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ObjectivesDuchenne muscular dystrophy, DMD, is an x-linked genetic condition known to be caused by mutations in the dystrophin gene. It presents in early childhood, with a variety of possible presentations, as described by the MUSCLE acronym.1 Increasingly, new treatments for DMD have been developed to target specific classes of mutations, namely ataluren for nonsense mutations and exon-skipping therapy for deletion mutations. This retrospective database study explores three key areas:[1] Clinical presentation of children in the East of England sample, characterised using the MUSCLE acronym and current mobility status.[2] Frequency of different mutations present in the East of England sample, and the specific mutations present.[3] Carrier status of mothers to DMD children in the East of England sample.MethodsThis retrospective study examined hospital electronic records for 54 children with DMD from the region, under the care of the paediatric neuromuscular team at the Cambridge University Hospitals NHS Foundation Trust (CUHFT).ResultsData was examined from 54 children, the majority of which between the ages of 6 and 15 and of White British ethnicity. The modal age of presentation was identified to be between the ages of 1 and 3 years. On classification with the MUSCLE acronym, the most frequent presentations were motor delay and unusual gait, in 19 and 11 children respectively. The other children presented with speech delay or due to a family history of DMD. 51% of children are currently ambulant. 65% of children were found to have a deletion mutation and 11% were found to have a nonsense mutation, with the remainder of children identified as having a point or duplication mutation, with percentages at 15% and 9% respectively. The commonest single exon deletion were exons 44 and 52. Information on carrier status was available for 35 children, of whom 19 children were identified as having a mother who is a carrier of a mutation in the dystrophin gene.ConclusionThis is the first study describing the type of mutations in the East of England cohort. It highlights the well described common clinical presentations of children with DMD that health professionals need to be aware of. Further natural history studies are needed for accurate genotype/phenotype correlation. Detailed descriptions of the mutations are important as new treatments such as gene therapy trials have started in the UK and to guide future developments.ReferenceVan Ruiten H, Improving recognition of Duchenne muscular dystrophy: a retrospective case note review, September 2014.

Abstract Missense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1 , these frameshift variants do not increase the propensity of hnRNPA2 protein to fibrillize. Rather, the frameshift variants have reduced affinity for the nuclear import receptor karyopherin β2, resulting in cytoplasmic accumulation of hnRNPA2 protein in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with HNRNPA2B1 to include an early-onset form of OPMD caused by frameshift variants that alter its nucleocytoplasmic transport dynamics.

Our patient was a previously normal boy who presented to his local hospital with an explosive onset of prolonged seizures and encephalopathy. He was treated for a presumed central nervous system infection and initial neuroimaging was normal. Despite treatment with antibiotics and antiepileptic drugs (AEDs), he remained encephalopathic and became ataxic over the next 48 hours, not related to medication. The seizures also proved resistant to treatment despite polytherapy with AEDs, and he required immune-modulatory treatment, intravenous methylprednisolone and intravenous immunoglobulin, in addition to the AEDs to achieve seizure control. The ataxia also improved following treatment. The initial EEG was normal but subsequent EEGs, separated by a week each, were abnormal and revealed subtle atypical ‘delta-brush-like waves’. The patient's serum and cerebrospinal fluid were tested for autoantibodies, and he was found to be positive for glycine receptor antibodies that are neuronal antibodies.

ANEC was initially described in 1995 as encephalopathy associated with hyperpyrexia, raised CSF protein and symmetrical necrotic lesions in the thalami and brainstem. 1 There is an association with upper respiratory tract illnesses, particularly influenza A. 2 3 It has significant morbidity and mortality. 4 5 Evidence regarding optimal therapy is limited; however, early steroids and immunoglobulin is associated with improved outcome. 5 Most children experience a monophasic illness but predisposition to recurrent episodes is associated with mutations in the RAN binding protein 2 (RANBP2) gene. 3 5 It is unclear whether this gene affects outcome.

