William S. Frye, Sydney R. Ward, Anh Thy H. Nguyen, Giovanni Cucchiaro, Dennis A. Hart
Introduction
Small-fiber neuropathy (SFN) affects thinly myelinated and unmyelinated nerve fibers and often presents with pain. While this condition is observed in pediatric chronic pain settings, it is unclear which patients are most appropriate for SFN testing, particularly for idiopathic cases. Skin biopsy is the most accurate diagnostic tool, but guidelines for its use are lacking. This study aimed to identify clinical and laboratory variables predictive of a positive skin biopsy for SFN in adolescents with chronic pain.
Methods
This retrospective study analyzed clinical, demographic, and laboratory characteristics of 104 adolescents with chronic pain who had undergone PGP9.5-immunolabeled distal-leg skin biopsy to assess for SFN. Fisher's exact tests, ANOVA, and logistic regression were used to identify predictive factors.
Results
Patient mean age was 15 years old and 51.9% had positive diagnostic skin biopsies. Results indicated adolescents with positive biopsies were more likely to have Juvenile Idiopathic Arthritis (JIA) compared to those without (33.3% vs. 14.3%, p = 0.02) and had higher median angiotensin-converting enzyme (ACE) levels (p < 0.01) and thyroid free T4 levels (p = 0.02). Logistic regression only showed increased odds of positive skin biopsies with JIA (OR = 3.27, p = 0.02). No clinical symptoms were predictive of positive skin biopsies.
Discussion
Findings suggest that common clinical observations and laboratory tests used to guide referrals for skin biopsies were not predictive of SFN diagnosis. Clinicians should consider the risks and benefits of skin biopsies for adolescents with chronic pain. Additional research is warranted to validate potentially predictive markers and improve diagnostic pathways for SFN in pediatric chronic pain settings.
小纤维神经病（SFN）累及细髓和无髓神经纤维，常表现为疼痛。虽然这种情况在儿童慢性疼痛情况下观察到，但尚不清楚哪些患者最适合进行SFN检测，特别是对于特发性病例。皮肤活检是最准确的诊断工具，但缺乏使用指南。本研究旨在确定预测慢性疼痛青少年SFN皮肤活检阳性的临床和实验室变量。方法：本回顾性研究分析了104例慢性疼痛青少年患者的临床、人口学和实验室特征，这些患者接受了pgp9.5免疫标记的远端腿部皮肤活检来评估SFN。使用Fisher精确检验、方差分析和逻辑回归来确定预测因素。结果患者平均年龄15岁，51.9%的患者皮肤活检诊断阳性。结果显示，活检阳性的青少年患幼年特发性关节炎（JIA）的可能性高于未活检的青少年（33.3% vs. 14.3%, p = 0.02），血管紧张素转换酶（ACE）水平中位数（p < 0.01）和游离甲状腺T4水平中位数（p = 0.02）较高。Logistic回归仅显示JIA患者皮肤活检阳性的几率增加（OR = 3.27, p = 0.02）。没有临床症状预示皮肤活检阳性。研究结果表明，用于指导转诊皮肤活检的常见临床观察和实验室检查不能预测SFN的诊断。临床医生应考虑慢性疼痛青少年皮肤活检的风险和益处。进一步的研究是必要的，以验证潜在的预测标记和改善诊断途径SFN在儿童慢性疼痛设置。
{"title":"Identifying Predictors of Idiopathic Small-Fiber Neuropathy in Adolescent Patients With Chronic Pain","authors":"William S. Frye, Sydney R. Ward, Anh Thy H. Nguyen, Giovanni Cucchiaro, Dennis A. Hart","doi":"10.1111/jns.70066","DOIUrl":"https://doi.org/10.1111/jns.70066","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Small-fiber neuropathy (SFN) affects thinly myelinated and unmyelinated nerve fibers and often presents with pain. While this condition is observed in pediatric chronic pain settings, it is unclear which patients are most appropriate for SFN testing, particularly for idiopathic cases. Skin biopsy is the most accurate diagnostic tool, but guidelines for its use are lacking. This study aimed to identify clinical and laboratory variables predictive of a positive skin biopsy for SFN in adolescents with chronic pain.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This retrospective study analyzed clinical, demographic, and laboratory characteristics of 104 adolescents with chronic pain who had undergone PGP9.5-immunolabeled distal-leg skin biopsy to assess for SFN. Fisher's exact tests, ANOVA, and logistic regression were used to identify predictive factors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Patient mean age was 15 years old and 51.9% had positive diagnostic skin biopsies. Results indicated adolescents with positive biopsies were more likely to have Juvenile Idiopathic Arthritis (JIA) compared to those without (33.3% vs. 14.3%, <i>p</i> = 0.02) and had higher median angiotensin-converting enzyme (ACE) levels (<i>p</i> < 0.01) and thyroid free T4 levels (<i>p</i> = 0.02). Logistic regression only showed increased odds of positive skin biopsies with JIA (OR = 3.27, <i>p</i> = 0.02). No clinical symptoms were predictive of positive skin biopsies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Discussion</h3>\u0000 \u0000 <p>Findings suggest that common clinical observations and laboratory tests used to guide referrals for skin biopsies were not predictive of SFN diagnosis. Clinicians should consider the risks and benefits of skin biopsies for adolescents with chronic pain. Additional research is warranted to validate potentially predictive markers and improve diagnostic pathways for SFN in pediatric chronic pain settings.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"30 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197321","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}
Sophie C. Queler, Ek Tsoon Tan, Ari Green, Carlo Milani, Ahmed Abdelhak, Darryl B. Sneag
Background and Aims
Parsonage–Turner syndrome (PTS), also known as neuralgic amyotrophy, is a peripheral neuropathy resulting in severe axonal loss. This study aimed to characterize initial elevation and longitudinal trends of serum neurofilament light chain (sNfL), a marker of neuro-axonal damage, in PTS.
