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.

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 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/).

Background Spinal muscular atrophy (SMA) is a rare neuromuscular disorder leading to early death in the majority of affected individuals without treatment. Recently, targeted treatment approaches including Onasemnogene Abeparvovec (OA) were introduced. This study describes the first real-world experience with OA in Switzerland. Methods Prospective observational case series study using data collected within the Swiss Registry for Neuromuscular Disorders from SMA patients treated with OA. Development of motor, bulbar and respiratory function, appearance of scoliosis, and safety data (platelet count, liver function, and cardiotoxicity) were analyzed. Results Nine individuals were treated with OA and followed for 383 ± 126 days: six SMA type 1 (of which two with nusinersen pretreatment), one SMA type 2, and two pre-symptomatic individuals. In SMA type 1, CHOP Intend score increased by 28.1 from a mean score of 20.5 ± 7.6 at baseline. At end of follow-up, 50% of SMA type 1 patients required nutritional support and 17% night-time ventilation; 67% developed scoliosis. The SMA type 2 patient and two pre-symptomatically treated individuals reached maximum CHOP Intend scores. No patient required adaptation of the concomitant prednisolone treatment, although transient decrease of platelet count and increase of transaminases were observed in all patients. Troponin-T was elevated prior to OA treatment in 100% and showed fluctuations in 57% thereafter. Conclusions OA is a potent treatment for SMA leading to significant motor function improvements. However, the need for respiratory and especially nutritional support as well as the development of scoliosis must be thoroughly evaluated in SMA type 1 patients even in the short term after OA treatment.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder causing progressive proximal muscular, respiratory, and bulbar weakness. We present outcome data on motor function, ventilation, nutrition, and language development of SMA patients treated with nusinersen in Switzerland. This multicenter, observational study included 44 patients. At treatment initiation, after 2 months and then every 4 months we assessed motor function with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), Hammersmith Functional Motor Scale expanded (HFMSE) and 6-Minute Walk Test (6MWT). At treatment initiation, patients were 0.1-44.6 years old, treatment duration ranged from 6 to 41 months. All 11 SMA type 1 children achieved higher CHOP-INTEND scores at the last assessment compared to treatment initiation, 4 acquired stable sitting. Six type 1 children were <18 months-old at treatment initiation. Two of them did not need ventilation or nutritional support at the last assessment; three had delayed language development and 3 articulation difficulties. 5/21 SMA type 2 patients achieved higher HFMSE scores. All ambulant type 3 patients showed a gain in the 6MWT. Nusinersen is an effective treatment, with gains in motor function occurring particularly in children and SMA type 1, but also in type 2 and 3, adolescents and adults. (c) 2022 The Authors. Published by Elsevier B.V.

The natural history of patients with spinal muscular atrophy (SMA) has changed due to advances in standard care and development of targeted treatments. Nusinersen was the first drug approved for the treatment of all SMA patients. The transfer of clinical trial data into a real-life environment is c hallenging, especially regarding the advice of patients and families to what extent they can expect a benefit from the novel treatment. We report the results of a modified Delphi consensus process among child neurologists from Germany, Austria and Switzerland about the indication or continuation of nusinersen treatment in children with SMA type 1 based on different clinical case scenarios.

BACKGROUND In Switzerland, complementary medicine (CM) is officially recognised within the healthcare system and mainly practised in an integrative manner, in conjunction with conventional medicine. As in other countries, there is high demand for and use of CM with children. However, there has so far been no research into the attitude towards, training in and offer of CM among paediatricians in Switzerland. Our study addresses this gap by investigating these topics with an online survey of paediatricians in Switzerland. METHODS We conducted a national online survey using a 19-item, self-reporting questionnaire among all ordinary and junior members of the Swiss Society of Paediatrics (SSP). A comparison of the study sample with the population of all paediatricians registered with the Swiss Medical Association (FMH) allowed an assessment of the survey’s representativeness. The data analysis was performed on the overall group level as well as for predefined subgroups (e.g. sex, age, language, workplace and professional experience). RESULTS 1890 paediatricians were approached and 640, from all parts of Switzerland, responded to the survey (response rate 34%). Two thirds of respondents were female, were aged between 35 and 55 years, trained as paediatric generalist and worked in a practice. Apart from young paediatricians in training, the study sample was representative of all Swiss paediatricians. 23% had attended training in CM, most frequently in phytotherapy, homeopathy, acupuncture/traditional Chinese medicine (TCM) and anthroposophic medicine. 65% were interested in CM courses and training. 16% provide CM services to their patients and almost all paediatricians (97%) are asked by patients/parents about CM therapies. More than half of the responding paediatricians use CM for themselves or their families. 42% were willing to contribute to paediatric CM research. CONCLUSIONS In a representative sample of paediatricians in Switzerland, their personal attitude towards CM is positive, emphasised by great interest in CM training, a willingness to contribute to CM research and a high rate of paediatricians who use CM for themselves and their families. In contrast, the percentage of paediatricians offering CM is currently rather low despite strong demand for CM for children. This study provides key pointers for the future development of complementary and integrative medicine for children in Switzerland.

