ObjectiveCharcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy and usually manifests in the first two decades of life. However, prospective data on the natural course during childhood remain scarce.MethodsThis two-year, prospective, observational cohort study was conducted at two German pediatric neuromuscular centers. Annual standardized clinical assessments were performed. Sixty-eight pediatric patients with CMT (age range: 4-18 years; 35 females) were included. The primary outcome was the CMTPedS score, assessed at baseline and after a mean interval of 2.03 ± 0.23 years. Changes in the 11 individual CMTPedS subitems were also analyzed.ResultsThe mean baseline CMTPedS score for the total cohort (n=68) was 20.5 ± 8.8. Stratified by genotype, mean scores were: CMT1A (n=31), 16.5 ± 7.6; CMT1B (n=6), 21.5 ± 9.4; CMT2A (n=4), 35.8 ± 10.0; CMT4C (n=4), 27.0 ± 3.7; CMTX (n=4), 24.3 ± 10.1); others (n=13), 24.6 ± 7.7; genetically unsolved (n=6), 19.8 ± 8.6. Over a two-year observation period, the mean change in CMTPedS was 0.0 ± 2.7, indicating overall no significant progression.ConclusionIn this well-characterized cohort, overall disease course was non-progressive over two years-most notably in CMT1A, the most prevalent subtype. CMT2A and CMT1B showed numerically greater changes, yet none reached statistical significance. These results emphasize the slow-progressive nature of pediatric CMT and highlight the limitations of using short-term clinical progression as an outcome measure in therapeutic trials.

ObjectivePLOD1-related kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is a rare autosomal recessive connective tissue disorder characterized by generalized joint laxity, severe congenital hypotonia, progressive kyphoscoliosis, hyperextensible and easily bruised skin, ocular abnormalities, and significant vascular complications.MethodsWe report on nine patients from seven families, eight of them carrying the common homozygous duplication of exons 10-16 in PLOD1. Longitudinal clinical assessments included muscle ultrasound (n=6) and vascular ultrasound (n=4). Genetic diagnostics varied, with most patients ultimately undergoing trio exome or genome sequencing. Urine pyridinoline analysis was performed in seven of nine patients. A literature review and age-stratified recalculation of vascular incidence, including our cohort, were conducted.ResultsDiagnosis was challenging in five families, as the exon 10-16 duplication often escaped detection due to its high allele frequency. Seven patients were initially diagnosed with congenital myopathy. Muscle ultrasound revealed abnormalities in five of six sonographically examined cases. Severe vascular events included neonatal intracranial hemorrhage, fatal aortic aneurysm rupture at the age of 13 years, multiple aneurysms/dissections (ages 14-19 years), and mesenteric dissection at the age of 10 years. Four younger patients (aged 3-9 years have had no vascular complications to date. Urine pyridinoline analysis was abnormal in all tested cases.DiscussionPLOD1-related kEDS often presents with a phenotype of congenital myopathy, complicating genetic diagnosis and potentially leading to underdiagnosis - especially in cases where the common PLOD1 duplication may be missed by strict frequency filters in exome or genome sequencing data. Literature and our data indicate a vascular event incidence from childhood age of ∼25%.

