Fatal neonatal lactic acidosis caused by a novel de novo mitochondrial G7453A tRNA-Serine ((UCN)) mutation.

INTRODUCTION: Heteroplasmic mitochondrial DNA (mtDNA) mutations are an important cause of childhood disorders, but the role of homoplasmic mtDNA mutations in severe neonatal manifestations is not well understood. METHODS: The following were performed: full mtDNA sequencing for mutation detection, blue-native protein analysis of autopsy-derived tissues to detect respiratory chain (RC) deficiency, light and electron microscopy for morphologic analysis, and northern blot and computational modeling to study the effect of mtDNA mutations on transfer RNA (tRNA) stability. RESULTS: We describe data from a patient with fatal neonatal lactic acidosis caused by a novel homoplasmic mutation at a highly conserved nucleotide G7453A within the tRNA(Ser (UCN)) in mtDNA. The patient's heart, skeletal muscle, brain, and liver showed severe combined complex I and IV (CI and CIV) deficiencies, accompanied by severe depletion of mature tRNA(Ser (UCN)). The mutation was absent in the patient's mother and in a placental sample from a subsequent pregnancy of the mother, suggesting a de novo mutation. DISCUSSION: We conclude that the G7453A mutation of mtDNA manifests with exceptional severity as compared with other tRNA(Ser (UCN)) mutations, typically associated with sensorineural deafness. De novo homoplasmic mtDNA tRNA-mutations should be considered as a cause of fatal neonatal lactic acidosis.

Birth weight and adult lung function: a within-pair analysis of twins followed up from birth.

BACKGROUND: The aim of the study was to evaluate whether there is any association between intrauterine growth and later lung function or bronchial reactivity in early adulthood in line with Barker's hypothesis. METHODS: Nineteen twin pairs with disproportionate intrauterine growth pattern were followed up from birth: either one of the pairs had intrauterine growth retardation (birth weight <2 SD) or the within-pair birth weight difference was >1.3 SD. Flow-volume spirometry, followed by isocapnic hyperventilation of cold air, was performed at the ages of 8-16 and 14-22 years in 1993 and 1999. Wilcoxon's matched-pairs analysis was used to compare smaller and larger twin pairs. RESULTS: In 1993, there were no significant differences between the groups in either spirometry or cold air challenge. In 1999, such a difference was found in forced expiratory volume % (FEV%) and forced expiratory flow (FEF) at 25%-75%, the smaller twin pairs having lower values. In 1993, nine subjects reacted to cold air (>9% decrease in FEV in 1 second). In 1999, only four subjects reacted to cold air, and they all belonged to the group of smaller twins (P=0.04). CONCLUSION: Lung function evaluated by FEV% and FEF25-75 was lower and responses to cold air were more common at the median age of 16 years in twins with impaired intrauterine growth.

Pretreatment cortisol values may predict responses to hydrocortisone administration for the prevention of bronchopulmonary dysplasia in high-risk infants.

OBJECTIVES: To investigate the effect of hydrocortisone treatment on survival without bronchopulmonary dysplasia (BPD) and to study whether serum cortisol concentrations predict the response. STUDY DESIGN: We performed a randomized, placebo-controlled trial on infants with gestation < or =30 weeks, body weight of 501 to 1250 g, and respiratory failure. Hydrocortisone was started before 36 hours of age and given for 10 days at doses from 2.0 to 0.75 mg/kg per day. Shortly before hydrocortisone treatment, basal and stimulated (ACTH, 0.1 microg/kg) serum cortisols were measured. RESULTS: The study was discontinued early, because of gastrointestinal perforations in the hydrocortisone group (4/25 vs 0/26, P = .05); 3 of the 4 had received indomethacin/ibuprofen. The incidence of BPD (28% vs placebo 42%, P = 0.28) tended to be lower, and patent ductus arteriosus (36% vs 73%, P = .01) was lower in the hydrocortisone group. The hydrocortisone-treated infants with serum cortisol concentrations above the median had a high risk of gastrointestinal perforation. In infants with cortisol values below the median, hydrocortisone treatment increased survival without BPD. CONCLUSIONS: Serum cortisol concentrations measured shortly after birth may identify those very high-risk infants who may benefit from hydrocortisone supplementation.

Vertebral artery insufficiency as a possible mechanism for sudden infant death--in vivo evidence does not support findings from postmortem studies.

Recent postmortem studies have suggested that sudden infant death syndrome (SIDS) might involve an underlying, gradual brain stem injury caused by repeated episodes of transiently compromised brain stem circulation. Autopsy studies have also reported that vertebral artery occlusion due to head rotations, such as occurs, e.g. during prone sleeping, would be a physiological phenomenon of infant atlantooccipital junction. The present study was undertaken to examine whether vertebral artery insufficiency does truly occur in live infants during such head rotations. We studied by transcranial doppler sonography the blood flow velocity of the basilar artery (BA) in 27 infants during head rotation from straight position to maximal rotation in three directions (left, right, dorsiflexion). No significant change in BA blood flow was seen between any head positions. Weight and gestational age, but not arterial pressure or hematocrit, of the infants were correlated with blood flow velocity. Our results suggest that brain stem circulation in live infants may not be compromised due to changing the head position, which is inconsistent with the postmortem findings showing insufficiency of brain stem circulation in both controls and those succumbed to SIDS. We hence propose that the brain stem pathology observed with SIDS is likely caused by other factors (e.g. systemic disturbance) rather than by mechanical obstruction of brain stem circulation.

Determinants of bronchial responsiveness to methacholine at school age in twin pairs.

The methacholine inhalation challenge test (MIC) was used to evaluate bronchial responsiveness in 67 children who were the products of multiple pregnancies when they were 7-15 years old. At birth, 30 (45%) infants had intrauterine growth retardation (IUGR; birth weight <2 SD below normal birth weight, or birth weight difference >1.3 SD between twin-pairs), and 59 (88%) were born before 37 weeks of gestation. None of the children had doctor-diagnosed asthma. The provocative dose of methacholine causing a 20% fall in Wright's peak expiratory flow (WPEF) (PD20) was below 1,000 microg in 10 (15%) children, and they were classified as MIC responders. There were no differences in perinatal or neonatal factors between MIC responders and nonresponders; in particular, MIC responses did not differ between IUGR infants, and children with appropriate growth for gestational age (AGA) at birth. There were seven discordant pairs in which one child was a MIC responder and the other was not; 5 responders were IUGR, and 2 were AGA children (ns). Respiratory tract infections after the neonatal period were equally common in IUGR and AGA children. However, these infections were associated with later bronchial hyperresponsiveness. Doctor-diagnosed respiratory infections, numbers of antibiotic courses, episodes of otitis media, and the need for adenoidectomy, tonsillectomy, and tympanostomy were more common in MIC responders than in nonresponders. We conclude that IUGR was not associated with subsequent bronchial hyperresponsiveness in twin pairs assessed by the MIC test. A significant relationship was seen between bronchial hyperresponsiveness and infections after the neonatal period.