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Gain of Function Nav1.7 Mutations in Idiopathic Small Fiber Neuropathy

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Gain of Function Nav1.7 Mutations in Idiopathic Small Fiber Neuropathy ORIGINAL ARTICLE Gain of Function NaV1.7 Mutations in Idiopathic Small Fiber Neuropathy Catharina G. Faber, MD, PhD,1 Janneke G. J. Hoeijmakers, MD,1 Hye-Sook Ahn, PhD,2,3 Xiaoyang Cheng, PhD,2,3 Chongyang Han, PhD,2,3 Jin-Sung Choi, PhD,2,3* Mark Estacion, PhD,2,3 Giuseppe Lauria, MD, PhD,4 Els K. Vanhoutte, MD,1 Monique M. Gerrits, PhD,5 Sulayman Dib-Hajj, PhD,2,3 Joost P. H. Drenth, MD, PhD,6 Stephen G. Waxman, MD, PhD,2,3 and Ingemar S. J. Merkies, MD, PhD1,7 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 mall nerve fiber neuropathy (SFN) is a relatively of large fiber functions (normal strength, tendon reflexes, Scommon disorder of thinly myelinated and unmyeli- and vibration sense), and normal nerve conduction stud- nated nerve fibers recently recognized as a distinct clini- ies (NCS), and is confirmed by demonstration of cal syndrome.1 The clinical picture is typically dominated reduced intraepidermal nerve fiber density (IENFD) or by onset in adulthood of neuropathic pain, often with a abnormal quantitative sensory testing (QST).7 Despite burning quality, and autonomic symptoms.2–6 The diag- intensive search for underlying causes such as diabetes nosis of pure SFN, in which small diameter nerve fibers mellitus, impaired glucose tolerance, Fabry disease, celiac are affected but large diameter fibers are spared, is usu- disease, sarcoidosis, human immunodeficiency virus ally made on the basis of the clinical picture, preservation (HIV), and other systemic illnesses that may be View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.22485 Received Apr 21, 2011, and in revised form May 10, 2011. Accepted for publication May 13, 2011. Address correspondence to Dr Faber, Department of Neurology/School of Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, PO-Box 5800, 6202 AZ, Maastricht, the Netherlands. E-mail: [email protected] Current address for Dr Choi: College of Pharmacy, Catholic University of Korea, Bucheon, South Korea. From the 1Department of Neurology, University Medical Center Maastricht, Maastricht, the Netherlands; 2Department of Neurology, Yale University School of Medicine, New Haven, CT; 3Center for Neuroscience and Regeneration Research, Veterans Affairs Medical Center, West Haven, CT; 4Neuromuscular Diseases Unit, IRCCS Foundation, Carlo Besta, Milan, Italy; 5Department of Clinical Genomics, University Medical Center Maastricht, Maastricht, the Netherlands; 6Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; and 7Department of Neurology, Spaarne Hospital, Hoofddorp, the Netherlands. Additional supporting information can be found in the online version of this article. 26 VC 2011 American Neurological Association Faber et al: NaV1.7 Mutations in SFN treatable,5,8 the proportion of patients with idiopathic signs of large nerve fiber involvement (muscle weakness, loss of SFN (I-SFN), in which no cause can be identified, vibration sense, hypo-/areflexia), abnormal NCS, and history or remains substantial, ranging in different series from 24% detection after screening of illnesses known to cause SFN, including to 93%.5,6,9 Observations of autosomal dominant inheri- diabetes mellitus, impaired glucose tolerance, hyperlipidemia, liver, tance suggest a genetic origin for the small fiber involve- kidney, or thyroid dysfunction, monoclonal gammopathy, connec- tive tissue disorders, sarcoidosis, Sjogren syndrome, amyloidosis, ment that is seen in burning feet syndrome.10 However, Fabry disease (alpha-galactosidase, in females combined with GLA no specific gene has been linked to, or mutations identi- gene sequencing), celiac disease, HIV, alcohol abuse, hemochroma- fied in, patients with adult onset I-SFN. tosis, antiphospholipid syndrome, B6 intoxication, and