Reply: Small fibre neuropathy, fibromyalgia and dorsal root ganglia sodium channels

BackgroundNeuropathic pain is common in peripheral neuropathy. Recent genetic studies have linked pathogenic voltage-gated sodium channel (VGSC) variants to human pain disorders. Our aims are to determine the frequency of SCN9A, SCN10A and SCN11A variants in patients with pure small fibre neuropathy (SFN), analyse their clinical features and provide a rationale for genetic screening.MethodsBetween September 2009 and January 2017, 1139 patients diagnosed with pure SFN at our reference centre were screened for SCN9A, SCN10A and SCN11A variants. Pathogenicity of variants was classified according to established guidelines of the Association for Clinical Genetic Science and frequencies were determined. Patients with SFN were grouped according to the VGSC variants detected, and clinical features were compared.ResultsAmong 1139 patients with SFN, 132 (11.6%) patients harboured 73 different (potentially) pathogenic VGSC variants, of which 50 were novel and 22 were found in ≥ 1 patient. The frequency of (potentially) pathogenic variants was 5.1% (n=58/1139) for SCN9A, 3.7% (n=42/1139) for SCN10A and 2.9% (n=33/1139) for SCN11A. Only erythromelalgia-like symptoms and warmth-induced pain were significantly more common in patients harbouring VGSC variants.Conclusion(Potentially) pathogenic VGSC variants are present in 11.6% of patients with pure SFN. Therefore, genetic screening of SCN9A, SCN10A and SCN11A should be considered in patients with pure SFN, independently of clinical features or underlying conditions.

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Contrasting temperature-dependenee in two types of sodium channels in rat dorsal root ganglia.

The Japanese Journal of Pharmacology ◽

10.1016/s0021-5198(19)50833-2 ◽

1994 ◽

Vol 64 ◽

pp. 300

Author(s):

Haruhiko Motomura ◽

Fujikawa Sadatoshi ◽

Nobukuni Ogata ◽

Yushi Ito

Keyword(s):

Sodium Channels ◽

Dorsal Root Ganglia ◽

Dorsal Root

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a pharmacological analysis of the two types of sodium channels in rat dorsal root ganglia.

The Japanese Journal of Pharmacology ◽

10.1016/s0021-5198(19)50823-x ◽

1994 ◽

Vol 64 ◽

pp. 297

Author(s):

Fujikawa Sadatoshi ◽

Haruhiko Motomura ◽

Nobukuni Ogata ◽

Yushi Ito

Keyword(s):

Sodium Channels ◽

Dorsal Root Ganglia ◽

Dorsal Root ◽

Pharmacological Analysis

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Clinical characterisation of sensory neuropathy with anti-FGFR3 autoantibodies

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2019-321849 ◽

2019 ◽

Vol 91 (1) ◽

pp. 49-57 ◽

Cited By ~ 8

Author(s):

Yannick Tholance ◽

Christian Peter Moritz ◽

Carole Rosier ◽

Karine Ferraud ◽

François Lassablière ◽

...

Keyword(s):

Dorsal Root ◽

Fibroblast Growth Factor Receptor ◽

Growth Factor Receptor ◽

Sensory Neuropathy ◽

Lower Limbs ◽

Clinical Pattern ◽

Small Fibre Neuropathy ◽

Small Fibre ◽

Immunological Mechanisms ◽

Pure Sn

ObjectiveSensory neuropathies (SNs) are often classified as idiopathic even if immunological mechanisms can be suspected. Antibodies against the intracellular domain of the fibroblast growth factor receptor 3 (FGFR3) possibly identify a subgroup of SN affecting mostly the dorsal root ganglion (DRG). The aim of this study was to identify the frequency of anti-FGFR3 antibodies and the associated clinical pattern in a large cohort of patients with SN.MethodsA prospective, multicentric, European and Brazilian study included adults with pure SN. Serum anti-FGRF3 antibodies were analysed by ELISA. Detailed clinical and paraclinical data were collected for each anti-FGFR3-positive patient and as control for anti-FGFR3-negative patients from the same centres (‘center-matched’).ResultsSixty-five patients out of 426 (15%) had anti-FGFR3 antibodies, which were the only identified autoimmune markers in 43 patients (66%). The neuropathy was non-length dependent in 89% and classified as sensory neuronopathy in 64%, non-length-dependent small fibre neuropathy in 17% and other neuropathy in 19%. Specific clinical features occurred after 5–6 years of evolution including frequent paresthesia, predominant clinical and electrophysiological involvement of the lower limbs, and a less frequent mixed large and small fibre involvement. Brazilians had a higher frequency of anti-FGFR3 antibodies than Europeans (36% vs 13%, p<0.001), and a more frequent asymmetrical distribution of symptoms (OR 169, 95% CI 3.4 to 8424).ConclusionsAnti-FGFR3 antibodies occur in a subgroup of SN probably predominantly affecting the DRG. Differences between Europeans and Brazilians could suggest involvement of genetic or environmental factors.

