Many children with hereditary proximal spinal muscular atrophy (SMA) develop joint contractures. With the introduction of disease-modifying treatments (DMTs) for SMA, the improved functional prognosis may change the focus of (preventive) contracture management. This study aimed to describe current approaches to contracture management among Dutch pediatric rehabilitation physicians caring for children with SMA receiving DMT, and to explore the underlying considerations and clinical reasoning that inform their decisions on contracture management in the evolving therapeutic landscape. All registered pediatric rehabilitation physicians (n = 151) received a survey, addressing two main topics: (1) indication and purpose of contracture management, and (2) alignment of clinical decision-making with current guidelines. To this end, three standardized case scenarios were presented. Respondents were asked to indicate whether their current choices, were consistent with the guideline recommendations. To obtain a deeper understanding of the considerations and clinical reasoning regarding contracture management in the era of DMTs, we held an advisory group meeting. We audio-recorded the discussions and analyzed the content thematically. The response rate was 56%; 41 of these respondents were not involved in SMA care. 38 of the 44 surveys, completed by participants involved in SMA care, were suitable for analysis. All respondents (strongly) agreed about 'optimal sitting posture' being an important treatment goal, 95% agreed on 'pain prevention' and 87% on 'maintaining function'. Physicians recommended daily use of hand splints less frequently in children who started DMT before onset of symptoms (35%) than in children who started DMT at an advanced disease stage (54%). Thematic analysis revealed three themes shaping clinical reasoning: (1) functional prognosis as key element in decision-making; (2) clinical uncertainty regarding contracture intervention; and (3) incorporation of contextual factors. Dutch pediatric rehabilitation physicians describe challenges in clinical decision-making regarding contracture management in a changing landscape for SMA. The use of key principles could facilitate the process, including: (1) assessing the child's functional prognosis; (2) engaging in open discussions with parents about uncertainties arising from limited clinical experience and the evolving understanding of disease trajectories in the early post-DMT era; and (3) applying the ICF framework to incorporate contextual factors into clinical decision-making regarding contracture management.

Proximal spinal muscular atrophy (SMA) is defined by a degeneration of the anterior horn cells resulting in muscle weakness predominantly in the proximal lower limbs. While most patients carry a biallelic deletion in the SMN1 gene (localized in chromosome 5q), little is known regarding patients without SMN1-mutation, and a genetic diagnosis is not always possible. Here, we report a cohort of 24 French patients with non-5q proximal SMA from five neuromuscular centers who all, except two, had next-generation sequencing (NGS) gene panel, followed by whole exome sequencing (WES) if gene panel showed a negative result. The two remaining patients benefited directly from WES or whole genome sequencing (WGS). A total of ten patients with causative variants were identified, nine of whom were index cases (9/23 families = 39%). Eight variants were identified by gene panel: five variants in DYNC1H1, and three in BICD2. Compound heterozygous causative variants in ASAH1 were identified directly by WES, and one variant in DYNC1H1 was identified directly by WGS. No causative variant was found using WES in patients with a previous panel with negative results (14 cases). We thus recommend using primarily NGS panels in patients with non-5q-SMA and using WES, especially when several members of the same family are affected and/or when trio analyses are possible, or WGS as second-line testing if available.

Proximal spinal muscular atrophy (SMA) is caused by deficiency of the ubiquitously expressed survival motor neuron protein. Although primarily a hereditary lower motor neuron disease, it is probably also characterized by abnormalities in other organs. Brain abnormalities and cognitive impairment have been reported in severe SMA. We aimed to systematically investigate brain structure in SMA using MRI. We acquired high-resolution T1-weighted images of treatment-naive patients with SMA, age- and sex-matched healthy and disease controls with other neuromuscular diseases, on a 3 T MRI scanner. We performed vertex-wise whole brain analysis and region of interest analysis of cortical thickness (CT), and volumetric analysis of the thalamus and compared findings in patients and controls using multiple linear regression models and Wald test. We correlated structural abnormalities with motor function as assessed by the Hammersmith Functional Motor Scale Expanded (HFMSE) and SMA Functional Rating Scale (SMA-FRS). We included 30 patients, 12-70 years old, with SMA type 2 and 3, 30 age- and sex-matched healthy controls and 17 disease controls (with distal SMA, hereditary motor and sensory neuropathy, multifocal motor neuropathy, progressive muscular atrophy and segmental SMA). We found a reduced CT in patients with SMA compared to healthy controls at the precentral, postcentral and medial orbitofrontal gyri and at the temporal pole (mean differences -0.059(p = 0.04); -0.055(p = 0.04), -0.06(p = 0.04); -0.17 mm(p = 0.001)). Differences at the precentral gyrus and temporal pole were most pronounced in SMA type 2 (mean differences -0.07(p = 0.045); -0.26 mm(p < 0.001)) and were also present compared to disease controls (mean differences -0.08(p = 0.048); -0.19 mm(p = 0.003)). There was a positive correlation between CT at the temporal pole with motor function. Compared to healthy controls, we found a reduced volume of the whole thalamus (mean difference -325 mm3(p = 0.03)) and of the anterior, ventral and intralaminar thalamic nuclei (mean differences -9.9(p = 0.02); -157(p = 0.01); -24.2 mm3(p = 0.02) in patients with SMA and a positive correlation between these volumes and motor function. MRI shows structural changes in motor and non-motor regions of the cortex and the thalamus of patients with SMA type 2 and 3, indicating that SMA pathology is not confined to motor neurons.

