed with pure SFN at our reference centre were screened for SCN9A, SCN10A and SCN11A variants. Pathogenicity of variants was classified according to established guidelines of the Association for Clinical Genetic Science and frequencies were determined. Patients with SFN were grouped according to the VGSC variants detected, and clinical features were compared.

Results Among 1139 patients with SFN, 132 (11.6%) patients harboured 73 different (potentially) pathogenic VGSC variants, of which 50 were novel and 22 were found in ≥ 1 patient. The frequency of (potentially) pathogenic variants was 5.1% (n=58/1139) for SCN9A, 3.7% (n=42/1139) for SCN10A and 2.9% (n=33/1139) for SCN11A. Only erythromelalgia-like symptoms and warmth-induced pain were significantly more common in patients harbouring VGSC variants.

Conclusion (Potentially) pathogenic VGSC variants are present in 11.6% of patients with pure SFN. Therefore, genetic screening of SCN9A, SCN10A and SCN11A should be considered in patients with pure SFN, independently of clinical features or underlying conditions.

  • small fibre neuropathy
  • painful neuropathy
  • neuropathic pain
  • voltage-gated sodium channels
  • SCN9A
  • SCN10A
  • SCN11A
  • frequency of (potentially) pathogenic variants

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Footnotes

  • IE and MS contributed equally.

  • Correction notice Since this paper was first published online a funding statement has been added to the proof.

  • Contributors Study concept and design: IE, MS, JGJH, BTADG, HJMS, ISJM, CGF, MMG. Acquisition, analysis or interpretation of the data: all authors. Statistical analysis: IE, MS, BTADG, PL, ISJM. Drafting of the manuscript: IE, MS, JH, BTADG, MMG. Review of the manuscript: RA, MM, JV, HJMS, SGW, GL, ISJM, CGF. Study supervision: JGJH, HJMS, ISJM, CGF, MMG.

  • Funding This work was supported in part by a grant from European Union’s Horizon 2020 research and innovation programme Marie Sklodowska-Curie grant for PAIN-Net, Molecule-to-man pain network (grant no. 721841).

  • Competing interests JGJH reports personal fees from Pfizer Inc. (travel funding and speakers’ honorarium) and grants from Prinses Beatrix Spierfonds (W.OK17-09), outside the submitted work. SGW reports grants from European Union’s Horizon 2020 research and innovation programme Marie Sklodowska-Curie grant for PAIN-Net, Molecule-to-man pain network (grant no. 721841) and European Union 7th Framework Programme (grant no. 602273) for the PROPANE study and was supported in part by the Rehabilitation Research and Development Service and Biomedical Laboratory Research Service, Department of Veterans Affairs, outside the submitted work. GL reports grants from European Union’s Horizon 2020 research and innovation programme Marie Sklodowska-Curie grant for PAIN-Net, Molecule-to-man pain network (grant no. 721841) and European Union 7th Framework Programme (grant n°602273) for the PROPANE study and participates in Steering committees/advisory boards for studies in small fibre neuropathy of Biogen/Convergence, Vertex and Chromocell, outside the submitted work. ISJM reports grants from Talecris Talents program, GSB CIDP Foundation International, Prinses Beatrix Spierfonds (W.OR12-01, W.OR15-25) and European Union 7th Framework Programme (grant no. 602273), participates Steering committees of the Talecris ICE Study, LFB, CSL Behring, Novartis, Grifols and Octapharma, serves on the editorial board of the Journal of Peripheral Nervous system and is a member of the Inflammatory Neuropathy Consortium (INC) and Peripheral Nerve Society, outside the submitted work. CGF reports grants from European Union’s Horizon 2020 research and innovation programme Marie Sklodowska-Curie grant for PAIN-Net, Molecule-to-man pain network (grant no. 721841), European Union 7th Framework Programme (grant n°602273) for the PROPANE study, Prinses Beatrix Spierfonds (W.OR12-01, W.OR15-25), Grifols and Lamepro for a trial on IVIg in small fibre neuropathy and participates in Steering committees/advisory boards for studies in small fibre neuropathy of Biogen/Convergence, Vertex and Chromocell, outside the submitted work. Other authors have no conflicts of interests to declare.

  • Patient consent Not required.

  • Ethics approval This study was approved by the Medical Ethics Committee and Board of Directors of the Maastricht UMC+.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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