TRPV4 neuromuscular disease registry highlights bulbar, skeletal and proximal limb manifestations.

Dominant missense mutations of the calcium-permeable cation channel TRPV4 cause Charcot-Marie-Tooth disease (CMT) type 2C and two forms of distal spinal muscular atrophy. These conditions are collectively referred to as TRPV4-related neuromuscular disease and share features of motor greater than sensory dysfunction and frequent vocal fold weakness. Pathogenic variants lead to gain of ion channel function that can be rescued by TRPV4 antagonists in cellular and animal models. As small molecule TRPV4 antagonists have proven safe in trials for other disease indications, channel inhibition is a promising therapeutic strategy for TRPV4 patients. However, the current knowledge of the clinical features and natural history of TRPV4-related neuromuscular disease is insufficient to enable rational clinical trial design. To address these issues, we developed a TRPV4 patient database and administered a TRPV4-specific patient questionnaire. Here, we report demographic and clinical information, including CMT examination scores (CMTES), from 68 patients with known pathogenic TRPV4 variants, 40 of whom also completed the TRPV4 patient questionnaire. TRPV4 patients showed a bimodal age of onset, with the largest peak occurring in the first 2 years of life. Compared to CMT1A patients, TRPV4 patients showed distinct symptoms and signs, manifesting more ambulatory difficulties and more frequent involvement of proximal arm and leg muscles. Although patients reported fewer sensory symptoms, sensory dysfunction was often detected clinically. Many patients were affected by vocal fold weakness (55%) and shortness of breath (55%), and 11% required ventilatory support. Skeletal abnormalities were common, including scoliosis (64%), arthrogryposis (33%), and foot deformities. Strikingly, patients with infantile onset of disease showed less sensory involvement and less progression of symptoms. These results highlight distinctive clinical features in TRPV4 patients, including motor-predominant disease, proximal arm and leg weakness, severe ambulatory difficulties, vocal fold weakness, respiratory dysfunction, and skeletal involvement. In addition, patients with infantile onset of disease appeared to have a distinct phenotype with less apparent disease progression based on CMTES. These collective observations indicate that clinical trial design for TRPV4-related neuromuscular disease should include outcome measures that reliably capture non-length dependent motor dysfunction, vocal fold weakness, and respiratory disease.

Changes in abilities over the initial 12 months of nusinersen treatment for type II SMA.

Several studies have shown the efficacy of new disease-modifying therapies in slowing down type II SMA progression using the Hammersmith Functional Motor Scale Expanded (HFMSE). This research aims to enhance understanding of activity changes across age groups post-nusinersen treatment using shift analysis, compared with untreated individuals. Retrospective data from the, international SMA consortium (iSMAc) dataset were analyzed, assessing individual item changes over 12 months. Shift analysis was used to determine the gain or loss of abilities, defining "gain" as a positive change between scores from 0 to either 1 or 2 and "loss" as a negative change from either 2 or 1 to 0. The cohort included 130 SMA II patients who underwent 12-month assessments from their first nusinersen dose, with age range between 0.6 and 49.6 years. One-third of the entire cohort experienced at least a loss in one activity, while 60% experienced a gain, particularly notable in children aged 2.5 to 5 years and 5 to 13 years. Overall, the study demonstrates a positive impact of nusinersen treatment on SMA II patients, showing a trend of increased activity gains and decreased probability of ability loss across different age groups.

Therapeutic Role of Nusinersen on Respiratory Progression in Pediatric Patients With Spinal Muscular Atrophy Type 2 and Nonambulant Type 3.