The epidemiology of suspected pediatric meningoencephalitis has shifted in the era of conjugate vaccines and multiplex PCR diagnostics, with viral pathogens now predominating over bacterial causes. Updated epidemiologic data are essential to adapt diagnostic and therapeutic algorithms to current clinical practice. This retrospective single-center study included children and adolescents <18 years who underwent lumbar puncture with cerebrospinal fluid multiplex PCR for suspected central nervous system infection at a tertiary-care pediatric hospital in Germany between 2016 and 2024. Clinical, laboratory, and outcome data were extracted from electronic medical records. Cerebrospinal fluid was analyzed using the BioFire® FilmArray® Meningitis/Encephalitis Panel. Statistical analyses included descriptive statistics, nonparametric group comparisons, receiver operating characteristic analyses. Among 1,198 included children, definite bacterial meningitis was diagnosed in 13 (1.1%), definite viral meningitis in 80 (6.7%), aseptic meningitis of unknown etiology in 131 (11.0%), confirmed/probable encephalitis in 53 (4.4%), and possible encephalitis in 34 (2.8%). Bacterial meningitis accounted for 5.8% of all meningitis cases. A causative pathogen was identified in all bacterial meningitis cases, most commonly Streptococcus pneumoniae (n = 7). Enterovirus (n = 52) and parechovirus (n = 9) predominated in viral meningitis, whereas an infectious etiology was identified in only 13 of 53 confirmed/probable encephalitis cases. The Bacterial Meningitis Score showed a sensitivity of 80.0% and a specificity of 57.6%. The recently published UK-ChiMES-pre- and post-lumbar puncture scores demonstrated sensitivities of 84.6% and 76.9% and specificities of 86.3% and 92.7%, respectively. Bacterial meningitis was rare in this contemporary cohort, while viral and etiologically unresolved infections predominated despite routine multiplex PCR diagnostics. Clinical prediction scores supported risk stratification, with the UK-ChiMES-pre–lumbar puncture score showing the most favorable balance between sensitivity and specificity and potential to guide diagnostic decisions and antiinfective therapy.

The epidemiology of suspected pediatric meningoencephalitis has changed in the era of conjugate vaccines and multiplex PCR. Updated epidemiologic data are needed to adapt diagnostic and therapeutic algorithms to current practice. This retrospective single-center study included children < 18 years who underwent lumbar puncture with cerebrospinal fluid multiplex PCR for suspected central nervous system infection at a tertiary pediatric hospital in Germany between 2016 and 2024. Clinical, laboratory, and outcome data were extracted from electronic medical records. Cerebrospinal fluid was analyzed using the BioFire® FilmArray® Meningitis/Encephalitis Panel. Statistical analyses included descriptive statistics, nonparametric comparisons, and receiver operating characteristic analyses. Among 1,198 children, definite bacterial meningitis was diagnosed in 13 (1.1

OBJECTIVE:In this study we investigated whether children with epilepsy (CWE) and behavioral problems score lower in health-related quality of life (HRQoL) measures compared to CWE with no behavioral problems. METHODS:We recruited 151 patients aged 3-17 years with epilepsy. Behavior was evaluated using the Child behavior checklist [1]. HRQoL of life was measured using the German version of KINDL questionnaire comprising both child report (from age of 3 ongoing) and parent report. The means and difference of means of KINDL scores [2] of the two groups were compared. RESULTS:151 pediatric patients with epilepsy and their parents or caregivers were included. 37% of children of the cohort had CBCL scores indicating behavioral problems. CWE with behavioral problems experienced reduced total HRQoL scores according to their parents and caregivers (difference mean ± sd, Z-score, adjusted p-value: 11,5 ± 1,6; -6,085; <0,001). This was also true, though to a lesser extent, for self-reports. CBCL subcategories revealed that CWE with 'internal behavioral problems' experience reduced total HRLQoL-scores according to self-reports and parent-reports. CWE with 'external behavioral problems' experience reduced total HRLQoL-scores only according to the parents' reports. SIGNIFICANCE:CWE with behavioral problems score lower in HRQOL-parameters of daily life. This study underlines the importance of evaluation of behavioral problems in CWE.

