QuestionIs vemircopan efficacious in adults with acetylcholine receptor antibody-positive generalized myasthenia gravis?FindingsIn this double-blind, multicenter, phase 2 randomized clinical trial, differences in the proportion of participants achieving the primary endpoint (>= 2-point reduction from baseline in total Myasthenia Gravis-Activities of Daily Living score for 4 consecutive weeks during the 8-week primary evaluation period, without rescue therapy use) were not statistically significant between vemircopan and placebo groups. No significant differences were observed in secondary efficacy end points either.MeaningThe trial was terminated, as the minimal efficacy threshold was not met; inhibition of the complement alternative pathway as a potentially viable and efficacious strategy to treat patients with acetylcholine receptor antibody-positive generalized myasthenia gravis requires further investigation in clinical settings. ImportanceInhibition of terminal complement component 5 has proven effective in acetylcholine receptor antibody-positive (AChR-Ab+) generalized myasthenia gravis (gMG) but requires intravenous or daily subcutaneous administration and is associated with an increased meningococcal infection risk. Targeting the complement alternative pathway (AP) may offer similar benefits while sparing the classical and lectin pathways, preserving some immune responses against infection.ObjectiveTo evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of vemircopan, an oral, selective factor D inhibitor that blocks AP-mediated complement activation and amplification, in adults with AChR-Ab+ gMG.Design, Setting, and ParticipantsThis double-blind, parallel-group, placebo-controlled phase 2 randomized clinical trial was conducted between April 14, 2022, and April 3, 2024, at 60 sites across 8 countries. Adults with AChR-Ab+ gMG, Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 5 or greater, and Myasthenia Gravis Foundation of America classes II through IV classification were eligible for inclusion. Data were unblinded in June 2024; final analysis was completed October 2024.InterventionRandomization 2:1:2 to twice-daily oral vemircopan, 180 mg or 120 mg, or placebo.Main Outcomes and MeasuresThe primary end point was the proportion of participants achieving a 2-point or greater reduction in MG-ADL total score from baseline for 4 consecutive weeks, without rescue therapy, during the 8-week, double-blind primary evaluation period. Secondary end points were change from baseline to week 8 in MG-ADL total score, Quantitative Myasthenia Gravis total score, and Neurological Disorders Fatigue questionnaire score.ResultsOf 99 individuals screened, 70 met eligibility criteria, and 29 were excluded. Of 70 participants randomized (vemircopan, 180 mg: n = 28; vemircopan, 120 mg: n = 14; placebo: n = 28), 38 participants (54%) were female; mean (SD) age at diagnosis was 45.4 (18.5) years. The proportion of participants achieving the primary end point did not differ significantly between placebo (18 of 28 [64%]; 90% CI, 47%-79%) and either vemircopan group (180 mg: 16 of 28 [57%]; 90% CI, 40%-73%; 120 mg: 8 of 14 [57%]; 90% CI, 33%-79%). No significant differences were observed for the secondary end points. No cases of meningococcal infection were reported; 1 participant died due to hepatic failure and 1 discontinued study treatment due to herpes simplex meningitis.Conclusions and RelevanceIn this double-blind, parallel-group, placebo-controlled phase 2 randomized clinical trial, vemircopan did not meet the prespecified threshold for efficacy, and consequently, the study was terminated.Trial RegistrationClinicalTrials.gov Identifier: NCT05218096 This phase 2 randomized clinical trial evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of vemircopan in adults with acetylcholine receptor antibody-positive generalized myasthenia gravis.