Background and Objectives: Nusinersen has shown significant functional motor benefit in the milder types of spinal muscular atrophy (SMA). Less is known on the respiratory outcomes in patients with nusinersen-treated SMA. The aim of this study was to describe changes in respiratory function in pediatric patients with SMA type 2 and 3 on regular treatment with nusinersen within the iSMAc international cohort and to compare their trajectory with the natural history (NH) data published by the consortium in 2020. Methods: This is a 5-year retrospective observational study of pediatric SMA type 2 and nonambulant type 3 (age ≤18 years) treated with nusinersen. The primary objective was to compare the slopes of decline in forced vital capacity % predicted (FVC% pred.), FVC, and age when FVC dropped below 60% between the treated patients and a control group from the natural history cohort. Data on peak cough flow and the use of noninvasive ventilation (NIV) and cough assist were collected. Results: Data were available for 69 treated patients, 53 were SMA type 2 and 16 type 3. The mean (SD) age at first injection was 8.5 (3.2) and 9.7 (3.7) years, respectively. The median (interquartile range) treatment duration was 1 (0.7; 1.9) and 1.2 (0.9; 1.9) years, respectively. At the time of the first nusinersen injection, 24 of 52 (46%) patients with SMA type 2 and 2 of 16 (13%) patients with SMA type 3 were on NIV. Forty-three of 53 (81%) and 4 of 16 (25%) patients used cough device. FVC% pred. in treated patients with SMA type 2 declined annually by 2.3% vs 3.9% in NH (p = 0.08) and in treated patients with type 3 by 2.6% vs 3.4% NH (p = 0.59). Patients treated reached FVC <60% later than untreated (12.1 vs 10 years, p = 0.05). A higher percentage of treated vs untreated patients maintained FVC% pred. equal/above their baseline after 12 (65% vs 36%) and 24 (50% vs 24%) months, respectively. NIV use among treated did not significantly change throughout 1-year follow-up. Discussion: This study included the largest real-world cohort of pediatric patients with milder SMA types. The results suggest a positive role of nusinersen in delaying the respiratory decline in patients treated longer than 1 year when compared with natural history. Larger cohorts and longer observation are planned. Classification of Evidence: This study provided Class III evidence that nusinersen slows progression for patients with SMA types 2 and 3 compared with a natural history cohort.

Beyond Contractures in Spinal Muscular Atrophy: Identifying Lower-Limb Joint Hypermobility.

Background: The natural history of spinal muscular atrophy (SMA) is well understood, with progressive muscle weakness resulting in declines in function. The development of contractures is common and negatively impacts function. Clinically, joint hypermobility (JH) is observed but is poorly described, and its relationship with function is unknown. Methods: Lower-limb ROM (range of motion) assessments of extension and flexion at the hip, knee, and ankle were performed. ROMs exceeding the published norms were included in the analysis. The functional assessments performed included the six-minute walk test (6 MWT) and the Hammersmith Functional Motor Scale-Expanded (HFMSE). Results: Of the 143 participants, 86% (n = 123) had at least one ROM measure that was hypermobile, and 22% (n = 32) had three or more. The HFMSE scores were inversely correlated with hip extension JH (r = -0.60, p = 0.21; n = 6) and positively correlated with knee flexion JH (r = 0.24, p = 0.02, n = 89). There was a moderate, inverse relationship between the 6 MWT distance and ankle plantar flexion JH (r = -0.73, p = 0.002; n = 15). Conclusions: JH was identified in nearly all participants in at least one joint in this study. Hip extension, knee flexion and ankle plantar flexion JH was associated with function. A further understanding of the trajectory of lower-limb joint ROM is needed to improve future rehabilitation strategies.

Determining minimal clinically important differences in the Hammersmith Functional Motor Scale Expanded for untreated spinal muscular atrophy patients: An international study.

BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is a rare and progressive neuromuscular disorder with varying severity levels. The aim of the study was to calculate minimal clinically important difference (MCID), minimal detectable change (MDC), and values for the Hammersmith Functional Motor Scale Expanded (HFMSE) in an untreated international SMA cohort. METHODS: The study employed two distinct methods. MDC was calculated using distribution-based approaches to consider standard error of measurement and effect size change in a population of 321 patients (176 SMA II and 145 SMA III), allowing for stratification based on age and function. MCID was assessed using anchor-based methods (receiver operating characteristic [ROC] curve analysis and standard error) on 76 patients (52 SMA II and 24 SMA III) for whom the 12-month HFMSE could be anchored to a caregiver-reported clinical perception questionnaire. RESULTS: With both approaches, SMA type II and type III patients had different profiles. The MCID, using ROC analysis, identified optimal cutoff points of -2 for type II and -4 for type III patients, whereas using the standard error we found the optimal cutoff points to be 1.5 for improvement and -3.2 for deterioration. Furthermore, distribution-based methods uncovered varying values across age and functional status subgroups within each SMA type. CONCLUSIONS: These results emphasize that the interpretation of a single MCID or MDC value obtained in large cohorts with different functional status needs to be made with caution, especially when these may be used to assess possible responses to new therapies.

Bulbar function in spinal muscular atrophy (SMA): State of art and new challenges. 21st July 2023, Rome, Italy.

Progressive bulbar involvement is frequent in spinal muscular atrophy, with prevalence and severity of deficits associated with type. The report provides an overview of the presentations made at the workshop grouped into 4 sessions: the first section was dedicated to videofluoroscopy with a revision of the existing protocols and discussion on which one should be used in routine clinical practice and in research settings. The second session was dedicated to interprofessional routine assessments of bulbar function, with a review of the recent clinical tools specifically developed for SMA. The third section was focused on the assessments performed by speech and language therapists/pathologists in the new SMA phenotypes. The last section focused on how the new therapies have changed the approach in rehabilitation for bulbar dysfunction. Finally, we present the consensus that was achieved on these aspects and possible action points from these.

Disease Trajectories in the Revised Hammersmith Scale in a Cohort of Untreated Patients with Spinal Muscular Atrophy types 2 and 3.

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterised by progressive motor function decline. Motor function is assessed using several functional outcome measures including the Revised Hammersmith Scale (RHS). Objective: In this study, we present longitudinal trajectories for the RHS in an international cohort of 149 untreated paediatric SMA 2 and 3 patients (across 531 assessments collected between March 2015 and July 2019). Methods: We contextualise these trajectories using both the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). At baseline, this cohort included 50% females and 15% of patients had undergone spinal fusion surgery. Patient trajectories were modelled using a natural cubic spline with age, sex, and random effects for each patient. Results: RHS and HFMSE scores show similar trends over time in this cohort not receiving disease modifying therapies. The results confirm the strong correlation between the RHS and RULM previously observed in SMA types 2 and 3a. Scoliosis surgery is associated with a reduction of 3 points in the RHS, 4.5 points in the HFMSE for the SMA 2 population, and a reduction of 11.8 points in the RHS, and 13.4 points in the HFMSE for the SMA 3a populations. When comparing the RHS and RULM, there is a lower correlation in the type 3a's than the type 2 patients. In the SMA 2 population, there is no significant difference between the sexes in either the RHS or HFMSE trajectories. There is no significant difference in the RULM trajectory in the SMA 2 or 3a participants by sex. Conclusions: This study demonstrates that the RHS could be used in conjunction with other functional measures such as the RULM to holistically detect SMA disease progression. This will assist with fully understanding changes that occur with treatments, further defining trajectories and therapy outcomes.

Draft Guidance for Industry Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Related Dystrophinopathies - Developing Potential Treatments for the Entire Spectrum of Disease.

Background: Duchenne muscular dystrophy (DMD) and related dystrophinopathies are neuromuscular conditions with great unmet medical needs that require the development of effective medical treatments. Objective: To aid sponsors in clinical development of drugs and therapeutic biological products for treating DMD across the disease spectrum by integrating advancements, patient registries, natural history studies, and more into a comprehensive guidance. Methods: This guidance emerged from collaboration between the FDA, the Duchenne community, and industry stakeholders. It entailed a structured approach, involving multiple committees and boards. From its inception in 2014, the guidance underwent revisions incorporating insights from gene therapy studies, cardiac function research, and innovative clinical trial designs. Results: The guidance provides a deeper understanding of DMD and its variants, focusing on patient engagement, diagnostic criteria, natural history, biomarkers, and clinical trials. It underscores patient-focused drug development, the significance of dystrophin as a biomarker, and the pivotal role of magnetic resonance imaging in assessing disease progression. Additionally, the guidance addresses cardiomyopathy's prominence in DMD and the burgeoning field of gene therapy. Conclusions: The updated guidance offers a comprehensive understanding of DMD, emphasizing patient-centric approaches, innovative trial designs, and the importance of biomarkers. The focus on cardiomyopathy and gene therapy signifies the evolving realm of DMD research. It acts as a crucial roadmap for sponsors, potentially leading to improved treatments for DMD.