ObjectivesDuchenne muscular dystrophy (DMD) is an X-linked disorder caused by mutations in the dystrophin gene, coding for dystrophin. There is a gradual decline in motor abilities, usually presenting before age five.1 DMD boys receive multiple supplementary services to their care including hydrotherapy, physiotherapy and school support. On the 23rd March, the UK government announced a national lockdown, leading to closure of schools and other in-person services, followed by further lockdowns. This provided a unique natural study opportunity into the use of habitual physical activity and regular therapies and their benefits in DMD patient ambulation. Parents have anecdotally reported declines in their child’s motor abilities beyond the expected rate. We sought to quantify this.MethodsThe North Star Ambulatory Assessment (NSAA) score was used to quantify mobility, ideally being performed 6-monthly. A lower age cut-off of 7 years was used and patients non-ambulant prior to 23rd March 2020 were excluded. 42/48 non-wheelchair-dependent patients were selected from Cambridge University Hospital’s (CUH) cohort and age-matched to historical patients using the North Star Network (NSN) database. Matching of a 2:1 historical-to-CUH was attempted, based on steroid regimen, age, NSAA trajectory,2 clinical trial participation and DMD genotype. CUH mean and individual NSAA scores were plotted over time. 19 CUH patients had sufficient data points to plot.ResultsCUH NSAA combined mean scores pre- versus post-March 2020 showed a 23% decrease (Graph 1, n=17). Individual patient NSAA scores from CUH (Graph 2, n=19) showed an average 9.43% decrease 2018–2019 and an average 10.8% decrease 2019–2020 (only second half of 2020 scores used). CUH and NSN data had incomplete entries with insufficient data points to extract meaningful matched results or calculate trends pre-2018.DiscussionResults show a general decline in CUH patient ambulation but insufficient matched data meant no decisive trend could be extrapolated looking at the impact of lockdown. Obtaining matched NSAA scores with historical patients was not possible due to gaps in data and post-lockdown data was insufficient in quantity. Decline of DMD ambulation occurs over a period of years and it is likely a one-year timeframe is insufficient to spot meaningful declines.2, 3 With clinical service restoration, patient data collection over longer periods will be possible. To increase study power, we aim to coordinate a national study observing trends before, during and after lockdowns. Emphasising NSAA form completion within CUH and the NSN is key to enabling future research.ReferencesGene Expression in Muscle, Rowland, 1985.Muntoni, et al. Categorising trajectories and individual item changes of the North Star Ambulatory Assessment in patients with Duchenne muscular dystrophy, 2019.Brogna, et al. Long-term natural history data in Duchenne muscular dystrophy ambulant patients with mutations amenable to skip exons 44, 45, 51 and 53, 2019.Abstract 261 Figure 1Line graph depicting mean CUH NSAA scores pre- and post-March 2020 (n=17). Line of best fit in red showing a 23% decrease in mean NSAA scores achieved pre- and post-March 2020[Image Omitted. See PDF.]

A 5-year-old boy of non-consanguineous Indian descent presented to the emergency department (ED) following a prolonged seizure, preceded by a minor head injury from a low-level unwitnessed fall. The seizure was described as focal with head and neck version to the right. There was urinary and faecal incontinence and foaming at the mouth. The seizure lasted for 30 min, following which the child made a rapid recovery and had no neurological deficit when examined in the ED. His initial observations were unremarkable, with him being afebrile, normotensive and having a blood sugar of 4.6 mmol/L.Question 1Which imaging modality, if any, should be performed?Question 2Initial imaging showed two parenchymal lesions, one within the left frontal lobe and the other in the right parietal lobe with possible areas of blood or calcification. MRI (figure 1A,B) was urgently undertaken and reported as likely to be either haemorrhage into cavernomatous malformations, haemorrhagic metastases or haemorrhage within infected lesions such as tuberculomas.What would be the most useful next step in view of the differential diagnosis?CT chest and abdomenPerform a C-reactive proteinPerform a Mantoux testRefer to neurosurgeryTake a detailed family history Question 3As the patient remained stable on the ward, with no signs of focal neurology and no mass effects on MRI, a lumbar puncture was performed the following day to exclude tuberculosis (TB) (table 1). What cell appearance would indicate TB infection?Question 4A review of the mother’s medical records and MRI scans revealed her to have multiple discrete cerebral cavernous malformations (CCMs) (figure 2).In view of this new information, what is the next step in investigating this child?

