A Missense Variant in PDK1 Associated with Severe Neurodevelopmental Delay and Epilepsy.

The pyruvate dehydrogenase complex (PDC) is responsible for the conversion of pyruvate into acetyl-CoA, which is used for energy conversion in cells. PDC activity is regulated by phosphorylation via kinases and phosphatases (PDK/PDP). Variants in all subunits of the PDC and in PDK3 have been reported, with varying phenotypes including lactic acidosis, neurodevelopmental delay, peripheral neuropathy, or seizures. Here, we report a de novo heterozygous missense variant in PDK1 (c.1139G > A; p.G380D) in a girl with developmental delay and early onset severe epilepsy. To investigate the role of PDK1G380D in energy metabolism and neuronal development, we used a zebrafish model. In zebrafish embryos we show a reduced number of cells with mitochondria with membrane potential, reduced movements, and a delay in neuronal development. Furthermore, we observe a reduction in the phosphorylation of PDH-E1α by PDKG380D, which suggests a disruption in the regulation of PDC activity. Finally, in patient fibroblasts, a mild reduction in the ratio of phosphorylated PDH over total PDH-E1α was detected. In summary, our findings support the notion that this aberrant PDK1 activity is the cause of clinical symptoms in the patient.

Short-term outcome predictors in infants born at 23-24 gestational weeks.

AIM: Outcome is uncertain in infants born at 23-24 gestational weeks. The aim of the present study was to identify possible early predictors of outcome in these infants. MATERIALS AND METHODS: Data from the Swedish medical birth register (MBR) for live-born infants with gestational ages (GAs) 23 and 24 weeks, born during the time-period 2000-2002, were analysed in relation to short-term outcomes, that is survival and survival without severe brain damage (intraventricular haemorrhage [IVH] grades 3 and 4 and/or periventricular leukomalacia [PVL]). RESULTS: In 57 infants born at 23 gestational weeks, survival was associated with birthweight (BW) (p = 0.018) and 5-min Apgar score (p = 0.020) on univariate analyses. In 99 infants born at 24 weeks of gestation, survival without severe brain damage correlated with BW (p = 0.039), birth type (singleton/multiple) (p = 0.017) and Apgar score at 1, 5 and 10 min (p = 0.028, 0.014 and 0.030, respectively). The best model for predicting survival without severe brain damage in infants born at 24 gestational weeks was based on 5-min Apgar score and birth type. The small number of live-born infants at 23 weeks of gestation did not allow for multiple logistic regression analyses. CONCLUSION: The 5-min Apgar score is associated with short-term outcome in live-born infants at 23-24 gestational weeks. The association is stronger for infants born at 24 weeks of gestation.

Apgar score predicts short-term outcome in infants born at 25 gestational weeks.

AIM: To identify early predictors of outcome in infants born at 25 gestational weeks. MATERIAL AND METHODS: Data from a regional perinatal database (time-period 1995-2001, total n = 108 000 births) were used. Apgar scores were available in 92 preterm infants, born at 25 + 0 to 25 + 6 gestational weeks, and analyzed in relation to short-term outcome (180-day survival with, or without, severe brain damage defined as intraventricular hemorrhage grade 3-4 or cystic periventricular leukomalacia). Based on multiple logistic regression analyses we constructed graphs of the estimated chance of survival. RESULTS: Apgar scores at 1, 5 and 10 min correlated with survival without severe brain damage (p = 0.02, 0.006 and 0.006, respectively). Survival without severe brain damage was higher in singleton than in multiple births (p = 0.03); there was no association with infant gender or mode of delivery. The strongest model for prediction of survival without severe brain damage was based on 5-min Apgar score and the Clinical Risk Index for Babies (CRIB), (p < 0.001). CONCLUSION: Apgar score predicts short-term outcome in extremely preterm infants at 25 gestational weeks. The precision for prediction of outcome increases when Apgar score is combined with CRIB.

Earlier Apgar score increase in severely depressed term infants cared for in Swedish level III units with 40% oxygen versus 100% oxygen resuscitation strategies: a population-based register study.

OBJECTIVES: The aim of this study was to evaluate whether a resuscitation strategy based on administration of 40% oxygen influences mortality rates and rates of improvement in 5-minute Apgar scores, compared with a strategy based on 100% oxygen administration. METHODS: A population-based study evaluated data from 4 Swedish perinatal level III centers during the period of 1998 to 2003. During this period, the centers used either of 2 resuscitation strategies (initial oxygen administration of 40% or 100%). Live-born, singleton, term infants with 1-minute Apgar scores of <4, with a birth weight appropriate for gestational age, and without major malformations were included in the study (n = 1223). RESULTS: Infants born in hospitals using a 40% oxygen strategy had a more rapid Apgar score increase than did infants born in hospitals using a 100% oxygen strategy; however, no difference remained at 10 minutes. The mean Apgar score increased from 2.01 at 1 minute to 6.74 at 5 minutes in the 2 hospitals initiating resuscitation with 40% oxygen, compared with 2.01 to 6.38 in the 2 hospitals using 100% oxygen, with a mean difference in Apgar score increases of 0.36. At 5 minutes, 44.3% of infants born in the hospitals using 100% oxygen had an Apgar score of <7, compared with 34.0% of infants at the hospitals using 40% oxygen. At 10 minutes, the mean Apgar scores were 8.16 at the hospitals using 40% oxygen and 8.07 at the hospitals using 100% oxygen. There were no significant differences in rates of neonatal death, hypoxic ischemic encephalopathy, or seizures in relation to the 2 oxygen strategies. CONCLUSION: Severely depressed term infants born in hospitals initiating resuscitation with 40% oxygen had earlier Apgar score recovery than did infants born in hospitals using a 100% oxygen strategy.