Cerebral palsy (CP), a neurodevelopmental disorder characterized by irreversible, nonprogressive central motor dysfunction, is commonly associated with prematurity or perinatal brain injury. However, accumulating evidence suggests deleterious genomic variants may contribute to CP in addition to environmental insults. To identify genes contributing to risk for CP, we performed whole-exome sequencing on 250 parent-offspring CP trios. We identified a significant contribution of damaging de novo mutations (DNMs), especially in genes that are intolerant to loss of function mutations. Eight genes had multiple, independently-arising damaging DNMs, including two novel CP-associated genes, FBXO31 and RHOB, and four genes previously implicated in cerebral palsy phenotypes, TUBA1A, CTNNB1, SPAST, and ATL1. Functional experiments, including molecular and biochemical assays and patient fibroblast studies indicate that the recurrent RHOB mutation identified in patients enhances Rho effector binding in the active state and that the FBXO31 mutation leads to elevated levels of cyclin D. Analysis of candidate CP risk genes highlighted genetic overlap with hereditary spastic paraplegia as well as intellectual disability, autism, and epilepsy, converging with epidemiologic findings. Computational network analysis of risk genes identified significant enrichment of Rho GTPase, extracellular matrix, focal adhesions, cytoskeleton, and cell projection pathways. CP risk genes in Rho GTPase, cytoskeleton and cell projection pathways were found to play an important role in neuromotor development via a Drosophila reverse genetics screen. Based on enrichment analysis, we estimate that an excess of damaging de novo and inherited recessive variants collectively account for ~14% of the cases in our cohort, whereas perinatal asphyxia is currently estimated to occur in 8-10% of CP cases. Together, these findings provide evidence for the role of genetically-mediated dysregulation of early brain connectivity in CP.

We report a 3-year-old girl with an unusual presentation of cerebellitis following ingestion of methadone. CT showed diffuse symmetrical swelling and oedema of the cerebellum resulting in compression of the fourth ventricle and hydrocephalus. The changes were confirmed on MRI with the addition of watershed injuries. These findings represent a toxic encephalopathy and have been reported in previous cases of heroin intoxication by inhalation, but rarely following opioid ingestion. The aetiology of the watershed infarcts is discussed.

This is the first study to evaluate the efficacy of riboflavin for migraine prophylaxis in children. This was a randomized, double-blind study of riboflavin (200 mg daily) versus placebo in 48 children. The primary efficacy measure was the number of patients achieving a 50% or greater reduction in the number of migraine attacks per 4 weeks. Other outcome measures were the mean severity of migraine per day, mean duration of migraine, days with nausea or vomiting, analgesic use, and adverse effects. A 50% or greater reduction in headaches was seen in 14/21 patients in the placebo group and 12/27 patients in the riboflavin group (not significant P = .125). There were no differences between riboflavin and placebo for primary or secondary outcome variables. These results suggest that riboflavin is not an effective therapy for preventing migraine in children. A high placebo responder rate was seen, with implications for other studies of migraine in children.

Objective: To provide a greater understanding of the tolerability, safety and clinical outcomes of onasemnogene abeparvovec in real-world practice, in a broad population of infants with spinal muscular atrophy (SMA). Methods: A prospective cohort study of children with SMA treated with onasemnogene abeparvovec at Sydney Children's Hospital Network, Australia was conducted from August 2019 to November 2021. Safety outcomes included clinical and laboratory evaluations. Efficacy assessments included World Health Organisation (WHO) motor milestones, oral and swallowing abilities, and requirements for respiratory support. The implementation of a model of care for onasemnogene abeparvovec administration in health practice is described. Results: 21 children were treated (age range, 0.65-24 months; body weight range, 2.5-12.5 kg) and 19/21 (90.4%) had previous nusinersen. Transient treatment-related side effects occurred in all children; vomiting (100%), transaminitis (57%) and thrombocytopaenia (33%). Incidence of moderate/severe transaminitis was significantly greater in infants weighing ≥8 kg compared with <8 kg (p < 0.05). Duration of prednisolone following treatment was prolonged (mean 87.5 days, range 57-274 days). 16/21 (76%) children gained at least one WHO motor milestone. Stabilisation or improvement in bulbar or respiratory function was observed in 20/21 (95.2%) patients. Implementation challenges were mitigated by developing standard operating procedures and facilitating exchange of knowledge. Interpretation: This study provides real-world evidence to inform treatment decisions and guide therapeutic expectations for onasemnogene abeparvovec and combination therapy for SMA in health practice, especially for children weighing ≥8 kg receiving higher vector loads. Proactive clinical and laboratory surveillance is essential to facilitate individualised management of risks.

