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This article presents long-term data on the efficacy of gene replacement therapy (GRT) for spinal muscular atrophy (SMA) using onasemnogene abeparvovec (OA). The study includes patients who were older, heavier, or more severely affected than those in previous clinical trials, as well as a large cohort of presymptomatic SMA patients identified through newborn screening. The results show that younger patients treated with OA had better motor function outcomes compared to those treated at a later age. The study provides valuable evidence for future treatment decisions, particularly for patients with limited trial data available. [Extracted from the article]

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 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, 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 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 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 first six weeks of life, but functional motor scores also increased significantly 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-risk ratio., Funding: The SMArtCARE and Swiss-Reg-NMD registries are funded by different sources (see acknowledgements)., Competing Interests: No author received financial support for the present manuscript. CW received honoraria for presentations and/or travel support from Novartis, Roche and Biogen and participated on advisory boards for Novartis, Roche and Biogen. JF received honoraria from Novartis for presentations. AB received honoraria for presentations from Roche and Pfizer and attend advisory boards for Roche and Pfizer. SI received honoraria for presentations and advisory board meetings from Novartis and Roche. OS received honoraria from Biogen, support for attending meetings from Novartis and participated on an advisory board for Novartis. GB received honoraria for advisory boards and/or presentations from Novartis, Roche and Biogen and support for attending meetings from Novartis. MvdH received grants from Deutsche Gesellschaft für Muskelkranke and Innovationsfond (INTEGRATE ATMP and KoCoN), honoraria from Pfizer, Biogen and PTC Therapeutics, and participated on advisory boards for Roche, Sarepta, Novartis, and Pfizer. RAH received consulting fees from Biogen and honoraria for presentations from Novartis, and participated on advisory boards by Novartis and Roche. KG participated on an industry symposium and an advisory board by Novartis. JK received funding for clinical research from Biogen, Novartis, Roche, ScholarRock and Biohaven, consulting fees from Biogen, Novartis and Roche, payment for educational activities from Biogen, Novartis and Roche and attended a data safety monitoring board for Biogen. AP received research funding form Roche, Novartis and Biogen. MFB received consulting fees for advisory boards from Roche, Novartis and Biogen and payment for presentations from Novartis and Biogen. GS received honoraria for a case report and participated on an advisory board for Novartis. US received honoraria for presentations from Biogen, Novartis and Roche and support for attending meetings from Roche and Novartis. BP received honoraria for a presentation from Biogen and participated on advisory boards for Novartis and Biogen. RT received honoraria for presentations from Desitin, PTC and Roche and participated on advisory boards for PTC, Roche and Santhera. VH attended an adivisory board for Biogen. MB received compensation for advisory boards and speakers honoraria from Novartis, Biogen and Roche and compensation for travel costs to meetings from Roche. AK is clinical lead of the Swiss Reg NMD, attended advisory board meetings of Novartis and received honorarium for a presentation by Novartis. AE received honoraria and payment for expert testimony from Biogen, Roche and Novartis, support for attending meetings from Biogen and Roche and participated on an advisory board for Biogen, Roche and Novartis. GMS participated on advisory boards from Biogen, Novartis and Roche and is member of the steering board for Swiss-Reg-NMD. SC received payment for a presentation. JJ received compensation for advisory boards and funding for travel or speaker honoraria from Avexis/Novartis, Biogen, IFT, Roche, PTC, Pfizer and Sarepta Therapeutics. AZ received compensation for advisory boards and funding for travel or speaker honoraria from Avexis/Novartis, Biogen, ITF, Roche, Pfizer and Sarepta Therapeutics. LLB, AH, EW, CK, OH, and SFG indicated no potential conflicts of interest to disclose., (© 2024 The Author(s).)

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).)