Efficacy and Safety of Vamorolone Over 48 Weeks in Boys With Duchenne Muscular Dystrophy: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone). METHODS: A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2. RESULTS: A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine [TTSTAND] velocity, week 24 least squares mean [LSM] [SE] 0.052 [0.0130] rises/s vs week 48 LSM [SE] 0.0446 [0.0138]). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM [SE] 0.49 [1.14]; 95% CI -1.80 to 2.78, p = 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups. DISCUSSION: Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03439670. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.

Real-World Outcomes in Patients with Spinal Muscular Atrophy Treated with Onasemnogene Abeparvovec Monotherapy: Findings from the RESTORE Registry.

Background: Long-term, real-world effectiveness and safety data of disease-modifying treatments for spinal muscular atrophy (SMA) are important for assessing outcomes and providing information for a larger number and broader range of SMA patients than included in clinical trials. Objective: We sought to describe patients with SMA treated with onasemnogene abeparvovec monotherapy in the real-world setting. Methods: RESTORE is a prospective, multicenter, multinational, observational registry that captures data from a variety of sources. Results: Recruitment started in September 2018. As of May 23, 2022, data were available for 168 patients treated with onasemnogene abeparvovec monotherapy. Median (IQR) age at initial SMA diagnosis was 1 (0-6) month and at onasemnogene abeparvovec infusion was 3 (1-10) months. Eighty patients (47.6%) had two and 70 (41.7%) had three copies of SMN2, and 98 (58.3%) were identified by newborn screening. Infants identified by newborn screening had a lower age at final assessment (mean age 11.5 months) and greater mean final (SD) CHOP INTEND score (57.0 [10.0] points) compared with clinically diagnosed patients (23.1 months; 52.1 [8.0] points). All patients maintained/achieved motor milestones. 48.5% (n = 81/167) experienced at least one treatment-emergent adverse event (AE), and 31/167 patients (18.6%) experienced at least one serious AE, of which 8/31 were considered treatment-related. Conclusion: These real-world outcomes support findings from the interventional trial program and demonstrate effectiveness of onasemnogene abeparvovec over a large patient population, which was consistent with initial clinical data and published 5-year follow-up data. Observed AEs were consistent with the established safety profile of onasemnogene abeparvovec.

Can the CHOP-INTEND be used as An Outcome Measure in the First Months of Age? Implications for Clinical Trials and Real World Data.

BACKGROUND: The CHOP-INTEND is an established outcome measure used to assess motor function in young and weak SMA patients previously validated in type I infants older than 3 months. OBJECTIVE: The aim of our study was to assess the maturation of the CHOP-INTEND scores in a group of healthy infants, establishing which items of the scale can be reliably used in individuals younger than 3 months. METHODS: This is a prospective observational study. The whole cohort was divided into 5 age groups. Each of the 16 CHOP-INTEND items was analyzed looking at the frequency distribution of the scores in each age subgroup. An item was considered developmentally appropriate when > 85% of the infants achieved a full score. RESULTS: our study includes 61 assessments collected < 2 weeks, 25 at 2-4 weeks, 20 at 5-8 weeks, 25 at 9-12 weeks and 20 at 13-17 weeks. Eight of the 16 items were developmentally appropriate already in the first week and another by the end of the first month. The remaining 7 items had more variable responses in the first three months and full scores were consistently achieved only after the third month. CONCLUSIONS: Our findings suggest that the CHOP-INTEND can be used before the age of 3 months, but the results should be interpreted with caution, considering which items are developmentally appropriate at the time of testing. This will also help to establish whether the changes observed following early treatments are a sign of efficacy or at least partly reflect maturational aspects.

