Gain of function Na V1.7 mutations in idiopathic small fiber neuropathy

Catharina G. Faber, Janneke G J Hoeijmakers, Hye Sook Ahn, Xiaoyang Cheng, Chongyang Han, Jin Sung Choi, Mark Estacion, Giuseppe Lauria, Els K. Vanhoutte, Monique M. Gerrits, Sulayman Dib-Hajj, Joost P H Drenth, Stephen G. Waxman, Ingemar S J Merkies

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Abstract

Objective: Small nerve fiber neuropathy (SFN) often occurs without apparent cause, but no systematic genetic studies have been performed in patients with idiopathic SFN (I-SFN). We sought to identify a genetic basis for I-SFN by screening patients with biopsy-confirmed idiopathic SFN for mutations in the SCN9A gene, encoding voltage-gated sodium channel Na V1.7, which is preferentially expressed in small diameter peripheral axons. Methods: Patients referred with possible I-SFN, who met the criteria of â¥2 SFN-related symptoms, normal strength, tendon reflexes, vibration sense, and nerve conduction studies, and reduced intraepidermal nerve fiber density (IENFD) plus abnormal quantitative sensory testing (QST) and no underlying etiology for SFN, were assessed clinically and by screening of SCN9A for mutations and functional analyses. Results: Twenty-eight patients who met stringent criteria for I-SFN including abnormal IENFD and QST underwent SCN9A gene analyses. Of these 28 patients with biopsy-confirmed I-SFN, 8 were found to carry novel mutations in SCN9A. Functional analysis revealed multiple gain of function changes in the mutant channels; each of the mutations rendered dorsal root ganglion neurons hyperexcitable. Interpretation: We show for the first time that gain of function mutations in sodium channel Na V1.7, which render dorsal root ganglion neurons hyperexcitable, are present in a substantial proportion (28.6%; 8 of 28) of patients meeting strict criteria for I-SFN. These results point to a broader role of Na V1.7 mutations in neurological disease than previously considered from studies on rare genetic syndromes, and suggest an etiological basis for I-SFN, whereby expression of gain of function mutant sodium channels in small diameter peripheral axons may cause these fibers to degenerate.

Original languageEnglish
Pages (from-to)26-39
Number of pages14
JournalAnnals of Neurology
Volume71
Issue number1
DOIs
Publication statusPublished - Jan 2012

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Mutation
Sodium Channels
Spinal Ganglia
Nerve Fibers
Axons
Voltage-Gated Sodium Channels
Biopsy
Neurons
Stretch Reflex
Neural Conduction
Vibration
Genes
Small Fiber Neuropathy

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Faber, C. G., Hoeijmakers, J. G. J., Ahn, H. S., Cheng, X., Han, C., Choi, J. S., ... Merkies, I. S. J. (2012). Gain of function Na V1.7 mutations in idiopathic small fiber neuropathy. Annals of Neurology, 71(1), 26-39. https://doi.org/10.1002/ana.22485

Gain of function Na V1.7 mutations in idiopathic small fiber neuropathy. / Faber, Catharina G.; Hoeijmakers, Janneke G J; Ahn, Hye Sook; Cheng, Xiaoyang; Han, Chongyang; Choi, Jin Sung; Estacion, Mark; Lauria, Giuseppe; Vanhoutte, Els K.; Gerrits, Monique M.; Dib-Hajj, Sulayman; Drenth, Joost P H; Waxman, Stephen G.; Merkies, Ingemar S J.

In: Annals of Neurology, Vol. 71, No. 1, 01.2012, p. 26-39.

Research output: Contribution to journalArticle

Faber, CG, Hoeijmakers, JGJ, Ahn, HS, Cheng, X, Han, C, Choi, JS, Estacion, M, Lauria, G, Vanhoutte, EK, Gerrits, MM, Dib-Hajj, S, Drenth, JPH, Waxman, SG & Merkies, ISJ 2012, 'Gain of function Na V1.7 mutations in idiopathic small fiber neuropathy', Annals of Neurology, vol. 71, no. 1, pp. 26-39. https://doi.org/10.1002/ana.22485
Faber CG, Hoeijmakers JGJ, Ahn HS, Cheng X, Han C, Choi JS et al. Gain of function Na V1.7 mutations in idiopathic small fiber neuropathy. Annals of Neurology. 2012 Jan;71(1):26-39. https://doi.org/10.1002/ana.22485
Faber, Catharina G. ; Hoeijmakers, Janneke G J ; Ahn, Hye Sook ; Cheng, Xiaoyang ; Han, Chongyang ; Choi, Jin Sung ; Estacion, Mark ; Lauria, Giuseppe ; Vanhoutte, Els K. ; Gerrits, Monique M. ; Dib-Hajj, Sulayman ; Drenth, Joost P H ; Waxman, Stephen G. ; Merkies, Ingemar S J. / Gain of function Na V1.7 mutations in idiopathic small fiber neuropathy. In: Annals of Neurology. 2012 ; Vol. 71, No. 1. pp. 26-39.
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abstract = "Objective: Small nerve fiber neuropathy (SFN) often occurs without apparent cause, but no systematic genetic studies have been performed in patients with idiopathic SFN (I-SFN). We sought to identify a genetic basis for I-SFN by screening patients with biopsy-confirmed idiopathic SFN for mutations in the SCN9A gene, encoding voltage-gated sodium channel Na V1.7, which is preferentially expressed in small diameter peripheral axons. Methods: Patients referred with possible I-SFN, who met the criteria of {\^a}¥2 SFN-related symptoms, normal strength, tendon reflexes, vibration sense, and nerve conduction studies, and reduced intraepidermal nerve fiber density (IENFD) plus abnormal quantitative sensory testing (QST) and no underlying etiology for SFN, were assessed clinically and by screening of SCN9A for mutations and functional analyses. Results: Twenty-eight patients who met stringent criteria for I-SFN including abnormal IENFD and QST underwent SCN9A gene analyses. Of these 28 patients with biopsy-confirmed I-SFN, 8 were found to carry novel mutations in SCN9A. Functional analysis revealed multiple gain of function changes in the mutant channels; each of the mutations rendered dorsal root ganglion neurons hyperexcitable. Interpretation: We show for the first time that gain of function mutations in sodium channel Na V1.7, which render dorsal root ganglion neurons hyperexcitable, are present in a substantial proportion (28.6{\%}; 8 of 28) of patients meeting strict criteria for I-SFN. These results point to a broader role of Na V1.7 mutations in neurological disease than previously considered from studies on rare genetic syndromes, and suggest an etiological basis for I-SFN, whereby expression of gain of function mutant sodium channels in small diameter peripheral axons may cause these fibers to degenerate.",
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AU - Lauria, Giuseppe

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