Importance Gefurulimab is a novel dual-binding nanobody that blocks complement component 5 activation. Complement activation is a key pathogenic mechanism in anti–acetylcholine receptor antibody–positive (AChR-Ab+) generalized myasthenia gravis (gMG). Objective To evaluate the efficacy and safety of gefurulimab in adults with AChR-Ab+ gMG. Design, Setting, and Participants This randomized clinical trial, PREVAIL, was a phase 3, double-blind, placebo-controlled study conducted at 113 sites in 20 countries. Patients were screened and randomized from November 2022 to November 2024; the randomized controlled treatment period was 26 weeks. Participants were adults (aged ≥18 years) with AChR-Ab+ gMG, a Myasthenia Gravis Foundation of America classification II through IV, and a Myasthenia Gravis Activities of Daily Living (MG-ADL) total score of 5 or higher. Intervention Gefurulimab or placebo via once-weekly subcutaneous self-injection. Main Outcomes and Measures The primary end point was change from baseline in MG-ADL total score at week 26. The key secondary end point was change from baseline in Quantitative Myasthenia Gravis (QMG) total score at week 26. Safety was also assessed. Results Of 405 patients screened, 145 were excluded; 260 met eligibility criteria and were randomized (gefurulimab, n = 131; placebo, n = 129); 249 patients completed the 26-week randomized controlled treatment period. The mean (SD) age was 52.8 (15.73) years; 157 (60.4%) patients were female and 103 (39.6%) were male. All primary and secondary end points were met with statistical significance. Improvements occurred within 1 week for MG-ADL score and 4 weeks for QMG score and were sustained through week 26. Least-squares mean change from baseline at week 26 for MG-ADL and QMG total scores for gefurulimab vs placebo were −4.2 vs −2.6 (treatment difference, −1.6; 95% CI, −2.4 to −0.8; P < .001) and −4.5 vs −2.4 (treatment difference, −2.1; 95% CI, −3.1 to −1.1; P < .001), respectively. The incidence of adverse events (AEs) was similar between groups. Most common treatment-emergent AEs with gefurulimab were injection site reactions, headache, back pain, and nasopharyngitis. No meningococcal infections were reported. Conclusions and Relevance Gefurulimab demonstrated both early and sustained clinical benefit in AChR-Ab+ gMG and was well tolerated, supporting its potential as a convenient, once-weekly, self-administered treatment regimen. Trial Registration ClinicalTrials.gov Identifier: NCT05556096

Importance:Gefurulimab is a novel dual-binding nanobody that blocks complement component 5 activation. Complement activation is a key pathogenic mechanism in anti-acetylcholine receptor antibody-positive (AChR-Ab+) generalized myasthenia gravis (gMG). Objective:To evaluate the efficacy and safety of gefurulimab in adults with AChR-Ab+ gMG. Design, Setting, and Participants:This randomized clinical trial, PREVAIL, was a phase 3, double-blind, placebo-controlled study conducted at 113 sites in 20 countries. Patients were screened and randomized from November 2022 to November 2024; the randomized controlled treatment period was 26 weeks. Participants were adults (aged ≥18 years) with AChR-Ab+ gMG, a Myasthenia Gravis Foundation of America classification II through IV, and a Myasthenia Gravis Activities of Daily Living (MG-ADL) total score of 5 or higher. Intervention:Gefurulimab or placebo via once-weekly subcutaneous self-injection. Main Outcomes and Measures:The primary end point was change from baseline in MG-ADL total score at week 26. The key secondary end point was change from baseline in Quantitative Myasthenia Gravis (QMG) total score at week 26. Safety was also assessed. Results:Of 405 patients screened, 145 were excluded; 260 met eligibility criteria and were randomized (gefurulimab, n = 131; placebo, n = 129); 249 patients completed the 26-week randomized controlled treatment period. The mean (SD) age was 52.8 (15.73) years; 157 (60.4%) patients were female and 103 (39.6%) were male. All primary and secondary end points were met with statistical significance. Improvements occurred within 1 week for MG-ADL score and 4 weeks for QMG score and were sustained through week 26. Least-squares mean change from baseline at week 26 for MG-ADL and QMG total scores for gefurulimab vs placebo were -4.2 vs -2.6 (treatment difference, -1.6; 95% CI, -2.4 to -0.8; P < .001) and -4.5 vs -2.4 (treatment difference, -2.1; 95% CI, -3.1 to -1.1; P < .001), respectively. The incidence of adverse events (AEs) was similar between groups. Most common treatment-emergent AEs with gefurulimab were injection site reactions, headache, back pain, and nasopharyngitis. No meningococcal infections were reported. Conclusions and Relevance:Gefurulimab demonstrated both early and sustained clinical benefit in AChR-Ab+ gMG and was well tolerated, supporting its potential as a convenient, once-weekly, self-administered treatment regimen. Trial Registration:ClinicalTrials.gov Identifier: NCT05556096.