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Electroacupuncture Reduces Carrageenan- and CFA-Induced Inflammatory Pain Accompanied by Changing the Expression of Nav1.7 and Nav1.8, rather than Nav1.9, in Mice Dorsal Root Ganglia

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/312184 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 11

Author(s):

Chun-Ping Huang ◽

Hsiang-Ni Chen ◽

Hong-Lin Su ◽

Ching-Liang Hsieh ◽

Wei-Hsin Chen ◽

...

Keyword(s):

Sodium Channels ◽

Dorsal Root Ganglia ◽

Inflammatory Pain ◽

Dorsal Root ◽

Low Frequency ◽

Thermal Hyperalgesia ◽

Nerve Fibers ◽

Drg Neurons ◽

Plantar Surface ◽

Voltage Gated Sodium Channels

Several voltage-gated sodium channels (Navs) from nociceptive nerve fibers have been identified as important effectors in pain signaling. The objective of this study is to investigate the electroacupuncture (EA) analgesia mechanism by changing the expression of Navs in mice dorsal root ganglia (DRG). We injected carrageenan and complete Freund's adjuvant (CFA) into the mice plantar surface of the hind paw to induce inflammation and examined the antinociception effect of EA at the Zusanli (ST36) acupoint at 2 Hz low frequency. Mechanical hyperalgesia was evaluated by using electronic von Frey filaments, and thermal hyperalgesia was assessed using Hargreaves' test. Furthermore, we observed the expression and quality of Navs in DRG neurons. Our results showed that EA reduced mechanical and thermal pain in inflammatory animal model. The expression of Nav1.7 and Nav1.8 was increased after 4 days of carrageenan- and CFA-elicited inflammatory pain and further attenuated by 2 Hz EA stimulation. The attenuation cannot be observed in Nav1.9 sodium channels. We demonstrated that EA at Zusanli (ST36) acupoint at 2 Hz low-frequency stimulation attenuated inflammatory pain accompanied by decreasing the expression of Nav1.7 and 1.8, rather than Nav1.9, sodium channels in peripheral DRG neurons.

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Dorsal root ganglia, sodium channels, and fibromyalgia sympathetic pain

Medical Hypotheses ◽

10.1016/j.mehy.2008.07.055 ◽

2009 ◽

Vol 72 (1) ◽

pp. 64-66 ◽

Cited By ~ 16

Author(s):

Manuel Martinez-Lavin ◽

Carla Solano

Keyword(s):

Sodium Channels ◽

Dorsal Root Ganglia ◽

Dorsal Root ◽

Sympathetic Pain

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Differential effect of lacosamide on Nav1.7 variants from responsive and non-responsive patients with small fibre neuropathy

Brain ◽

10.1093/brain/awaa016 ◽

2020 ◽

Vol 143 (3) ◽

pp. 771-782 ◽

Cited By ~ 4

Author(s):

Julie I R Labau ◽

Mark Estacion ◽

Brian S Tanaka ◽

Bianca T A de Greef ◽

Janneke G J Hoeijmakers ◽

...

Keyword(s):

Sodium Channel ◽

Dorsal Root ◽

Voltage Dependence ◽

Dependent Manner ◽

Slow Inactivation ◽

Fast Inactivation ◽

Small Fibre Neuropathy ◽

Small Fibre ◽

Dependent Inhibition ◽

Hyperpolarizing Shift

Abstract Small fibre neuropathy is a common pain disorder, which in many cases fails to respond to treatment with existing medications. Gain-of-function mutations of voltage-gated sodium channel Nav1.7 underlie dorsal root ganglion neuronal hyperexcitability and pain in a subset of patients with small fibre neuropathy. Recent clinical studies have demonstrated that lacosamide, which blocks sodium channels in a use-dependent manner, attenuates pain in some patients with Nav1.7 mutations; however, only a subgroup of these patients responded to the drug. Here, we used voltage-clamp recordings to evaluate the effects of lacosamide on five Nav1.7 variants from patients who were responsive or non-responsive to treatment. We show that, at the clinically achievable concentration of 30 μM, lacosamide acts as a potent sodium channel inhibitor of Nav1.7 variants carried by responsive patients, via a hyperpolarizing shift of voltage-dependence of both fast and slow inactivation and enhancement of use-dependent inhibition. By contrast, the effects of lacosamide on slow inactivation and use-dependence in Nav1.7 variants from non-responsive patients were less robust. Importantly, we found that lacosamide selectively enhances fast inactivation only in variants from responders. Taken together, these findings begin to unravel biophysical underpinnings that contribute to responsiveness to lacosamide in patients with small fibre neuropathy carrying select Nav1.7 variants.

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