Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin.

Pyruvate carboxylase is a mitochondrial enzyme essential for the tricarboxylic acid cycle (TCA), gluconeogenesis and fatty-acid synthesis. Pyruvate carboxylase deficiency (PCD) mostly presents with life-limiting encephalopathy (types A/B). A milder type C presentation is rare, with a comparatively favourable prognosis. Therapies remain essentially supportive. Triheptanoin is an odd-chain triglyceride, with the potential to replenish TCA intermediates (anaplerosis), and its metabolites cross the blood-brain-barrier. Outcomes of triheptanoin treatment in PCD types A/B have been disappointing, but have not been reported in type C. Here, we present two new patients with PCD type C, and report the response to treatment with triheptanoin in one. Patient 1 (P1) presented with neonatal-onset lactic acidosis and recurrent symptomatic lactic acidosis following exercise and during illnesses, with frequent hospitalisations. Speech development was delayed. MRI-brain showed delayed cerebral myelination. Patient 2 (P2) presented with episodic ketoacidosis, hyperlactataemia and hypoglycaemia at 2 years of age, with gross motor delay and mild global volume loss on MRI brain. Treatment with triheptanoin was commenced in P1 at 3 years of age with up-titration to 35 mL/day (25% of daily energy intake) over 6 months, due to transient diarrhoea. Dietary long-chain triglycerides were restricted, with fat-soluble vitamin supplementation. Subsequently, hospitalisations during intercurrent illnesses decreased, post-exertional hyperlactataemia resolved and exercise tolerance improved. Continued developmental progress was observed, and repeat MRI 18 months after initiation showed improved myelination. Triheptanoin was well-tolerated and appeared efficacious during 2 years' follow-up, and has potential to restore energy homeostasis and myelin synthesis in PCD type C.

Body composition of New Zealand-born term babies differs by ethnicity, gestational age and sex.

BACKGROUND: Body composition provides important information on nutrition and future metabolic risk. New Zealand has a diverse ethnic population for which there are no newborn body composition data. AIM: To determine body composition in a cohort of New Zealand-born term babies. STUDY DESIGN: Observational study. SUBJECTS: Healthy, term infants between 37+0 and 41+6 weeks' gestation in two hospitals in Auckland, New Zealand. OUTCOME MEASURES: Body composition by air displacement plethysmography and anthropometry measured within 5 days of birth. Parent-identified ethnicity was prioritised according to Ministry of Health criteria. Data were analysed using t-test, ANOVA with Tukey post-hoc tests, quantile regression and are mean(SD). RESULTS: 440 babies (54% male) were included. Pacific Island/Maori (PI/M) were heavier at birth than Asian/Middle Eastern/Latin American/African (Asian+) babies (3403(506) vs 3181(485) g, p < .05). PI/M and European (E) babies were longer with larger head and waist circumferences than Asian+ babies (all p < .05). Absolute fat mass (FM) was not different amongst ethnicities (E, 365(156), PI/M, 347(183), Asian+, 357(188) g) but PI/M babies had significantly lower FM% than Asian+ (9.8(4.3) vs 10.9(4.5) %, p < .05). Fat-free mass (FFM) was greater in PI/M (3056(400) g) than E (2952(345) g (p < .05) and both PI/M and E had greater FFM than Asian+ (2824(363) g, p < .05). Early term babies had less FFM than term and late-term babies (2732(370), 3012(352), 3173(302)g, p < .001) respectively. CONCLUSIONS: Asian+ babies were the smallest babies with the least FFM yet had similar FM and the highest FM%, indicative of a thin, fat phenotype from birth.

SARS-CoV-2 spike protein predicted to form complexes with host receptor protein orthologues from a broad range of mammals.

SARS-CoV-2 has a zoonotic origin and was transmitted to humans via an undetermined intermediate host, leading to infections in humans and other mammals. To enter host cells, the viral spike protein (S-protein) binds to its receptor, ACE2, and is then processed by TMPRSS2. Whilst receptor binding contributes to the viral host range, S-protein:ACE2 complexes from other animals have not been investigated widely. To predict infection risks, we modelled S-protein:ACE2 complexes from 215 vertebrate species, calculated changes in the energy of the complex caused by mutations in each species, relative to human ACE2, and correlated these changes with COVID-19 infection data. We also analysed structural interactions to better understand the key residues contributing to affinity. We predict that mutations are more detrimental in ACE2 than TMPRSS2. Finally, we demonstrate phylogenetically that human SARS-CoV-2 strains have been isolated in animals. Our results suggest that SARS-CoV-2 can infect a broad range of mammals, but few fish, birds or reptiles. Susceptible animals could serve as reservoirs of the virus, necessitating careful ongoing animal management and surveillance.

Feralisation targets different genomic loci to domestication in the chicken.

Feralisation occurs when a domestic population recolonizes the wild, escaping its previous restricted environment, and has been considered as the reverse of domestication. We have previously shown that Kauai Island's feral chickens are a highly variable and admixed population. Here we map selective sweeps in feral Kauai chickens using whole-genome sequencing. The detected sweeps were mostly unique to feralisation and distinct to those selected for during domestication. To ascribe potential phenotypic functions to these genes we utilize a laboratory-controlled equivalent to the Kauai population-an advanced intercross between Red Junglefowl and domestic layer birds that has been used previously for both QTL and expression QTL studies. Certain sweep genes exhibit significant correlations with comb mass, maternal brooding behaviour and fecundity. Our analyses indicate that adaptations to feral and domestic environments involve different genomic regions and feral chickens show some evidence of adaptation at genes associated with sexual selection and reproduction.