Etiology of small‐fiber neuropathy

Bednařík, Josef; Vlčková, Eva; Buršová, Šárka; Bělobrádková, Jana; Dušek, Ladislav; Sommer, Claudia

doi:10.1111/j.1529-8027.2009.00229.x

Cited by 68 publications

(63 citation statements)

References 26 publications

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“…5,6,9 In this study we show, in 8 of 28 (28.6%) patients with skin biopsyand QST-confirmed I-SFN, missense mutations in the SCN9A gene, which encodes a voltage-gated sodium channel, Na V 1.7, that is present within small peripheral nerve fibers. Electrophysiological analysis demonstrated gain of function changes in the mutant channels and showed that the mutations share the common feature of rendering DRG neurons hyperexcitable.…”

Section: Discussionmentioning

confidence: 93%

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Gain of function Na_V1.7 mutations in idiopathic small fiber neuropathy

Faber

Hoeijmakers

Ahn

et al. 2011

Annals of Neurology

501

436

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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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Section: Discussionmentioning

confidence: 93%

“…5,6,9 Observations of autosomal dominant inheritance suggest a genetic origin for the small fiber involvement that is seen in burning feet syndrome. 10 However, no specific gene has been linked to, or mutations identified in, patients with adult onset I-SFN.…”

mentioning

confidence: 98%

Gain of function Na_V1.7 mutations in idiopathic small fiber neuropathy

Faber

Hoeijmakers

Ahn

et al. 2011

Annals of Neurology

501

436

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“…Diabetes and toxic causes are best known [80], but several systemic autoimmune conditions are also associated [14]. In addition to ganglionitis, Sjögren's also causes painful distal SFPN [81].…”

Section: Small-fiber Polyneuropathymentioning

confidence: 99%

Immunotherapy Prospects for Painful Small-fiber Sensory Neuropathies and Ganglionopathies

Oaklander

2016

Neurotherapeutics

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The best-known peripheral neuropathies are those affecting the large, myelinated motor and sensory fibers. These have well-established immunological causes and therapies. Far less is known about the somatic and autonomic "small fibers"; the unmyelinated C-fibers, thinly myelinated A-deltas, and postganglionic sympathetics. The small fibers sense pain and itch, innervate internal organs and tissues, and modulate the inflammatory and immune responses. Symptoms of small-fiber neuropathy include chronic pain and itch, sensory impairment, edema, and skin color, temperature, and sweating changes. Small-fiber polyneuropathy (SFPN) also causes cardiovascular, gastrointestinal, and urological symptoms, the neurologic origin of which often remains unrecognized. Routine electrodiagnostic study does not detect SFPN, so skin biopsies immunolabeled to reveal axons are recommended for diagnostic confirmation. Preliminary evidence suggests that dysimmunity causes some cases of small-fiber neuropathy. Several autoimmune diseases, including Sjögren and celiac, are associated with painful small-fiber ganglionopathy and distal axonopathy, and some patients with "idiopathic" SFPN have evidence of organ-specific dysimmunity, including serological markers. Dysimmune SFPN first came into focus in children and teenagers as they lack other risk factors, for example diabetes or toxic exposures. In them, the rudimentary evidence suggests humoral rather than cellular mechanisms and complement consumption. Preliminary evidence supports efficacy of corticosteroids and immunoglobulins in carefully selected children and adult patients. This paper reviews the evidence of immune causality and the limited data regarding immunotherapy for small-fiberpredominant ganglionitis, regional neuropathy (complex regional pain syndrome), and distal SFPN. These demonstrate the need to develop case definitions and outcome metrics to improve diagnosis, enable prospective trials, and dissect the mechanisms of small-fiber neuropathy.