Methods
This prospective cohort included 29 adults with electromyography (EMG)–confirmed PTS ≤ 6 months from symptom onset. Patients underwent sNfL testing and EMG at baseline (median 86 days from symptom onset) and again at 3- and 6-month follow-up intervals. Age- and BMI-adjusted Z-scores were analyzed. Linear mixed-effects models assessed associations between sNfL and time from onset, number of nerves involved, EMG metrics, and corticosteroid use.
Results
Mean sNfL Z-scores were significantly elevated (1.64, SD 1.32, p < 0.001) compared with healthy controls at 0 (1.64, p < 0.001) and 3 months (0.49, SD 1.06, p = 0.020). At 6 months, statistically significant elevations were not detected (0.39, SD 0.96, p = 0.106). sNfL declined by 0.17 Z-scores per month (95% CI: 0.11–0.23; p < 0.001). On EMG, the presence of nascent motor units, reflecting reinnervation, was associated with lower sNfL (p = 0.043).
Interpretation
sNfL elevation was detected in PTS patients within the first 6 months from symptom onset and decreased as reinnervation ensued. These findings suggest sNfL deserves further consideration as a blood-based biomarker for detection and monitoring of PTS.
{"title":"Serum Neurofilament Light Chain Level as an Indicator of Axonal Injury in Parsonage–Turner Syndrome (Neuralgic Amyotrophy)","authors":"Sophie C. Queler, Ek Tsoon Tan, Ari Green, Carlo Milani, Ahmed Abdelhak, Darryl B. Sneag","doi":"10.1111/jns.70063","DOIUrl":"10.1111/jns.70063","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Parsonage–Turner syndrome (PTS), also known as neuralgic amyotrophy, is a peripheral neuropathy resulting in severe axonal loss. This study aimed to characterize initial elevation and longitudinal trends of serum neurofilament light chain (sNfL), a marker of neuro-axonal damage, in PTS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This prospective cohort included 29 adults with electromyography (EMG)–confirmed PTS ≤ 6 months from symptom onset. Patients underwent sNfL testing and EMG at baseline (median 86 days from symptom onset) and again at 3- and 6-month follow-up intervals. Age- and BMI-adjusted <i>Z</i>-scores were analyzed. Linear mixed-effects models assessed associations between sNfL and time from onset, number of nerves involved, EMG metrics, and corticosteroid use.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Mean sNfL <i>Z</i>-scores were significantly elevated (1.64, SD 1.32, <i>p</i> < 0.001) compared with healthy controls at 0 (1.64, <i>p</i> < 0.001) and 3 months (0.49, SD 1.06, <i>p</i> = 0.020). At 6 months, statistically significant elevations were not detected (0.39, SD 0.96, <i>p</i> = 0.106). sNfL declined by 0.17 <i>Z</i>-scores per month (95% CI: 0.11–0.23; <i>p</i> < 0.001). On EMG, the presence of nascent motor units, reflecting reinnervation, was associated with lower sNfL (<i>p</i> = 0.043).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>sNfL elevation was detected in PTS patients within the first 6 months from symptom onset and decreased as reinnervation ensued. These findings suggest sNfL deserves further consideration as a blood-based biomarker for detection and monitoring of PTS.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"30 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186217","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}
Zeinab Rajabally, Lydia Spencer, Niraj Mistry, Yusuf A. Rajabally
Background
Whether ethnicity impacts on epidemiology, presentation, management, and outcome is unknown in chronic inflammatory demyelinating polyneuropathy (CIDP).
Methods
We studied the prevalence/incidence of CIDP in Asian (Indian/Pakistani/Bangladeshi) and white subjects in Birmingham, UK, and associations of ethnicity with demographics/deprivation/phenotype/treatment and outcomes.
Results
On 10th July 2025, CIDP prevalence was 6.18 per 100 000 (95% CI: 4.66–8.05). Prevalence was lower in Asian (Indian/Pakistani/Bangladeshi) compared to white subjects (2.64 per 100 000 vs. 10.15 per 100 000; RR: 0.260, 95% CI: 0.111–0.609; p < 0.001). Prevalence in ≥ 50-year-olds was lower in Asian (Indian/Pakistani/Bangladeshi) compared to white subjects (8.00 per 100 000 vs. 46.68 per 100 000; RR: 0.172; 95% CI: 0.061–0.479; p < 0.001) but similar in 18–49-year-olds (2.48 per 100 000 vs. 1.83 per 100 000; RR: 1.355, 95% CI: 0.273–6.712; p = 0.661). Mean incidence of CIDP was 0.54 per 100 000 per year (95% CI: 0.404–0.713). CIDP incidence was lower in Asian (Indian/Pakistani/Bangladeshi) than in white subjects (0.24 per 100 000 per year vs. 0.86 per 100 000 per year, RR: 0.278; 95% CI: 0.118–0.654; p = 0.002). Asian (Indian/Pakistani/Bangladeshi) ethnicity was independently associated with younger age (p = 0.037), greater social deprivation (p = 0.045), and noncompliance to treatment (p = 0.016). No association of Asian (Indian/Pakistani/Bangladeshi) ethnicity was found with CIDP sub-type, diagnostic delay, pretreatment disability, access to high-cost therapies, or posttreatment outcomes.