Objectives The objective of this study is to analyse retrospective, observational, longitudinal growth (weight, height and BMI) data in ambulatory boys aged 5–12 years with Duchenne muscular dystrophy (DMD). Background We considered glucocorticoids (GC) use, dystrophin isoforms and amenability to exon 8, 44, 45, 51 and 53 skipping drug subgroups, and the impact of growth on loss of ambulation. We analysed 598 boys, with 2604 observations. This analysis considered patients from the UK NorthStar database (2003–2020) on one of five regimes: “GC naïve”, “deflazacort daily” (DD), “deflazacort intermittent” (DI), “prednisolone daily” (PD) and “prednisolone intermittent” (PI). A random slope model was used to model the weight, height and BMI SD scores (using the UK90). Results The daily regime subgroups had significant yearly height stunting compared to the GC naïve subgroup. Notably, the average height change for the DD subgroup was 0.25 SD (95% CI − 0.30, − 0.21) less than reference values. Those with affected expression of Dp427, Dp140 and Dp71 isoforms were 0.77 (95% CI 0.3, 1.24) and 0.82 (95% CI 1.28, 0.36) SD shorter than those with Dp427 and/or Dp140 expression affected respectively. Increased weight was not associated with earlier loss of ambulation, but taller boys still ambulant between the age of 10 and 11 years were more at risk of losing ambulation. Conclusion These findings may provide further guidance to clinicians when counselling and discussing GCs commencement with patients and their carers and may represent a benchmark set of data to evaluate the effects of new generations of GC.

Children with chronic headache are a common referral to paediatric outpatients. This article suggests an approach to the assessment and management of chronic headaches, offering practical strategies for management as there is limited literature in paediatrics for this.

The investigation of children presenting with infantile and childhood epileptic encephalopathies (ICEE) is challenging due to diverse aetiologies, overlapping phenotypes and the relatively low diagnostic yield of MRI, electroencephalography (EEG) and biochemical investigations. Careful history and thorough examination remain essential as these may identify an acquired cause or indicate more targeted investigation for a genetic disorder. Whole exome sequencing (WES) with analysis of a panel of candidate epilepsy genes has increased the diagnostic yield. Whole genome sequencing (WGS), particularly as a trio with both parents’ DNA, is likely to supersede WES. Modern genomic investigation impacts on the timing and necessity of other testing. We propose a structured approach for children presenting with ICEE where there is diagnostic uncertainty, emphasising the importance of WGS or, if unavailable, WES early in the investigative process. We note the importance of expert review of all investigations, including radiology, neurophysiology and biochemistry, to confirm the technique used was appropriate as well as the results. It is essential to counsel families on the risks associated with the procedures, the yield of the procedures, findings that are difficult to interpret and implication of ‘negative’ results. Where children remain without a diagnosis despite comprehensive investigation, we note the importance of ongoing multidisciplinary care.

Charcot-Marie-Tooth disease (CMT) refers to a genetically heterogeneous group of disorders which cause a peripheral motor and sensory neuropathy. The overall prevalence is 1 in 2500 individuals. Mutations in the MFN2 gene are the commonest cause for the axonal (CMT2) type. We describe a Caucasian 5-year old girl affected by CMT2A since the age of 2 years. She presented with unsteady gait, in-turning of the feet and progressive foot deformities. Nerve conduction studies suggested an axonal neuropathy and molecular testing identified a previously reported pathogenic variant c.1090C > T, p.(Arg364Trp) in the MFN2 gene. This variant was also detected in a mosaic state in blood and saliva by Sanger sequencing in her subjectively healthy father. Next generation sequencing showed that the level of mosaicism was 21% in blood and 24% in saliva. A high recurrence risk was given because the father had proven somatic mosaicism and an affected child implying gonadal mosaicism. The parents were referred for pre-implantation genetic diagnosis. To the best of our knowledge, this is the first reported case of somatic mosaicism for MFN2 . This study has important implications for genetic counselling in families with CMT2A.