Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment.

In the folate cycle MTHFD1, encoded by MTHFD1, is a trifunctional enzyme containing 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase activity. To date, only one patient with MTHFD1 deficiency, presenting with hyperhomocysteinemia, megaloblastic anaemia, hemolytic uremic syndrome (HUS) and severe combined immunodeficiency, has been identified (Watkins et al J Med Genet 48:590-2, 2011). We now describe four additional patients from two different families. The second patient presented with hyperhomocysteinemia, megaloblastic anaemia, HUS, microangiopathy and retinopathy; all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid. The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia, and was successfully treated with a regime that included and was eventually reduced to folic acid. The other two, elder siblings of the third patient, died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis and had MTFHD1 deficiency diagnosed retrospectively. We identified a missense mutation (c.806C > T, p.Thr296Ile) and a splice site mutation (c.1674G > A) leading to exon skipping in the second patient, while the other three harboured a missense mutation (c.146C > T, p.Ser49Phe) and a premature stop mutation (c.673G > T, p.Glu225*), all of which were novel. Patient fibroblast studies revealed severely reduced methionine formation from [(14)C]-formate, which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid. These additional cases increase the clinical spectrum of this intriguing defect, provide in vitro evidence of disturbed methionine synthesis and substantiate the effectiveness of folic or folinic acid treatment.

Spectrum of chronic lung disease in a population of newborns with extremely low gestational age.

AIMS: To determine how the ability to oxygenate the blood develops after birth in infants of extremely low gestational age (ELGANs) and to find risk factors for chronic lung disease. METHOD: A prospective, population-based, cohort study was undertaken in one tertiary-care centre. The alveolar-arterial oxygen pressure difference (AaDO(2)) was monitored. RESULTS: Of 41 survivors, 21 had a period of normal lung function in the first week of life, after which oxygenation deteriorated. Low gestational age and low Apgar score at 5 min were found to be strong and independent predictors of AaDO(2) in the first month of life. Mechanical ventilation did not appear as a risk factor. Lung function at 36 weeks of gestation and duration of oxygen treatment could be better predicted by the severity of lung disease in the first month than by gestational age at birth. CONCLUSIONS: Difficulty in oxygenation was a general observation in ELGANs and not only a particular subset. Gestational age and Apgar score were independent predictors of the degree of difficulty over the first month of life. As oxygenation failure often developed after a few days, the process may be possible to treat or prevent once the pathogenesis is known.

Fetal heart rate pattern and risk for respiratory disturbance in full-term newborns.

Etiologic and pathogenetic factors responsible for respiratory disturbances in full-term infants are still unclear. The authors' intention was to analyze to what extent fetal stress, expressed in terms of abnormal fetal heart rate pattern, was reflected in neonatal respiratory disturbance. The study was performed prospectively over one year and included 157 term infants. Contrary to general belief, there was a significantly lower incidence of respiratory disturbances after ominous fetal heart rate pattern, ie, basal bradycardia, late or severe variable decelerations, and reduced variability than after a normal fetal heart rate pattern. It is suggested that these results may be due to a favorable effect on the fetal lung of systemic or local factors, produced in response to intrauterine stress.

3-Methylglutaconic aciduria in two infants.

We studied two children who developed normally for the first 3-4 months of life and then displayed a failure-to-thrive syndrome, regression in psychomotor development, pronounced muscular hypotonia, and liver damage. At the age of about 1-2 years, optic atrophy and spastic parapareses were evident. One child died at the age of 2.5 years the other at an age of 4 years. Both children excreted 3-methylglutaconic acid, 0.1-0.4 mol/mol creatinine and 3-methylglutaric acid, 0.02-0.05 mol/mol creatinine. The excretion of 3-hydroxy-3-methylglutaric acid was not increased. One of the children was available for further biochemical studies. The activity of hydroxymethylglutaryl-CoA lyase (EC 4.1.3.4) was moderately reduced in leucocytes and fibroblasts. During a 21-h fast there was a normal formation of ketone bodies and we conclude that the cause of the syndrome is not a deficiency of hydroxymethylglutaryl-CoA lyase. Normal formation of 14CO2 from [1-14C]isovaleric acid and [2-14C]leucine in fibroblasts and leucocytes apparently excludes a deficiency of methylglutaconyl CoA-hydratase (EC 4.2.1.18).

Moment analysis of multibreath nitrogen washout in healthy preterm infants.

Moment analysis (MA) of multibreath nitrogen washout (MBNW) has not previously been applied to newborn infants. The aim of the present study was to adapt this method to healthy preterm infants using an improved technique suitable for small infants, and to determine reference values of MA. Twenty healthy preterm infants with a mean birth weight (+/-SD) of 1,666+/-402 g and a mean gestational age of 31.3+/-2.1 weeks were studied during their first 7-28 days of life. Computerized bedside equipment with very low dead space was constructed. The limits of normal variability were determined from results of duplicate studies. Outcome variables included functional residual capacity (FRC), the first-to-zeroth moment ratio (M1/M0), the second-to-zeroth moment ratio (M2/M0), and the lung clearance index (LCI). The starting point for MA had considerable impact on the results. Mean M1/M0 and M2/M0 were 2.18+/-0.18 and 8.71+/-1.24, respectively. No significant relation between moment ratios and weight, gender or age was found. Intrasubject coefficients of variation (CV) for M1/M0 (7.9+/-5.9%) and for M2/M0 (12.1+/-9.1%) and intersubject CV for M1/M0 (8%) and M2/M0 (14%) were similar to those reported in children and adults. Mean lung clearance index was 10.8+/-1.4 and intra- and intersubject CVs were 11.3+/-8.9% and 13%, respectively. Mean functional residual capacity (FRC) was 22.5+/-2.1 ml/kg. Mean intra- and intersubject CVs for FRC were 8.3% and 9%, respectively. We conclude that the MBNW test can be performed by a simple bedside method and that MA appears to be a suitable method for measuring gas mixing in preterm infants.