Introduction: Double seronegative myasthenia gravis (dSnMG) is defined as myasthenia gravis (MG) without detectable antibodies to acetylcholine receptor (AChR) and muscle-specific kinase (MuSK). Absence of a disease-specific biomarker and clinical heterogeneity can significantly complicate diagnostic pathway. This study aimed to identify cases misdiagnosed as dSnMG. Methodology: The study included 33 patients [64% females, median age at onset 30 (22.5-40) years, median age at testing 46 (34-58) years] previously diagnosed with dSnMG. Disease severity was assessed using MG-ADL and QMG at testing, peak MGFA, intensive care unit (ICU) hospitalization and MG crisis history. Indirect immunofluorescence was performed to detect low-density lipoprotein receptor-related protein 4 (LRP4) antibodies. Whole exome sequencing (WES) was conducted, along with genetic testing for myotonic dystrophy type 1 and 2 (DM1 and DM2) and oculopharyngeal muscular dystrophy (OPMD). Results: Mean MG-ADL and QMG scores at testing were 1 (0-3) and 6 (3-9), respectively. More than half of the patients had ocular MG (52%). One patient experienced myasthenic crisis. One patient tested positive for LRP4 antibodies, and one was diagnosed with paraneoplastic Lambert-Eaton myasthenic syndrome. WES showed likely pathogenic variant c.517G > A in the CHRNA1 gene associated with autosomal dominant slow channel congenital myasthenic syndrome and only one variant c.2368G > A in the MUSK gene. One patient displayed a DM2 premutation (32-35 CCTG repeats). Conclusion: This study highlights the importance of considering alternative diagnoses in patients with dSnMG and emphasizes the value of comprehensive testing. Early recognition of causative etiologies can significantly improve patient management and outcome and prevent unnecessary exposure to prolonged immunosuppression.

BACKGROUND AND AIMS:Differentiating hereditary axonal polyneuropathies caused by distinct gene variants remains a clinical challenge. This comparative case study of DNAJB2- and HINT1-related neuropathies aimed to broaden the phenotypic spectrum associated with these genes and to explore non-motor symptoms and quality of life (QoL) in affected individuals. METHODS:Six patients carrying two novel DNAJB2 variants and six age-matched patients with HINT1 variants underwent detailed clinical and electrophysiological characterization. Motor function was assessed longitudinally using the Medical Research Council (MRC) scale. Non-motor symptoms (neuropathic pain, autonomic dysfunction, depression, fatigue, restless legs syndrome) and QoL were evaluated with patient-reported outcomes and compared to four healthy controls (HC). RESULTS:Both patient groups exhibited a CMT2 phenotype. Nerve conduction studies revealed a length-dependent axonal predominantly motor but not pure motor neuropathy in most of the patients. Disease onset tended to occur later in patients with DNAJB2 variants, who yet developed more severe neuropathy. The spectrum of additional clinical features differed between the two groups. All patients with DNAJB2 variants fulfilled criteria for depression, compared with one with a HINT1 variant. Significant fatigue was present in the majority of both groups, while restless legs syndrome was observed in four patients with a DNAJB2 variant but in none with a HINT1. QoL was significantly reduced in DNAJB2 versus HC, with no difference in QoL between patients with DNAJB2 and HINT1 variants. INTERPRETATION:This study expands the clinical spectrum of DNAJB2- and HINT1-related neuropathies, highlighting distinct non-motor features and their impact on QoL, and providing the first direct comparison of these two rare axonal disorders.