BACKGROUND:Systematic protocols for long-term surveillance of children with spinal muscular atrophy treated with onasemnogene abeparvovec are lacking. Together with best practice recommendations for safety monitoring and management, such recommendations should increase patient safety and confidence levels of healthcare providers. OBJECTIVE:Based on systematic literature review and evidence grading from part 1, this initiative aims to develop a structured treatment plan applicable across all treatment centers in Germany, Austria and Switzerland. Additionally, it seeks to establish consensus recommendations for the clinical management of safety alerts. METHODS:Part 2 describes the methodology used to formulate Delphi consensus statements, the development of a structured treatment plan for OA treatment, and the anonymous consensus voting process with standardized follow-up in case of disagreement. RESULTS:A total of 12 consensus statements were developed, addressing diagnostic work-up, safety evaluation, and best practice management of common adverse drug reactions associated with OA gene therapy. All statements achieved >95% consensus in the anonymous Delphi voting. Additionally, two consensus recommendations for handling of positive newborn screening result achieved consensus of 97% and 87%, respectively. A structured treatment plan for gene therapy was consented with 100% agreement, as were standardized recommendations for laboratory testing and a consensus-based algorithm for management of liver transaminase elevations. CONCLUSIONS:Delphi-based expert recommendations, developed in co-creation with patient representatives, provide a framework to minimize complications associated with gene therapy and establish the basis for standardized post-marketing data collections. The methodology used in this Delphi-consensus-group can serve as a blueprint for future gene therapy approvals.

An increasing number of adults with spinal muscular atrophy (SMA) wish to become parents. New disease-modifying therapies (DMT) have improved health outcomes and are expected to reduce disability in adults with SMA, but their current label prevents their use in pregnancy. While there is some information on pregnancy outcomes in the pre-DMT era, little has been published recently, and no ubiquitously accepted guidelines exist. Nonetheless, it is crucial to provide knowledgeable and open counselling, ideally in the context of treatments. Counseling for both adolescent and adult patients should include the subject of 'reproductive choices' when discussing the selection of DMTs for those considering parenthood. A multi-disciplinary team, including gynecologists and neurologists with expertise in neuromuscular disorders must closely monitor pregnant patients with SMA, preferably within disease registries, to detect potential complications early and ensure optimal treatment options are available. Real-world data in so far three patients with SMA showed a beneficial pregnancy outcome with nusinersen. It is anticipated that forthcoming real-world data will finally clarify the safety of administering Nusinersen during pregnancy, particularly in relation to child health and for preserving muscle function and preventing motor deterioration in the affected mother.

What is this summary about? This summary describes the results of a research study (clinical trial) called ASPIRO that was published in the Lancet Neurology in 2023. This study looked at an investigational gene therapy called resamirigene bilparvovec (also known as AT132) as a possible treatment for children with a disease called X-linked myotubular myopathy (abbreviated as XLMTM).

Adult reports of unexpected severe disease worsening, often termed "rebound," shortly after discontinuing fingolimod in a subset of patients with multiple sclerosis (MS), have grown over the last decade. This phenomenon, however, remains poorly described in pediatric MS patients. We present findings of a 15-year-old who experienced a debilitating relapse 4 weeks after stopping fingolimod to switch to ocrelizumab. Imaging revealed multiple large new lesions far exceeding any previously observed activity level in the patient. Despite prompt high-dose corticosteroids, plasma exchange, and prolonged rehabilitation therapy, significant residual deficits involving cognition, balance, and vision remain from the attack. This case underscores that pediatric MS patients are also at risk of severe disease deterioration after fingolimod withdrawal and require close monitoring when switching therapies.

Background Since the approval of onasemnogen abeparvovec (OA) for gene addition therapy in children with spinal muscular atrophy (SMA), there has been a considerable increase of evidence regarding its effectiveness and safety. Consequently, the previous recommendations needed to be revised. Objective The primary objective was to develop an evidence- and expert-based best practice protocol ensuring optimal patient safety and comprehensive support for affected families. The harmonization of treatment algorithms is expected to facilitate the collection of standardized real-world data, laying the foundation for future evidence-based adjustments. Methods A modified, two-part Delphi process was selected as a standardized methodology. Experts specializing in SMA from all 31 neuromuscular treatment centers within Germany, Austria and Switzerland, and patient advocacy groups participated in an industry-independent Delphi panel. Existing evidence concerning effectiveness, safety, and guidelines of OA was analyzed in a systematic literature followed by development of consensus statements regarding its effectiveness. Results Strong consensus was reached regarding the following statements on effectiveness: (1) OA gene addition therapy for SMA demonstrates a clear advantage compared to the natural progression of the disease. (2) Superiority of any of the three approved disease-modifying therapies has not been proven. (3) Earlier initiation of therapy with fewer symptoms and shorter disease duration leads to better outcomes. (4) There is no clinical evidence supporting the superiority of combining two treatments over monotherapy. Conclusions: The systematic literature analysis constitutes the basis for the subsequent part 2, which involves the generation of expert-based recommendations for the surveillance of SMA gene addition therapy.

