Aims/hypothesis Raised maternal plasma total homocysteine (tHcy) concentrations predict small size at birth, which is a risk factor for type 2 diabetes mellitus. We studied the association between maternal vitamin B 12 , folate and tHcy status during pregnancy, and offspring adiposity and insulin resistance at 6 years. Methods In the Pune Maternal Nutrition Study we studied 700 consecutive eligible pregnant women in six villages. We measured maternal nutritional intake and circulating concentrations of folate, vitamin B 12 , tHcy and methylmalonic acid (MMA) at 18 and 28 weeks of gestation. These were correlated with offspring anthropometry, body composition (dual-energy X-ray absorptiometry scan) and insulin resistance (homeostatic model assessment of insulin resistance [HOMA-R]) at 6 years. Results Two-thirds of mothers had low vitamin B 12 (<150 pmol/l), 90% had high MMA (>0.26 μmol/l) and 30% had raised tHcy concentrations (>10 μmol/l); only one had a low erythrocyte folate concentration. Although short and thin (BMI), the 6-year-old children were relatively adipose compared with the UK standards (skinfold thicknesses). Higher maternal erythrocyte folate concentrations at 28 weeks predicted higher offspring adiposity and higher HOMA-R (both p <0.01). Low maternal vitamin B 12 (18 weeks; p=0.03) predicted higher HOMA-R in the Diabetologia (2008)
Modifiable maternal nutritional factors may influence bone health in the offspring. Fathers play a role in determining their child's bone mass, possibly through genetic mechanisms or through shared environment.
Objective: To study associations of size and body proportions at birth, and growth during infancy and childhood, to body composition and cardiovascular disease (CVD) risk factors at the age of 6 years. Design: The Pune Maternal Nutrition Study, a prospective population-based study of maternal nutrition and CVD risk in rural Indian children. Methods: Body composition and CVD risk factors measured in 698 children at 6 years were related to body proportions and growth from birth. Measurements: Anthropometry was performed every 6 months from birth. At 6 years, fat and lean mass (dual X-ray absorptiometry) and CVD risk factors (insulin resistance, blood pressure, glucose tolerance, plasma lipids) were measured. Results: Compared with international references (NCHS, WHO) the children were short, light and thin (mean weight oÀ1.0 s.d. at all ages). Larger size and faster growth in all body measurements from birth to 6 years predicted higher lean and fat mass at 6 years. Weight and height predicted lean mass more strongly than fat mass, mid-upper arm circumference (MUAC) predicted them both approximately equally and skinfolds predicted only fat mass. Neither birthweight nor the 'thin-fat' newborn phenotype, was related to CVD risk factors. Smaller MUAC at 6 months predicted higher insulin resistance (Po0.001) but larger MUAC at 1 year predicted higher systolic blood pressure (Po0.001). After infancy, higher weight, height, MUAC and skinfolds, and faster growth of all these parameters were associated with increased CVD risk factors. Conclusions: Slower muscle growth in infancy may increase insulin resistance but reduce blood pressure. After infancy larger size and faster growth of all body measurements are associated with a more adverse childhood CVD risk factor profile. These rural Indian children are growing below international 'norms' for body size and studies are required in other populations to determine the generalizability of the findings.
COX5A is a nuclear-encoded subunit of mitochondrial respiratory chain complex IV (cytochrome c oxidase). We present patients with a homozygous pathogenic variant in the COX5A gene. Clinical details of two affected siblings suffering from early-onset pulmonary arterial hypertension, lactic acidemia, failure to thrive, and isolated complex IV deficiency are presented. We show that the variant lies within the evolutionarily conserved COX5A/COX4 interface domain, suggesting that it alters the interaction between these two subunits during complex IV biogenesis. In patient skin fibroblasts, the enzymatic activity and protein levels of complex IV and several of its subunits are reduced. Lentiviral complementation rescues complex IV deficiency. The monomeric COX1 assembly intermediate accumulates demonstrating a function of COX5A in complex IV biogenesis. A potential therapeutic lead is demonstrated by showing that copper supplementation leads to partial rescue of complex IV deficiency in patient fibroblasts.
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