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

Department of Neurology, University Medical Center Maastricht, Maastricht, The Netherlands.
Annals of Neurology (Impact Factor: 9.98). 01/2012; 71(1):26-39. DOI: 10.1002/ana.22485
Source: PubMed


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(V)1.7, which is preferentially expressed in small diameter peripheral axons.
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.
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.
We show for the first time that gain of function mutations in sodium channel Na(V)1.7, 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(V)1.7 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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    • "The development of the SFN-RODS © and transforming the SFN-SIQ © into an interval measure contribute to the pallet needed to evaluate the impact of SFN at all levels of assessing outcome, ranging from pathology (skin biopsy), to impairments (biophysical properties; SFN-SIQ © , pain assessment), to activity limitations and participation restrictions (newly developed SFN-RODS © ), and to quality of life expectations (as demonstrated recently using the SF-36), which reflects the WHO framework of understanding the consequences of an illness (Bakkers et al., 2009; Faber et al., 2012a; Hoeijmakers et al., 2012; Lauria et al., 2012; Ware, et al., 2000; World Health Organization, 2001). In addition, the Rasch-built SFN- RODS © and SFN-SIQ © outcomes also reflect a higher level of measurement precision, bypassing the known deficiencies of ordinal-based scales (DeVellis, 2006; Merbitz et al., 1989; Wright and Linacre, 1989). "
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    ABSTRACT: Interval measures at the impairment level addressing symptoms and at the activity/participation level addressing daily and social restrictions have not been developed for Small Fiber Neuropathy (SFN). We developed a SFN-specific Rasch-built overall disability scale (SFN-RODS(©) ), an activity/participation scale at the interval level. A preliminary SFN-RODS containing 146 activity/participation items was assessed twice (reliability studies) in 238 patients with SFN. The ordinal-based 13-item SFN-symptoms inventory questionnaire (SFN-SIQ(©) ) and pain-visual-analogue-scale were also assessed (validity studies). The pre-SFN-RODS and SFN-SIQ data were subjected to the Rasch analyses. The pre-SFN-RODS did not meet Rasch model expectations. Based on requirements like misfit statistics, differential item functioning, and local dependency, items were systematically removed and model fit improved. Finally, a 32-item SFN-RODS(©) scale was constructed that fulfilled all Rasch requirements, demonstrating acceptable reliability and validity scores. The 13-item SFN-SIQ(©) was successfully transformed to an interval Rasch-built measure fulfilling model's requirements. In conclusion, the 32-item SFN-RODS(©) is a disease-specific interval measure suitable for detecting activity limitations and participation restrictions in patients with SFN. The 13-item SFN-SIQ(©) was transformed through Rasch to an interval measure. The use of these scales is recommended in future clinical interventional trials involving patients with SFN. This article is protected by copyright. All rights reserved.
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    • "Persistent and chronic pain by definition involve sensitization or remodeling of the nervous system, and neuropathies and other chronic pain indications represent the main unmet medical need for analgesics [30]. Although it seems clear that Nav1.7 is crucial for nociceptive pain, and clinical genetics indicate aberrant Nav1.7 can play a role in human neuropathies [5], it is unclear to what extent Nav1.7 governs pain following pathological neuronal sensitization. To address one form of this we evaluated Nav1.7 KOs on the Hargreaves apparatus for withdrawal latency to radiant heat stimulus before and after injection of complete Freund’s adjuvant (CFA) into the paw (Figure 5). "
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    ABSTRACT: Clinical genetic studies have shown that loss of Nav1.7 function leads to the complete loss of acute pain perception. The global deletion is reported lethal in mice, however, and studies of mice with promoter-specific deletions of Nav1.7 have suggested that the role of Nav1.7 in pain transduction depends on the precise form of pain. We developed genetic and animal husbandry strategies that overcame the neonatal-lethal phenotype and enabled construction of a global Nav1.7 knockout mouse. Knockouts were anatomically normal, reached adulthood, and had phenotype wholly analogous to human congenital indifference to pain (CIP): compared to littermates, knockouts showed no defects in mechanical sensitivity or overall movement yet were completely insensitive to painful tactile, thermal, and chemical stimuli and were anosmic. Knockouts also showed no painful behaviors resulting from peripheral injection of nonselective sodium channel activators, did not develop complete Freund's adjuvant-induced thermal hyperalgesia, and were insensitive to intra-dermal histamine injection. Tetrodotoxin-sensitive sodium current recorded from cell bodies of isolated sensory neurons and the mechanically-evoked spiking of C-fibers in a skin-nerve preparation each were reduced but not eliminated in tissue from knockouts compared to littermates. Results support a role for Nav1.7 that is conserved between rodents and humans and suggest several possibly translatable biomarkers for the study of Nav1.7-targeted therapeutics. Results further suggest that Nav1.7 may retain its key role in persistent as well as acute forms of pain.
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    • "The clinical phenotype of paroxysmal itch in the presently described family is different from that previously reported in patients carrying the I739 variant, in whom distal pain and dysautonomia were prominent.[9; 11; 12] However, one of those patients complained of itch at the face, feet and lower limbs since childhood.[9] Also in one SFN patient of a kindred harboring the L554P variant of SCN10A gene, which encodes Nav1.8 sodium channel, nocturnal itch was the prominent feature [10]. "
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