Background Early onset pediatric multiple sclerosis (EOPMS) provides an early window of opportunity to understand the mechanisms leading to MS. Objective To investigate clinical, laboratory and imaging differences between children with early onset pediatric MS (<11 years, EOPMS) and late onset pediatric MS (≥11 years, LOPMS). Methods Mostly prospectively collected data of children with MS including clinical presentation, MRI at onset, time to second relapse, relapse rate, treatment history, and CSF markers were eligible. Results In total 274 children were included, n = 53 children with EOPMS and n = 221 children with LOPMS. In children with EOPMS both sexes were equally affected, while in LOPMS the female sex was more prevalent (p < 0.001). Presence of additional oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF) was comparable in both age groups (92.3 % vs 89.5 %). Children with EOPMS had more relapses in the first 2 years (p = 0.004). Children with LOPMS had significantly more spinal lesions (p = 0.001). Presence of a prior EBV infection tested in a subset of children with EOPMS (n = 34) was only detected in 27/34 (79 %). Conclusion Our findings suggest that both groups share important similarities but also important differences such as an increased relapse rate and a higher amount of infratentorial lesions in EOPMS. Furthermore, our results allude to a prior EBV-infection possibly not being an indispensable requirement for the development of MS in children with EOPMS.

BACKGROUND:Data regarding treatment in pediatric relapsing MOGAD are limited. OBJECTIVE:To evaluate response of intravenous immunoglobulin (IVIG) compared to other therapies in relapsing pediatric MOGAD. METHODS:In this retrospective multicenter study, children with MOGAD were recruited from different medical centers. Inclusion criteria encompassed: age <18 years, MOGAD diagnosis, relapsing disease course, >6 months of maintenance treatment and >12 months follow-up. RESULTS:Seventy children with relapsing MOGAD were stratified into two groups. The first group received IVIG alone (n = 23), IVIG preceded by (n = 16) or in combination with other immunomodulating therapies (IMT) (n = 7). The second group received mycophenolate mofetil, azathioprine, rituximab, or other IMTs (n = 24). 13 % (6/46) of patients with IVIG relapsed in the first year, compared to 33 % (8/24) in the IMT group (relative risk 0.70, 95 % CI 0.53 to 0.99, p = 0.061). Annual relapse rate (ARR) was decreased under therapy compared to pre-treatment in both groups (IVIG: p < 0.001; other IMTs: p = 0.006). ARR was lower in the IVIG group (p = 0.040) in addition to a reduced risk of an early relapse compared to the other IMT group (hazard ratio 0.36, 95 % CI 0.15 to 0.87, p = 0.023). CONCLUSION:Our study supports monthly IVIG as maintenance therapy in children after the second MOGAD episode.