Background Gastro-oesophageal reflux (GOR) is an extremely common and usually self-limiting condition in infants. When treatment is required, Cisapride, a pro-kinetic agent, has been commonly prescribed for the symptomatic management of GOR. There have been recent reports of possibly serious adverse events, e.g. an increased QTc interval, cardiac arrhythmias, and death, associated with the use of Cisapride. 1 Cisapride treatment for gastro-oesophageal reflux in children (Review)

We present eight families with arthrogryposis multiplex congenita and myopathy bearing a TTN intron 213 extended splice-site variant (NM_001267550.1:c.39974-11T>G), inherited in trans with a second pathogenic TTN variant. Muscle-derived RNA studies of three individuals confirmed mis-splicing induced by the c.39974-11T>G variant; in-frame exon 214 skipping or use of a cryptic 3′ splice-site effecting a frameshift. Confounding interpretation of pathogenicity is the absence of exons 213-217 within the described skeletal muscle TTN N2A isoform. However, RNAsequencing from 365 adult human gastrocnemius samples revealed that 56% specimens predominantly include exons 213-217 in TTN transcripts (inclusion rate ≥66%). Further, RNA-sequencing of five fetal muscle samples confirmed that 4/5 specimens predominantly include exons 213-217 (fifth sample inclusion rate 57%). Contractures improved significantly with age for four individuals, which may be linked to decreased expression of pathogenic fetal transcripts. Our study extends emerging evidence supporting a vital developmental role for TTN isoforms containing metatranscript-only exons. K E Y W O R D S alternative splicing, arthrogryposis, congenital titinopathies, intronic splice variant, TTN metatranscript-only

Pelvic joint syndrome nearly always follows pelvic girdle relaxation of pregnancy and may have prolonged debilitating effects which do not respond long term to current therapies. The incidence of developmental dysplasia of the hip in the children of these women was high. A genetic susceptibility to joint dysfunction in both mother and fetus, possibly due to an aberration of relaxin physiology, is surmized. Identification of possible relaxin receptor changes in affected joints is a hypothesis worthy of testing with a view to the design of selective relaxin receptor modulators in pregnancy.

Background Gastro-oesophageal reflux (GOR) is common and usually self-limiting in infants. Cisapride, a pro-kinetic agent, was commonly prescribed until reports of possible serious adverse events were associated with its use. Objectives To determine the e ectiveness of cisapride versus placebo or non-surgical treatments for symptoms of GOR. Search methods We searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Specialised Register and Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE, reference lists of relevant review articles and searched in the Science Citation Index for all the trials identified. All searches were updated in February 2009. Selection criteria Randomised controlled trials comparing oral cisapride therapy with placebo or other non-surgical treatments for children diagnosed with GOR were included. We excluded trials with a majority of participants less than 28 days of age. Data collection and analysis Primary outcomes were a change in symptoms at the end of treatment, presence of adverse events, occurrence of clinical complications and weight gain. Secondary outcomes included physiological measures of GOR or histological evidence of oesophagitis. We dichotomised symptoms into 'same or worse' versus 'improved' and calculated summary odds ratios (OR). Continuous measures of GOR (for example reflux index) were summarised as a weighted mean di erence. All outcomes were analysed using a random-e ects method. Main results Ten trials in total met the inclusion criteria. Nine trials compared cisapride with placebo or no treatment, of which eight (262 participants) reported data on symptoms of gastro-oesophageal reflux. There was no statistically significant di erence between the two interventions (OR 0.34; 95% CI 0.10 to 1.19) for 'same or worse' versus 'improved symptoms' at the end of treatment. There was significant heterogeneity between the studies, suggesting publication bias. Four studies reported adverse events (mainly diarrhoea); this di erence was not statistically significant (OR 1.80; 95% CI 0.87 to 3.70). Another trial found no di erence in the electrocardiographic QTc interval a er three to eight weeks of treatment. Cisapride significantly reduced the reflux index (weighted mean di erence-6.49; 95% CI-10.13 to-2.85; P = Cisapride treatment for gastro-oesophageal reflux in children (Review)