Journal of the Peripheral Nervous System最新文献

{"title":"Abstract","authors":"","doi":"10.1111/jns.12627","DOIUrl":"10.1111/jns.12627","url":null,"abstract":"","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 S2","pages":"S3-S51"},"PeriodicalIF":3.8,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.12627","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141159364","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":"Longitudinal follow-up and prognostic factors in nitrous oxide-induced neuropathy","authors":"Etienne Fortanier,&nbsp;Emilien Delmont,&nbsp;Giovanni Corazza,&nbsp;Ludivine Kouton,&nbsp;Joelle Micallef,&nbsp;Shahram Attarian","doi":"10.1111/jns.12634","DOIUrl":"10.1111/jns.12634","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aim</h3>\u0000 \u0000 <p>Recreational use of nitrous oxide (N₂O) has been associated with the development of severe nitrous oxide-induced neuropathy (N₂On). Follow-up of these patients poses challenges, and their clinical progression remains largely unknown. The identification of prognostic factors is made difficult by the lack of standardized longitudinal assessments in most studies. The objective was to document the course of neuropathy through systematic follow-up assessments in N₂On patients to identify prognostic factors for persistent disability after 6 months.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We gathered demographic, clinical, biological, and electrophysiological data from N₂On patients hospitalized in the Referral center in Marseille, both at baseline and during a standardized follow-up assessment at 6 months.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We retrospectively included 26 N₂On patients (mean age 22.6 ± 4.4). Significant improvements were observed in all main clinical scores including Rankin, ONLS, and MRC testing (<i>p</i> &lt; .01). Electrophysiological studies (EDX) revealed a predominantly motor neuropathy with marked reduction in CMAP in the lower limbs at baseline, and no significant improvement in motor parameters (<i>p</i> = .543). Rankin score at 6 months correlated with the initial weekly N₂O consumption (<i>r</i> = .43, <i>p</i> = .03) and the CMAP sum score in the lower limbs at the first EDX (<i>r</i> = −.47, <i>p</i> = .02). Patients with and without myelitis showed similar Rankin and ONLS score after 6 months.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>The clinical course generally improved favorably at 6 months with notable amelioration in the primary disability scores, sensory deficits, and ataxia. However, distal motor impairment associated with peripheral neuropathy persisted, with distal axonal loss emerging as the main prognostic factor for long-term disability in these young patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 2","pages":"252-261"},"PeriodicalIF":3.9,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141076156","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":"Genotype–phenotype correlations of AR-CMT2S in a cohort of axonal Charcot–Marie–Tooth patients from Central South China","authors":"Lei Liu,&nbsp;Sen Zeng,&nbsp;Xiaobo Li,&nbsp;Yongzhi Xie,&nbsp;Ke Xu,&nbsp;Honglan Yang,&nbsp;Shunxiang Huang,&nbsp;Huadong Zhao,&nbsp;Ruxu Zhang","doi":"10.1111/jns.12633","DOIUrl":"10.1111/jns.12633","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>This study aimed to report nine Charcot–Marie–Tooth disease (CMT) families with six novel <i>IGHMBP2</i> mutations in our CMT2 cohort and to summarize the genetic and clinical features of all AR-CMT2S patients reported worldwide.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>General information, clinical and neurophysiological data of 275 axonal CMT families were collected. Genetic screening was performed by inherited peripheral neuropathy related genes panel or whole exome sequencing. The published papers reporting AR-CMT2S from 2014 to 2023 were searched in Pubmed and Wanfang databases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In our CMT2 cohort, we detected 17 AR-CMT2S families carrying <i>IGHMBP2</i> mutations and eight were published previously. Among these, c.743 T &gt; A (p.Val248Glu), c.884A &gt; G (p.Asp295Gly), c.1256C &gt; A (p.Ser419*), c.2598_2599delGA (p.Lys868Sfs*16), c.1694_1696delATG (p.Asp565del) and c.2509A &gt; T (p.Arg837*) were firstly reported. These patients prominently presented with early-onset typical axonal neuropathy and without respiratory dysfunction. So far, 56 AR-CMT2S patients and 57 different mutations coming from 43 families have been reported in the world. Twenty-nine of 32 missense mutations were clustered in helicase domain and ATPase region. The age at onset ranged from 0.11to 20 years (Mean ± SD: 3.43 ± 3.88 years) and the majority was infantile-onset (&lt;2 years). The initial symptoms included weakness of limbs (19, 29.7%), delayed milestones (12, 18.8%), gait disturbance (11, 17.2%), feet deformity (8, 12.5%), feet drop (8, 12.5%), etc.