Myotonic dystrophy type 1 (DM1) is caused by an expansion of CTG repeats in the DMPK gene. In a proportion of patients, the expanded allele contains variant repeats, which have been associated with later disease onset and different clinical presentation, although their full impact remains incompletely defined. We compared sociodemographic, neuromuscular, and multisystem clinical features between DM1 patients with pure CTG expansions (n = 66) and those with variant repeats (n = 9), who formed a consecutive cohort of unrelated index cases evaluated at the age of diagnosis in routine clinical practice. Patients with variant repeats were nine years older at diagnosis than patients with pure repeat expansions (p = 0.025), had more years of formal education (p = 0.024), and showed reduced muscle strength in proximal lower limbs (p = 0.049). No childhood or juvenile forms were observed among patients with variant repeats. Sex, disease duration, and most other clinical parameters, including multisystem involvement, did not differ between groups. The results of our exploratory study support variant repeats as disease modifiers in both age at onset and pattern of muscle involvement, and imply a two-sequential-component hypothesis in DM1 pathogenesis.

BACKGROUND AND AIMS:This study aimed to systematically phenotype autonomic nervous system (ANS) involvement in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), monoclonal gammopathy of undetermined significance-associated neuropathy (MGUS-PNP), Charcot-Marie-Tooth disease Type 1A (CMT1A), and hereditary neuropathy with liability to pressure palsies (HNPP). METHODS:Autonomic symptoms were assessed using the SCales for Outcomes in Parkinson's Disease-Autonomic Dysfunction (SCOPA-AUT). Muscle strength and functional disability were evaluated using the Medical Research Council (MRC) scale, the Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale, and the Overall Neuropathy Limitation Scale (ONLS). RESULTS:A total of 343 participants were included: 98 with CIDP (mean age: 59.2 ± 13.2 years), 51 with MGUS-PNP (66.0 ± 11.3 years), 51 with CMT1A (51.2 ± 13.1 years), 18 with HNPP (40.6 ± 15.1 years), and 125 healthy controls (58.2 ± 13.3 years). Compared with healthy controls, patients with CIDP, MGUS-PNP, and CMT1A showed significantly higher total SCOPA-AUT scores (p < 0.01). Distinct, disease-specific ANS symptom patterns were observed across neuropathy subtypes. Overall disability was independently associated with overall autonomic symptom burden in MGUS-PNP (β = 0.42, p < 0.05) and CMT1A (β = 0.68, p < 0.05). In CIDP, patients with active disease showed higher autonomic symptom burden than those with inactive disease (12.7 ± 11.7 vs. 8.6 ± 7.9, p = 0.042). INTERPRETATION:Patients with CIDP, MGUS-PNP, and CMT1A exhibit a substantial autonomic symptom burden with distinct disease-specific ANS patterns. These findings highlight the relevance of autonomic dysfunction in immune-mediated and hereditary neuropathies and warrant further studies to clarify their clinical and prognostic significance.

