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BackgroundPrior to the introduction of disease-modifying treatments (DMTs), children with type 1 spinal muscular atrophy (SMA) typically did not survive beyond the age of 2 years; management was mainly palliative. Novel therapies have made this a treatable condition, resulting in increased life expectancy and more time spent upright. Survival and improved function mean spinal asymmetry is a new complication with limited data on its prevalence and severity and no current guidelines on management and treatment. This study aimed to evaluate the spinal presentation and management of type 1 SMA children on nusinersen across the SMA-REACH UK network.MethodsSpinal presentation and management of 80 children (age range 4 months–14 years, median 4 years 2 months) with type 1 SMA on nusinersen across the SMA-REACH UK network were reviewed through retrospective data analysis.ResultsThere were 60 type 1 children who developed a spinal asymmetry, of which 40 had kyphosis and 50 used a supportive thoraco-lumbar-sacral orthosis (TLSO). TLSOs were predominantly a one-piece jacket with abdominal hole, advised to be worn when upright during the day. Reduced neck range of movement was found in 33, 1 of these had plagiocephaly and 5 had torticollis. Of those with reduced neck range of movement, 26 (79%) had spinal asymmetry. Spinal surgery was performed in 7.ConclusionsOur study confirms high prevalence of spinal asymmetry in this cohort, requiring long-term management planning. It provides information on presentation and treatment options, facilitating development of guidelines for these new complications observed in children surviving longer with DMTs.

Drug repurposing could provide novel treatment options for Duchenne muscular dystrophy. Because tamoxifen—an oestrogen receptor regulator—reduced signs of muscular pathology in a Duchenne muscular dystrophy mouse model, we aimed to assess the safety and efficacy of tamoxifen in humans as an adjunct to corticosteroid therapy over a period of 48 weeks. We did a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 12 study centres in seven European countries. We enrolled ambulant boys aged 6·5–12·0 years with a genetically confirmed diagnosis of Duchenne muscular dystrophy and who were on stable corticosteroid treatment for more than 6 months. Exclusion criteria included ophthalmological disorders, including cataracts, and haematological disorders. We randomly assigned (1:1) participants using an online randomisation tool to either 20 mg tamoxifen orally per day or matched placebo, stratified by centre and corticosteroid intake. Participants, caregivers, and clinical investigators were masked to treatment assignments. Tamoxifen was taken in addition to standard care with corticosteroids, and participants attended study visits for examinations every 12 weeks. The primary efficacy outcome was the change from baseline to week 48 in scores on the D1 domain of the Motor Function Measure in the intention-to-treat population (defined as all patients who fulfilled the inclusion criteria and began treatment). This study is registered with ClinicalTrials.gov (NCT03354039) and is completed. Between May 24, 2018, and Oct 14, 2020, 95 boys were screened for inclusion, and 82 met inclusion criteria and were initially enrolled into the study. Three boys were excluded after initial screening due to cataract diagnosis or revoked consent directly after screening, but before randomisation. A further boy assigned to the placebo group did not begin treatment. Therefore, 40 individuals assigned tamoxifen and 38 allocated placebo were included in the intention-to-treat population. The primary efficacy outcome did not differ significantly between tamoxifen (–3·05%, 95% CI –7·02 to 0·91) and placebo (–6·15%, –9·19 to –3·11; 2·90% difference, –3·02 to 8·82, p=0·33). Severe adverse events occurred in two participants: one participant who received tamoxifen had a fall, and one who received placebo suffered a panic attack. No deaths or life-threatening serious adverse events occurred. Viral infections were the most common adverse events. Tamoxifen was safe and well tolerated, but no difference between groups was reported for the primary efficacy endpoint. Slower disease progression, defined by loss of motor function over time, was indicated in the tamoxifen group compared with the placebo group, but differences in outcome measures were neither clinically nor statistically significant. Currently, we cannot recommend the use of tamoxifen in daily clinical practice as a treatment option for boys with Duchenne muscular dystrophy due to insufficient clinical evidence. Thomi Hopf Foundation, ERA-Net, Swiss National Science Foundation, Duchenne UK, Joining Jack, Duchenne Parent Project, Duchenne Parent Project Spain, Fondation Suisse de Recherche sur les Maladies Musculaires, Association Monegasque contre les Myopathies.