Journal of the Peripheral Nervous System最新文献

{"title":"Digenic FLNA and UCHL1 variants resulting in a complex phenotype","authors":"Helena F. Pernice,&nbsp;Luke F. O'Donnell,&nbsp;Alexander M. Rossor,&nbsp;Matilde Laura,&nbsp;Christopher J. Record,&nbsp;Mariola Skorupinska,&nbsp;Julian Blake,&nbsp;Roy Poh,&nbsp;James Polke,&nbsp;Mary M. Reilly","doi":"10.1111/jns.12611","DOIUrl":"10.1111/jns.12611","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>X-linked variants in Filamin A (<i>FLNA)</i> are associated with the Ehlers-Danlos-syndrome-variant form of periventricular heterotopia, and autosomal dominant variants in ubiquitin C-terminal hydrolase L1 (<i>UCHL1</i>) are associated with a late-onset spastic ataxia, peripheral neuropathy and optic atrophy. Here we present a rare case involving both a novel heterozygous whole-gene deletion of <i>UCHL1</i> and a heterozygous frameshift variant in the <i>FLNA</i> gene resulting in a complex phenotype.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A 67-year-old female with a confirmed pathogenic variant in the <i>FLNA</i> gene, resulting in an enlarged aorta and joint pains, presented with a 4-year history of severe sensory ataxia, upper motor neuron signs, eye movement abnormalities and severe sensory loss.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Neurophysiology including Somatosensory-evoked potentials confirmed the sensory loss as predominantly preganglionic with denervation. Genetic testing revealed a digenic cause of her complex presentation, confirming a pathogenic frameshift variant in the <i>FLNA</i> gene and a heterozygous loss of function deletion in the <i>UCHL1</i> gene.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>To the best of our knowledge, this is the first case with concomitant pathogenic variants in the <i>FLNA</i> and <i>UCHL1</i> genes which explain the complex phenotype. The severe preganglionic sensory loss is also a rare finding and expands the phenotype of <i>UCHL1</i> variants.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 1","pages":"111-115"},"PeriodicalIF":3.8,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138830211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of age on metabolomic changes in a model of paclitaxel-induced peripheral neurotoxicity","authors":"Roberta Bonomo,&nbsp;Annalisa Canta,&nbsp;Alessia Chiorazzi,&nbsp;Valentina Alda Carozzi,&nbsp;Cristina Meregalli,&nbsp;Eleonora Pozzi,&nbsp;Paola Alberti,&nbsp;Cecile F. Frampas,&nbsp;Daan R. Van der Veen,&nbsp;Paola Marmiroli,&nbsp;Debra J. Skene,&nbsp;Guido Cavaletti","doi":"10.1111/jns.12609","DOIUrl":"10.1111/jns.12609","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most common dose-limiting side effects of paclitaxel (PTX) treatment. Many age-related changes have been hypothesized to underlie susceptibility to damage or impaired regeneration/repair after nerve injury. The results of these studies, however, are inconclusive and other potential biomarkers of nerve impairment need to be investigated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Twenty-four young (2 months) and 24 adult (9 months) Wistar male rats were randomized to either PTX treatment (10 mg/kg i.v. once/week for 4 weeks) or vehicle administration. Neurophysiological and behavioral tests were performed at baseline, after 4 weeks of treatment and 2-week follow-up. Skin biopsies and nerve specimens collected from sacrificed animals were examined for intraepidermal nerve fiber (IENF) density assessment and nerve morphology/morphometry. Blood and liver samples were collected for targeted metabolomics analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>At the end of treatment, the neurophysiological studies revealed a reduction in sensory nerve action potential amplitude (<i>p</i> &lt; .05) in the caudal nerve of young PTX-animals, and in both the digital and caudal nerve of adult PTX-animals (<i>p</i> &lt; .05). A significant decrease in the mechanical threshold was observed only in young PTX-animals (<i>p</i> &lt; .001), but not in adult PTX-ones. Nevertheless, both young and adult PTX-rats had reduced IENF density (<i>p</i> &lt; .0001), which persisted at the end of follow-up period. Targeted metabolomics analysis showed significant differences in the plasma metabolite profiles between PTX-animals developing peripheral neuropathy and age-matched controls, with triglycerides, diglycerides, acylcarnitines, carnosine, long chain ceramides, sphingolipids, and bile acids playing a major role in the response to PTX administration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Our study identifies for the first time multiple related metabolic axes involved in PTX-induced peripheral neurotoxicity, and suggests age-related differences in CIPN manifestations and in the metabolic profile.