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Epileptic encephalopathies (EEs) are the most clinically important group of severe early-onset epilepsies. Next-generation sequencing has highlighted the crucial contribution of de novo mutations to the genetic architecture of EEs as well as to their underlying genetic heterogeneity. Our previous whole-exome sequencing study of 264 parent-child trios revealed more than 290 candidate genes in which only a single individual had a de novo variant. We sought to identify additional pathogenic variants in a subset (n = 27) of these genes via targeted sequencing in an unsolved cohort of 531 individuals with a diverse range of EEs. We report 17 individuals with pathogenic variants in seven of the 27 genes, defining a genetic etiology in 3.2% of this unsolved cohort. Our results provide definitive evidence that de novo mutations in SLC1A2 and CACNA1A cause specific EEs and expand the compendium of clinically relevant genotypes for GABRB3. We also identified EEs caused by genetic variants in ALG13, DNM1, and GNAO1 and report a mutation in IQSEC2. Notably, recurrent mutations accounted for 7/17 of the pathogenic variants identified. As a result of high-depth coverage, parental mosaicism was identified in two out of 14 cases tested with mutant allelic fractions of 5%-6% in the unaffected parents, carrying significant reproductive counseling implications. These results confirm that dysregulation in diverse cellular neuronal pathways causes EEs, and they will inform the diagnosis and management of individuals with these devastating disorders.

Little is currently known about the nutrition and growth outcomes in children with neuromuscular disorders (NMDs), and these are likely disease dependent. The aim of this study was to describe the range of nutritional issues in pediatric NMDs and identify similarities and differences in growth outcomes and nutritional needs in children with a variety of NMDs at different ages, with the goal of informing future services. In this cross-sectional study we collected data on growth, dietetic interventions and nutrition-related issues in 160 children who attended a multidisciplinary clinic in a tertiary children's hospital, from February to December 2019. Children with significant weakness affecting mobility before the age of 3 years were clinically grouped into 'early-onset NMDs'. Across our clinic, 42.5% children had a history of chronic gastrointestinal issues, and 34.4% received dietetic care on the day of clinical visit. Children with early-onset NMDs had significantly higher prevalence of swallowing issues, gastroesophageal reflux, and vomiting, as well as higher frequency of dietetic consultations, high energy diet, swallowing assessment and tube-feeding, compared to later-onset NMDs (p < 0.05). In total, 49.2% children with NMDs had an abnormal weight, in which the prevalence of underweight (n = 24, 19.2%) was significantly higher compared to normal Australian children (8.2%) (p < 0.05). In Duchenne muscular dystrophy, over 50% children were overweight/obese. Among children with NMDs, there were many disease-specific nutrition-related symptoms, growth issues, and dietetic practices that were tailored to individual needs. Future studies should focus on measuring the impact of specific dietetic practices on growth and nutritional outcomes, as well as developing a precision medicine approach tailored to the individual nutritional needs of children with NMDs. • Abnormal body mass index is common in children with neuromuscular disorders (NMDs), as seen in almost half our cohort. • Chronic gastrointestinal problems are common in children with NMDs, as seen in 42.5% of our cohort. • Children with early-onset rather than later-onset NMDs have more issues with swallowing and being underweight. • Children with Duchenne muscular dystrophy are more likely to be overweight. • A precision medicine approach is needed to optimise growth and nutritional outcomes of each patient. [ABSTRACT FROM AUTHOR]

Children with neuromuscular disorders (NMDs) may experience a spectrum of nutritional issues with adverse health consequences. This review summarizes the current understanding of nutritional care in pediatric NMDs, recognizing disease-specific aspects of nutrition alongside the challenges and needs in dietetic care. General or disease-related nutritional issues for children with NMDs include being underweight, overweight, or obese and having swallowing difficulty, gastroesophageal reflux, diarrhea, and/or constipation. Specific challenges in NMD nutritional assessment include alterations in body composition and energy requirements and difficulties in measuring anthropometry. Multidisciplinary dietetic intervention focuses on optimizing nutrient intakes to avert growth failure or obesity and managing feeding difficulties and gastrointestinal problems. Care guidelines are disease specific and vary in approach and detail. To promote best clinical practice across diverse settings, a standardized approach to assessing growth and nutrition across all pediatric NMDs is needed to direct optimal care centered on individual requirements. Future studies should focus on determining the prevalence of specific nutritional issues and the effectiveness of specific interventions among various pediatric NMD populations. [ABSTRACT FROM AUTHOR]

Introduction: Biomarkers of disease severity in Charcot-Marie-Tooth disease (CMT) are required to evaluate early responses to treatment. In this study we used magnetic resonance imaging (MRI) to evaluate the relationship between muscle volume and intramuscular fat accumulation with weakness, disability, and impaired gait in affected children and adolescents.Methods: Fifty-five participants underwent MRI of the anterior compartment of the lower leg. Muscle and fat volumes were calculated. Strength was measured using hand-held dynamometry, disability using the CMT Pediatric Scale, and 3-dimensional gait analysis using an 8-camera Vicon Nexus motion capture system.Results: Lower muscle volume was significantly associated with reduced dorsiflexion strength, increased disability, impaired gait profile score, and foot drop. Intramuscular fat accumulation was associated with reduced dorsiflexion strength and impaired gait profile score.Discussion: The MRI protocol described was feasible, reliable, and sensitive to the magnitude of weakness, disability, and walking difficulties in children with CMT. Muscle Nerve 59:213-217, 2019. [ABSTRACT FROM AUTHOR]