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: Itch is a common experience. It can occur in the course of systemic diseases and be one manifestation of allergies, or the consequence of diseases affecting the somatosensory pathway. We describe a kindred characterized by paroxysmal itch caused by a variant in SCN9A gene encoding for the Nav1.7 sodium channel. Patients underwent clinical and somatosensory profile assessment by quantitative sensory testing, nerve conduction study, autonomic cardiovascular reflex and sympathetic skin response examination, skin biopsy with quantification of intraepidermal nerve fiber density and SCN9A mutational analysis. The index patient, her mother and a sister presented with a stereotypical clinical picture characterized by paroxysmal itch attacks involving the shoulders, upper back and upper limbs, followed by transient burning pain, triggered by environmental warmth, hot drinks and spicy food. Somatosensory profile assessment demonstrated a remarkably identical pattern of increased cold and pain thresholds and paradoxical heat sensation. Autonomic tests were negative, whereas skin biopsy revealed decreased intraepidermal nerve fiber density in two of the three patients. All affected members harbored the 2215A>G I739V substitution in exon 13 of SCN9A gene. Pregabalin treatment reduced itch intensity and attack frequency in all patients. The co-segregation of the I739V variant in the affected members of the family provides evidence, for the first time, that paroxysmal itch can be related to a mutation in sodium channel gene.
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