Conclusions
Subjects of Asian (Indian/Pakistani/Bangladeshi) ethnicity in the UK may have a lower risk of CIDP after 50 years of age, but an equivalent risk between 18 and 49 years, compared to white subjects. They may present younger, be more socially deprived, and be more likely noncompliant to treatment, compared to white subjects.
{"title":"Epidemiology, Presentation, Management and Outcomes in Chronic Inflammatory Demyelinating Polyneuropathy in Birmingham, UK: The Impact of Ethnicity","authors":"Zeinab Rajabally, Lydia Spencer, Niraj Mistry, Yusuf A. Rajabally","doi":"10.1111/jns.70065","DOIUrl":"10.1111/jns.70065","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Whether ethnicity impacts on epidemiology, presentation, management, and outcome is unknown in chronic inflammatory demyelinating polyneuropathy (CIDP).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We studied the prevalence/incidence of CIDP in Asian (Indian/Pakistani/Bangladeshi) and white subjects in Birmingham, UK, and associations of ethnicity with demographics/deprivation/phenotype/treatment and outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>On 10th July 2025, CIDP prevalence was 6.18 per 100 000 (95% CI: 4.66–8.05). Prevalence was lower in Asian (Indian/Pakistani/Bangladeshi) compared to white subjects (2.64 per 100 000 vs. 10.15 per 100 000; RR: 0.260, 95% CI: 0.111–0.609; <i>p</i> < 0.001). Prevalence in ≥ 50-year-olds was lower in Asian (Indian/Pakistani/Bangladeshi) compared to white subjects (8.00 per 100 000 vs. 46.68 per 100 000; RR: 0.172; 95% CI: 0.061–0.479; <i>p</i> < 0.001) but similar in 18–49-year-olds (2.48 per 100 000 vs. 1.83 per 100 000; RR: 1.355, 95% CI: 0.273–6.712; <i>p</i> = 0.661). Mean incidence of CIDP was 0.54 per 100 000 per year (95% CI: 0.404–0.713). CIDP incidence was lower in Asian (Indian/Pakistani/Bangladeshi) than in white subjects (0.24 per 100 000 per year vs. 0.86 per 100 000 per year, RR: 0.278; 95% CI: 0.118–0.654; <i>p</i> = 0.002). Asian (Indian/Pakistani/Bangladeshi) ethnicity was independently associated with younger age (<i>p</i> = 0.037), greater social deprivation (<i>p</i> = 0.045), and noncompliance to treatment (<i>p</i> = 0.016). No association of Asian (Indian/Pakistani/Bangladeshi) ethnicity was found with CIDP sub-type, diagnostic delay, pretreatment disability, access to high-cost therapies, or posttreatment outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Subjects of Asian (Indian/Pakistani/Bangladeshi) ethnicity in the UK may have a lower risk of CIDP after 50 years of age, but an equivalent risk between 18 and 49 years, compared to white subjects. They may present younger, be more socially deprived, and be more likely noncompliant to treatment, compared to white subjects.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"30 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.70065","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186188","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}
Kayla M. D. Cornett, Tim Estilow, Paula Bray, Melissa R. Mandarakas, Gabrielle A. Donlevy, Jennifer N. Baldwin, Kate Eichinger, Richard S. Finkel, Joshua Burns, Marnee J. McKay
Background and Aims
Accurate, reliable and sensitive clinical outcome measures in rare neurologic conditions, such as Charcot–Marie–Tooth disease (CMT), are essential for monitoring disease progression and evaluating treatment efficacy. Ensuring measures such as the CMTPedS, CMTInfS and CMT-FOM are easily accessible removes a barrier to implementation. The aims of this project were to: (1) design a web-based platform to enable real-time scoring of CMT outcome measures; (2) implement co-designed training and quality assurance resources; and (3) establish a Global Certification Standard for clinical evaluators.
Methods
A consultation process informed the design of the web-based platform and included a process evaluation of current users (n = 65). Training resources were co-designed with key stakeholders (n = 51) including CMT physicians and scientists, clinical evaluators, pharmaceutical representatives, and patients through a mixed-methods approach. A Global Certification Standard was developed through the co-design process and Master Trainer expertise.
Results
A web-based platform, www.ClinicalOutcomeMeasures.org was designed and implemented in June 2020 as a freely available trial readiness resource for clinicians and researchers. The platform now has > 1400 registered users from > 45 countries. Clinical evaluators identified a lack of accessible training resources as the top barrier to accurate and reliable administration of CMT outcome measures. Video demonstrations, online workshops, and labelled photographs were ranked as the top training methods. Five guiding principles for the Global Certification Standard for CMT outcome measures were established.