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“…SFN is associated with diabetes, HIV infection, and chemotherapy treatment, but many patients suffer from idiopathic SFN (3)(4)(5). SFN patients can exhibit a large variety of symptoms, including loss of sensation and chronic pain.…”

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confidence: 99%

Treating small fiber neuropathy by topical application of a small molecule modulator of ligand-induced GFRα/RET receptor signaling

Hedstrom

Murtie

Albers

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Small-fiber neuropathy (SFN) is a disorder of peripheral nerves commonly found in patients with diabetes mellitus, HIV infection, and those receiving chemotherapy. The complexity of disease etiology has led to a scarcity of effective treatments. Using two models of progressive SFN, we show that overexpression of glial cell line-derived neurotrophic factor (GDNF) in skin keratinocytes or topical application of XIB4035, a reported nonpeptidyl agonist of GDNF receptor α1 (GFRα1), are effective treatments for SFN. We also demonstrate that XIB4035 is not a GFRα1 agonist, but rather it enhances GFRα family receptor signaling in conjunction with ligand stimulation. Taken together, our results indicate that topical application of GFRα/RET receptor signaling modulators may be a unique therapy for SFN, and we have identified XIB4035 as a candidate therapeutic agent.topical drug | pain | thermonociception | sensory | trophic factor S mall-fiber neuropathy (SFN), i.e., damage or dysfunction of small-diameter axons (C fibers) in peripheral nerves, is a prevalent neurological disorder that afflicts an estimated 1.5% of the world's population and millions of people in the United States (1-3). SFN is associated with diabetes, HIV infection, and chemotherapy treatment, but many patients suffer from idiopathic SFN (3-5). SFN patients can exhibit a large variety of symptoms, including loss of sensation and chronic pain. Despite the pervasiveness of SFN, its etiology is poorly understood, resulting in a lack of disease-modifying treatments.Initial stages of SFN commonly involve nerve terminal degeneration before sensory neuron death (6), and reduction in targetderived trophic factor expression has been observed in multiple models of peripheral neuropathy (7,8). Therefore, replenishing or replacing neurotrophic factors promptly after disease onset could potentially be used as a treatment to promote the survival and restore the function of C-fiber neurons (9, 10). One group of trophic factors necessary for development and survival of C fibers is the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) (10, 11). Each family member interacts selectively with a different high affinity receptor: GDNF with GDNF receptor α1 (GFRα1), neurturin (NRTN) with GFRα2, artemin (ARTN) with GFRα3, and persephin (PSPN) with GFRα4, although GDNF and NRTN have the capacity to bind and activate GFRα2 and GFRα1, respectively (12). Each ligand/receptor pair forms a complex with the RET receptor tyrosine kinase, resulting in downstream effects that include tyrosine hydroxylase (TH) gene transcription (13,14). GFLs not only play a pivotal role in sensory neuron development, but also appear to be beneficial in the context of peripheral nerve injury. For example, systemic, transgenic, or viral delivery of GFLs has been shown to attenuate neuropathic symptoms in mouse models of nerve injury (15-19). Thus, we hypothesized that topical delivery of GDNF receptor agonists to the skin would be an effective, noninvasive therapeutic approach for t...

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Etiology of small‐fiber neuropathy

Cited by 68 publications

References 26 publications

Gain of function Na_V1.7 mutations in idiopathic small fiber neuropathy

Gain of function Na_V1.7 mutations in idiopathic small fiber neuropathy

Immunotherapy Prospects for Painful Small-fiber Sensory Neuropathies and Ganglionopathies

Treating small fiber neuropathy by topical application of a small molecule modulator of ligand-induced GFRα/RET receptor signaling

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Etiology of small‐fiber neuropathy

Cited by 68 publications

References 26 publications

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

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

Immunotherapy Prospects for Painful Small-fiber Sensory Neuropathies and Ganglionopathies

Treating small fiber neuropathy by topical application of a small molecule modulator of ligand-induced GFRα/RET receptor signaling

Contact Info

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Gain of function Na_V1.7 mutations in idiopathic small fiber neuropathy

Gain of function Na_V1.7 mutations in idiopathic small fiber neuropathy