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 1","pages":"58-71"},"PeriodicalIF":3.8,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138826110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Successful autologous hematopoietic stem cell transplantation in a refractory anti-Caspr1 antibody nodopathy","authors":"Vadim Afanasiev,&nbsp;Pinelopi Tsouni,&nbsp;Thierry Kuntzer,&nbsp;Anne Cairoli,&nbsp;Emilien Delmont,&nbsp;Jean-Michel Vallat,&nbsp;Jérôme Devaux,&nbsp;Marie Théaudin","doi":"10.1111/jns.12610","DOIUrl":"10.1111/jns.12610","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Autoimmune nodopathies have specific clinicopathologic features, antibodies directed against nodal proteins (neurofascin 186) or paranodal proteins (neurofascin 155, contactin 1, contactin-associated protein 1 (Caspr1)), and usually have a poor response to first-line therapies for chronic inflammatory demyelinating polyradiculoneuropathy. Anti-Caspr1 nodopathy treated with autologous hematopoietic stem cell transplantation (AHSCT) has not been previously reported.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We report the first case of an anti-Caspr1 antibody-positive nodopathy refractory to high-intensity immunosuppressive treatment, including rituximab, that responded dramatically to AHSCT.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A 53-year-old woman presented with a rapidly progressive generalized ataxic, painful motor, and inflammatory neuropathy supported by neurophysiologic and MRI studies. Initial tests for antibodies to nodal/paranodal proteins were negative. She was treated with multiple courses of intravenous immunoglobulin and methylprednisolone, plasma exchange, rituximab, and cyclophosphamide without significant clinical benefit. Repeated testing for antibodies to nodal/paranodal proteins yielded a positive result for anti-Caspr1/IgG4 isotype antibodies. Given the poor response to multiple high intensity treatments and the relatively young age of the patient, we decided to perform AHSCT at 30 months post-onset. Immediately after AHSCT, she stopped all immunomodulatory or immunosuppressive therapy. The Overall Neuropathy Limitation Score improved from 8/12 to 4/12 at 6 months post-AHSCT. At 3 months post-AHSCT, IgG4 against Caspr1 was negative and no reactivity against paranodes could be detected.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We report a particularly severe anti-Caspr1 antibody autoimmune nodopathy that responded dramatically to AHSCT. Although the rarity of the disease limits the possibility of larger studies, AHSCT may be a valuable therapy in treatment-refractory cases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 1","pages":"116-119"},"PeriodicalIF":3.8,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138826998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic value of neurofilament light in blood in patients with polyneuropathy: A systematic review","authors":"Louise Sloth Kodal,&nbsp;Anne Møller Witt,&nbsp;Britt Stævnsbo Pedersen,&nbsp;Morten Müller Aagaard,&nbsp;Tina Dysgaard","doi":"10.1111/jns.12608","DOIUrl":"10.1111/jns.12608","url":null,"abstract":"<p>Neurofilament light protein (NfL) is a part of the neuronal skeleton, primarily expressed in axons, and is released when nerves are damaged. NfL has been found to be a potential diagnostic biomarker in different types of polyneuropathies. However, whether NfL levels can be used as a predictor for the risk of disease progression is currently less understood. We searched MEDLINE (PubMed), Embase, Cochrane Library, and Web of Science Searches and included longitudinal studies with a baseline and follow-up examination of adult patients with polyneuropathy and NfL measured in blood. Twenty studies investigating NfL as a predictor of disease progression were identified, examining eight polyneuropathy subtypes. The results from studies in Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) patients were divergent, with two out of five studies finding a significant association between NfL levels and clinical outcomes. Meta-analysis of the three Guillian-Barré Syndrome (GBS) studies found higher odds for the inability to run after 1 year in patients with high levels of NfL (odds ratio 2.18, 95% confidence interval 1.04–4.56). Results from studies examining other subacute or chronic polyneuropathies like Charcot–Marie–Tooth (CMT) varied in study design and results. Our findings suggest NfL can be used as a predictor of disease progression, particularly in polyneuropathies such as CIDP and GBS. However, NfL may not serve as a reliable and cost-effective biomarker for slowly progressive polyneuropathies like CMT. Future standardized studies considering NfL as a prognostic blood biomarker in patients with different types of polyneuropathies are warranted.