BACKGROUND AND OBJECTIVES:Key terms describing the activity status and clinical outcomes of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) lack standardized definitions. To address the need for uniform definitions, we sought to develop formal consensus-based terminology to define key aspects pertinent to the management of CIDP. METHODS:In April 2025, the GBS|CIDP Foundation International convened a Task Force of 17 international CIDP experts, 2 guest experts from related specialties, and 3 patient representatives. Task Force panels iteratively reviewed, discussed, and voted on proposed definitions for No Evidence of Disease Activity, Relapse, Response, Refractory, Remission, and Residual Symptoms. Relevant literature was reviewed to inform each definition. A modified Delphi approach was used to achieve consensus, defined as a median rating ≥7 on a 9-point scale with ≥80% agreement. Voting included 17 content experts and 3 patient representatives. Guest experts provided nonvoting input. RESULTS:Composite metrics incorporating disability, strength impairment, and patient perception were determined to provide the most sensitive and specific assessment of clinical change in CIDP. Using commonly used clinical outcome measures, including minimally clinically important differences where available, unique definitions were developed for each clinical term. Definitions for No Evidence of Disease Activity, Relapse, Response (minimal, partial, and optimal), Refractory, Remission, and Residual Symptoms were iteratively refined to integrate patient-reported experiences, standardized disability scores, and objective measures of strength impairment, ensuring that each term captured a multidimensional view of disease status. DISCUSSION:The development of consensus-based definitions for key clinical terms in CIDP addresses a longstanding gap in standardizing the assessment of disease activity and treatment outcomes. By combining patient-reported experiences with objective disability and strength measures, the Task Force created comprehensive definitions reflecting the patient experience. The iterative Delphi process ensured broad expert agreement while allowing patient perspectives to inform the terminology. These standardized definitions may improve consistent evaluations in clinical practice, facilitate communication among healthcare providers, and support more robust design and interpretation of clinical trials. Furthermore, the incorporation of composite metrics sensitive to meaningful clinical changes may enhance the ability to detect treatment effects and disease progression, ultimately promoting more precise and patient-centered management of CIDP.

Polyneuropathies are common and often require specialist expertise for accurate diagnosis. This study evaluated the diagnostic performance of ChatGPT-4o on real-world polyneuropathy cases, comparing it to peripheral neuropathy specialists and non-specialist neurologists. One hundred cases were selected from two tertiary centers in Milan, Italy. Standardized summaries included clinical, laboratory, and electrophysiological data. ChatGPT-4o was prompted to provide a leading diagnosis, two differentials, and a confirmatory test. Neurologists reviewed the same cases and generated comparable outputs, then could revise their responses after viewing ChatGPT-4o's suggestions. ChatGPT-4o achieved 65.5% leading diagnosis accuracy, comparable to non-specialists (63.0%) but lower than specialists (74.0%, p = 0.002). For differential diagnoses, it outperformed non-specialists (82.0% vs. 77.5%, p = 0.043) and recommended more appropriate tests (68.0% vs. 53.0%, p < 0.001). After reviewing ChatGPT-4o outputs, non-specialists revised their assessments in 21.8% of cases, improving accuracy. ChatGPT-4o shows potential as a diagnostic aid, particularly in non-specialist or resource-limited settings.

Importance:Inhibition of terminal complement component 5 has proven effective in acetylcholine receptor antibody-positive (AChR-Ab+) generalized myasthenia gravis (gMG) but requires intravenous or daily subcutaneous administration and is associated with an increased meningococcal infection risk. Targeting the complement alternative pathway (AP) may offer similar benefits while sparing the classical and lectin pathways, preserving some immune responses against infection. Objective:To evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of vemircopan, an oral, selective factor D inhibitor that blocks AP-mediated complement activation and amplification, in adults with AChR-Ab+ gMG. Design, Setting, and Participants:This double-blind, parallel-group, placebo-controlled phase 2 randomized clinical trial was conducted between April 14, 2022, and April 3, 2024, at 60 sites across 8 countries. Adults with AChR-Ab+ gMG, Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 5 or greater, and Myasthenia Gravis Foundation of America classes II through IV classification were eligible for inclusion. Data were unblinded in June 2024; final analysis was completed October 2024. Intervention:Randomization 2:1:2 to twice-daily oral vemircopan, 180 mg or 120 mg, or placebo. Main Outcomes and Measures:The primary end point was the proportion of participants achieving a 2-point or greater reduction in MG-ADL total score from baseline for 4 consecutive weeks, without rescue therapy, during the 8-week, double-blind primary evaluation period. Secondary end points were change from baseline to week 8 in MG-ADL total score, Quantitative Myasthenia Gravis total score, and Neurological Disorders Fatigue questionnaire score. Results:Of 99 individuals screened, 70 met eligibility criteria, and 29 were excluded. Of 70 participants randomized (vemircopan, 180 mg: n = 28; vemircopan, 120 mg: n = 14; placebo: n = 28), 38 participants (54%) were female; mean (SD) age at diagnosis was 45.4 (18.5) years. The proportion of participants achieving the primary end point did not differ significantly between placebo (18 of 28 [64%]; 90% CI, 47%-79%) and either vemircopan group (180 mg: 16 of 28 [57%]; 90% CI, 40%-73%; 120 mg: 8 of 14 [57%]; 90% CI, 33%-79%). No significant differences were observed for the secondary end points. No cases of meningococcal infection were reported; 1 participant died due to hepatic failure and 1 discontinued study treatment due to herpes simplex meningitis. Conclusions and Relevance:In this double-blind, parallel-group, placebo-controlled phase 2 randomized clinical trial, vemircopan did not meet the prespecified threshold for efficacy, and consequently, the study was terminated. Trial Registration:ClinicalTrials.gov Identifier: NCT05218096.