Objective: Numerous studies have consistently found that reduced SMN protein expression does not severely affect cognitive function in SMA patients. However, the average intelligence quotient of SMA patients has ranged above to below average in different studies. The cognitive development of SMA patients identified through newborn screening remains largely unknown. Methods: 40 of 47 eligible SMA patients (23 females/17 males) from 39 families identified through newborn screening between January 2018 and December 2020 underwent developmental testing using Bayley III (BSID) after the 2 years of age. The mean age was 29.25 months (23–42 months). 17 patients had 2, 11 patients had 3 and 12 patients had ≥4 copies of SMN2. Results: cognitive scale: mean 94.55 (SD 24.01); language scale: mean 86.09 (SD 26.41); motor scale: 81.28 (SD 28.07). Overall, the cognitive scales show that 14 children were below average, 20 children were average and 6 children were above average. 10/14 children with below average scores had 2 SMN2 copies. The post-hoc pairwise comparisons showed that the cognition main scale was significantly more sensitive to the number of SMN2 copies than the motor main scale of the BSID (MΔ= 10.27, p = 0.014). There is also evidence that cognition scored higher than the language main scale (MΔ= 7.11, p = 0.090). Conclusion: The impaired cognitive development of SMA children with 2 SMN2 copies, despite early initiation of therapy, underscores the critical role of the SMN protein in the early stages of brain development.

Background and purpose: Rituximab (RTX) is frequently used off-label in multiple sclerosis. However, studies on the risk-benefit profile of RTX in pediatric-onset multiple sclerosis are scarce. Methods: In this multicenter retrospective cohort study, patients with pediatric-onset multiple sclerosis from Sweden, Austria and Germany, who received RTX treatment were identified by chart review. Annualized relapse rates, Expanded Disability Status Scale scores and magnetic resonance imaging parameters (new T2 lesions and contrast-enhancing lesions) were assessed before and during RTX treatment. The proportion of patients who remained free from clinical and disease activity (NEDA-3) during RTX treatment was calculated. Side effects such as infusion-related reactions, infections and laboratory abnormalities were assessed. Results: Sixty-one patients received RTX during a median (interquartile range) follow-up period of 20.9 (35.6) months. The annualized relapse rate decreased from 0.6 (95% confidence interval [CI] 0.38-0.92) to 0.03 (95% CI 0.02-0.14). The annual rate of new T2 lesions decreased from 1.25 (95% CI 0.70-2.48) to 0.08 (95% CI 0.03-0.25) and annual rates of new contrast-enhancing lesions decreased from 0.86 (95% CI 0.30-3.96) to 0. Overall, 70% of patients displayed no evidence of disease activity (NEDA-3). Adverse events were observed in 67% of patients. Six patients discontinued treatment due to ongoing disease activity or adverse events. Conclusion: Our study provides class IV evidence that RTX reduces clinical and radiological activity in pediatric-onset multiple sclerosis.

BACKGROUND:X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital muscle disease caused by mutations in the MTM1 gene that result in profound muscle weakness, significant respiratory insufficiency, and high infant mortality. There is no approved disease-modifying therapy for XLMTM. Resamirigene bilparvovec (AT132; rAAV8-Des-hMTM1) is an investigational adeno-associated virus (AAV8)-mediated gene replacement therapy designed to deliver MTM1 to skeletal muscle cells and achieve long-term correction of XLMTM-related muscle pathology. The clinical trial ASPIRO (NCT03199469) investigating resamirigene bilparvovec in XLMTM is currently paused while the risk:benefit balance associated with this gene therapy is further investigated.METHODS:Muscle biopsies were taken before treatment and 24 and 48 weeks after treatment from ten boys with XLMTM in a clinical trial of resamirigene bilparvovec (ASPIRO; NCT03199469). Comprehensive histopathological analysis was performed.FINDINGS:Baseline biopsies uniformly showed findings characteristic of XLMTM, including small myofibres, increased internal or central nucleation, and central aggregates of organelles. Biopsies taken at 24 weeks post-treatment showed marked improvement of organelle localisation, without apparent increases in myofibre size in most participants. Biopsies taken at 48 weeks, however, did show statistically significant increases in myofibre size in all nine biopsies evaluated at this timepoint. Histopathological endpoints that did not demonstrate statistically significant changes with treatment included the degree of internal/central nucleation, numbers of triad structures, fibre type distributions, and numbers of satellite cells. Limited (predominantly mild) treatment-associated inflammatory changes were seen in biopsy specimens from five participants.INTERPRETATION:Muscle biopsies from individuals with XLMTM treated with resamirigene bilparvovec display statistically significant improvement in organelle localisation and myofibre size during a period of substantial improvements in muscle strength and respiratory function. This study identifies valuable histological endpoints for tracking treatment-related gains with resamirigene bilparvovec, as well as endpoints that did not show strong correlation with clinical improvement in this human study.FUNDING:Astellas Gene Therapies (formerly Audentes Therapeutics, Inc.).