Numerous contiguous gene deletion syndromes causing neurodevelopmental disorders have previously been defined using cytogenetics for which only in the current genomic era the disease-causing genes have become elucidated. One such example is deletion at Xq22.2, previously associated with a neurodevelopmental disorder which has more recently been found to be caused by de novo loss-of-function variants in TCEAL1. So far, a single study reported six unrelated individuals with this monogenetic disorder, presenting with syndromic features including developmental delay especially affecting expressive speech, intellectual disability, autistic-like behaviors, hypotonia, gait abnormalities and mild facial dysmorphism, in addition to ocular, gastrointestinal, and immunologic abnormalities. Here we report on four previously undescribed individuals, including two adults, with de novo truncating variants in TCEAL1, identified through trio exome or genome sequencing, further delineating the phenotype of the TCEAL1-related disorder. Whereas overall we identify similar features compared to the original report, we also highlight features in our adult individuals including hyperphagia, obesity, and endocrine abnormalities including hyperinsulinemia, hyperandrogenemia, and polycystic ovarian syndrome. X chromosome inactivation and RNA-seq studies further provide functional insights in the molecular mechanisms. Together this report expands the phenotypic and molecular spectrum of the TCEAL1-related disorder which will be useful for counseling of newly identified individuals and their families., (© 2024. The Author(s).)

Background and Objectives: To report on prevalence, associated impairments, severity, and neuroimaging findings in children with ataxic cerebral palsy (CP)., Methods: In children coded as having ataxic CP in the Central database of Joint Research Center-Surveillance of Cerebral Palsy in Europe (JRC-SCPE) and born during 1980-2010, birth characteristics, severity profiles including associated impairments, neuroimaging patterns, and the presence of syndromes were analyzed. Definitions were according to validated SCPE guidelines. Prevalence over time was estimated using Poisson regression., Results: In total, 679 children with ataxic CP were identified in 20 European CP registers. The proportion with ataxic CP was 3.8% and varied from 0% to 12.9%. Prevalence over time showed no significant trend. Approximately 70% of children with ataxic CP were able to walk, and 40% had severe intellectual impairment and a high impairment index. Children with ataxic CP were mostly born at term (79%) and with normal birth weight (77%). Neuroimaging patterns revealed normal findings in 29%, brain maldevelopments in 28.5%, miscellaneous findings in 23.5%, and brain injuries in 19%, according to the SCPE classification. Genetic syndromes were described in 9%., Discussion: This register-based multicenter study on children with ataxic CP provides a large sample size for the analysis of prevalence, severity, and origin of this rare CP subtype. Even with strict inclusion and classification criteria, there is variation between registers on how to deal with this subtype, and diagnosis of ataxic CP remains a challenge. Ataxic cerebral palsy differs from other CP subtypes: children with ataxic CP have a disability profile that is more pronounced in terms of cognitive than gross motor dysfunction. They are mostly term born and the origin rarely suggests acquired injuries. In addition to neuroimaging, a comprehensive genetic workup is particularly recommended for children with this CP type.

Background: Spinal muscular atrophy (SMA) is a genetic neurodegenerative disease leading to muscular weakness and premature death. Three therapeutic options are currently available including gene replacement therapy (GRT), which is potentially cardiotoxic. High-sensitive cardiac troponin I (hs-cTnI) is widely used to monitor potential cardiac contraindications or side effects of GRT, but reference data in healthy newborns are limited and lacking in neonates with SMA. The aim of this study is to determine the range of pre-therapeutic hs-cTnI concentrations in neonates with SMA and to provide guidance for the assessment of these values., Methods: Hs-cTnI levels, genetic and clinical data of 30 newborns (age range 2-26 days) with SMA were retrospectively collected from 6 German neuromuscular centers. In addition, hs-cTnI levels were measured in 16 neonates without SMA., Results: The median hs-cTnI concentration in neonates with SMA was 39.5 ng/L (range: 4-1205). In 16 newborns with SMA, hs-cTnI levels were above the test-specific upper reference limit (URL). Exploratory statistical analysis revealed no relevant correlation between hs-cTnI levels and gender, gestational age, mode of delivery, SMN2 copy number, symptoms of SMA or abnormal cardiac findings., Discussion: Our results suggest higher hs-cTnI plasma levels in newborns with and without SMA compared to assay-specific reference values generated in adults. Given the wide range of hs-cTnI values in neonates with SMA, hs-cTnI levels must be determined before treatment in each patient and post-treatment elevations should be interpreted in the context of the course rather than as individual values., Competing Interests: JJ received compensation for advisory boards and funding for travel or speaker honoraria from Avex-is/Novartis, Biogen, Roche, PTC, Pfizer and Sarepta Therapeutics. DW received compensation for advi-sory boards and speaker honoraria from Roche. RT received compensation for advisory boards and speaker honoraria from Biogen, Roche, PTC, Desitin, Eisai. HK is serving on a scientific advisory board for Avexis and received travel expenses and speaker honoraria from Biogen, Pfizer, Roche and Sanofi-Aventis. US received compensation for Adboard meetings from Novartis / Avexis, Biogen and Roche and invited talks and industry symposia from Novartis / Avexis, Biogen and Roche. JK received compensation for advisory boards, training activities and research grants from Biogen, Novartis, Pfizer, PTC and Roche. AP received compensation for advisory boards, training activities and research grants from Novartis and Biogen. AB received compensation for advisory boards and funding for travel or speaker honoraria from Avexis/Novartis, Roche. VH received compensation for advisory boards and workshops from Avexis/Novartis and Biogen. JDe received speaker honoraria from Biogen and Roche. JDR, JO, FS, FM and MS have no declarations of interests. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Johannsen, Weiss, Driemeyer, Olfe, Stute, Müller, Schütt, Trollmann, Kölbel, Schara-Schmidt, Kirschner, Pechmann, Blaschek, Horber and Denecke.)