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>AR-CMT2S accounted for 6.2% in our CMT2 cohort. We firstly reported six novel <i>IGHMBP2</i> mutations which expanded the genotypic spectrum of AR-CMT2S. Furthermore, 17 AR-CMT2S families could provide more resources for natural history study, drug research and development.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 2","pages":"243-251"},"PeriodicalIF":3.9,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141076155","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 previously unreported NARS1 variant causes dominant distal hereditary motor neuropathy in a French family","authors":"Julian Theuriet,&nbsp;Sheila Marte,&nbsp;Arnaud Isapof,&nbsp;Alix de Becdelièvre,&nbsp;Marina Konyukh,&nbsp;Stephanie M. Laureano-Figueroa,&nbsp;Philippe Latour,&nbsp;Isabelle Quadrio,&nbsp;Thierry Maisonobe,&nbsp;Anthony Antonellis,&nbsp;Tanya Stojkovic","doi":"10.1111/jns.12635","DOIUrl":"10.1111/jns.12635","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Pathogenic variants in the <i>NARS1</i> gene, which encodes for the asparaginyl-tRNA synthetase1 (NARS1) enzyme, were associated with complex central and peripheral nervous system phenotypes. Recently, Charcot–Marie–Tooth (CMT) disease has been linked to heterozygous pathogenic variants in <i>NARS1</i> in nine patients. Here, we report two brothers and their mother from a French family with distal hereditary motor neuropathy (dHMN) carrying a previously unreported <i>NARS1</i> variant.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The <i>NARS1</i> variant (c.1555G&gt;C; p.(Gly519Arg)) was identified through whole-genome sequencing (WGS) performed on the family members. Clinical findings, nerve conduction studies (NCS), needle electromyography (EMG), and functional assays in yeast complementation assays are reported here.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The family members showed symptoms of dHMN, including distal weakness and osteoarticular deformities. They also exhibited brisk reflexes suggestive of upper motor neuron involvement. All patients were able to walk independently at the last follow-up. NCS and EMG confirmed pure motor neuropathy. Functional assays in yeast confirmed a loss-of-function effect of the variant on NARS1 activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Our findings expand the clinical spectrum of <i>NARS1</i>-associated neuropathies, highlighting the association of <i>NARS1</i> mutations with dHMN. The benign disease course observed in our patients suggests a slowly progressive phenotype. Further reports could contribute to a more comprehensive understanding of the spectrum of NARS1-associated neuropathies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 2","pages":"275-278"},"PeriodicalIF":3.9,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.12635","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141071489","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":"Genetic and clinical profile of 15 Chinese families with GDAP1-related Charcot–Marie–Tooth disease and identification of H256R as a frequent mutation","authors":"Zhongzheng Li,&nbsp;Sen Zeng,&nbsp;Yongzhi Xie,&nbsp;Xiaobo Li,&nbsp;Shunxiang Huang,&nbsp;Huadong Zhao,&nbsp;Wanqian Cao,&nbsp;Lei Liu,&nbsp;Mengli Wang,&nbsp;Qiaoyu Gong,&nbsp;Jun Liu,&nbsp;Pengfei Rong,&nbsp;Ruxu Zhang","doi":"10.1111/jns.12628","DOIUrl":"10.1111/jns.12628","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Mutations in ganglioside-induced differentiation-associated protein 1 (<i>GDAP1</i>) cause axonal or demyelinating Charcot–Marie–Tooth disease (CMT) with autosomal dominant or recessive inheritance. In this study, we aim to report the genotypic and phenotypic features of <i>GDAP1</i>-related CMT in a Chinese cohort.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Clinical, neurophysiological, genetic data, and available muscle/brain imaging information of 28 CMT patients with <i>GDAP1</i> variants were retrospectively collected.