Interpretation
The web-based platform provides real-time scoring of CMT outcome measures, access to standardized training, and a Global Certification Standard to support accurate and reliable assessment of disease severity, progression, and treatment efficacy.
{"title":"Designing and Implementing a Web-Based Platform for Accurate and Reliable Clinical Outcome Measures and Global Certification for Evaluating Charcot–Marie–Tooth disease","authors":"Kayla M. D. Cornett, Tim Estilow, Paula Bray, Melissa R. Mandarakas, Gabrielle A. Donlevy, Jennifer N. Baldwin, Kate Eichinger, Richard S. Finkel, Joshua Burns, Marnee J. McKay","doi":"10.1111/jns.70062","DOIUrl":"10.1111/jns.70062","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Accurate, reliable and sensitive clinical outcome measures in rare neurologic conditions, such as Charcot–Marie–Tooth disease (CMT), are essential for monitoring disease progression and evaluating treatment efficacy. Ensuring measures such as the CMTPedS, CMTInfS and CMT-FOM are easily accessible removes a barrier to implementation. The aims of this project were to: (1) design a web-based platform to enable real-time scoring of CMT outcome measures; (2) implement co-designed training and quality assurance resources; and (3) establish a Global Certification Standard for clinical evaluators.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A consultation process informed the design of the web-based platform and included a process evaluation of current users (<i>n</i> = 65). Training resources were co-designed with key stakeholders (<i>n</i> = 51) including CMT physicians and scientists, clinical evaluators, pharmaceutical representatives, and patients through a mixed-methods approach. A Global Certification Standard was developed through the co-design process and Master Trainer expertise.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A web-based platform, www.ClinicalOutcomeMeasures.org was designed and implemented in June 2020 as a freely available trial readiness resource for clinicians and researchers. The platform now has > 1400 registered users from > 45 countries. Clinical evaluators identified a lack of accessible training resources as the top barrier to accurate and reliable administration of CMT outcome measures. Video demonstrations, online workshops, and labelled photographs were ranked as the top training methods. Five guiding principles for the Global Certification Standard for CMT outcome measures were established.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>The web-based platform provides real-time scoring of CMT outcome measures, access to standardized training, and a Global Certification Standard to support accurate and reliable assessment of disease severity, progression, and treatment efficacy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"30 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.70062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086564","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}
TTC19 encodes a mitochondrial protein involved in the assembly of complex III of the respiratory chain. Biallelic pathogenic variants cause a rare mitochondrial disorder typically associated with cerebellar ataxia, neuropsychiatric symptoms, and characteristic brain MRI findings within the Leigh syndrome spectrum. Peripheral motor involvement has been described in a minority of cases but has rarely been documented with detailed neurophysiological data. We report a novel TTC19 variant in a patient presenting with a distinctive combination of central and peripheral motor involvement.
Case Report
A male patient of Malian origin presented with cerebellar ataxia and attention deficits from early childhood. During adolescence, he developed additional features including dysarthria, dysphagia, dysexecutive syndrome, and signs of peripheral motor neuropathy. Brain MRI revealed T2-FLAIR hyperintensities in the basal ganglia and brainstem. Genetic testing identified a novel homozygous nonsense variant in TTC19 (c.235G>T, p.(Gly79*)). At age 19, he experienced two acute deteriorations associated with respiratory infections, leading to severe tetraparesis and diaphragmatic weakness. Neurophysiological studies confirmed a diffuse, axonal, pure distal motor neuropathy. Follow-up imaging showed progression and cavitation of brainstem lesions. The patient died from respiratory failure at age 20.
Interpretation
This case, featuring a novel TTC19 variant and detailed electrophysiological data, further supports the presence of pure motor neuropathy within the phenotypic spectrum of TTC19-related disease. The co-occurrence of Leigh syndrome MRI findings and motor neuropathy represents a specific diagnostic clue that may help prioritize genetic testing in patients with overlapping central and peripheral motor involvement.