Background: Recognizing neuromuscular disease in newborns, infants, and toddlers is even for the experienced neuropediatrician a challenging task. Many neuromuscular diseases in the beginning present only with very minor symptoms; other cases are quite severe, that is, generalized muscular hypotonia requiring mechanical ventilation and making a proper clinical assessment difficult. However, early treatment of neuromuscular conditions can alter the prognosis significantly. Therefore, precise diagnosis is important.

Congenital myasthenic syndromes result from defects in the neuromuscular junction. Using whole exome sequencing, O'Connor et al. identify mutations in a novel candidate gene, MYO9A, which encodes an unconventional myosin. They provide preliminary evidence that MYO9A contributes to formation of the neuromuscular junction via effects on the presynaptic motor axon.Congenital myasthenic syndromes result from defects in the neuromuscular junction. Using whole exome sequencing, O'Connor et al. identify mutations in a novel candidate gene, MYO9A, which encodes an unconventional myosin. They provide preliminary evidence that MYO9A contributes to formation of the neuromuscular junction via effects on the presynaptic motor axon.Congenital myasthenic syndromes are a group of rare and genetically heterogenous disorders resulting from defects in the structure and function of the neuromuscular junction. Patients with congenital myasthenic syndrome exhibit fatigable muscle weakness with a variety of accompanying phenotypes depending on the protein affected. A cohort of patients with a clinical diagnosis of congenital myasthenic syndrome that lacked a genetic diagnosis underwent whole exome sequencing in order to identify genetic causation. Missense biallelic mutations in the MYO9A gene, encoding an unconventional myosin, were identified in two unrelated families. Depletion of MYO9A in NSC-34 cells revealed a direct effect of MYO9A on neuronal branching and axon guidance. Morpholino-mediated knockdown of the two MYO9A orthologues in zebrafish, myo9aa/ab, demonstrated a requirement for MYO9A in the formation of the neuromuscular junction during development. The morphants displayed shortened and abnormally branched motor axons, lack of movement within the chorion and abnormal swimming in response to tactile stimulation. We therefore conclude that MYO9A deficiency may affect the presynaptic motor axon, manifesting in congenital myasthenic syndrome. These results highlight the involvement of unconventional myosins in motor axon functionality, as well as the need to look outside traditional neuromuscular junction-specific proteins for further congenital myasthenic syndrome candidate genes.

Rosenbaum PL, Ronen GM, Dan B, Johannesen J, Racine E, eds. Ethics in Child Health: Principles and Cases in Neurodisability. London, UK: Mac Keith Press; 2016 (397 pages), ISBN: 978–1-909962–63–7 Hardcover £ 39.95, € 50.00