5q-associated spinal muscular atrophy is a rare neuromuscular disorder with the leading symptom of a proximal muscle weakness. Three different drugs have been approved by the European Medicines Agency and Food and Drug Administration for the treatment of spinal muscular atrophy patients, however, long-term experience is still scarce. In contrast to clinical trial data with restricted patient populations and short observation periods, we report here real-world evidence on a broad spectrum of patients with early-onset spinal muscular atrophy treated with nusinersen focusing on effects regarding motor milestones, and respiratory and bulbar insufficiency during the first years of treatment. Within the SMArtCARE registry, all patients under treatment with nusinersen who never had the ability to sit independently before the start of treatment were identified for data analysis. The primary outcome of this analysis was the change in motor function evaluated with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders and motor milestones considering World Health Organization criteria. Further, we evaluated data on the need for ventilator support and tube feeding, and mortality. In total, 143 patients with early-onset spinal muscular atrophy were included in the data analysis with a follow-up period of up to 38 months. We observed major improvements in motor function evaluated with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders. Improvements were greater in children >2 years of age at start of treatment than in older children. 24.5% of children gained the ability to sit independently. Major improvements were observed during the first 14 months of treatment. The need for intermittent ventilator support and tube feeding increased despite treatment with nusinersen. Our findings confirm the increasing real-world evidence that treatment with nusinersen has a dramatic influence on disease progression and survival in patients with early-onset spinal muscular atrophy. Major improvements in motor function are seen in children younger than 2 years at the start of treatment. Bulbar and respiratory function needs to be closely monitored, as these functions do not improve equivalent to motor function., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Now that targeted therapies for spinal muscular atrophy are available, attempts are being made worldwide to include screening for spinal muscular atrophy in general newborn screening. In Germany, after pilot projects from 2018-2021, it was included in the general newborn screening from October 2021. To ensure a smooth transition, criteria for follow-up were developed together with key stakeholders. At the beginning of the transition to nationwide screening, false positive findings were reported in 3 patients. After optimization of the screening method in the laboratories concerned, all findings have been subsequently confirmed. On average, the first presentation to a neuromuscular center occurred on day 12 of life, and in patients with 2 or 3 SMN2 copies, therapy started on day 26 of life. Compared with the pilot project, there was no significant delay in timing.