{"title":"Motor Neuropathy in a Patient With Mitochondrial Disease and a Novel TTC19 Variant: An Underrecognized Phenotypic Feature","authors":"Daniele Mandia, Charline Benoit, Tanya Stojkovic, Yann Nadjar","doi":"10.1111/jns.70060","DOIUrl":"https://doi.org/10.1111/jns.70060","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>TTC19 encodes a mitochondrial protein involved in the assembly of complex III of the respiratory chain. Biallelic pathogenic variants cause a rare mitochondrial disorder typically associated with cerebellar ataxia, neuropsychiatric symptoms, and characteristic brain MRI findings within the Leigh syndrome spectrum. Peripheral motor involvement has been described in a minority of cases but has rarely been documented with detailed neurophysiological data. We report a novel TTC19 variant in a patient presenting with a distinctive combination of central and peripheral motor involvement.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Case Report</h3>\u0000 \u0000 <p>A male patient of Malian origin presented with cerebellar ataxia and attention deficits from early childhood. During adolescence, he developed additional features including dysarthria, dysphagia, dysexecutive syndrome, and signs of peripheral motor neuropathy. Brain MRI revealed T2-FLAIR hyperintensities in the basal ganglia and brainstem. Genetic testing identified a novel homozygous nonsense variant in TTC19 (c.235G>T, p.(Gly79*)). At age 19, he experienced two acute deteriorations associated with respiratory infections, leading to severe tetraparesis and diaphragmatic weakness. Neurophysiological studies confirmed a diffuse, axonal, pure distal motor neuropathy. Follow-up imaging showed progression and cavitation of brainstem lesions. The patient died from respiratory failure at age 20.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>This case, featuring a novel TTC19 variant and detailed electrophysiological data, further supports the presence of pure motor neuropathy within the phenotypic spectrum of TTC19-related disease. The co-occurrence of Leigh syndrome MRI findings and motor neuropathy represents a specific diagnostic clue that may help prioritize genetic testing in patients with overlapping central and peripheral motor involvement.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"30 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145057888","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}
Svea Nolte, Naser B. N. Shehab, Stefan P. Berger, Celina Oldag, Ilja M. Nolte, Bianca T. A. de Greef, Fiete Lange, Marco van Londen, Catharina G. Faber, Stephan J. L. Bakker, Pieter A. van Doorn, Harmen R. Moes, Gea Drost
Background and Aims
Polyneuropathy is highly prevalent among kidney transplant recipients (KTR), underscoring the need for an accurate yet easy-to-perform diagnostic method to improve understanding and enable early identification of treatable cases.
Methods
This study included KTR at least 12 months post-transplant at the University Medical Centre Groningen, the Netherlands. An expert panel assessed polyneuropathy through a structured neurological examination, quantitative sensory testing, and nerve conduction studies. The modified Toronto Clinical Neuropathy Score (mTCNS) was obtained from all participants. Logistic regression analyses with Firth penalization validated the mTCNS components. A new model, the Kidney Transplant Neuropathy Score (KTNS), was developed through stepwise elimination. Diagnostic performance was evaluated with bootstrapped metrics and ROC curve analyses.
Results
Among 160 KTR, 91 (57%) were diagnosed with polyneuropathy. All 10 mTCNS components were univariably associated with polyneuropathy; numbness (OR = 4.9 [1.8–18.0]), tingling (OR = 2.5 [1.2–5.9]), impaired nociception (OR = 1.5 [1.1–2.2]), and reduced vibration perception (OR = 1.5 [1.0–2.4]) remained independently associated in multivariable analysis. The mTCNS achieved an area under the curve (AUC) in ROC analysis of 0.83 [0.76–0.89]. Two KTNS were derived: the KTNSBasic, including history of numbness, tingling in the feet, and pinprick and vibration perception testing (AUC–ROC: 0.85 [0.79–0.90]); and the KTNSAdvanced, replacing vibration perception with Achilles and patellar deep tendon reflex testing (AUC–ROC: 0.90 [0.85–0.94]).
Interpretation
The mTCNS is a valid diagnostic tool for polyneuropathy in KTR. The KTNS offers a simplified alternative based on key symptoms and sensory tests, with reflex testing included in the KTNSAdvanced for settings with neurological expertise.
{"title":"Polyneuropathy in Kidney Transplant Recipients: Accuracy of a New Clinical Diagnostic Scoring System","authors":"Svea Nolte, Naser B. N. Shehab, Stefan P. Berger, Celina Oldag, Ilja M. Nolte, Bianca T. A. de Greef, Fiete Lange, Marco van Londen, Catharina G. Faber, Stephan J. L. Bakker, Pieter A. van Doorn, Harmen R. Moes, Gea Drost","doi":"10.1111/jns.70058","DOIUrl":"https://doi.org/10.1111/jns.70058","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Polyneuropathy is highly prevalent among kidney transplant recipients (KTR), underscoring the need for an accurate yet easy-to-perform diagnostic method to improve understanding and enable early identification of treatable cases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study included KTR at least 12 months post-transplant at the University Medical Centre Groningen, the Netherlands. An expert panel assessed polyneuropathy through a structured neurological examination, quantitative sensory testing, and nerve conduction studies. The modified Toronto Clinical Neuropathy Score (mTCNS) was obtained from all participants. Logistic regression analyses with Firth penalization validated the mTCNS components. A new model, the Kidney Transplant Neuropathy Score (KTNS), was developed through stepwise elimination. Diagnostic performance was evaluated with bootstrapped metrics and ROC curve analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among 160 KTR, 91 (57%) were diagnosed with polyneuropathy. All 10 mTCNS components were univariably associated with polyneuropathy; numbness (OR = 4.9 [1.8–18.0]), tingling (OR = 2.5 [1.2–5.9]), impaired nociception (OR = 1.5 [1.1–2.2]), and reduced vibration perception (OR = 1.5 [1.0–2.4]) remained independently associated in multivariable analysis. The mTCNS achieved an area under the curve (AUC) in ROC analysis of 0.83 [0.76–0.89]. Two KTNS were derived: the KTNS<sub>Basic</sub>, including history of numbness, tingling in the feet, and pinprick and vibration perception testing (AUC–ROC: 0.85 [0.79–0.90]); and the KTNS<sub>Advanced</sub>, replacing vibration perception with Achilles and patellar deep tendon reflex testing (AUC–ROC: 0.90 [0.85–0.94]).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>The mTCNS is a valid diagnostic tool for polyneuropathy in KTR. The KTNS offers a simplified alternative based on key symptoms and sensory tests, with reflex testing included in the KTNS<sub>Advanced</sub> for settings with neurological expertise.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial Registration</h3>\u0000 \u0000 <p>ClinicalTrials.gov identifier: NCT04664426</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"30 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.70058","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012108","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}
Catherine M. Daley, Michael P. Skolka, JaNean K. Engelstad, Karen L. Rech, P. James B. Dyck
Aim
To report a novel case of biopsy-proven, mass spectrometry-confirmed, wild-type transthyretin amyloidosis (ATTRwt) in nerve.