BACKGROUND AND AIMS:Hereditary neuropathies are a group of genetically and phenotypically heterogeneous neuropathies. These are classified into: hereditary sensory motor neuropathy (HSMN) aka Charcot-Marie-Tooth disease (CMT), distal motor neuropathy (dMN), hereditary sensory autonomic neuropathy (HSAN), episodic neuropathies and polyneuropathy as part of a complex clinical presentation. The aim of this study was to determine final diagnoses in patients referred from the tertiary center in Serbia under suspicion of hereditary neuropathy. METHODS AND MATERIALS:This research included 340 patients directed for genetic testing from the Neurology Clinic, University Clinical Center of Serbia during the period from 2009 to 2023, who underwent complete genetic analyses available. RESULTS:The most prominent demyelinating neuropathy was group consisted of patients with CMT1A (93 (27.3%)), followed by CMT1B (10 (2.9%)). In the group of patients with axonal form of the disease, the most prevalent was the one with pathogenic variant in HINT1 (18 (5.3%)). Nineteen (5.6%) patients have had variants in GJB1 gene. DMN group was composed of seven (2%) patients. HSAN was final diagnosis in 2 (0.6%) patients. Group of 16 (4.7%) patients have had neuropathy as part of a complex clinical presentation. In 70 (20.6%) patients no significant genetic variant was found, even though clinical presentation was highly suggestive of hereditary neuropathy. INTERPRETATION:In line with other populations, CMT1A was the most common cause of hereditary neuropathy in Serbia. The axonal cohort predominantly included patients with variants in the HINT1 gene, which represents a population-specific characteristic. These findings highlight the importance of targeted genetic analysis in diagnosing hereditary neuropathies in certain populations.

Hereditary transthyretin-mediated (ATTRV; v, variant) amyloidosis is a genetic disorder that causes abnormal accumulation of amyloid deposits in organs and tissues. The most common neurological manifestation is polyneuropathy (PN) of the autonomic nervous system, cardiac involvement and average survival of 6–12 years since onset of symptoms. Recent years have been marked by advancements in diagnosis and management of ATTRv amyloidosis with PN. In Balkan countries, endemic regions for some TTR gene mutations exist, with particularities in patient’s access to care given the different health infrastructure set-up. A panel of multidisciplinary experts from Bulgaria, Croatia, Serbia and Slovenia have gathered to discuss country-specific insights and approaches on the current ATTRv amyloidosis with PN diagnosis and management, sharing challenges and best practices. Each country has instituted various strategies for screening, genetic testing, treatment and follow-up of patients. As an endemic country with an older center of excellence in place, Bulgaria has currently a high rate (95%) of patients with ATTRv amyloidosis with PN diagnosed in the early stages of the disease. Across the other countries, delays in referral to a specialist for diagnosis and initiation of treatment have been noted due to insufficient awareness of the disease among other healthcare professionals, low availability of therapies or issues with reimbursement. Enhancement of interdisciplinary collaboration, clinical awareness and screening programs are the key areas of improvement in the Balkan region.