This study explores the potential of 1H-NMR spectroscopy-based metabolic profiling in various biofluids as a diagnostic and predictive modality to assess disease severity in individuals with 5q spinal muscular atrophy. A total of 213 biosamples (urine, plasma, and CSF) from 153 treatment-naïve patients with SMA across five German centers were analyzed using 1H-NMR spectroscopy. Prediction models were developed using machine learning algorithms which enabled the patients with SMA to be grouped according to disease severity. A quantitative enrichment analysis was employed to identify metabolic pathways associated with disease progression. The results demonstrate high sensitivity (84–91%) and specificity (91–94%) in distinguishing treatment-naïve patients with SMA from controls across all biofluids. The urinary and plasma profiles differentiated between early-onset (type I) and later-onset (type II/III) SMA with over 80% accuracy. Key metabolic differences involved alterations in energy and amino acid metabolism. This study suggests that 1H-NMR spectroscopy based metabolic profiling may be a promising, non-invasive tool to identify patients with SMA and for severity stratification, potentially complementing current diagnostic and prognostic strategies in SMA management.

Background Real-world data on gene addition therapy (GAT) with onasemnogene abeparvovec (OA), including all age groups and with or without symptoms of the disease before treatment are needed to provide families with evidence- based advice and realistic therapeutic goals. Aim of this study is therefore a population-based analysis of all patients with SMA treated with OA across Germany, Austria and Switzerland (D-A-CH). Methods This observational study included individuals with Spinal Muscular Atrophy (SMA) treated with OA in 29 specialized neuromuscular centers in the D-A-CH-region. A standardized data set including WHO gross motor milestones, SMA validated motor assessments, need for nutritional and respiratory support, and adverse events was collected using the SMArtCARE registry and the Swiss-Reg-NMD. Outcome data were analyzed using a prespecified fi ed statistical analysis plan including potential predictors such as age at GAT, SMN2 copy number, past treatment, and symptom status. Findings 343 individuals with SMA (46% male, 54% female) with a mean age at OA of 14.0 months (range 0-90, - 90, IQR 20.0 months) were included in the analysis. 79 (23%) patients were clinically presymptomatic at the time of treatment. 172 (50%) patients received SMN2 splice-modifying drugs prior to GAT (risdiplam: n = 16, nusinersen: n = 154, both: n = 2). Functional motor improvement correlated with lower age at GAT, with the best motor outcome in those younger than 6 weeks, carrying 3 SMN2 copies, and being clinically presymptomatic at time of treatment. The likelihood of requiring ventilation or nutritional support showed a significantly fi cantly increase with older age at the time of GAT and remained stable thereafter. Pre-treatment had no effect on disease trajectories. Liver- related adverse events occurred significantly fi cantly less frequently up to 8 months of age. All other adverse events showed an even distribution across all age and weight groups. Interpretation Overall, motor, respiratory, and nutritional outcome were dependent on timing of GAT and initial symptom status. It was best in presymptomatic children treated within the fi rst six weeks of life, but functional motor scores also increased significantly fi cantly after treatment in all age groups up to 24 months. Additionally, OA was best tolerated when administered at a young age. Our study therefore highlights the need for SMA newborn screening and immediate treatment to achieve the best possible benefit fi t-risk ratio. Funding The SMArtCARE and Swiss-Reg-NMD registries are funded by different sources (see acknowledgements). Copyright (c) 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).