Background: The development and approval of disease modifying treatments have dramatically changed disease progression in patients with spinal muscular atrophy (SMA). Nusinersen was approved in Europe in 2017 for the treatment of SMA patients irrespective of age and disease severity. Most data on therapeutic efficacy are available for the infantile-onset SMA. For patients with SMA type 2 and type 3, there is still a lack of sufficient evidence and long-term experience for nusinersen treatment. Here, we report data from the SMArtCARE registry of non-ambulant children with SMA type 2 and typen 3 under nusinersen treatment with a follow-up period of up to 38 months., Methods: SMArtCARE is a disease-specific registry with data on patients with SMA irrespective of age, treatment regime or disease severity. Data are collected during routine patient visits as real-world outcome data. This analysis included all non-ambulant patients with SMA type 2 or 3 below 18 years of age before initiation of treatment. Primary outcomes were changes in motor function evaluated with the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM)., Results: Data from 256 non-ambulant, pediatric patients with SMA were included in the data analysis. Improvements in motor function were more prominent in upper limb: 32.4% of patients experienced clinically meaningful improvements in RULM and 24.6% in HFMSE. 8.6% of patients gained a new motor milestone, whereas no motor milestones were lost. Only 4.3% of patients showed a clinically meaningful worsening in HFMSE and 1.2% in RULM score., Conclusion: Our results demonstrate clinically meaningful improvements or stabilization of disease progression in non-ambulant, pediatric patients with SMA under nusinersen treatment. Changes were most evident in upper limb function and were observed continuously over the follow-up period. Our data confirm clinical trial data, while providing longer follow-up, an increased number of treated patients, and a wider range of age and disease severity., (© 2022. The Author(s).)

Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by biallelic mutations in the SMN1 (survival motor neuron 1) gene on chromosome 5q13.2, which leads to a progressive degeneration of alpha motor neurons in the spinal cord and in motor nerve nuclei in the caudal brainstem. It is characterized by progressive proximally accentuated muscle weakness with loss of already acquired motor skills, areflexia and, depending on the phenotype, varying degrees of weakness of the respiratory and bulbar muscles, although the facial muscles and eye muscles are not affected. The previously purely symptom-oriented treatment has undergone a significant expansion since 2017 with the approval of three drugs (nusinersen, onasemnogene abeparvovec and risdiplam) that modify the course of the disease at the gene expression level and have led to a change in the natural disease course of SMA. The effect of these new forms of treatment can only be fully assessed in the coming years. New aspects and challenges in this context are discussed in this article., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

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.)

Cerebral magnetic resonance imaging (MRI) is considered an important tool in the assessment of a child with cerebral palsy (CP), as it is abnormal in more than 80% of children with CP, disclosing the pathogenic pattern responsible for the neurological condition. MRI, therefore, is recommended as the first diagnostic step after medical history taking and neurological examination. With the advances in genetic diagnostics, the genetic contribution to CP is increasingly discussed, and the question arises about the role of genetic testing in the diagnosis of cerebral palsy. The paper gives an overview on genetic findings reported in CP, which are discussed with respect to the underlying brain pathology according to neuroimaging findings. Surveillance of Cerebral Palsy in Europe (SCPE) classifies neuroimaging findings in CP into five categories, which help to stratify decisions concerning genetic testing. Predominant white and gray matter injuries are by far predominant (accounting for around 50 and 20% of the findings). They are considered to be acquired. Here, predisposing genetic factors may play a role to increase vulnerability (and should especially be considered, when family history is positive and/or causative external factors are missing). In maldevelopments and normal findings (around 11% each), monogenic causes are more likely, and thus, genetic testing is clearly recommended. In the miscellaneous category, the precise nature of the MRI finding has to be considered as it could indicate a genetic origin., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Horber, Grasshoff, Sellier, Arnaud, Krägeloh-Mann and Himmelmann.)

