Idiopathic neuropathy: new paradigms, new promise

Singer, Mike A.; Vernino, Steven; Wolfe, Gil I.

doi:10.1111/j.1529-8027.2012.00395.x

Cited by 50 publications

(34 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…35,36 Cases with late onset have reduced likelihood of finding a genetic cause, highlighting the longstanding polygenic enigma of chronic idiopathic axonal polyneuropathy (CIAP). 37 In this study, no patients with CIAP phenotypes had pathologic mutations, consistent with evidence-based practice guidelines discouraging genetic testing in them. 12 However, accurately determining the age at onset can be difficult and careful clinical judgment is emphasized.…”

mentioning

confidence: 68%

Target-enrichment sequencing and copy number evaluation in inherited polyneuropathy

Wang

Dawson

et al. 2016

Neurology

View full text Add to dashboard Cite

Objective: To assess the efficiency of target-enrichment next-generation sequencing (NGS) with copy number assessment in inherited neuropathy diagnosis.Methods: A 197 polyneuropathy gene panel was designed to assess for mutations in 93 patients with inherited or idiopathic neuropathy without known genetic cause. We applied our novel copy number variation algorithm on NGS data, and validated the identified copy number mutations using CytoScan (Affymetrix). Cost and efficacy of this targeted NGS approach was compared to earlier evaluations.Results: Average coverage depth was ;7603 (median 5 600, 99.4% . 1003). Among 93 patients, 18 mutations were identified in 17 cases (18%), including 3 copy number mutations: 2 PMP22 duplications and 1 MPZ duplication. The 2 patients with PMP22 duplication presented with bulbar and respiratory involvement and had absent extremity nerve conductions, leading to axonal diagnosis. Average onset age of these 17 patients was 25 years (2-61 years), vs 45 years for those without genetic discovery. Among those with onset age less than 40 years, the diagnostic yield of targeted NGS approach is high (27%) and cost savings is significant (;20%). However, the cost savings for patients with late onset age and without family history is not demonstrated. Conclusions:Incorporating copy number analysis in target-enrichment NGS approach improved the efficiency of mutation discovery for chronic, inherited, progressive length-dependent polyneuropathy diagnosis. The new technology is facilitating a simplified genetic diagnostic algorithm utilizing targeted NGS, clinical phenotypes, age at onset, and family history to improve diagnosis efficiency. Our findings prompt a need for updating the current practice parameters and payer guidelines. Neurology ® 2016;86:1762-1771 GLOSSARY CIAP 5 chronic idiopathic axonal polyneuropathy; CMT 5 Charcot-Marie-Tooth; CNV 5 copy number variation; DGV 5 Database of Genomic Variants; HMSN 5 hereditary motor and sensory polyneuropathy; MAF 5 minor allele frequency; NGS 5 next-generation sequencing; VUS 5 variants of unclear significance; WES 5 whole exome sequencing.Polyneuropathies are common, with overall prevalence of 1.7%, and 6.6% among persons over 60 years old.1 The high prevalence, multiple impairments, and complicated diagnostic procedures lead to high health care cost.1,2 Separating inherited from acquired causes is often difficult for insidious adult-onset cases, due to overlapping phenotypes.3,4 Furthermore, inherited and acquired polyneuropathies may coexist, resulting in worse severity. [5][6][7][8] One large prospective study indicated that as many as 42% of patients with previously undiagnosed polyneuropathy coming to tertiary care referral had familial occurrence. 9Pragmatic diagnostic strategies have long been sought to improve testing effectiveness and reduce costs in neuropathy diagnosis. [10][11][12] In Charcot-Marie-Tooth clinics, algorithms have been developed for selecting candidate genes.13 This approach is helpful for patients who have c...

show abstract

mentioning

confidence: 68%

Target-enrichment sequencing and copy number evaluation in inherited polyneuropathy

Wang

Dawson

et al. 2016

Neurology

View full text Add to dashboard Cite

show abstract

“…CIAP is diagnosed by slowly progressive distal symmetric sensory or sensorimotor polyneuropathy [52]. NCS shows reduced amplitude [46], EMG examination shows abnormalities, laboratory tests show normal values, and skin biopsy confirms the diagnosis of CIAP by evaluation of density and structure of epidermal nerve fibers [46,52]. Erdmann et al (2010) found that 69% of CIAP patients have pain [52].…”

Section: Diabetic Neuropathymentioning

confidence: 99%

“…Risk factors that contribute to development of CIAP include hypertension, impaired glucose tolerance, obesity, hypercholesterolemia, and environmental toxins [47,[49][50][51]. All these risk factors cause oxidative stress [46]. CIAP is diagnosed by slowly progressive distal symmetric sensory or sensorimotor polyneuropathy [52].…”