Combination disease-modifying treatment in spinal muscular atrophy: A proposed classification.

We sought to devise a rational, systematic approach for defining/grouping survival motor neuron-targeted disease-modifying treatment (DMT) scenarios. The proposed classification is primarily based on a two-part differentiation: initial DMT, and persistence/discontinuation of subsequent DMT(s). Treatment categories were identified: monotherapy add-on, transient add-on, combination with onasemnogene abeparvovec, bridging to onasemnogene abeparvovec, and switching to onasemnogene abeparvovec. We validated this approach by applying the classification to the 443 patients currently in the RESTORE registry and explored the demographics of these different groups of patients. This work forms the basis to explore the safety and efficacy profile of the different combinations of DMT in SMA.

Nusinersen Treatment of Children with Later-Onset Spinal Muscular Atrophy and Scoliosis Is Associated with Improvements or Stabilization of Motor Function.

Nusinersen has been shown to improve or stabilize motor function in individuals with spinal muscular atrophy (SMA). We evaluated baseline scoliosis severity and motor function in nusinersen-treated non-ambulatory children with later-onset SMA. Post hoc analyses were conducted on 95 children initiating nusinersen treatment in the CHERISH study or SHINE long-term extension trial. Participants were categorized by baseline Cobb angle (first nusinersen dose): ≤10°, >10° to ≤20°, and >20° to <40° (no/mild/moderate scoliosis, respectively). Outcome measures included the Hammersmith Functional Motor Score-Expanded (HFMSE) and the Revised Upper Limb Module (RULM). Regression analysis determined the relationships between baseline scoliosis severity and later motor function. For children with no, mild, and moderate scoliosis, the mean increase in HFMSE from baseline to Day 930 was 6.0, 3.9, and 0.7 points, and in RULM was 6.1, 4.6, and 2.3 points. In the linear model, a 10° increase in baseline Cobb angle was significantly associated with a -1.4 (95% CI -2.6, -0.2) point decrease in HFMSE (p = 0.02) and a -1.2 (95% CI -2.1, -0.4) point decrease in RULM (p = 0.006) at Day 930. Treatment with nusinersen was associated with improvements/stabilization in motor function in all groups, with greater response in those with no/mild scoliosis at baseline.

Continued benefit of nusinersen initiated in the presymptomatic stage of spinal muscular atrophy: 5-year update of the NURTURE study.

INTRODUCTION/AIMS: NURTURE (NCT02386553) is an open-label study of nusinersen in children (two SMN2 copies, n = 15; three SMN2 copies, n = 10) who initiated treatment in the presymptomatic stage of spinal muscular atrophy (SMA). A prior analysis after ~3 y showed benefits on survival, respiratory outcomes, motor milestone achievement, and a favorable safety profile. An additional 2 y of follow-up (data cut: February 15, 2021) are reported. METHODS: The primary endpoint is time to death or respiratory intervention (≥6 h/day continuously for ≥7 days or tracheostomy). Secondary outcomes include overall survival, motor function, and safety. RESULTS: Median age of children was 4.9 (3.8-5.5) y at last visit. No children have discontinued the study or treatment. All were alive. No additional children utilized respiratory intervention (defined per primary endpoint) since the prior data cut. Children with three SMN2 copies achieved all World Health Organization (WHO) motor milestones, with all but one milestone in one child within normal developmental timeframes. All 15 children with two SMN2 copies achieved sitting without support, 14/15 walking with assistance, and 13/15 walking alone. Mean Hammersmith Functional Motor Scale Expanded total scores showed continued improvement. Subgroups with two SMN2 copies, minimum baseline compound muscle action potential amplitude ≥2 mV, and no baseline areflexia had better motor and nonmotor outcomes versus all children with two SMN2 copies. DISCUSSION: These results demonstrate the value of early treatment, durability of treatment effect, and favorable safety profile after ~5 y of nusinersen treatment. Inclusion/exclusion criteria and baseline characteristics should be considered when interpreting presymptomatic SMA trial data.