Background: Cerebral palsy (CP) is a disorder of movement and posture and every child with CP has a unique composition of neurological symptoms, motor severity, and associated impairments, constituting the functional profile. Although not part of the CP definition, magnetic resonance imaging (MRI) sheds light on the localization, nature, and severity of brain compromise. The MRI classification system (MRICS), developed by the Surveillance of Cerebral Palsy in Europe (SCPE), describes typical MRI patterns associated with specific timing of vulnerability in different areas of the brain. The classification has proven to be reliable and easy to use. Aims: The aim of this study is to apply the MRICS on a large dataset and describe the functional profile associated with the different MRI patterns of the MRICS. Materials and Methods: Data on children with CP born in 1999-2009 with a post-neonatal MRI from 20 European registers in the JRC-SCPE Central Registry was included. The CP classification and the MRICS was applied, and The Gross Motor Function Classification (GMFCS) and the Bimanual Fine Motor Function (BFMF) classification were used. The following associated impairments were documented: intellectual impairment, active epilepsy, visual impairment, and hearing impairment. An impairment index was used to characterize severity of impairment load. Results: The study included 3,818 children with post-neonatal MRI. Distribution of CP type, motor, and associated impairments differed by neuroimaging patterns. Functional profiles associated with neuroimaging patterns were described, and the impairment index showed that bilateral findings were associated with a more severe outcome both regarding motor impairment and associated impairments than unilateral compromise. The results from this study, particularly the differences in functional severity regarding uni- and bilateral brain compromise, may support counseling and service planning of support of children with CP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Himmelmann, Horber, Sellier, De la Cruz, Papavasiliou, Krägeloh-Mann and the Surveillance of Cerebral Palsy in Europe (SCPE) Collaboration.)

Synaptotagmins are integral synaptic vesicle membrane proteins that function as calcium sensors and regulate neurotransmitter release at the presynaptic nerve terminal. Synaptotagmin-2 (SYT2), is the major isoform expressed at the neuromuscular junction. Recently, dominant missense variants in SYT2 have been reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Here we report seven patients of five families, with biallelic loss of function variants in SYT2, clinically manifesting with a remarkably consistent phenotype of severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings were consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in three patients showed clinical improvement with increased strength and function. This series further establishes SYT2 as a CMS-disease gene and expands its clinical and genetic spectrum to include recessive loss-of-function variants, manifesting as a severe congenital onset presynaptic CMS with potential treatment implications., (© 2020 Wiley Periodicals LLC.)

De novo pathogenic variants in the GATAD2B gene have been associated with a syndromic neurodevelopmental disorder (GAND) characterized by severe intellectual disability (ID), impaired speech, childhood hypotonia, and dysmorphic features. Since its first description in 2013, nine patients have been reported in case reports and a series of 50 patients was recently published, which is consistent with the relative frequency of GATAD2B pathogenic variants in public databases. We report the detailed phenotype of 19 patients from various ethnic backgrounds with confirmed pathogenic GATAD2B variants including intragenic deletions. All individuals presented developmental delay with a median age of 2.5 years for independent walking and of 3 years for first spoken words. GATAD2B variant carriers showed very little subsequent speech progress, two patients over 30 years of age remaining non-verbal. ID was mostly moderate to severe, with one profound and one mild case, which shows a wider spectrum of disease severity than previously reported. We confirm macrocephaly as a major feature in GAND (53%). Most common dysmorphic features included broad forehead, deeply set eyes, hypertelorism, wide nasal base, and pointed chin. Conversely, prenatal abnormalities, non-cerebral malformations, epilepsy, and autistic behavior were uncommon. Other features included feeding difficulties, behavioral abnormalities, and unspecific abnormalities on brain MRI. Improving our knowledge of the clinical phenotype is essential for correct interpretation of the molecular results and accurate patient management., (Copyright © 2020. Published by Elsevier Masson SAS.)

Background: Spinal muscular atrophy (SMA) is a severe, life-limiting neurodegenerative disease. A disease-modifying and approved therapy with nusinersen has been available in Germany since July 2017. Gene therapies offer another promising treatment option through a once in a lifetime administration. In May 2019 a gene replacement therapy for the treatment of SMA was approved for the first time by the U.S. Food and Drug Administration (FDA). An application for approval in Europe has been submitted and is currently pending., Objective: This consensus paper was compiled at the invitation of the German Society for Muscular Diseases (DGM) with the participation of all potential German neuromuscular treatment centers, the German section of the Society for Pediatric Neurology (GNP) and with the involvement of the medical scientific advisory board of the DGM. The aim was to define and establish the necessary prerequisites for a safe and successful application of the new gene replacement therapy in clinical practice., Conclusion: Gene replacement therapy with onasemnogene abeparvovec has the potential to significantly influence the course of SMA. Long-term data on sustainability of effects and possible adverse effects of gene replacement therapy are not yet available. The application of this innovative therapy must be carried out in specialized and appropriately qualified treatment centers under strict safety conditions. This article makes suggestions for the necessary framework conditions and gives recommendations for a systematic pretreatment and posttreatment assessment schedule under gene therapy. The effectiveness and safety of the therapy should be systematically documented in an industry-independent and disease-specific register.