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified 16 <i>GDAP1</i> pathogenic variants, among which two novel variants c.980dup(p.L328FfsX25) and c.480+4T&gt;G were first reported. Most patients (16/28) presented with AR or AD CMT2K phenotype. Clinical characteristics in our cohort demonstrated that the AR patients presented earlier onset, more severe phenotype compared with the AD patients. Considerable intra-familial phenotypic variability was observed among three AD families. Muscle atrophy and fatty infiltration in the lower extremity were detected by Muscle magnetic resonance imaging (MRI) scans in four patients. MRI showed two AR patients showed more severe muscle involvement of the posterior compartment than those of the anterolateral compartment in the calf. One patient carrying Q38*/H256R variants accompanied with mild periventricular leukoaraiosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In this study, we conducted an analysis of clinical features of the <i>GDAP1</i>-related CMT patients, expanded the mutation spectrum in <i>GDAP1</i> by reporting two novel variants, and presented the prevalent occurrence of the H256R mutation in China. The screening of <i>GDAP1</i> should be particularly emphasized in Chinese patients with CMT2, given the incomplete penetrance and pathogenic inheritance patterns involving dominant and recessive modes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 2","pages":"232-242"},"PeriodicalIF":3.9,"publicationDate":"2024-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140856578","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":"Cutaneous biomarkers of therapeutic efficacy in early treatment of hereditary ATTR amyloid polyneuropathy with tafamidis","authors":"Karla Cárdenas-Soto,&nbsp;Xel-Ha Dominguez,&nbsp;Giovanni Cortes,&nbsp;Felix Tsai,&nbsp;Maria del Mar Saniger,&nbsp;Paola Guraieb-Chahin,&nbsp;Benjamín Torres-Ocatvo,&nbsp;Christopher Gibbons,&nbsp;Jeffery W. Kelly,&nbsp;Roy Freeman,&nbsp;Alejandra González-Duarte","doi":"10.1111/jns.12624","DOIUrl":"10.1111/jns.12624","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;ATTR (ATTRv) amyloidosis neuropathy is characterized by progressive sensorimotor and autonomic nerve degeneration secondary to amyloid deposition caused by a misfolded transthyretin protein (TTR). Small nerve fiber neuropathy is an early clinical manifestation of this disease resulting from the dysfunction of the Aδ and C small nerve fibers. Tafamidis, a selective TTR stabilizer, has proven its efficacy in the earlier stages of hATTR.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Objectives&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;To evaluate the clinical course and utility of cutaneous pathological biomarkers in patients with ATTR amyloidosis treated with tafamidis compared to control patients.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Forty patients diagnosed with early stages of ATTRv amyloidosis (polyneuropathy disability [PND] scores 0-II) underwent small and large nerve fiber neurological evaluations, and annual skin biopsies for intraepidermal nerve fiber density (IENFD) and amyloid deposition index (ADI) estimation. Thirty patients were allocated to receive tafamidis, and 10 patients served as controls. Tafamidis pharmacokinetics analysis was performed in patients who received the treatment.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;At baseline, 12% of patients in stage PND 0 and 28% in PND I displayed small nerve fiber denervation in the distal thigh, whereas 23% and 38%, respectively, in the distal leg. Similarly, 72% and 84% had amyloid deposition in the distal thigh and 56% and 69% in the distal leg. Following 1 year of treatment, the tafamidis group showed significant clinical improvement compared to the control group, revealed by the following mean differences (1) −9.3 versus −4 points (&lt;i&gt;p&lt;/i&gt; = &lt;.00) in the patient's neuropathy total symptom score 6 (NTSS-6) questionnaire, (2) −2.5 versus +2.8 points (&lt;i&gt;p&lt;/i&gt; = &lt;.00) in the Utah Early Neuropathy Score (UENS), and (3) +1.2°C versus −0.6 (&lt;i&gt;p&lt;/i&gt; = .01) in cold detection thresholds. Among the patients who received tafamidis, 65% had stable or increased IENFD in their distal thigh and 27% in the distal leg. In contrast, all patients in the control group underwent denervation. The ADI either decreased or remained constant in 31% of the biopsies in the distal thigh and in 24% of the biopsies in the distal leg of the tafamidis-treated patients, whereas it rose across all the biopsies in the control group. At the 4-year follow-up, the tafamidis group continued to display less denervation in the distal thigh (mean difference [MD] of −3.0 vs. −9.3 