Efficacy and safety of onasemnogene abeparvovec in children with spinal muscular atrophy type 1: real-world evidence from 6 infusion centres in the United Kingdom.

peer reviewed[en] BACKGROUND: Real-world data on the efficacy and safety of onasemnogene abeparvovec (OA) in spinal muscular atrophy (SMA) are needed, especially to overcome uncertainties around its use in older and heavier children. This study evaluated the efficacy and safety of OA in patients with SMA type 1 in the UK, including patients ≥2 years old and weighing ≥13.5 kg. METHODS: This observational cohort study used data from patients with genetically confirmed SMA type 1 treated with OA between May 2021 and January 2023, at 6 infusion centres in the United Kingdom. Functional outcomes were assessed using age-appropriate functional scales. Safety analyses included review of liver function, platelet count, cardiac assessments, and steroid requirements. FINDINGS: Ninety-nine patients (45 SMA therapy-naïve) were treated with OA (median age at infusion: 10 [range, 0.6-89] months; median weight: 7.86 [range, 3.2-20.2] kg; duration of follow-up: 3-22 months). After OA infusion, mean ± SD change in CHOP-INTEND score was 11.0 ± 10.3 with increased score in 66/78 patients (84.6%); patients aged 100 U/L (95% CI, 2.3-223.7; P = 0.008) and 21.2-fold increased odds of steroid doubling, as per treatment protocol (95% CI, 2.2-209.2; P = 0.009) in patients weighing ≥13.5 kg versus <8.5 kg. Weight at infusion was positively correlated with steroid treatment duration (r = 0.43; P < 0.001). Worsening transaminitis, despite doubling of oral prednisolone, led to treatment with intravenous methylprednisolone in 5 children. Steroid-sparing immunosuppressants were used in 5 children to enable steroid weaning. Two deaths apparently unrelated to OA were reported. INTERPRETATION: OA led to functional improvements and was well tolerated with no persistent clinical complications, including in older and heavier patients. FUNDING: Novartis Innovative Therapies AG provided a grant for independent medical writing services

Clinical Neuroimaging Features and Outcome in Molybdenum Cofactor Deficiency

Molybdenum cofactor deficiency predominantly affects the central nervous system. There are limited data on long-term outcome or brain magnetic resonance imaging (MRI) features. We examined the clinical, brain MRI, biochemical, genetic, and electroencephalographic features and outcome in 8 children with a diagnosis of molybdenum cofactor deficiency observed in our institution over 10 years. Two modes of presentation were identified: early (classical) onset with predominantly epileptic encephalopathy in 6 neonates, and late (atypical) with global developmental impairment in 2 children. Children in both groups had varying degrees of motor, language, and visual impairment. There were no deaths. Brain MRI demonstrated cerebral infarction in all but one child in the atypical group. Distinctive features were best observed on early brain MRI: acute symmetrical involvement of the globus pallidi and subthalamic regions coexisting with older cerebral hemisphere infarction, chronic lesions suggestive of a prenatal insult, pontocerebellar hypoplasia with retrocerebellar cyst, and presence of a distinctive band at the cortical/subcortical white matter. Sequential imaging revealed progressive pontine atrophy and enlargement of retrocerebellar cyst. The brain MRI of one child with atypical presentation (verbal dyspraxia, lens dislocation) showed symmetrical cerebellar deep nuclei signal abnormality without cerebral infarction. Imaging pattern on early brain MRI (<1 week) may prompt the diagnosis, potentially allowing early treatment and disease modifications