Niemann-Pick disease type C is a rare lysosomal storage disorder. We evaluated the safety and efficacy of N-acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann-Pick disease type C. In this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann-Pick disease type C in a 1:1 ratio to receive NALL for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day. The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status). Secondary end points included scores on the Clinical Global Impression of Improvement, the Spinocerebellar Ataxia Functional Index, and the Modified Disability Rating Scale. Crossover data from the two 12-week periods in each group were included in the comparisons of NALL with placebo. A total of 60 patients 5 to 67 years of age were enrolled. The mean baseline SARA total scores used in the primary analysis were 15.88 before receipt of the first dose of NALL (60 patients) and 15.68 before receipt of the first dose of placebo (59 patients; 1 patient never received placebo). The mean (±SD) change from baseline in the SARA total score was -1.97±2.43 points after 12 weeks of receiving NALL and -0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, -1.28 points; 95% confidence interval, -1.91 to -0.65; P<0.001). The results for the secondary end points were generally supportive of the findings in the primary analysis, but these were not adjusted for multiple comparisons. The incidence of adverse events was similar with NALL and placebo, and no treatment-related serious adverse events occurred. Among patients with Niemann-Pick disease type C, treatment with NALL for 12 weeks led to better neurologic status than placebo. A longer period is needed to determine the long-term effects of this agent in patients with Niemann-Pick disease type C. (Funded by IntraBio; ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.).

Evidence for the efficacy of nusinersen in adults with 5q-associated spinal muscular atrophy (SMA) has been demonstrated up to a period of 16 months in relatively large cohorts but whereas patients reach a plateau over time is still to be demonstrated. We investigated the efficacy and safety of nusinersen in adults with SMA over 38 months, the longest time period to date in a large cohort of patients from multiple clinical sites. Our prospective, observational study included adult patients with SMA from Germany, Switzerland, and Austria (July 2017 to May 2022). All participants had genetically-confirmed, 5q-associated SMA and were treated with nusinersen according to the label. The total Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores, and 6-min walk test (6 MWT; metres), were recorded at baseline and 14, 26, and 38 months after treatment initiation, and pre and post values were compared. Adverse events were also recorded. Overall, 389 patients were screened for eligibility and 237 were included. There were significant increases in all outcome measures compared with baseline, including mean HFMSE scores at 14 months (mean difference 1.72 [95% CI 1.19–2.25]), 26 months (1.20 [95% CI 0.48–1.91]), and 38 months (1.52 [95% CI 0.74–2.30]); mean RULM scores at 14 months (mean difference 0.75 [95% CI 0.43–1.07]), 26 months (mean difference 0.65 [95% CI 0.27–1.03]), and 38 months (mean difference 0.72 [95% CI 0.25–1.18]), and 6 MWT at 14 months (mean difference 30.86 m [95% CI 18.34–43.38]), 26 months (mean difference 29.26 m [95% CI 14.87–43.65]), and 38 months (mean difference 32.20 m [95% CI 10.32–54.09]). No new safety signals were identified. Our prospective, observational, long-term (38 months) data provides further real-world evidence for the continuous efficacy and safety of nusinersen in a large proportion of adult patients with SMA. Financial support for the registry from 10.13039/100005614 Biogen , 10.13039/100004336 Novartis and 10.13039/100004337 Roche .

Background and Objective: GM2 gangliosidoses (Tay-Sachs and Sandhoff diseases) are rare, autosomal-recessive, neurodegenerative diseases with no available symptomatic or disease modifying treatments. This clinical trial investigated N-acetyl-L-leucine (NALL), an orally administered, modified amino acid in pediatric (≥ 6 years) and adult patients with GM2 gangliosidoses. Methods: In this Phase IIb, multi-national, open-label, rater-blinded study (IB1001-202), male and female patients aged ≥6 years with a genetically confirmed diagnosis of GM2 gangliosidoses received orally-administered NALL for a 6-week treatment period (4 g/day in patients ≥13 years, weight-tiered doses for patients 6-12 years), followed by a 6-week post-treatment washout period. For the primary Clinical Impression of Change in Severity analysis, patient performance on a pre-determined primary anchor test (the 8-Meter Walk Test or the 9-Hole Peg Test) at baseline, after 6 weeks on NALL, and again after a 6-week washout period, was videoed and evaluated centrally by blinded raters. Secondary outcomes included assessments of ataxia, clinical global impression, and quality of life. Results: 30 patients between the age of 6 and 55 were enrolled. 29 had an on-treatment assessment and were included in the primary modified intention-to-treat analysis. The study met its CI-CS primary endpoint (mean difference 0.71, SD=2.09, 90% CI 0.00, 1.50, p=0.039), as well as secondary measures of ataxia and global impression. NALL was safe and well-tolerated, with no serious adverse reactions. Conclusions: Treatment with NALL was associated with statistically significant and clinically-relevant changes in functioning and quality of life in patients with GM2 gangliosidosis. NALL was safe and well-tolerated, contributing to an overall favourable risk: benefit profile. NALL is a promising, easily administered (oral) therapeutic option for these rare, debilitating diseases with immense unmet medical needs. Classification of Evidence: This study provides Class IV evidence that NALL improves outcomes for patients with GM2 gangliosidoses. Trial Registration Information: The trial is registered with ClinicalTrials.gov (NCT03759665; registered 30-Nov-2018), EudraCT (2018-004406-25), and DRKS (DRKS00017539). The first patient was enrolled 07-June-2019.

Aim: To assess the diagnostic performance of body mass index (BMI) cut‐off values according to recommendations of the World Health Organization (WHO), the World Obesity Federation (WOF), and the German Society for Adiposity (DAG) to identify excess body fat in children with cerebral palsy (CP).Method: The present study was a monocentric retrospective analysis of prospectively collected data among children and adolescents with CP participating in a rehabilitation programme. Excess body fat was defined as a body fat percentage above the 85th centile assessed by dual‐energy X‐ray absorptiometry.Results: In total, 329 children (181 males, 148 females) with CP were eligible for analysis. The mean age was 12 years 4 months (standard deviation 2y 9mo). The BMI cut‐off values for ‘overweight’ according to the WHO, WOF, and DAG showed the following sensitivities and specificities for the prediction of excess body fat in our population: WHO: sensitivity 0.768 (95% confidence interval [CI] 0.636–0.870), specificity 0.894 (95% CI 0.851–0.928); WOF: sensitivity 0.696 (95% CI 0.559–0.812), specificity 0.934 (95% CI 0.898–0.960); DAG: sensitivity 0.411 (95% CI 0.281–0.550), specificity 0.993 (95% CI 0.974–0.999).Interpretation: Body mass index showed high specificity, but low sensitivity in children with CP. Thus, ‘normal‐weight obese’ children with CP were overlooked, when assessing excess body fat only using BMI.What this paper adds: Excess body fat in children with cerebral palsy (CP) is less common than previously reported. Body mass index (BMI) had high specificity but low sensitivity in detecting excess body fat in children with CP. BMI evaluation criteria of the German Society for Adiposity could be improved in children with CP.