</p>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 1","pages":"17-27"},"PeriodicalIF":3.8,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138563778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Morphofunctional characterisation of axonal damage in different rat models of chemotherapy-induced peripheral neurotoxicity: The role of nerve excitability testing","authors":"Alessia Chiorazzi,&nbsp;Annalisa Canta,&nbsp;Valentina Alda Carozzi,&nbsp;Cristina Meregalli,&nbsp;Eleonora Pozzi,&nbsp;Elisa Ballarini,&nbsp;Virginia Rodriguez-Menendez,&nbsp;Paola Marmiroli,&nbsp;Guido Cavaletti,&nbsp;Paola Alberti","doi":"10.1111/jns.12607","DOIUrl":"10.1111/jns.12607","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common and long-lasting adverse event of several anticancer compounds, for which treatment has not yet been developed. To fill this gap, preclinical studies are warranted, exploiting highly translational outcome measure(s) to transfer data from bench to bedside. Nerve excitability testing (NET) enables to test <i>in vivo</i> axonal properties and can be used to monitor early changes leading to axonal damage.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We tested NET use in two different CIPN rat models: oxaliplatin (OHP) and paclitaxel (PTX). Animals (female) were chronically treated with either PTX or OHP and compared to respective control animals. NET was performed as soon as the first injection was administered. At the end of the treatment, CIPN onset was verified via a multimodal and robust approach: nerve conduction studies, nerve morphometry, behavioural tests and intraepidermal nerve fibre density.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>NET showed the typical pattern of axonal hyperexcitability in the 72 h following the first OHP administration, whereas it showed precocious signs of axonal damage in PTX animals. At the end of the month of treatment, OHP animals showed a pattern compatible with a mild axonal sensory polyneuropathy. Instead, PTX cohort was characterised by a rather severe sensory axonal polyneuropathy with minor signs of motor involvement.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>NET after the first administration demonstrated the ongoing OHP-related channelopathy, whereas in PTX cohort it showed precocious signs of axonal damage. Therefore, NET could be suggested as an early surrogate marker in clinical trials, to detect precocious changes leading to axonal damage.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 1","pages":"47-57"},"PeriodicalIF":3.8,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.12607","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138445147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma proteomic analysis on neuropathic pain in idiopathic peripheral neuropathy patients","authors":"Perry T. C. van Doormaal,&nbsp;Simone Thomas,&nbsp;Senda Ajroud-Driss,&nbsp;Robert N. Cole,&nbsp;Lauren R. DeVine,&nbsp;Mazen M. Dimachkie,&nbsp;Stefanie Geisler,&nbsp;Roy Freeman,&nbsp;David M. Simpson,&nbsp;J. Robinson Singleton,&nbsp;A. Gordon Smith,&nbsp;Amro Stino,&nbsp;PNRR Study Group,&nbsp;Ahmet Höke","doi":"10.1111/jns.12606","DOIUrl":"10.1111/jns.12606","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Why only half of the idiopathic peripheral neuropathy (IPN) patients develop neuropathic pain remains unknown. By conducting a proteomics analysis on IPN patients, we aimed to discover proteins and new pathways that are associated with neuropathic pain.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted unbiased mass-spectrometry proteomics analysis on blood plasma from 31 IPN patients with severe neuropathic pain and 29 IPN patients with no pain, to investigate protein biomarkers and protein–protein interactions associated with neuropathic pain. Univariate modeling was done with linear mixed modeling (LMM) and corrected for multiple testing. Multivariate modeling was performed using elastic net analysis and validated with internal cross-validation and bootstrapping.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In the univariate analysis, 73 proteins showed a <i>p</i>-value &lt;.05 and 12 proteins showed a <i>p</i>-value &lt;.01. None were significant after Benjamini–Hochberg adjustment for multiple testing. Elastic net analysis created a model containing 12 proteins with reasonable discriminatory power to differentiate between painful and painless IPN (false-negative rate 0.10, false-positive rate 0.18, and an area under the curve 0.75). Eight of these 12 proteins were clustered into one interaction network, significantly enriched for the complement and coagulation pathway (Benjamini–Hochberg adjusted <i>p</i>-value = .0057), with complement component 3 (C3) as the central node. Bootstrap validation identified insulin-like growth factor-binding protein 2 (IGFBP2), complement factor H-related protein 4 (CFHR4), and ferritin light chain (FTL), as the most discriminatory proteins of the original 12 identified.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>This proteomics analysis suggests a role for the complement system in neuropathic pain in IPN.