Methods
The patient was identified and evaluated in the peripheral nerve clinic. Our nerve laboratory's pathology database and the literature were searched for prior evidence of pathologically confirmed cases of ATTRwt.
Results
A 94-year-old man with a history of lumbar spinal stenosis presented to the neurology clinic with subacute-on-chronic progressive, upper limb predominant weakness along with numbness and tingling paresthesia. Electromyography (EMG) revealed multiple mononeuropathies involving the right median nerve at the wrist, right ulnar nerve, and right distal radial nerve superimposed upon an axonal predominant peripheral neuropathy along with multilevel lumbosacral radiculopathies. Extensive serology for causes of neuropathy and multiple mononeuropathies returned unremarkable. A diagnostic right superficial radial nerve biopsy was performed and showed congophilic material within a small epineurial vessel wall in the nerve tissue. Amyloid typing by mass spectrometry was performed and revealed ATTRwt. TTR gene sequencing returned normal. The patient was diagnosed with ATTRwt neuropathy and started on diflunisal therapy for neuropathy treatment.
Conclusion
This case confirms the presence of ATTRwt deposition directly in nerve tissue as the likely cause of the patient's large fiber and multiple mononeuropathies, expanding our current understanding of ATTRwt-associated disease. Proving the direct association of ATTRwt and neuropathy may open up amyloid-specific treatments for this disease.
{"title":"A Novel Case of Nerve Biopsy Proven Wild Type Transthyretin (TTR) Amyloidosis","authors":"Catherine M. Daley, Michael P. Skolka, JaNean K. Engelstad, Karen L. Rech, P. James B. Dyck","doi":"10.1111/jns.70056","DOIUrl":"https://doi.org/10.1111/jns.70056","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>To report a novel case of biopsy-proven, mass spectrometry-confirmed, wild-type transthyretin amyloidosis (ATTRwt) in nerve.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The patient was identified and evaluated in the peripheral nerve clinic. Our nerve laboratory's pathology database and the literature were searched for prior evidence of pathologically confirmed cases of ATTRwt.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A 94-year-old man with a history of lumbar spinal stenosis presented to the neurology clinic with subacute-on-chronic progressive, upper limb predominant weakness along with numbness and tingling paresthesia. Electromyography (EMG) revealed multiple mononeuropathies involving the right median nerve at the wrist, right ulnar nerve, and right distal radial nerve superimposed upon an axonal predominant peripheral neuropathy along with multilevel lumbosacral radiculopathies. Extensive serology for causes of neuropathy and multiple mononeuropathies returned unremarkable. A diagnostic right superficial radial nerve biopsy was performed and showed congophilic material within a small epineurial vessel wall in the nerve tissue. Amyloid typing by mass spectrometry was performed and revealed ATTRwt. TTR gene sequencing returned normal. The patient was diagnosed with ATTRwt neuropathy and started on diflunisal therapy for neuropathy treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This case confirms the presence of ATTRwt deposition directly in nerve tissue as the likely cause of the patient's large fiber and multiple mononeuropathies, expanding our current understanding of ATTRwt-associated disease. Proving the direct association of ATTRwt and neuropathy may open up amyloid-specific treatments for this disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"30 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144929911","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}
Young Gi Min, Bo-Kyung Ko, Hee Jo Han, MinGi Kim, Do Hoon Lee, Seung-Woo Kim, Jung-Joon Sung, Ha Young Shin
Background
Autoimmune nodopathy (AN) is caused by autoantibodies targeting the nodes of Ranvier or paranodes. AN frequently affects cranial nerves and spinal nerve roots and may accompany central demyelination, all of which belong to the intrathecal compartment. We aimed to ascertain the frequency of intrathecal antibody synthesis and blood–CSF barrier (BCSFB) dysfunction in AN and their clinical correlates.
Methods
We analyzed paired cerebrospinal fluid (CSF) and serum samples from 110 patients with AN, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and Guillain-Barré syndrome (GBS). BCSFB dysfunction and intrathecal total IgG synthesis were assessed using QAlb, QIgG-total, and IgG index. Flow cytometry was used to evaluate intrathecal autoantibody synthesis.
Results
Compared to CIDP and GBS, AN patients more frequently exhibited BCSFB dysfunction (87.5%) and intrathecal total IgG synthesis (68.8%). Among AN patients with cranial nerve or brain involvement (8/16, 50%), all had either an elevated IgG index (n = 7) or CSF-specific oligoclonal bands (n = 1). Intrathecal autoantibody synthesis was confirmed in 2 patients. Notably, both patients initially presented with cranial neuropathies. No CSF-restricted AN autoantibodies were found in the 39 seronegative CIDP and GBS patients.