neurotoxic Voltage-gated sodium channel NaV1.7 is preferentially drugs (eg, chemotherapy). Patients were not screened for mutations expressed in dorsal root ganglion (DRG) and sympathetic associated with hereditary sensory and autonomic neuropathy, 11,12 13 ganglion neurons and their axons, and opens in which usually has an early onset and clinical characteristics19 that response to small depolarizations close to resting potential.14 are different from those seen in our cohort of patients with I-SFN, Gain of function mutations in the SCN9A gene encoding or for antibodies to peripherin, which have recently been associated 20 NaV1.7 have been found to cause the painful disorders inher- with small fiber neuropathy. 15,16 ited erythromelalgia (IEM) and paroxysmal extreme FINAL PATIENT SELECTION, BIOPSY, AND QST CON- 17 pain disorder (PEPD), which are characterized by increased FIRMATION OF SFN. Of 248 patients initially screened fol- excitability of DRG neurons, and loss of function mutations lowing referral with a suspected clinical diagnosis of SFN, 44 of NaV1.7 have been linked to channelopathy-associated patients met inclusion/exclusion criteria and underwent skin bi- 18 insensitivity to pain. Sodium channel mutations have not, opsy and QST. From this group, 28 met strict criteria for I-SFN however, been linked to axonal degeneration. Reasoning that (ie, reduced IENFD and abnormal QST compared to normative 13 SCN9A NaV1.7 is present in small diameter peripheral axons, in values). gene analysis was carried out in all 28 patients this study we asked whether mutations in the SCN9A gene with biopsy-confirmed I-SFN. The current study describes 8 could be found in a clinically well-defined cohort of patients patients, from this group of 28 patients with I-SFN, who were SCN9A with biopsy-confirmed I-SFN. found to carry a mutation in the gene (Fig 1). Our results demonstrate, for the first time, the pres- ence of sodium channel mutations in a substantial pro- Clinical Characterization portion of patients with I-SFN, show that these missense SKIN BIOPSY. Punch biopsy (10cm above lateral malleolus) mutations occur in an ion channel that is preferentially specimens were fixed (2% paraformaldehyde-lysine-sodium peri- expressed in peripheral axons and share the common fea- odate at 4C),cryoprotected,andstoredatÀ80Cincryoprotec- ture of rendering DRG neurons hyperexcitable, and tive solution (20% glycerol) before sectioning (50lm).21 The point to a broader role of NaV1.7 mutations in neurolog- numbers of individual nerve fibers crossing the dermal–epidermal ical diseases than previously considered from studies on junctions were analyzed in each of 3 sections, immunostained with rare genetic hyperexcitability syndromes. polyclonal rabbit antiprotein gene product-9.5 antibody (Ultra- clone; Wellow, Isle-of-Wight, UK), by bright field microscopy using a stereology workstation (Olympus [Tokyo, Japan] BX50, PlanApo Patients and Methods oil-objective Â40/numerical aperture (NA) ¼ 1.0). Linear quantifi- cation of intraepidermal nerve fiber density was compared with Patients available age- and gender-adjusted normative values.22 INCLUSION/EXCLUSION CRITERIA: PRESELEC- QST. QST, performed in accordance with previous guidelines,23 TION. To accrue a cohort of patients with I-SFN, we initially using a TSA-2001 (Medoc, Ramat-Yishai, Israel) instrument, assessed all patients aged 18 years seen at Maastricht University assessed thresholds at the dorsum of both feet and thenar eminen- Medical Center neurological clinic with a clinical diagnosis of SFN ces, using ascending/descending (warm/cool) thermal ramp stimuli between 2006 and 2009 and excluded those in whom, after full delivered through a thermode.24 Heat pain modality was also exam- workup, a cause for SFN was identified. All patients with a clinical ined. Results were compared with reported normative values.25 diagnosis of I-SFN were asked to participate
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