DEVOTE Study Exploring Higher Dose of Nusinersen in Spinal Muscular Atrophy: Study Design and Part A Results.

BACKGROUND: Pharmacokinetic/pharmacodynamic modeling indicates that the higher dose of nusinersen may be associated with a clinically meaningful increase in efficacy above that seen with the 12-mg approved dose. OBJECTIVE: Here we describe both the design of DEVOTE (NCT04089566), a 3-part clinical study evaluating safety, tolerability, and efficacy of higher dose of nusinersen, and results from the initial Part A. METHODS: DEVOTE Part A evaluates safety and tolerability of a higher nusinersen dose; Part B assesses efficacy in a randomized, double-blind design; and Part C assesses safety and tolerability of participants transitioning from the 12-mg dose to higher doses. RESULTS: In the completed Part A of DEVOTE, all 6 enrolled participants aged 6.1-12.6 years have completed the study. Four participants experienced treatment-emergent adverse events (TEAEs), the majority of which were mild. Common TEAEs of headache, pain, chills, vomiting, and paresthesia were considered related to the lumbar puncture procedure. There were no safety concerns regarding clinical or laboratory parameters. Nusinersen levels in the cerebrospinal fluid were within the range of modeled predictions for higher dose of nusinersen. While Part A was not designed for assessing efficacy, most participants showed stabilization or improvement in motor function. Parts B and C of DEVOTE are ongoing. CONCLUSIONS: The findings from Part A of the DEVOTE study support further development of higher dose of nusinersen.

Association of Body Mass Index With Disease Progression in Children With Charcot-Marie-Tooth Disease.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the impact of body mass index (BMI) on disease progression over 2 years in children with Charcot-Marie-Tooth disease (CMT). METHODS: BMI was classified in 242 participants aged 3-20 years with CMT enrolled in the Inherited Neuropathy Consortium, using the International Obesity Task Force (based on adult BMI values, kg/m2) criteria. Groups were categorized as severely underweight (BMI <17 kg/m2), underweight (BMI ≥17 to <18.5 kg/m2), healthy weight (BMI ≥18.5 to <25 kg/m2), overweight (BMI ≥25 to <30 kg/m2), and obese (BMI ≥30 kg/m2). Disease severity was assessed using the CMT Pediatric Scale (CMTPedS), a clinical outcome assessment of disability (0-44 points, mild to severe). RESULTS: At baseline, compared with individuals being of a healthy weight (mean CMTPedS 15.48, SD 9.22), children who were severely underweight (mean CMTPedS difference 9.03, 95% CI 0.94-17.12; p = 0.02), underweight (mean CMTPedS difference 5.97, 95% CI 0.62-11.31; p = 0.02), or obese (mean CMTPedS difference 7.96, 95% CI 1.03-14.88; p = 0.015) exhibited greater disability. At 2 years, compared with individuals being of a healthy weight (mean CMTPedS 17.53, SD 9.41), children who were severely underweight exhibited greater disability (mean CMTPedS difference 9.27, 95% CI 0.90-17.64; p = 0.02). Over the 2-year periods, the mean CMTPedS for the whole sample deteriorated by 1.72 points (95% CI 1.09-2.38; p < 0.001), with severely underweight children progressing at the fastest rate (mean CMTPedS change of 2.3, 95% CI 1.53-6.13; p = 0.21). In children who did not have a change in BMI categories over 2 years (69% of sample), CMTPedS scores deteriorated faster in those who were severely underweight (mean CMTPedS change 6.40 points, 95% CI 2.42-10.38; p = 0.01) than those of healthy weight (mean CMTPedS change 1.79 points, 95% CI 0.93-2.69; p < 0.001). For children who changed BMI categories (31% of sample), CMTPedS scores deteriorated faster in children who became overweight/obese (mean CMTPedS change 2.76 points, 95% CI 0.11-5.41; p = 0.031). DISCUSSION: Children with CMT who were severely underweight, underweight, or obese exhibited greater disability at baseline. Over the 2-year period in those whose BMI remained stable, severely underweight children deteriorated at the fastest rate. For children who changed BMI categories over the 2 years, CMTPedS scores deteriorated faster in children who became overweight/obese. Interventions that maintain or improve BMI toward healthy weight may reduce disability in children with CMT.

