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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]