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 1","pages":"88-96"},"PeriodicalIF":3.8,"publicationDate":"2023-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.12606","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138291270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergistic effects of immune checkpoints and checkpoint inhibitors in inflammatory neuropathies: Implications and mechanisms","authors":"Aritrani Sarkar,&nbsp;Madhu Nagappa,&nbsp;Saikat Dey,&nbsp;Sandipan Mondal,&nbsp;Gopika Suresh Babu,&nbsp;Saptamita Pal Choudhury,&nbsp;Pokala Akhil,&nbsp;Monojit Debnath","doi":"10.1111/jns.12605","DOIUrl":"10.1111/jns.12605","url":null,"abstract":"<p>Immune checkpoint molecules play pivotal roles in the regulation of immune homeostasis. Disruption of the immune checkpoints causes autoimmune/inflammatory as well as malignant disorders. Over the past few years, the immune checkpoint molecules with inhibitory function emerged as potential therapeutic targets in oncological conditions. The inhibition of the function of these molecules by using immune checkpoint inhibitors (ICIs) has brought paradigmatic changes in cancer therapy due to their remarkable clinical benefits, not only in improving the quality of life but also in prolonging the survival time of cancer patients. Unfortunately, the ICIs soon turned out to be a “double-edged sword” as the use of ICIs caused multiple immune-related adverse effects (irAEs). The development of inflammatory neuropathies such as Guillain–Barré syndrome (GBS) and Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) as the secondary effects of immunotherapy appeared very challenging as these conditions result in significant and often permanent disability. The underlying mechanism(s) through which ICIs trigger inflammatory neuropathies are currently not known. Compelling evidence suggests autoimmune reaction and/or inflammation as the independent risk mechanism of inflammatory neuropathies. There is a lack of understanding as to whether prior exposure to the risk factors of inflammatory neuropathies, the presence of germline genetic variants in immune function-related genes, genetic variations within immune checkpoint molecules, the existence of autoantibodies, and activated/memory T cells act as determining factors for ICI-induced inflammatory neuropathies. Herein, we highlight the available pieces of evidence, discuss the mechanistic basis, and propose a few testable hypotheses on inflammatory neuropathies as irAEs of immunotherapy.</p>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 1","pages":"6-16"},"PeriodicalIF":3.8,"publicationDate":"2023-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138291271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel de novo variant in POLR3B gene associated with a primary axonal involvement of the largest nerve fibers","authors":"Alessandro Geroldi,&nbsp;Stefano Tozza,&nbsp;Chiara Fiorillo,&nbsp;Maria Nolano,&nbsp;Paola Fossa,&nbsp;Floriana Vitale,&nbsp;Regi Domi,&nbsp;Andrea Gaudio,&nbsp;Alessia Mammi,&nbsp;Serena Patrone,&nbsp;Andrea La Barbera,&nbsp;Paola Origone,&nbsp;Clarissa Ponti,&nbsp;Francesca Sanguineri,&nbsp;Federico Zara,&nbsp;Matteo Cataldi,&nbsp;Vincenzo Salpietro,&nbsp;Consuelo Barbara Venturi,&nbsp;Sara Massucco,&nbsp;Angelo Schenone,&nbsp;Fiore Manganelli,&nbsp;Paola Mandich,&nbsp;Emilia Bellone,&nbsp;Fabio Gotta","doi":"10.1111/jns.12602","DOIUrl":"10.1111/jns.12602","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p><i>POLR3B</i> gene encodes a subunit of RNA polymerase III (Pol III). Biallelic mutations in <i>POLR3B</i> are associated with leukodystrophies, but recently de novo heterozygous mutations have been described in early onset peripheral demyelinating neuropathies with or without central involvement. Here, we report the first Italian case carrying a de novo variant in <i>POLR3B</i> with a pure neuropathy phenotype and primary axonal involvement of the largest nerve fibers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Nerve conduction studies, sympathetic skin response, dynamic sweat test, tactile and thermal quantitative sensory testing and brain magnetic resonance imaging were performed according to standard procedures. Histopathological examination was performed on skin and sural nerve biopsies. Molecular analysis of the proband and his relatives was performed with Next Generation Sequencing. The impact of the identified variant on the overall protein structure was evaluated through rotamers method.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Since his early adolescence, the patient presented with signs of polyneuropathy with severe distal weakness, atrophy, and reduced sensation. Neurophysiological studies showed a sensory-motor axonal polyneuropathy, with confirmed small fiber involvement. In addition, skin biopsy and sural nerve biopsy showed predominant large fibers involvement. A trio's whole exome sequencing revealed a novel de novo variant p.(Arg1046Cys) in <i>POLR3B</i>, which was classified as Probably Pathogenic. Molecular modeling data confirmed a deleterious effect of the variant on protein structure.