Genetic analysis and natural history of Charcot-Marie-Tooth disease CMTX1 due to GJB1 variants.

Charcot-Marie-Tooth disease (CMT) due to GJB1 variants (CMTX1) is the second most common form of CMT. It is an X-linked disorder characterized by progressive sensory and motor neuropathy with males affected more severely than females. Many reported GJB1 variants remain classified as variants of uncertain significance (VUS). In this large, international, multicentre study we prospectively collected demographic, clinical and genetic data on patients with CMT associated with GJB1 variants. Pathogenicity for each variant was defined using adapted American College of Medical Genetics criteria. Baseline and longitudinal analyses were conducted to study genotype-phenotype correlations, to calculate longitudinal change using the CMT Examination Score (CMTES), to compare males versus females, and pathogenic/likely pathogenic (P/LP) variants versus VUS. We present 387 patients from 295 families harbouring 154 variants in GJB1. Of these, 319 patients (82.4%) were deemed to have P/LP variants, 65 had VUS (16.8%) and three benign variants (0.8%; excluded from analysis); an increased proportion of patients with P/LP variants compared with using ClinVar's classification (74.6%). Male patients (166/319, 52.0%, P/LP only) were more severely affected at baseline. Baseline measures in patients with P/LP variants and VUS showed no significant differences, and regression analysis suggested the disease groups were near identical at baseline. Genotype-phenotype analysis suggested c.-17G>A produces the most severe phenotype of the five most common variants, and missense variants in the intracellular domain are less severe than other domains. Progression of disease was seen with increasing CMTES over time up to 8 years follow-up. Standard response mean (SRM), a measure of outcome responsiveness, peaked at 3 years with moderate responsiveness [change in CMTES (ΔCMTES) = 1.3 ± 2.6, P = 0.00016, SRM = 0.50]. Males and females progressed similarly up to 8 years, but baseline regression analysis suggested that over a longer period, females progress more slowly. Progression was most pronounced for mild phenotypes (CMTES = 0-7; 3-year ΔCMTES = 2.3 ± 2.5, P = 0.001, SRM = 0.90). Enhanced variant interpretation has yielded an increased proportion of GJB1 variants classified as P/LP and will aid future variant interpretation in this gene. Baseline and longitudinal analysis of this large cohort of CMTX1 patients describes the natural history of the disease including the rate of progression; CMTES showed moderate responsiveness for the whole group at 3 years and higher responsiveness for the mild group at 3, 4 and 5 years. These results have implications for patient selection for upcoming clinical trials.

Onasemnogene abeparvovec in spinal muscular atrophy: predictors of efficacy and safety in naïve patients with spinal muscular atrophy and following switch from other therapies.