Backgrounds: We have aimed to establish nerve ultrasound reference data in 8 to 17-year-old children and adolescents and to compare those data to younger children, adults, and age-matched children with polyneuropathies. Methods: High-resolution ultrasounds of the nerves were performed in 117 healthy children and adolescents at 20 predefined landmarks in the neck and the extremities of both sides. Mean values, side-to-side differences and intraneural ratios, as well as upper limits have been calculated. In a second step, a comparison between 25 children and adolescents of the same age range with proven hereditary and acquired neuropathies and lysosomal storage diseases has been carried out. Results: Nerve growth correlates significantly with age and reaches adult values at the age of around 15 years. The influence of body mass index and gender is negligible at most segments. By the use of age-specific upper limits, nerve enlargement could be seen in distinct types of neuropathies, particularly in demyelinating hereditary and inflammatory types, which is comparable to findings in adults, but also in rare lysosomal storage diseases. Conclusion: Nerve size correlates with age during childhood and reaches a climax in younger adults. Age-matched reference data are inevitable to differ between hypertrophic and non-hypertrophic nerve damage, e.g., in neuropathies., (Copyright © 2020 Grimm, Schubert, Grimm, Stahl, Küpper, Horber, Kegele, Willikens, Wittlinger, Serna-Higuita, Winter and Groeschel.)

Background: Surveillance of cerebral palsy in Europe (SCPE) presents the first population-based results on neuroimaging findings in children with cerebral palsy (CP) using a magnetic resonance imaging classification system (MRICS)., Method: MRIs of children with CP born between 1999 and 2009 from 18 European countries were analyzed. MRICS identifies patterns of brain pathology according to timing during brain development which was analyzed with respect to CP subtypes and gestational age., Results: MRIs or written reports from 3,818 children were available. The main clinical characteristics were similar to the 5,415 without such data. Most frequent was predominant white matter injury (49%), followed by predominant gray matter injury (21%). Maldevelopments were found in 11% of cases. Miscellaneous findings were present in 8.5% and normal findings in 10.6%. MRI patterns of children with unilateral spastic, bilateral spastic, and dyskinetic CP were mainly lesional (77, 71, and 59%, respectively), whereas children with ataxic CP had more maldevelopments, miscellaneous, and normal findings (25, 21, and 32%, respectively). In children born preterm, predominant white matter injury was most prevalent (80% in children born <32 weeks of gestation)., Conclusion: Analysis of MRI in the European CP database identified CP as a mainly lesional condition on a large population basis, maldevelopments were relatively uncommon. An exception was ataxic CP. Children born preterm mostly presented with a lesion typical for their gestational age (GA) at birth. The decreasing prevalence of CP in this group suggests that progress in perinatal and neonatal medicine may lead to a reduction of these lesions., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Objective: This article describes associated impairments in children with cerebral palsy (CP) and its subtypes., Method: Children born between 1990 and 2006 recorded in the Surveillance of Cerebral Palsy in Europe common database were studied. An "impairment index" characterized severity of impairments and their combinations., Results: Amongst the 11,015 children analyzed, 56% ( n  = 5,968) could walk unaided, 54% (4,972) had normal or near-normal intellect (intelligence quotient ≥ 70). Except for ataxic CP, associated impairments were less frequent when walking ability was preserved. The impairment index was low (walking unaided and normal or near-normal intellect) in 30% of cases; 54% ( n  = 1,637) in unilateral spastic, 24% ( n  = 79) in ataxic, 18% ( n  = 913) in bilateral spastic, and 7% ( n  = 50) in dyskinetic CP. Around 40% had a high impairment index (inability to walk and/or severe intellectual impairment ± additional impairments)-highest in dyskinetic (77%, n  = 549) and bilateral spastic CP (54%, n  = 2,680). The impairment index varied little in birth weight and gestational age groups. However, significantly fewer cases in the birth weight group ≤ 1,000 g or gestational age group ≤ 27 weeks had a low impairment index compared to the other birth weight and gestational age groups (23 and 24% vs. between 27 and 32%)., Conclusion: Thirty percent of the children with CP had a low impairment index (they were able to walk unaided and had a normal or near-normal intellect). Severity in CP was strongly associated to subtype, whereas the association was weak with birth weight or gestational age., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

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.