IntroductionMultifocal motor neuropathy (MMN) is a chronic immune-mediated disorder associated with long-term disability and reduced quality of life (QoL). Longitudinal real-world data on QoL in MMN are scarce, particularly during the COVID-19 era. This study aimed to evaluate long-term changes in QoL and disease outcomes in MMN patients over a 6-year follow-up and to assess the multidimensional impact of the COVID-19 pandemic.MethodsTwelve MMN patients were re-evaluated 6 years after baseline assessment. Functional disability was assessed using the INCAT disability score and I-RODS scale. QoL was measured using the SF-36 questionnaire, while depressive symptoms and fatigue were evaluated using the Beck Depression Inventory (BDI) and Fatigue Severity Scale (FSS). Pandemic-related impact was assessed using a specifically designed questionnaire.ResultsFunctional disability remained overall stable during follow-up (INCAT total score 3.4 ± 2.2 vs. 3.3 ± 1.9). However, fatigue and depressive symptoms increased significantly, with the prevalence of fatigue rising from 17 to 58% and depression from 8 to 25% (p < 0.05). Mean FSS scores increased from 20.1 ± 13.3 to 35.3 ± 15.0, and BDI scores from 3.3 ± 7.8 to 9.2 ± 15.4. Physical QoL domains declined over time, particularly Physical Functioning (76.7 ± 29.9 to 57.5 ± 31.6) and Bodily Pain (82.8 ± 28.9 to 71.7 ± 28.5), while mental domains remained relatively preserved (MCS 69.1 ± 19.5 vs. 69.4 ± 21.3). During the COVID-19 pandemic, 33% of patients developed SARS-CoV-2 infection, 17% experienced treatment interruption, and one patient died from severe COVID-19.ConclusionLong-term immunotherapy in MMN appears to stabilize motor disability but does not prevent the progressive increase of fatigue and depressive symptoms, which emerge as major contributors to long-term disease burden. The COVID-19 pandemic further affected healthcare access and psychosocial wellbeing. These findings support routine screening for fatigue and mental health symptoms and highlight the need for a multidisciplinary approach to MMN management.

BACKGROUND AND AIMS:Restless legs syndrome (RLS) is frequently reported in peripheral neuropathies, but its prevalence and clinical correlates in Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) remain poorly defined. We aimed to determine RLS prevalence in CMT1A and HNPP and to assess associations with disease severity, muscle strength, disability, and quality of life (QoL). METHODS:Forty-seven CMT1A and 18 HNPP patients were included. RLS was diagnosed according to the International Restless Legs Syndrome Study Group criteria, and RLS severity was assessed with the International Restless Legs Syndrome Severity Scale (IRLS-SS). MRC Sum Score (MRC-SS), Charcot-Marie-Tooth Examination Score (CMTES), Overall Neuropathy Limitations Scale (ONLS), Beck Depression Inventory (BDI), Fatigue Severity Scale (FSS), and the 36-Item Short Form Health Survey (SF-36) were recorded. RESULTS:RLS was present in 29.8% of CMT1A and 38.9% of HNPP patients. CMT1A patients with RLS had longer disease duration (p = 0.05), worse muscle strength (p = 0.014), higher disease severity (p = 0.014), higher upper-limb (p = 0.005) and overall disability (p = 0.011), and higher fatigue severity (p = 0.011) compared with those without RLS. HNPP patients with RLS showed higher upper-limb (p = 0.034) and overall disability (p = 0.032), higher depression (p = 0.005), and fatigue severity (p = 0.018) than those without RLS. QoL was significantly impaired in patients with RLS in both groups, and RLS severity negatively correlated with physical and mental QoL domains. INTERPRETATION:RLS is common in CMT1A and HNPP and is associated with increased disease severity, greater functional disability, and reduced QoL. Clinicians should screen for RLS in PMP22-related neuropathies and consider symptomatic management.