Section: Diabetic Neuropathymentioning

confidence: 99%

See 1 more Smart Citation

Autophagy in Peripheral Neuropathy

Osman¹

2017

Linköping University Medical Dissertations

View full text Add to dashboard Cite

Peripheral neuropathy includes a wide range of diseases affecting millions around the world, and many of these diseases have unknown etiology. Peripheral neuropathy in diabetes represents a large proportion of peripheral neuropathies. Nerve damage can also be caused by trauma. Peripheral neuropathies are a significant clinical problem and efficient treatments are largely lacking. In the case of a transected nerve, different methods have been used to repair or reconstruct the nerve, including the use of nerve conduits, but functional recovery is usually poor. Autophagy, a cellular mechanism that recycles damaged proteins, is impaired in the brain in many neurodegenerative diseases affecting animals and humans. No research, however, has investigated the presence of autophagy in the human peripheral nervous system. In this study, I present the first structural evidence of autophagy in human peripheral nerves. I also show that the density of autophagy structures is higher in peripheral nerves of patients with chronic idiopathic axonal polyneuropathy (CIAP) and inflammatory neuropathy than in controls. The density of these structures increases with the severity of the neuropathy. In animal model, using Goto-Kakizaki (GK) rats with diabetes resembling human type 2 diabetes, activation of autophagy by local administration of rapamycin incorporated in collagen conduits that were used for reconnection of the transected sciatic nerve led to an increase in autophagy proteins LC3 and a decrease in p62 suggesting that the autophagic flux was activated. In addition, immunoreactivity of neurofilaments, which are parts of the cytoskeleton of axons, was increased indicating increased axonal regeneration. I also show that many proteins involved in axonal regeneration and cell survival were up-regulated by rapamycin in the injured sciatic nerve of GK rats four weeks after injury. Taken together, these findings provide new knowledge about the involvement of autophagy in neuropathy and after peripheral nerve injury and reconstruction using collagen conduits. 6 Populärvetenskaplig sammanfattningNervskador (neuropati) orsakade av sjukdomar eller olycksfall påverkar miljontals individer runt om i världen. Nervskador som orsakas av diabetes kallas diabetesneuropati och drabbar varannan patient med diabetes. Neuropati kan också orsakas av kronisk inflammation i nerven eller uppstå utan känd orsak, så kallad kronisk idiopatisk axonal polyneuropati. Patienterna som drabbas av neuropati uppvisar varierande symptom beroende på vilka nerver som drabbas men domningar, stickningar, smärta, känselbortfall och muskelsvaghet finns ofta i symptombilden. Nervskador efter trauma kräver oftast kirurgisk rekonstruktion. För närvarande finns det ingen behandling för diabetesneuropati. Allt fler människor i fysiskt aktiv ålder drabbas av åldersdiabetes (typ 2 diabetes). Detta leder till att fler patienter med diabetes drabbas av traumatiska nervskador som kräver nervreparation. Det är därför viktigt att utveckla reparationsmetoder som fungerar br...

show abstract

“…This is true to a greater degree in patients with small fiber neuropathy where 50% or more of patients have idiopathic neuropathy (Periquet et al, 1999;Venkataramana et al, 2005;De Sousa et al, 2006) (Table 1). Singer et al (2012) discussed current research being done in idiopathic neuropathy. The only treatment that we have for peripheral neuropathy is when we can treat the identifiable cause.…”

mentioning

confidence: 99%

Current issues in peripheral neuropathy

Brannagan¹

2012

J Peripheral Nervous Sys

View full text Add to dashboard Cite

Twenty million people in the United States are estimated to have peripheral neuropathy. However, many patients are not aware of their diagnosis, are not given the diagnosis or being treated, or the diagnosis is delayed. Currently, the only treatments available for neuropathy are aimed at treating the underlying medical conditions that cause the neuropathy or treating symptoms such as pain. Neither treats the actual nerve fiber dysfunction or fiber loss, or helps nerve fibers regenerate. Idiopathic neuropathy, that is neuropathy for which a cause is not identified, is common, accounting in referral series for 25% in all neuropathy patients and 50% or more of patients with small fiber neuropathy. Currently, there is only one FDA-approved medication for a specific neuropathy (chronic inflammatory demylinating polyneuropathy) while there are two FDA approved medications for diabetic neuropathy pain and four that are approved for post-herpetic neuralgia pain. For many patients with painful neuropathy, these medications are ineffective or not tolerated. Continued research into the underlying mechanisms of neuropathy and an increased understanding of nerve regeneration and neuropathic pain are needed to address this unmet medical need among patients with neuropathy.Key words: chronic inflammatory demyelinating polyradiculoneuropathy, diabetic neuropathy, nerve regeneration, neuropathic pain, peripheral neuropathy Despite the enormous physical, emotional, and financial toll neuropathy takes on Americans' health and our health care system, neuropathy remains one of the least recognized illnesses in the United States today. In a survey of patients with diabetes mellitus about symptoms of neuropathy, only one of four patients with symptoms of neuropathy had been diagnosed with the disease. Fifty-six percent of those with symptoms were unaware of the term diabetic neuropathy. Over half believed their symptoms were related to diabetes mellitus, but only 42% had been told by their doctor that diabetes was the cause. And one in seven said no cause was mentioned

show abstract

Idiopathic neuropathy: new paradigms, new promise

Cited by 50 publications

References 47 publications

Target-enrichment sequencing and copy number evaluation in inherited polyneuropathy

Target-enrichment sequencing and copy number evaluation in inherited polyneuropathy

Autophagy in Peripheral Neuropathy

Current issues in peripheral neuropathy

Contact Info

Product

Resources

About