Hereditary proximal spinal muscular atrophy (SMA) is characterized by abnormal alpha motor neuron function in brainstem and spinal cord. Bulbar dysfunction, including limited mouth opening, is present in the majority of patients with SMA but it is unknown if and how these problems change during disease course. In this prospective, observational, longitudinal natural history study we aimed to study bulbar dysfunction in patients with SMA types 2 and 3. We included 44 patients with SMA types 2 and 3 (mean age was 33.6 (95% CI 28.4;38.9) and re-examined them after on average 4 years. None were treated with SMN-modulating treatments before or during the course of this study. Longitudinal assessments included a questionnaire on mandibular and bulbar function, the Mandibular Function Impairment Questionnaire (MFIQ), and a clinical examination of masticatory performance, maximum voluntary bite force, and mandibular movements including the active maximal mouth opening. We found significant higher MFIQ scores and a significant decrease of all mandibular movements in patients with SMA type 2 (p < 0.001), but not in SMA type 3. Masticatory performance and maximum voluntary bite force did not change significantly. Mean reduction of active maximal mouth opening at follow-up was 3.5 mm in SMA type 2 (95% CI: 2.3; 4.7, p < 0.001). SMA type 2 was an independent predictor for a more severe reduction of the mouth opening (β= -2.0 mm (95% CI: -3.8; -0.1, p = 0.043)). Bulbar functions such as mandibular mobility and active maximum mouth opening decrease significantly over the course of four years in patients with SMA type 2.

Hereditary proximal spinal muscular atrophy causes weakness and increased fatigability of repetitive motor functions. The neuromuscular junction is anatomically and functionally abnormal in patients with spinal muscular atrophy. Pharmacological improvement of neuromuscular transmission may therefore represent a promising additional treatment strategy. We conducted a Phase II, monocentre, placebo-controlled, double-blind, cross-over trial with the acetylcholinesterase inhibitor pyridostigmine in treatment-naïve patients with spinal muscular atrophy types 2-4. We investigated the safety and efficacy of pyridostigmine on fatigability and motor function. Each participant received pyridostigmine and a placebo for 8 weeks, in random order. Primary outcomes were the repeated nine-hole peg test for fatigability and motor function measure. Secondary outcomes were patient-reported effects, endurance shuttle test combined scores and adverse events. We included 35 patients. For the repeated nine-hole peg test, the mean difference was 0.17 s/trial (95% confidence interval: -1.17-1.49; P = 0.8), favouring placebo, and for the motor function measure, 0.74% (95% confidence interval: 0.00-1.49; P = 0.05), favouring pyridostigmine. Around 74% of patients reported medium-to-large beneficial effects of pyridostigmine on fatigability, compared with 29.7% in the placebo arm. This was paralleled by a reduced dropout risk of 70% on the endurance shuttle test combined scores (hazard ratio: 0.30; 95% confidence interval: 0.15-0.58) under pyridostigmine. Adverse events, mostly mild and self-limiting, occurred more frequently under pyridostigmine. No serious adverse events related to the study medication were observed. Patients with spinal muscular atrophy tolerated pyridostigmine well. There were no significant differences in primary outcomes, but the self-reported reduction of fatigability and improved endurance shuttle test combined score performance suggest that pyridostigmine may be useful as an additional therapy to survival motor neuron-augmenting drugs. Trial registration number: EudraCT: 2011-004369-34, NCT02941328.