Background:This study aimed to adapt the Facioscapulohumeral Muscular Dystrophy - Health Index (FSHD-HI) for Serbian patients with facioscapulohumeral muscular dystrophy (FSHD) in order to measure their disease burden. Patients and method:Forty-one patients with genetically confirmed FSHD1 were included in the study. Validation involved reliability analysis (internal consistency), content validity, construct validity, and criterion validity analyses. The Comprehensive Clinical Evaluation Form (CCEF) was employed to capture various FSHD phenotypes. All patients completed the Serbian version of the Short Form Health Survey (SF-36) questionnaire, serving as a generic measure of the health-related quality of life (QoL). Results:All patients found Serbian version of FSHD-HI (FSHD-HI-RS) understandable and that the language was appropriate and simple. The internal consistency of FSHD-HI-RS was excellent for the whole questionnaire (Cronbach's alpha >0.90). Test-retest reliability met the required level (intraclass correlation coefficient 0.91). FSHD-HI scores showed significant correlations with disease duration (rho = 0.564, p < 0.01), muscle strength measured with Medical Research Council (MRC) sum score (rho = -0.708, p < 0.01), and CCEF (rho = +0.716, p < 0.01). FSHD-HI total score correlated significantly with the total SF-36 score (rho = -0.733, p < 0.01). Conclusion:Our data demonstrate that FSHD-HI-RS is an understandable, reliable, and valid measure of the disease burden in FSHD. It is easy to administer and complete, and it can capture disease-specific features that may be omitted with generic QoL questionnaires.

Biallelic loss-of-function mutations in the sorbitol dehydrogenase (SORD) gene cause the most common recessive type of Charcot-Marie-Tooth disease (CMT), CMT-SORD. However, the full genotype-phenotype spectrum and progression of the disease remain to be defined. Notably, a multicentre phase 2/3 study to test the efficacy of govorestat (NCT05397665), a new aldose reductase inhibitor, is currently ongoing. Diagnosing CMT-SORD will become imperative when disease-modifying therapies become available. In this cross-sectional multicentre study, we identified 144 patients from 126 families, including 99 males (69%) and 45 females (31%). Patients represented multiple ancestries, including European, Hispanic, Chinese, Near Eastern and Northern African. We confirmed c.757delG (p.Ala253GlnfsTer27) as the most common pathogenic allele, followed by c.458C>A (p.Ala153Asp), while other variants were identified, mostly in single cases. The average sorbitol level in CMT-SORD patients was significantly higher compared to controls and heterozygous carriers, independently from serum storage duration, sex or variant type. Two-thirds of cases were diagnosed with CMT2 while one-third had distal hereditary motor neuropathy. Disease onset was usually in the second decade of life. Although foot dorsiflexion was the most affected muscle group, dorsal and plantar flexion had a similar degree of weakness in most cases (difference of Medical Research Council score <= 1). One-fourth of patients used ankle foot orthoses, usually in their 30s, but most patients maintained independent ambulation later in life. Nerve conduction studies were suggestive of a motor predominant axonal neuropathy, with reduced conduction velocities in the intermediate range in a quarter of the cases. Sensory conductions in the upper limbs appeared more frequently affected than in the lower limbs. Foot dorsiflexion and plantar flexion decreased significantly with age. Male sex was significantly associated with the severity of distal lower limb weakness (plantar flexion) and a larger change over time (dorsiflexion). In conclusion, CMT-SORD is a frequent recessive form of axonal, motor predominant CMT, with prominent foot dorsiflexion and plantar flexion involvement. Fasting serum sorbitol is a reliable biomarker of the condition that can be utilized for pathogenicity assessment of identified rare SORD variants.