Aim: To develop and evaluate a classification system for magnetic resonance imaging (MRI) findings of children with cerebral palsy (CP) that can be used in CP registers., Method: The classification system was based on pathogenic patterns occurring in different periods of brain development. The MRI classification system (MRICS) consists of five main groups: maldevelopments, predominant white matter injury, predominant grey matter injury, miscellaneous, and normal findings. A detailed manual for the descriptions of these patterns was developed, including test cases (www.scpenetwork.eu/en/my-scpe/rtm/neuroimaging/cp-neuroimaging/). A literature review was performed and MRICS was compared with other classification systems. An exercise was carried out to check applicability and interrater reliability. Professionals working with children with CP or in CP registers were invited to participate in the exercise and chose to classify either 18 MRIs or MRI reports of children with CP., Results: Classification systems in the literature were compatible with MRICS and harmonization possible. Interrater reliability was found to be good overall (k=0.69; 0.54-0.82) among the 41 participants and very good (k=0.81; 0.74-0.92) using the classification based on imaging reports., Interpretation: Surveillance of Cerebral Palsy in Europe (SCPE) proposes the MRICS as a reliable tool. Together with its manual it is simple to apply for CP registers., (© 2016 Mac Keith Press.)

Background: Human cytomegalovirus is the most common cause of vertically transmitted viral infection, affecting around 1% of liveborns. Infection is symptomatic in nearly 10% of infected children who are at higher risk of development of severe neurological disorders, including cerebral palsy., Aims: To study the clinical profile of children with cerebral palsy caused by symptomatic congenital cytomegalovirus infection in a multicenter study involving six countries from the Surveillance of Cerebral Palsy in Europe (SCPE) Network., Methods: Data on 35 children (13 males, 22 females; mean age at last assessment 12y 6mo, age range 14y 6mo, min 4y, max 18y 6mo) on pre/peri/neonatal history and last clinical assessment were collected. Classification of cerebral palsy and associated impairments was performed according to SCPE criteria., Results: The majority of children had bilateral spastic cerebral palsy, 85.7%, with a confidence interval (CI) [69.7-95.2], and 71.4% [CI 53.7-85.4] were unable to walk (GMFCS levels IV-V) while fine motor function was severely affected in 62.8% [CI 44.9-78.5] (BFMF levels IV and V). Most of the children with severe CP had severe associated impairments. 11.4% of children had severe visual and 42.8% severe hearing impairment, 77.1% [CI 59.9-89.6] suffered from epilepsy, also 77.1% had severe intellectual impairment, and speech was undeveloped in 71.4%. Female:male ratio was 1.69:1 and 80% of children were term born., Conclusions: Cerebral palsy following symptomatic congenital cytomegalovirus infection seems to be in most cases a severe condition and associated impairments are overrepresented., (Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Interstitial deletions of the short arm of chromosome 3 are rare. We report on a 3-year-old girl with intellectual disability, muscular hypotonia, strabismus, and facial anomalies in whom an interstitial 1.24 Mb deletion in 3p25.3-p26.1 was detected by SNP array analysis. The deleted region harbors 11 RefSeq genes including CAV3 and SRGAP3/MEGAP, which had been associated with muscle disorders and intellectual disability, respectively. The deletion overlaps with a slightly larger deletion in a girl with a more complex phenotype including congenital heart defect and epilepsy, which indicates that haploinsufficiency of one or several of the genes in the deleted interval causes intellectual deficits, but not heart defects or epilepsy. Thus, the patient broadens our knowledge of the phenotypic consequences of deletions in 3p25.3-p26.1 and facilitates genotype-phenotype correlations for chromosome aberrations of this region., (Copyright © 2012 Wiley Periodicals, Inc.)

