Phenotypic, molecular, and functional characterization of COQ7-related primary CoQ10 deficiency: Hypomorphic variants and two distinct disease entities.

Primary coenzyme Q10 (CoQ10) deficiency is a group of inborn errors of metabolism caused by defects in CoQ10 biosynthesis. Biallelic pathogenic variants in COQ7, encoding mitochondrial 5-demethoxyubiquinone hydroxylase, have been reported in nine patients from seven families. We identified five new patients with COQ7-related primary CoQ10 deficiency, performed clinical assessment of the patients, and studied the functional effects of current and previously reported COQ7 variants and potential treatment options. The main clinical features included a neonatal-onset presentation with severe neuromuscular, cardiorespiratory and renal involvement and a late-onset disease presenting with progressive neuropathy, lower extremity weakness, abnormal gait, and variable developmental delay. Baker's yeast orthologue of COQ7, CAT5, is required for growth on oxidative carbon sources and cat5Δ strain demonstrates oxidative growth defect. Expression of wild-type CAT5 could completely rescue the defect; however, yeast CAT5 harboring equivalent human pathogenic variants could not. Interestingly, cat5Δ yeast harboring p.Arg57Gln (equivalent to human p.Arg54Gln), p.Arg112Trp (equivalent to p.Arg107Trp), p.Ile69Asn (equivalent to p.Ile66Asn) and combination of p.Lys108Met and p.Leu116Pro (equivalent to the complex allele p.[Thr103Met;Leu111Pro]) partially rescued the growth defects, indicating these variants are hypomorphic alleles. Supplementation with 2,4 dihydroxybenzoic acid (2,4-diHB) rescued the growth defect of both the leaky and severe mutants. Overexpression of COQ8 and 2,4-diHB supplementation synergistically restored oxidative growth and respiratory defect. Overall, we define two distinct disease presentations of COQ7-related disorder with emerging genotype-phenotype correlation and validate the use of the yeast model for functional studies of COQ7 variants.

Advancement of a standardised enteral feeding protocol in functional single ventricle patients following stage I palliation using cerebro-somatic near-infrared spectroscopy.

INTRODUCTION: Infants with single ventricle following stage I palliation are at risk for poor nutrition and growth failure. We hypothesise a standardised enteral feeding protocol for these infants that will result in a more rapid attainment of nutritional goals without an increased incidence of gastrointestinal co-morbidities. MATERIALS AND METHODS: Single-centre cardiac ICU, prospective case series with historical comparisons. Feeding cohort consisted of consecutive patients with a single ventricle admitted to cardiac ICU over 18 months following stage I palliation (n = 33). Data were compared with a control cohort and admitted to the cardiac ICU over 18 months before feeding protocol implementation (n = 30). Feeding protocol patients were randomised: (1) protocol with cerebro-somatic near-infrared spectroscopy feeding advancement criteria (n = 17) or (2) protocol without cerebro-somatic near-infrared spectroscopy feeding advancement criteria (n = 16). RESULTS: Median time to achieve goal enteral volume was significantly higher in the control compared to feeding cohort. There were no significant differences in enteral feeds being held for feeding intolerance or necrotising enterocolitis between cohorts. Feeding cohort had significant improvements in discharge nutritional status (weight, difference admit to discharge weight, weight-for-age z score, volume, and caloric enteral nutrition) and late mortality compared to the control cohort. No infants in the feeding group with cerebro-somatic near-infrared spectroscopy developed necrotising enterocolitis versus 4/16 (25%) in the feeding cohort without cerebro-somatic near-infrared spectroscopy (p = 0.04). CONCLUSIONS: A feeding protocol is a safe and effective means of initiating and advancing enteral nutrition in infants following stage I palliation and resulted in improved nutrition delivery, weight gain, and nourishment status at discharge without increased incidence of gastrointestinal co-morbidities.