Conclusions
AN exhibits distinct immunopathogenesis compared to CIDP and GBS. Intrathecal synthesis of total IgG is associated with cranial nerve or central nervous system involvement, while that of AN-specific autoantibodies relates to cranial nerve onset diseases.
{"title":"Intrathecal Antibody Synthesis in Autoimmune Nodopathy","authors":"Young Gi Min, Bo-Kyung Ko, Hee Jo Han, MinGi Kim, Do Hoon Lee, Seung-Woo Kim, Jung-Joon Sung, Ha Young Shin","doi":"10.1111/jns.70057","DOIUrl":"https://doi.org/10.1111/jns.70057","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Autoimmune nodopathy (AN) is caused by autoantibodies targeting the nodes of Ranvier or paranodes. AN frequently affects cranial nerves and spinal nerve roots and may accompany central demyelination, all of which belong to the intrathecal compartment. We aimed to ascertain the frequency of intrathecal antibody synthesis and blood–CSF barrier (BCSFB) dysfunction in AN and their clinical correlates.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed paired cerebrospinal fluid (CSF) and serum samples from 110 patients with AN, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and Guillain-Barré syndrome (GBS). BCSFB dysfunction and intrathecal total IgG synthesis were assessed using Q<sub>Alb</sub>, Q<sub>IgG-total</sub>, and IgG index. Flow cytometry was used to evaluate intrathecal autoantibody synthesis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared to CIDP and GBS, AN patients more frequently exhibited BCSFB dysfunction (87.5%) and intrathecal total IgG synthesis (68.8%). Among AN patients with cranial nerve or brain involvement (8/16, 50%), all had either an elevated IgG index (<i>n</i> = 7) or CSF-specific oligoclonal bands (<i>n</i> = 1). Intrathecal autoantibody synthesis was confirmed in 2 patients. Notably, both patients initially presented with cranial neuropathies. No CSF-restricted AN autoantibodies were found in the 39 seronegative CIDP and GBS patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>AN exhibits distinct immunopathogenesis compared to CIDP and GBS. Intrathecal synthesis of total IgG is associated with cranial nerve or central nervous system involvement, while that of AN-specific autoantibodies relates to cranial nerve onset diseases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"30 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.70057","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144923747","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}
Simon Frachet, Aurore Danigo, Mathilde Latil, Pierre J. Dilda, Flavien Bessaguet, Laurence Richard, Franck Sturtz, Laurent Magy, Claire Demiot
Background and Aims
Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect that limits the dosage of many anticancer therapies, such as vincristine. At present, there are no effective pharmacological treatments to prevent CIPN. The Mas receptor (MasR) is expressed in the peripheral nervous system and plays a role in pain modulation. While the antinociceptive properties of MasR activation in CIPN have been documented, its potential neuroprotective effects have not been explored in the peripheral nervous system. BIO101, a highly purified form of the MasR activator 20-hydroxyecdysone, exhibits a positive safety profile in a Phase 1 study without any serious adverse events.
Methods
This study aimed to investigate the neuroprotective effects of BIO101 in a mouse model of vincristine-induced peripheral neuropathy (VIPN). Swiss mice were treated with daily doses of vincristine. VIPN was evaluated through repeated measurements of tactile sensitivity, quantification of intraepidermal nerve fibers (IENF) and dorsal root ganglion (DRG) neurons, and ultrastructural analysis of the sciatic nerve.
Results
Vincristine led to mechanical allodynia and reduced the density of IENF, DRG neurons, and unmyelinated nerve fibers in the sciatic nerve. Prophylactic administration of BIO101 mitigated vincristine-induced symptoms and nerve damage. The neuroprotective effect of BIO101 was nullified when the MasR antagonist A779 was administered; confirming the involvement of MasR.
Interpretation
Therefore, BIO101 emerges as a safe and promising preventive treatment against vincristine-induced small fiber neuropathy.