Aim: To evaluate the interrater reliability of the inclusion in registries and classification of children with cerebral palsy (CP)., Method: Two studies were conducted. In study 1, 12 paediatricians from 11 countries viewed video sequences of 12 children with or without CP (nine males, three females; median age 6y; range 2-16). In study 2, 19 professionals from eight countries participated in an online exercise. They had to classify the same children but based on written vignettes. All participants had to evaluate whether the child had CP, the neurological subtype (Surveillance of Cerebral Palsy in Europe classification system), and gross motor function level (Gross Motor Function Classification System [GMFCS]). Kappa (κ) coefficients were calculated for categorical variables and intraclass correlation coefficients (ICCs) for ordinal data., Results: Reliability was excellent in assessing whether or not a child had CP in study 1 (κ=1.00) and substantial in study 2 (κ=0.73); 95% confidence interval [CI] 0.58-0.87). For the neurological subtype, overall κ between paediatricians was 0.85 (95% CI 0.68-0.98), with full agreement observed for eight children. In study 2, overall κ was 0.78 (95% CI 0.61-0.91) with full agreement seen for five children. For the GMFCS, the ICC was 0.88 (95% CI 0.78-0.95) in study 1 and 0.80 (95% CI 0.64-0.91) in study 2., Interpretation: Reliability was excellent for all characteristics classified by paediatricians viewing the videos and substantial for professionals reading vignettes., (© The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.)

Primary extradural ependymomas are rare neoplasms usually of the myxopapillary type. Reports on malignant primary extradural ependymal tumors are exceptionally rare. We here report on a 3-year-old boy with Schinzel-Giedion syndrome (SGS), who presented with lumbar spina bifida occulta and a progressive extraspinal lesion in the subcutaneous sacrococcygeal region. Microscopic examinations revealed an uncommon ependymal tumor with well-differentiated regions reflecting myxopapillary ependymoma and highly anaplastic regions with numerous mitoses, necroses, ependymal rosettes and ependymoblastic rosettes. Final neuropathologic diagnosis was an extraspinal anaplastic ependymal tumor with myxopapillary and ependymoblastic differentiation, corresponding to WHO grade IV. SGS is a very rare disorder with a likely autosomal recessive pattern of inheritance. So far, 42 cases have been reported, among them 7 were diagnosed to have malignant neoplasms, including three malignant sacrococcygeal teratomas, two sacrococcygeal primitive neuroectodermal tumors (PNET), one hepatoblastoma and one malignant kidney tumor. The present case is the first report on an ependymal tumor with a mixture of myxopapillary, anaplastic and ependymoblastic features and the first report on an ependymal tumor arising on the genetic background of SGS.

The aim of this study was to show the role of magnetic resonance imaging (MRI) in elucidating the aetiology, or at least pathogenesis, of cerebral palsy (CP). A systematic review of studies using MRI in children with CP was performed according to pathogenetic patterns characterizing different timing periods of occurence of the lesions, and with respect to gestational age (term vs preterm) and CP subtypes. Out of the studies published since 1990 in English, six met all the inclusion criteria; they involved children with spastic and dyskinetic CP. Abnormal MRI was reported in 334 out of 388 (86%) patients and gave clues to pathogenesis in 83%. Fourteen studies met only part of the inclusion criteria and abnormal MRIs were reported even more frequently in these (91%; 930/1022). Periventricular white matter lesions were most frequent (56%) followed by cortical and deep grey matter lesions (18%); brain maldevelopments were rather rare, described in 9%. Brain maldevelopments and grey matter lesions were more often seen in term than in preterm-born children with CP (brain maldevelopments: 16% vs 2.5%; grey matter lesions: 33% vs 3.5%); periventricular white matter lesions occurred significantly more often in preterm than in term-born children (90% vs 20%). CP is mainly characterized by brain lesions which can be identified by MRI in around 75% of preterm infants; brain maldevelopments occur in around 10%.