Search

BackgroundEpilepsy-associated dysbiosis in gut microbiota has been previously described, but the mechanistic roles of the gut microbiome in epileptogenesis among children with cerebral palsy (CP) have yet to be illustrated.MethodsUsing shotgun metagenomic sequencing coupled with untargeted metabolomics analysis, this observational study compared the gut microbiome and metabolome of eight children with non-epileptic cerebral palsy (NECP) to those of 13 children with cerebral palsy with epilepsy (CPE). Among children with CPE, 8 had drug-sensitive epilepsy (DSE) and five had drug-resistant epilepsy (DRE). Characteristics at enrollment, medication history, and 7-day dietary intake were compared between groups.ResultsAt the species level, CPE subjects had significantly lower abundances of Bacteroides fragilis and Dialister invisus but higher abundances of Phascolarctobacterium faecium and Eubacterium limosum. By contrast, DRE subjects had a significantly higher colonization of Veillonella parvula. Regarding microbial functional pathways, CPE subjects had decreased abundances of pathways for serine degradation, quinolinic acid degradation, glutamate degradation I, glycerol degradation, sulfate reduction, and nitrate reduction but increased abundances of pathways related to ethanol production. As for metabolites, CPE subjects had higher concentrations of kynurenic acid, 2-oxindole, dopamine, 2-hydroxyphenyalanine, 3,4–dihydroxyphenylglycol, L-tartaric acid, and D-saccharic acid; DRE subjects had increased concentrations of indole and homovanilic acid.ConclusionsIn this study, we found evidence of gut dysbiosis amongst children with cerebral palsy and epilepsy in terms of gut microbiota species, functional pathways, and metabolites. The combined metagenomic and metabolomic analyses have shed insights on the potential roles of B. fragilis and D. invisus in neuroprotection. The combined analyses have also provided evidence for the involvement of GMBA in the epilepsy-related dysbiosis of kynurenine, serotonin, and dopamine pathways and their complex interplay with neuroimmune and neuroendocrinological pathways.

Abstract Background Neuromuscular disorders (NMDs) comprise a group of heterogeneous genetic diseases with a broad spectrum of overlapping the clinical presentations that makes diagnosis challenging. Notably, the recent introduction of whole‐exome sequencing (WES) is introducing rapid changes on the genetic diagnosis of NMDs. We aimed to investigate the diagnostic value of WES for pediatric‐onset NMDs. Methods We applied integrated diagnostic approach and performed WES in 50 Chinese subjects (30 males, 20 females) with undiagnosed pediatric‐onset NMDs despite previous specific tests. The patients were categorized in four subgroups according to phenotyping and investigation findings. Variants on NMDs gene list and open exome analysis for those with initial negative findings were identified. Results WES identified causative variants in ACTA1 (n = 2), POMT1, COL6A1 (n = 2), MTMR2, LMNA, SELENON, DNM2, TGFB1, MPZ, IGHMBP2, and LAMA2 in 13 patients. Two subjects have variants of uncertain significance (VUSs) in TTN and SCN11A, unlikely to be pathogenic due to incompatible phenotypes. The mean interval time from symptom onset to genetic diagnosis was 10.4 years (range from 1 month to 33 years). The overall diagnostic yield of WES in our cohort was 26%. Open exome analysis was necessary to identify the pathogenic variant in TGFB1 that caused skeletal dysplasia with neuromuscular presentation. Conclusion Our study shows a clear role of WES in the pathway of integrated diagnostic approach to shorten the diagnostic odyssey in patients with rare NMDs.

Abstract Background Primary coenzyme Q10 (CoQ10) deficiencies are clinically and genetically heterogeneous group of disorders associated with defects of genes involved in the CoQ10 biosynthesis pathway. COQ7‐associated CoQ10 deficiency is very rare and only two cases have been reported. Methods and Results We report a patient with encephalo‐myo‐nephro‐cardiopathy, persistent lactic acidosis, and basal ganglia lesions resulting in early infantile death. Using whole exome sequencing, we identified compound heterozygous variants in the COQ7 gene consisting of a deletion insertion resulting in frameshift [c.599_600delinsTAATGCATC, p.(Lys200Ilefs*56)] and a missense substitution [c.319C>T, p.(Arg107Trp), NM_016138.4]. Skin fibroblast studies showed decreased combined complex II + III activity and reduction in CoQ10 level. Conclusion This third patient presenting with lethal encephalo‐myo‐nephro‐cardiopathy represents the severe end of this ultra‐rare mitochondrial disease caused by biallelic COQ7 mutations. The response to CoQ10 supplement is poor and alternative treatment strategies should be developed for a more effective management of this disorder.