Background: Efficacy and safety of onasemnogene abeparvovec (OA) for Spinal Muscular Atrophy infants under 7 months and <8.5 kg has been reported in clinical trials. This study examines efficacy and safety predictors in a wide age (22 days-72 months) and weight (3.2-17 kg) range, also including patients previously treated with other drugs. Methods: 46 patients were treated for 12 months between January 2020 and March 2022. Safety profile was also available for another 21 patients with at least 6 month follow-up after OA infusion. 19/67 were treatment naïve when treated with OA. Motor function was measured with the CHOP-INTEND. Findings: CHOP-INTEND changes varied among age groups. Baseline score and age at OA treatment best predicted changes. A mixed model post-hoc analysis showed that in patients treated before the age of 24 months the CHOP-INTEND changes were already significant 3 months after OA while in those treated after the age of 24 months the difference was only significant 12 months after OA. Adverse events occurred in 51/67. The risk for elevated transaminases serum levels was higher in older patients. This was also true for weight and for pre-treatment with nusinersen when analysed individually. A binomial negative regression analysis showed that only age at OA treatment had a significant effect on the risk of elevated transaminases. Interpretation: Our paper describes OA 12-month follow-up showing efficacy across various age and weight groups not targeted by clinical trials. The study identifies prognostic factors for safety and efficacy in treatment selection. Funding: None.

Development of an International SMA Bulbar Assessment for Inter-professional Administration.

BACKGROUND: Progressive weakness can affect bulbar muscles in individuals with moderate to severe forms of spinal muscular atrophy (SMA). The paucity of standardized, valid bulbar assessments capturing clinically significant deficits in SMA impedes the ability to monitor function, facilitate intervention, or detect treatment response. OBJECTIVE: To fill this void, an international multidisciplinary team gathered to develop an agreed upon consensus-derived assessment of bulbar function in SMA for inter-professional administration to enhance our ability to monitor disease progression, support clinical management, and evaluate treatment effects. METHODS: Fifty-six international clinicians experienced in SMA were invited and engaged using the Delphi method over multiple rounds of web-based surveys to establish consensus. RESULTS: Serial virtual meetings occurred with 42 clinicians (21 speech and language therapists, 11 physical therapists, 5 neurologists, 4 occupational therapists, and 1 dentist). Seventy-two validated assessments of bulbar function were identified for potential relevance to individuals with SMA (32 accessible objective, 11 inaccessible objective, 29 patient-reported outcomes). Delphi survey rounds (n = 11, 15, 15) achieved consensus on individual items with relevance and wording discussed. Key aspects of bulbar function identified included: oral intake status, oral facial structure and motor strength, swallowing physiology, voice & speech, and fatigability. CONCLUSIONS: Multidisciplinary clinicians with expertise in bulbar function and SMA used Delphi methodology to reach consensus on assessments/items considered relevant for SMA across all age groups. Future steps include piloting the new scale moving towards validation/reliability. This work supports the advancement of assessing bulbar function in children and adults with SMA by a variety of professionals.

Validation of the parent-proxy version of the pediatric Charcot-Marie-Tooth disease quality of life instrument for children aged 0-7 years.

OBJECTIVE: To evaluate the parent-proxy version of the pediatric Charcot Marie Tooth specific quality of life (pCMT-QOL) outcome instrument for children aged 7 or younger with CMT. We have previously developed and validated the direct-report pCMT-QOL for children aged 8-18 years and a parent proxy version of the instrument for children 8-18 years old. There is currently no CMT-QOL outcome measure for children aged 0-7 years old. METHODS: Testing was conducted in parents or caregivers of children aged 0-7 years old with CMT evaluated at participating INC sites from the USA, United Kingdom, and Australia. The development of the instrument was iterative, involving identification of relevant domains, item pool generation, prospective pilot testing and clinical assessments, structured focus group interviews, and psychometric testing. The parent-proxy instrument was validated rigorously by examining previously identified domains and undergoing psychometric tests for children aged 0-7. RESULTS: The parent-proxy pCMT-QOL working versions were administered to 128 parents/caregivers of children aged 0-7 years old between 2010 and 2016. The resulting data underwent rigorous psychometric analysis, including factor analysis, internal consistency, and convergent validity, and longitudinal analysis to develop the final parent-proxy version of the pCMT-QOL outcome measure for children aged 0-7 years old. CONCLUSIONS: The parent-proxy version of the pCMT-QOL outcome measure, known as the pCMT-QOL (0-7 years parent-proxy) is a valid and sensitive proxy measure of health-related QOL for children aged 0-7 years with CMT.