fibers/mm) and the distal leg (mean difference [MD] −4.9 vs. −8.6 fibers/mm). ADI in tafamidis-treated patients was also","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 2","pages":"221-231"},"PeriodicalIF":3.9,"publicationDate":"2024-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140857134","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":"Cytokines and chemokines in patients with chronic inflammatory demyelinating polyradiculoneuropathy and multifocal motor neuropathy: A systematic review","authors":"Claudia Cutellè,&nbsp;Alberto De Lorenzo,&nbsp;Pietro Emiliano Doneddu,&nbsp;Maria Francesca Creta,&nbsp;Carlo Selmi,&nbsp;Giuseppe Liberatore,&nbsp;Andrea Giordano,&nbsp;Francesco Gentile,&nbsp;Gian Luca Erre,&nbsp;Eduardo Nobile-Orazio","doi":"10.1111/jns.12622","DOIUrl":"10.1111/jns.12622","url":null,"abstract":"<p>Advances in the understanding of cytokines have revolutionized mechanistic treatments for chronic inflammatory and autoimmune diseases, as exemplified by rheumatoid arthritis. We conducted a systematic literature review on the role of cytokines and chemokines in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN). Ovid Medline, EMBASE and Web of Science were searched until August 31, 2022 for human studies investigating cytokines levels in CIDP or MMN. Fifty-five articles on 1061 CIDP patients and 86 MMN patients were included, with a median of 18 patients per study (range 3–71). Studies differed in the inclusion criteria, type of assay, manufacturer, control subjects, and tested biological material. Only a minority of studies reported data on disease activity. Interleukin (IL)-6, IL-17, CXCL10, and tumor necrosis factor alpha (TNF-α), were elevated in CIDP compared to controls in most of the studies. IL-6 and TNF-α levels are also correlated with disability. In MMN patients, IL-1Ra was elevated in the majority of the reports. While acknowledging the challenges in comparing studies and the various limitations of the studies, including small patient numbers, particularly in MMN, our review suggests that IL-6, IL-17, CXCL10, and TNF-α might play a role in CIDP pathogenesis. Larger studies are needed in MMN.</p>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 2","pages":"124-134"},"PeriodicalIF":3.9,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140571129","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":"Conduction slowing, conduction block and temporal dispersion in demyelinating, dysmyelinating and axonal neuropathies: Electrophysiology meets pathology","authors":"Antonino Uncini,&nbsp;Tiziana Cavallaro,&nbsp;Gian Maria Fabrizi,&nbsp;Fiore Manganelli,&nbsp;Jean-Michel Vallat","doi":"10.1111/jns.12625","DOIUrl":"10.1111/jns.12625","url":null,"abstract":"<p>Nerve conduction studies are usually the first diagnostic step in peripheral nerve disorders and their results are the basis for planning further investigations. However, there are some commonplaces in the interpretation of electrodiagnostic findings in peripheral neuropathies that, although useful in the everyday practice, may be misleading: (1) conduction block and abnormal temporal dispersion are distinctive features of acquired demyelinating disorders; (2) hereditary neuropathies are characterized by uniform slowing of conduction velocity; (3) axonal neuropathies are simply diagnosed by reduced amplitude of motor and sensory nerve action potentials with normal or slightly slow conduction velocity. In this review, we reappraise the occurrence of uniform and non-uniform conduction velocity slowing, conduction block and temporal dispersion in demyelinating, dysmyelinating and axonal neuropathies attempting, with a translational approach, a correlation between electrophysiological and pathological features as derived from sensory nerve biopsy in patients and animal models. Additionally, we provide some hints to navigate in this complex field.