OBJECTIVE:Short-chain enoyl-CoA hydratase (ECHS1) is a multifunctional mitochondrial matrix enzyme that is involved in the oxidation of fatty acids and essential amino acids such as valine. Here, we describe the broad phenotypic spectrum and pathobiochemistry of individuals with autosomal-recessive ECHS1 deficiency.METHODS:Using exome sequencing, we identified ten unrelated individuals carrying compound heterozygous or homozygous mutations in ECHS1. Functional investigations in patient-derived fibroblast cell lines included immunoblotting, enzyme activity measurement, and a palmitate loading assay.RESULTS:Patients showed a heterogeneous phenotype with disease onset in the first year of life and course ranging from neonatal death to survival into adulthood. The most prominent clinical features were encephalopathy (10/10), deafness (9/9), epilepsy (6/9), optic atrophy (6/10), and cardiomyopathy (4/10). Serum lactate was elevated and brain magnetic resonance imaging showed white matter changes or a Leigh-like pattern resembling disorders of mitochondrial energy metabolism. Analysis of patients' fibroblast cell lines (6/10) provided further evidence for the pathogenicity of the respective mutations by showing reduced ECHS1 protein levels and reduced 2-enoyl-CoA hydratase activity. While serum acylcarnitine profiles were largely normal, in vitro palmitate loading of patient fibroblasts revealed increased butyrylcarnitine, unmasking the functional defect in mitochondrial β-oxidation of short-chain fatty acids. Urinary excretion of 2-methyl-2,3-dihydroxybutyrate - a potential derivative of acryloyl-CoA in the valine catabolic pathway - was significantly increased, indicating impaired valine oxidation.INTERPRETATION:In conclusion, we define the phenotypic spectrum of a new syndrome caused by ECHS1 deficiency. We speculate that both the β-oxidation defect and the block in l-valine metabolism, with accumulation of toxic methacrylyl-CoA and acryloyl-CoA, contribute to the disorder that may be amenable to metabolic treatment approaches.

Objective:To determine whether patients with pyridoxine-responsive seizures but normal biomarkers for antiquitin deficiency and normal sequencing of the ALDH7A1 gene may have PNPO mutations.Methods:We sequenced the PNPO gene in 31 patients who fulfilled the above-mentioned criteria.Results:We were able to identify 11 patients carrying 3 novel mutations of the PNPO gene. In 6 families, a homozygous missense mutation p.Arg225His in exon 7 was identified, while 1 family was compound heterozygous for a novel missense mutation p.Arg141Cys in exon 5 and a deletion c.279_290del in exon 3. Pathogenicity of the respective mutations was proven by absence in 100 control alleles and expression studies in CHO-K1 cell lines. The response to pyridoxine was prompt in 4, delayed in 2, on EEG only in 2, and initially absent in another 2 patients. Two unrelated patients homozygous for the p.Arg225His mutation experienced status epilepticus when switched to pyridoxal 5-phosphate (PLP).Conclusions:This study challenges the paradigm of exclusive PLP responsiveness in patients with pyridoxal 5-phosphate oxidase deficiency and underlines the importance of consecutive testing of pyridoxine and PLP in neonates with antiepileptic drug-resistant seizures. Patients with pyridoxine response but normal biomarkers for antiquitin deficiency should undergo PNPO mutation analysis.

We describe a 3.5-year-old female with Alpers disease with a POLG genotype of p.A467T/p.G848S and with a lethal outcome. Laboratory investigation revealed elevated CSF neopterin, IL-6, IL-8, IFN-gamma, reduced CSF 5-methyltetrahydrofolate (5MTHF), and increased serum as well as CSF folate receptor blocking autoantibodies. Treatment with oral Leucovorine (5-formyl-tetrahydrofolate) was initiated at 0.25mg/kg bid, and later increased to 4mg/kg bid. Under treatment CSF levels of 5MTHF, seizure frequency and communicative abilities improved. Over a time span of 17months, CSF levels of IL-6 and IFN-gamma decreased, levels of folate receptor blocking autoantibodies continued to raise, whereas CSF IL-8 remained elevated 1500-fold above normal. The child died without apparent stress at the age of 5.5years. Alpers disease, a neurodegenerative disease usually presents in the first years of life as a progressive encephalopathy with multifocal myoclonic seizures, developmental regression, cortical blindness and early death. The underlying genetic defect has been attributed to mutations of the catalytic subunit of the mitochondrial DNA polymerase-gamma leading to an organ-specific mitochondrial DNA depletion syndrome with reduced activity of respiratory chain enzyme complexes in the brain and the liver. A curative therapy is not available. This case report of Alpers disease provides new insights into the pathophysiology of Alpers disease, where mitochondrial dysfunction in conjunction with inflammatory cytokines and blocking folate receptor autoantibodies may lead to a secondary cerebral folate deficiency syndrome. The treatment of the latter provides relief to the patient without stopping the underlying disease.