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Newborn screening for 5qSMA offers the potential for early, ideally pre-symptomatic, therapeutic intervention. However, limited data exist on the outcomes of individuals with 4 copies of SMN2, and there is no consensus within the SMA treatment community regarding early treatment initiation in this subgroup. To provide evidence-based insights into disease progression, we performed a retrospective analysis of 268 patients with 4 copies of SMN2 from the SMArtCARE registry in Germany, Austria and Switzerland. Inclusion criteria required comprehensive baseline data and diagnosis outside of newborn screening. Only data prior to initiation of disease-modifying treatment were included. The median age at disease onset was 3.0 years, with a mean of 6.4 years. Significantly, 55% of patients experienced symptoms before the age of 36 months. 3% never learned to sit unaided, a further 13% never gained the ability to walk independently and 33% of ambulatory patients lost this ability during the course of the disease. 43% developed scoliosis, 6.3% required non-invasive ventilation and 1.1% required tube feeding. In conclusion, our study, in line with previous observations, highlights the substantial phenotypic heterogeneity in SMA. Importantly, this study provides novel insights: the median age of disease onset in patients with 4 SMN2 copies typically occurs before school age, and in half of the patients even before the age of three years. These findings support a proactive approach, particularly early treatment initiation, in this subset of SMA patients diagnosed pre-symptomatically. However, it is important to recognize that the register will not include asymptomatic individuals., (© 2024. The Author(s).)

Background: Given the novelty of gene replacement therapy with onasemnogene abeparvovec in spinal muscular atrophy, efficacy and safety data are limited, especially for children older than 24 months, those weighing more than 8·5 kg, and those who have received nusinersen. We aimed to provide real-world data on motor function and safety after gene replacement therapy in different patient subgroups., Methods: We did a protocol-based, multicentre prospective observational study between Sept 21, 2019, and April 20, 2021, in 18 paediatric neuromuscular centres in Germany and Austria. All children with spinal muscular atrophy types 1 and 2 receiving onasemnogene abeparvovec were included in our cohort, and there were no specific exclusion criteria. Motor function was assessed at the time of gene replacement therapy and 6 months afterwards, using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and Hammersmith Functional Motor Scale-Expanded (HFMSE) scores. Additionally, in children pretreated with nusinersen, motor function was assessed before and after treatment switch. Off-target adverse events were analysed with a focus on liver function, thrombocytopaenia, and potential cardiotoxicity., Findings: 76 children (58 pretreated with nusinersen and 18 who were nusinersen naive) with spinal muscular atrophy were treated with onasemnogene abeparvovec at a mean age of 16·8 months (range 0·8-59·0, IQR 9-23) and a mean weight of 9·1 kg (range 4·0-15·0, IQR 7·4-10·6). In 60 patients with available data, 49 had a significant improvement on the CHOP-INTEND score (≥4 points) and HFMSE score (≥3 points). Mean CHOP INTEND scores increased significantly in the 6 months after therapy in children younger than 8 months (n=16; mean change 13·8 [SD 8·5]; p<0·0001) and children aged between 8 and 24 months (n=34; 7·7 [SD 5·2]; p<0·0001), but not in children older than 24 months (n=6; 2·5 [SD 5·2]; p=1·00). In the 45 children pretreated with nusinersen and had available data, CHOP INTEND score increased by 8·8 points (p=0·0003) at 6 months after gene replacement therapy. No acute complications occurred during infusion of onasemnogene abeparvovec, but 56 (74%) patients had treatment-related side-effects. Serious adverse events occurred in eight (11%) children. Liver enzyme elevation significantly increased with age and weight at treatment. Six (8%) patients developed acute liver dysfunction. Other adverse events included pyrexia (n=47 [62%]), vomiting or loss of appetite (41 [54%]), and thrombocytopenia (n=59 [78%]). Prednisolone treatment was significantly prolonged with a mean duration of 15·7 weeks (IQR 9-19), mainly due to liver enzyme elevation. Cardiac adverse events were rare; only two patients had abnormal echocardiogram and echocardiography findings., Interpretation: This study provides class IV evidence that children with spinal muscular atrophy aged 24 months or younger and patients pretreated with nusinersen significantly benefit from gene replacement therapy, but adverse events can be severe and need to be closely monitored., Funding: None., Translation: For the German translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests No author received financial support for the present manuscript. CW declares consulting fees from Novartis and Biogen (paid personally) and Roche (paid to institution); honoraria from Novartis and Biogen; and travel support from Biogen. AZ declares grants and travel support from Biogen; consulting fees and honoraria from Novartis, Roche, and Biogen; and advisory board participation for Novartis and Roche. JJ declares honoraria for review writing from Biogen; and travel support and personal fees for advisory board participation from Biogen, Roche, Novartis/Avexis, Sarepta Therapeutics, and PTC. GS declares payment for consulting from Novartis. MF-B declares consulting fees from Novartis Gene Therapy, Biogen, and Roche. CS declares training support from Biogen. HH declares support from the SMArtCARE registry (paid to institution) and payment for participation on advisory board from Novartis; and is a board member of the International Child Neurology Association. SI declares support from SMArtCARE (paid to institution) and payments for advisory board participation from Novartis. AP declares financial support from Biogen for the SMArtCARE registry; compensation for training activities from Biogen; and advisory board participation for Novartis Gene Therapy. WM-F declares consulting fees and honoraria from Novartis and Roche; honoraria from Biogen; and advisory board participation for Novartis and Roche. KV declares speaker's honoraria from Biogen and travel fees from Biogen and Santhera. AB declares speaker's honoraria from Biogen and Genzyme; travel support from Merck group; and advisory board participation for Novartis. MS declares payments for lectures from Novartis, Biogen, and Genzyme. BW declares honoraria for lectures, interviews, and workshops from Novartis, Biogen, and Pfizer; travel support for meetings from Novartis and Biogen; and advisory board participation for Novartis and Biogen. BP declares support for advisory board participation from Novartis, Biogen, Roche, Zogenix, and PCT; payment for manuscript writing from Novartis; and payment for workshop from Biogen. GB declares consulting fee from PTC; honoraria for lectures and information events; payment for participation on advisory boards from PTC, Roche, Novartis, Pfizer, and Biogen; and being an unpaid consultant for Wiener Gesundheitsverbund (WiGeV), Austrian Social Insurance, and Austrian Department of Pharmaceutical Affairs. RAF declares consulting fees, payment for lecture, and travel support from Biogen; and payment for advisory board participation from AveXis/Novartis. CR declares consulting fees from Biogen, EISAI, Novartis, PTC, Roche, and UCB; and payment for participation on advisory boards from Biogen, Novartis, and Roche. MvdH declares payment for lecture from Avexis/Novartis, Biogen, and PTC; payment for manuscript writing from Biogen; and advisory board participation for Avexis/Novartis, Biogen, Roche, and Sarepta. AMK declares grants from the German Research Foundation; consulting fees from Covance; payment for lecture from Ethypharm; and advisory board participation from Novartis, GW Pharma, and Ethypharm. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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 challenging, 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.