</p>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 2","pages":"135-160"},"PeriodicalIF":3.9,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140570706","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 study concept of expeditious clinical enrollment for genetic modifier studies in Charcot–Marie–Tooth neuropathy 1A","authors":"Isaac R. L. Xu,&nbsp;Matt C. Danzi,&nbsp;Ariel Ruiz,&nbsp;Jacquelyn Raposo,&nbsp;Yeisha Arcia De Jesus,&nbsp;Mary M. Reilly,&nbsp;Andrea Cortese,&nbsp;Michael E. Shy,&nbsp;Steven S. Scherer,&nbsp;David N. Herrmann,&nbsp;Vera Fridman,&nbsp;Jonathan Baets,&nbsp;Mario Saporta,&nbsp;Reza Seyedsadjadi,&nbsp;Tanya Stojkovic,&nbsp;Kristl G. Claeys,&nbsp;Pooja Patel,&nbsp;Shawna Feely,&nbsp;Adriana P. Rebelo,&nbsp;Inherited Neuropathy Consortium,&nbsp;Maike F. Dohrn,&nbsp;Stephan Züchner","doi":"10.1111/jns.12621","DOIUrl":"10.1111/jns.12621","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Caused by duplications of the gene encoding peripheral myelin protein 22 (PMP22), Charcot–Marie–Tooth disease type 1A (CMT1A) is the most common hereditary neuropathy. Despite this shared genetic origin, there is considerable variability in clinical severity. It is hypothesized that genetic modifiers contribute to this heterogeneity, the identification of which may reveal novel therapeutic targets. In this study, we present a comprehensive analysis of clinical examination results from 1564 CMT1A patients sourced from a prospective natural history study conducted by the RDCRN-INC (Inherited Neuropathy Consortium). Our primary objective is to delineate extreme phenotype profiles (mild and severe) within this patient cohort, thereby enhancing our ability to detect genetic modifiers with large effects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We have conducted large-scale statistical analyses of the RDCRN-INC database to characterize CMT1A severity across multiple metrics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We defined patients below the 10th (mild) and above the 90th (severe) percentiles of age-normalized disease severity based on the CMT Examination Score V2 and foot dorsiflexion strength (MRC scale). Based on extreme phenotype categories, we defined a statistically justified recruitment strategy, which we propose to use in future modifier studies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Leveraging whole genome sequencing with base pair resolution, a future genetic modifier evaluation will include single nucleotide association, gene burden tests, and structural variant analysis. The present work not only provides insight into the severity and course of CMT1A, but also elucidates the statistical foundation and practical considerations for a cost-efficient and straightforward patient enrollment strategy that we intend to conduct on additional patients recruited globally.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 2","pages":"202-212"},"PeriodicalIF":3.9,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140570707","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":"Lack of effect from genetic deletion of Hdac6 in a humanized mouse model of CMT2D","authors":"Abigail L. D. Tadenev,&nbsp;Courtney L. Hatton,&nbsp;Robert W. Burgess","doi":"10.1111/jns.12623","DOIUrl":"10.1111/jns.12623","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Inhibition of HDAC6 has been proposed as a broadly applicable therapeutic strategy for Charcot–Marie–Tooth disease (CMT). Inhibition of HDAC6 increases the acetylation of proteins important in axonal trafficking, such as α-tubulin and Miro, and has been shown to be efficacious in several preclinical studies using mouse models of CMT.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Here, we sought to expand on previous preclinical studies by testing the effect of genetic deletion of <i>Hdac6</i> on mice carrying a humanized knockin allele of <i>Gars1</i>, a model of CMT-type 2D.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p><i>Gars1</i>^ΔETAQ mice were bred to an <i>Hdac6</i> knockout strain, and the resulting offspring were evaluated for clinically relevant outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The genetic deletion of <i>Hdac6</i> increased α-tubulin acetylation in the sciatic nerves of both wild-type and <i>Gars1</i>^ΔETAQ mice. However, when tested at 5 weeks of age, the <i>Gars1</i>^ΔETAQ mice lacking <i>Hdac6</i> showed no changes in body weight, muscle atrophy, grip strength or endurance, sciatic motor nerve conduction velocity, compound muscle action potential amplitude, or peripheral nerve histopathology compared to <i>Gars1</i>^ΔETAQ mice with intact <i>Hdac6</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Our results differ from those of two previous studies that demonstrated the benefit of the HDAC6 inhibitor tubastatin A in mouse models of CMT2D. While we cannot fully explain the different outcomes, our results offer a counterexample to the benefit of inhibiting HDAC6 in CMT2D, suggesting additional research is necessary.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"29 2","pages":"213-220"},"PeriodicalIF":3.9,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140318589","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}