Gain of function NaV1.7 mutations in idiopathic small fiber neuropathy

Authors

  • Catharina G. Faber MD, PhD,

    Corresponding author
    1. Department of Neurology, University Medical Center Maastricht, Maastricht, the Netherlands
    • Department of Neurology/School of Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, PO-Box 5800, 6202 AZ, Maastricht, the Netherlands
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  • Janneke G. J. Hoeijmakers MD,

    1. Department of Neurology, University Medical Center Maastricht, Maastricht, the Netherlands
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  • Hye-Sook Ahn PhD,

    1. Department of Neurology, Yale University School of Medicine, New Haven, CT
    2. Center for Neuroscience and Regeneration Research, Veterans Affairs Medical Center, West Haven, CT
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  • Xiaoyang Cheng PhD,

    1. Department of Neurology, Yale University School of Medicine, New Haven, CT
    2. Center for Neuroscience and Regeneration Research, Veterans Affairs Medical Center, West Haven, CT
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  • Chongyang Han PhD,

    1. Department of Neurology, Yale University School of Medicine, New Haven, CT
    2. Center for Neuroscience and Regeneration Research, Veterans Affairs Medical Center, West Haven, CT
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  • Jin-Sung Choi PhD,

    1. Department of Neurology, Yale University School of Medicine, New Haven, CT
    2. Center for Neuroscience and Regeneration Research, Veterans Affairs Medical Center, West Haven, CT
    Current affiliation:
    1. College of Pharmacy, Catholic University of Korea, Bucheon, South Korea
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  • Mark Estacion PhD,

    1. Department of Neurology, Yale University School of Medicine, New Haven, CT
    2. Center for Neuroscience and Regeneration Research, Veterans Affairs Medical Center, West Haven, CT
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  • Giuseppe Lauria MD, PhD,

    1. Neuromuscular Diseases Unit, IRCCS Foundation, Carlo Besta, Milan, Italy
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  • Els K. Vanhoutte MD,

    1. Department of Neurology, University Medical Center Maastricht, Maastricht, the Netherlands
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  • Monique M. Gerrits PhD,

    1. Department of Clinical Genomics, University Medical Center Maastricht, Maastricht, the Netherlands
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  • Sulayman Dib-Hajj PhD,

    1. Department of Neurology, Yale University School of Medicine, New Haven, CT
    2. Center for Neuroscience and Regeneration Research, Veterans Affairs Medical Center, West Haven, CT
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  • Joost P. H. Drenth MD, PhD,

    1. Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
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  • Stephen G. Waxman MD, PhD,

    1. Department of Neurology, Yale University School of Medicine, New Haven, CT
    2. Center for Neuroscience and Regeneration Research, Veterans Affairs Medical Center, West Haven, CT
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  • Ingemar S. J. Merkies MD, PhD

    1. Department of Neurology, University Medical Center Maastricht, Maastricht, the Netherlands
    2. Department of Neurology, Spaarne Hospital, Hoofddorp, the Netherlands
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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 NaV1.7, which is preferentially expressed in small diameter peripheral axons.

Methods:

Patients referred with possible I-SFN, who met the criteria of ≥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 NaV1.7, 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 NaV1.7 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. ANN NEUROL 2012;71:26–39

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