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Neurophysiological and morphological findings suggest a primary axonal involvement of the largest nerve fibers in <i>POLR3B</i>-related neuropathies. A partial loss of function mechanism is proposed for both neuropathy and leukodystrophy phenotypes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"28 4","pages":"620-628"},"PeriodicalIF":3.8,"publicationDate":"2023-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.12602","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66783962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the clinical and electrophysiological profile of CMTX6: Insights from two Brazilian families","authors":"Victor Augusto Zanesi Maciel,&nbsp;Gustavo Maximiano-Alves,&nbsp;Rodrigo Siqueira Soares Frezatti,&nbsp;Anna Letícia De Moraes Alves,&nbsp;Bianca Mara Alves Andrade,&nbsp;Rita De Cassia Carvalho Leal,&nbsp;Pedro José Tomaselli,&nbsp;Mary M. Reilly,&nbsp;Wilson Marques","doi":"10.1111/jns.12601","DOIUrl":"10.1111/jns.12601","url":null,"abstract":"BACKGROUND AND AIMS\u0000X-linked Charcot-Marie-Tooth disease type 6 (CMTX6) is an extremely rare condition associated with mutations in the PDK3 gene. To date, only three families from different countries have been reported (Australia, South Korea and Germany). In this study, we sought to provide a comprehensive clinical and electrophysiological characterization of two Brazilian families.\u0000\u0000\u0000METHODS\u0000We conducted comprehensive clinical assessments, extensive electrophysiological evaluations, and performed whole-exome sequencing in the probands to investigate the genetic basis of the disease.\u0000\u0000\u0000RESULTS\u0000Males in the family carrying the Arg162His mutation displayed early-onset motor and/or sensory axonal neuropathy, absence of tendon jerks, pes cavus, and frequently reported pain. Females in the same family exhibited a milder phenotype of the disease with later onset and some remained asymptomatic into their 50s. In the unrelated family with a single affected male, the clinical presentation was characterized by severe progressive sensorimotor polyneuropathy accompanied by neuropathic pain.\u0000\u0000\u0000INTERPRETATION\u0000We report two Brazilian families with CMTX6 including one harboring a previously unpublished variant in the PDK3 gene, which co-segregates with the disease as expected in a X-linked disease. Notably, the clinical presentations across the five families with available descriptions, including our study, share striking similarities. Furthermore, the proximity of the three reported mutations suggests potential functional similarities and common underlying mechanisms. This study contributes to the growing knowledge of CMTX6 and underscores the importance of international collaborations in studying rare genetic disorders. This article is protected by copyright. All rights reserved.","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"28 4","pages":"614-619"},"PeriodicalIF":3.8,"publicationDate":"2023-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41236386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of blood metabolic biomarkers associated with diabetic distal symmetric sensorimotor polyneuropathy in patients with type 2 diabetes mellitus","authors":"Kuo-Hsuan Chang,&nbsp;Chiung-Mei Chen,&nbsp;Chia-Ni Lin,&nbsp;Sung-Sheng Tsai,&nbsp;Rong-Kuo Lyu,&nbsp;Chun-Che Chu,&nbsp;Long-Sun Ro,&nbsp;Ming-Feng Liao,&nbsp;Hong-Shiu Chang,&nbsp;Yi-Ching Weng,&nbsp;Jawl-Shan Hwang,&nbsp;Hung-Chou Kuo","doi":"10.1111/jns.12600","DOIUrl":"10.1111/jns.12600","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Distal symmetric sensorimotor polyneuropathy (DSPN) is a common neurologic complication of type 2 diabetes mellitus (T2DM), but the underlying mechanisms and changes in serum metabolites remain largely undefined. This study aimed to characterize the plasma metabolite profiles of participants with T2DM using targeted metabolomics analysis and identify potential biomarkers for DSPN.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A combined liquid chromatography MS/MS and direct flow injection were used to quantify plasma metabolite obtained from 63 participants with T2DM, 81 with DSPN, and 33 nondiabetic control participants. A total of 130 metabolites, including amino acids, biogenic amines, sphingomyelins (SM), phosphatidylcholines, carnitines, and hexose, were analyzed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 16 plasma metabolites and 3 cholesterol-related laboratory parameters were found to have variable importance in the projection score &gt;1.0 and false discovery rate &lt;5.0% between control, T2DM, and DSPN. Among these variables, five serum metabolites, including phenylalanine (AUC = 0.653), alanine (AUC = 0.630), lysine (AUC = 0.622) tryptophan (AUC = 0.620), and SM C16:0 (AUC = 0.630), are potential biomarkers (all <i>p</i> &lt; .05) in distinguishing T2DM with DSPN from those without (AUC = 0.720).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In this cross-sectional study, derangement of several metabolites in the plasma was observed in T2DM with and without DSPN, and these metabolites may be potential biomarkers for predicting DSPN. Longitudinal studies are warranted.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"28 4","pages":"651-663"},"PeriodicalIF":3.8,"publicationDate":"2023-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41204138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}