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Infantile cardiomyopathies are devastating fatal disorders of the neonatal period or the first year of life. Mitochondrial dysfunction is a common cause of this group of diseases, but the underlying gene defects have been characterized in only a minority of cases, because tissue specificity of the manifestation hampers functional cloning and the heterogeneity of causative factors hinders collection of informative family materials. We sequenced the exome of a patient who died at the age of 10 months of hypertrophic mitochondrial cardiomyopathy with combined cardiac respiratory chain complex I and IV deficiency. Rigorous data analysis allowed us to identify a homozygous missense mutation in AARS2, which we showed to encode the mitochondrial alanyl-tRNA synthetase (mtAlaRS). Two siblings from another family, both of whom died perinatally of hypertrophic cardiomyopathy, had the same mutation, compound heterozygous with another missense mutation. Protein structure modeling of mtAlaRS suggested that one of the mutations affected a unique tRNA recognition site in the editing domain, leading to incorrect tRNA aminoacylation, whereas the second mutation severely disturbed the catalytic function, preventing tRNA aminoacylation. We show here that mutations in AARS2 cause perinatal or infantile cardiomyopathy with near-total combined mitochondrial respiratory chain deficiency in the heart. Our results indicate that exome sequencing is a powerful tool for identifying mutations in single patients and allows recognition of the genetic background in single-gene disorders of variable clinical manifestation and tissue-specific disease. Furthermore, we show that mitochondrial disorders extend to prenatal life and are an important cause of early infantile cardiac failure.

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Objective To assess whether intrapartum acidosis affects specific components of fetal heart rate variability.Design Prospective clinical study.Setting Twelve Nordic delivery units.Subjects Fetal heart rate variability was studied in 334 fetuses divided into two groups according to cord pH value: the acidotic group (cord arterial pH <7.05 at birth, n ¼ 15) and the control group (cord arterial pH !7.05 at birth, n ¼ 319). Methods In spectral analysis of fetal heart rate variability, frequencies were integrated over the total frequency band (0.04 -1.0 Hz), low-frequency band (0.04 -0.15 Hz) and high-frequency band (0.15 -1.0 Hz). We also calculated the low-to-high frequency ratio. Main outcome measures The spectral bands of fetal heart rate variability were compared between the acidotic and control fetuses. Results We found that during the last hour of monitoring, baseline fetal heart rate gradually decreased, whereas total, low-frequency and high-frequency fetal heart rate variability initially increased but then, near the delivery, decreased in the acidotic fetuses when compared with the controls. Low-to-high frequency ratio was greater in the acidotic group during the whole study period (P ¼ 0.002). Cord artery pH was inversely associated with total fetal heart rate variability (P < 0.001), low-frequency fetal heart rate variability (P < 0.001) and low-to-high frequency ratio (P ¼ 0.004). Conclusions Marked fetal acidosis was associated with frequency-specific changes in fetal heart rate variability as reflecting the compensation ability of autonomic nervous activation during the last hour of labour.

Long-term childhood cancer survivors treated with TBI during early childhood display significant signs of premature arterial aging during young adulthood.

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Objectives: To evaluate the impact of maternal diet and intensive dietary counselling during pregnancy and breastfeeding on the infant's metabolic status. Subjects/Methods: At the first trimester of pregnancy, 256 women were randomized into a control/placebo group and two dietary counselling groups (diet/probiotics and diet/placebo). The counselling, with double-blind randomization to probiotics (Lactobacillus rhamnosus GG and Bifidobacterium lactis) or placebo, targeted excessive saturated fat and low fibre consumption. Maternal diet was evaluated repeatedly during pregnancy and postpartum by means of 3 days' food diaries. Metabolic markers, serum 32-33 split and intact proinsulin, leptin/adiponectin ratio, skinfold thickness and waist circumference were measured of 194 healthy infants at the age of 6 months, and the high levels were taken to mirror adverse metabolic status. Results: The proportion of infants with a high 32-33 split proinsulin was significantly lower in dietary counselling with probiotics (n ¼ 6/62, 9.7%) or placebo (n ¼ 7/69, 10.1%) compared with the control/placebo group (n ¼ 17/63, 27.0%). The high split proinsulin was associated with larger skinfold thickness, waist circumference and higher leptin/adiponectin ratio in the infants (Po0.05). With respect to maternal diet during pregnancy, the highest and lowest tertiles of fat intake increased the infant's risk of high split proinsulin, whereas those of butter associated correspondingly with the infant's waist circumference. Further, breastfed infants showed a reduced risk of high split proinsulin and leptin/adiponectin ratio compared with formula-fed infants. Conclusions: Modification of maternal diet during pregnancy and breastfeeding may benefit infant metabolic health. High split proinsulin reflects adverse metabolic status in infancy, which can be improved by early dietary counselling.

The aim of this study was to analyze the prevalence of frailty and physical health limitations among long-term survivors of high-risk neuroblastoma (HR NBL) and to investigate whether frail health is associated with variables of cardiovascular function, markers of inflammation and telomere length. A national study cohort of 19 (median age 22, range 16-30 years) long-term (>10 years) HR NBL survivors was studied and the findings were compared with 20 age- and sex-matched controls. Frailty was defined as ⩾3 of the following conditions: low muscle mass, low energy expenditure, slow running and weakness. The prevalence of frailty was significantly higher among the HR NBL survivors 9/19 (47%) than among the controls (0%). Thirteen (68%) of the survivors reported significant physical health limitations in vigorous activities, as opposed to none of the controls. The HR NBL survivors had significantly shorter telomere length and higher serum levels of high sensitivity C-reactive protein than did the controls. Frail health and poor physical functioning are prevalent among HR NBL survivors and suggest premature aging. Survivors with gonadal damage, very low fat mass percentage, low glycosylated hemoglobin A1c and increased common carotid artery intima-media thickness may be more prone to early aging after high dose therapy.