{"title":"Neuroprotective Effect of Mas Activation by BIO101 in Vincristine-Induced Small Fiber Neuropathy","authors":"Simon Frachet, Aurore Danigo, Mathilde Latil, Pierre J. Dilda, Flavien Bessaguet, Laurence Richard, Franck Sturtz, Laurent Magy, Claire Demiot","doi":"10.1111/jns.70055","DOIUrl":"https://doi.org/10.1111/jns.70055","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect that limits the dosage of many anticancer therapies, such as vincristine. At present, there are no effective pharmacological treatments to prevent CIPN. The Mas receptor (MasR) is expressed in the peripheral nervous system and plays a role in pain modulation. While the antinociceptive properties of MasR activation in CIPN have been documented, its potential neuroprotective effects have not been explored in the peripheral nervous system. BIO101, a highly purified form of the MasR activator 20-hydroxyecdysone, exhibits a positive safety profile in a Phase 1 study without any serious adverse events.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study aimed to investigate the neuroprotective effects of BIO101 in a mouse model of vincristine-induced peripheral neuropathy (VIPN). Swiss mice were treated with daily doses of vincristine. VIPN was evaluated through repeated measurements of tactile sensitivity, quantification of intraepidermal nerve fibers (IENF) and dorsal root ganglion (DRG) neurons, and ultrastructural analysis of the sciatic nerve.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Vincristine led to mechanical allodynia and reduced the density of IENF, DRG neurons, and unmyelinated nerve fibers in the sciatic nerve. Prophylactic administration of BIO101 mitigated vincristine-induced symptoms and nerve damage. The neuroprotective effect of BIO101 was nullified when the MasR antagonist A779 was administered; confirming the involvement of MasR.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Therefore, BIO101 emerges as a safe and promising preventive treatment against vincristine-induced small fiber neuropathy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"30 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jns.70055","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144869725","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}
Alaura D. Rice, Abigail L. D. Tadenev, Timothy J. Hines, Jonathan R. Funke, Robert W. Burgess
Background
Charcot-Marie-Tooth (CMT) disease can be caused by mutations in over 100 different genes, most of which lead to demyelination (type 1) or degeneration (type 2) of peripheral motor and sensory axons. SARM1 is a protein involved in the active process of Wallerian degeneration after axonal injury. Inhibition of SARM1 protects against axon degeneration following injury or in cases such as chemotherapy-induced peripheral neuropathy. However, the effects of SARM1 inhibition on axon degeneration in genetic diseases such as CMT are less clear.
Aims
Here we tested whether SARM1 inhibition may be of benefit in three different mouse models of axonal CMT: GarsETAQ/CTM2D, NeflN98S/CMT2E, and Ighmbp2Y918C/CMT2S.
Methods
For these proof-of-concept studies, mice were treated as neonates with an AAV9 to deliver a dominant negative SARM1 construct (dnSARM1) to the nervous system by intracerebroventricular injection. At ages appropriate for each mouse model, animals were then evaluated with a combination of behavioral, neurophysiological, and histological outcomes.
Results
We reproduced the protective effects of the dnSARM1 construct in positive control experiments following sciatic nerve crush. However, we did not see a change in the phenotypes of any of the CMT mouse models examined. The neuropathy-related phenotypes neither worsened nor improved. Wild-type littermate controls treated with the AAV9 dnSARM1 had minor reductions in body weight and variable changes in motor performance compared to untreated controls, but no deficits by neurophysiology or histology.
Interpretation
Inhibiting SARM1 using a virally delivered dominant negative construct was not efficacious in any of the three mouse models of CMT we tested. These mouse models were chosen for their relevance to the human disease and their prominent axon degeneration, and not for metabolic changes that would suggest SARM1 as a therapeutic target. SARM1 inhibition may remain an option for some forms of CMT, but a method for prescreening CMT subtypes to predict efficacy is needed.
{"title":"SARM1 Inhibition in Three Mouse Models of Charcot-Marie-Tooth Disease","authors":"Alaura D. Rice, Abigail L. D. Tadenev, Timothy J. Hines, Jonathan R. Funke, Robert W. Burgess","doi":"10.1111/jns.70053","DOIUrl":"https://doi.org/10.1111/jns.70053","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Charcot-Marie-Tooth (CMT) disease can be caused by mutations in over 100 different genes, most of which lead to demyelination (type 1) or degeneration (type 2) of peripheral motor and sensory axons. SARM1 is a protein involved in the active process of Wallerian degeneration after axonal injury. Inhibition of SARM1 protects against axon degeneration following injury or in cases such as chemotherapy-induced peripheral neuropathy. However, the effects of SARM1 inhibition on axon degeneration in genetic diseases such as CMT are less clear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Here we tested whether SARM1 inhibition may be of benefit in three different mouse models of axonal CMT: <i>Gars</i><sup>ETAQ</sup>/CTM2D, <i>Nefl</i><sup>N98S</sup>/CMT2E, and <i>Ighmbp2</i><sup>Y918C</sup>/CMT2S.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>For these proof-of-concept studies, mice were treated as neonates with an AAV9 to deliver a dominant negative SARM1 construct (dnSARM1) to the nervous system by intracerebroventricular injection. At ages appropriate for each mouse model, animals were then evaluated with a combination of behavioral, neurophysiological, and histological outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We reproduced the protective effects of the dnSARM1 construct in positive control experiments following sciatic nerve crush. However, we did not see a change in the phenotypes of any of the CMT mouse models examined. The neuropathy-related phenotypes neither worsened nor improved. Wild-type littermate controls treated with the AAV9 dnSARM1 had minor reductions in body weight and variable changes in motor performance compared to untreated controls, but no deficits by neurophysiology or histology.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Inhibiting SARM1 using a virally delivered dominant negative construct was not efficacious in any of the three mouse models of CMT we tested. These mouse models were chosen for their relevance to the human disease and their prominent axon degeneration, and not for metabolic changes that would suggest SARM1 as a therapeutic target. SARM1 inhibition may remain an option for some forms of CMT, but a method for prescreening CMT subtypes to predict efficacy is needed.</p>\u0000 </section>\u0000 </div>","PeriodicalId":17451,"journal":{"name":"Journal of the Peripheral Nervous System","volume":"30 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144869724","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}
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