Mitochondrial myopathy and cardiomyopathy in siblings.

Two siblings with infantile lactic acidosis and mitochondrial myopathy are described. The first child, a girl, died at 5 months of age from severe lactic acidosis after about 3 weeks of progressive muscular hypotonia. The younger brother had congenital lactic acidosis but no other symptoms until 6 months of age when progressive muscle weakness appeared. Treatment with dichloroacetate lowered the serum lactic acid level but did not affect his clinical condition. At 13 months of age, cardiomyopathy was diagnosed and he died at the age of 29 months of circulatory failure. Both children had mitochondrial myopathy. Postmortem examination of the boy revealed marked morphologic changes of the mitochondria in both skeletal muscle and the myocardium; biochemical investigation of skeletal muscle mitochondria demonstrated deficiencies in both complex I (NADH ferricyanide reductase) and complex IV (cytochrome c oxidase). The disease in these siblings differs in several respects from previously reported patients with mitochondrial myopathy and cytochrome c oxidase deficiency.

Lung function testing--useless in ventilated newborns?

Several methods have been used for lung function testing in the ventilated newborn. The interest in the field has been stimulated by the recent appearance of commercially available equipment for assessment of mechanical parameters and of functional residual capacity in this group. Nevertheless, lung function testing is rarely used as a clinical routine, even such simple variables as tidal volume and minute ventilation. Among the many possible reasons for this condition, the fragile nature of the infants and the hands-off policy usually exercised, the difficulties in measuring flow accurately, and the complexity of the present methods deserve special attention. In order to change this situation more work needs to be done to elucidate basal physiology of the ventilated lung and the relationships between ventilator settings, lung function and side-effects in different conditions. If then sufficiently simple, safe and accurate methods to assess the most important functions can be offered, lung function testing would be likely to become a useful component of routine care in future neonatal intensive care.

Epidemiology and classification of acute, neonatal respiratory disorders. A prospective study.

In a prospective study a population of 32 281 newborn infants in Sweden was screened for signs of respiratory disease. All affected infants (2.9%) were investigated systematically and classified. Incidence and case fatality rates were calculated and related to gestational age, birth weight, sex and postnatal asphyxia, all of which strongly influenced one or both rates. The diagnostic system used was found suitable for future epidemiological research.

Need of hospital care for newborn infants. A population analysis of preterm infants and infants with respiratory disturbances.

In a prospective study of a total population the hospital resources required for the care of preterm infants and infants with respiratory disturbances (RD) were analyzed. 5.2% of all the infants were preterm and 7.6% developed RD. For the care of preterm infants the requirements were 63.8 beds per 1,000 annual preterm births of which 8.3 beds were attributable to the care of RD in these infants. Full term infants needed 0.88 hospital beds per 1,000 annual full term births for respiratory care. The number of days on ventilator for preterms was calculated to 2,044 per 1,000 annual preterm births. For preterm infants the mode of delivery was not found to affect the length of hospitalization. For the total population the average need of hospital days for full term infants because of RD was 0.29 days after vaginal delivery compared with 0.78 days after elective Caesarean section.

Impaired gas mixing and low lung volume in preterm infants with mild chronic lung disease.

The aim of this study was to assess the possible role of gas mixing inefficiency in spontaneously breathing infants with mild chronic lung disease (CLD) of prematurity in relation to changes in other functional parameters. A simple bedside technique for recording and analysis of multiple breath nitrogen washout curves was applied together with occlusion mechanics. Fifteen preterm infants with mild or moderately severe CLD were studied at a mean postconceptional age of 35 wk, together with 15 healthy preterm infants at the same maturity. All infants breathed spontaneously, and the test was performed by a continuous bypass flow system, connected to a face mask, a pneumotachograph, and a nitrogen meter. The results showed impaired gas mixing with moment ratios above the 95th percentile of the normal group in 11/15 infants with CLD. Functional residual capacity (FRC) was low in 13/15 infants, but specific compliance and resistance of the respiratory system did not differ between the groups. As FRC and moment ratios were not correlated, it is suggested that they may reflect different aspects of the pathophysiology in CLD. It is concluded that low FRC and disturbed gas mixing are characteristic disturbances in CLD at different degrees of severity. The multiple breath nitrogen washout test, followed by moment analysis of end-tidal nitrogen concentrations, is a simple and sensitive method for detection of these disturbances and for monitoring purposes.

Bilateral renal asplasia without Potter's syndrome.

A newborn infant with bilateral aplasia of kidneys and ureters and a rudimentary bladder is reported. Other manifestations of Potter's syndrome (oligohydramnios, lung hypoplasia and an abnormal face) were missing as were other congenital malformations. Deviations from the full picture of Potter's syndrome seem to be rare. This case, however, shows that bilateral renal aplasia cannot be excluded as a cause of anuria in a newborn infant, even if all other manifestations of Potter's syndrome are missing.

Efficiency of ventilation in neonatal pulmonary maladaptation.

Lung physiology was studied in sixteen infants with pulmonary maladaptation (PMA) during the course of the disease and after clinical recovery. A sensitive nitrogen washout method was used. During the disease the infants showed reduced ventilatory efficiency and increased dead space. Total ventilation increased simultaneously, while alveolar ventilation was maintained. The majority of the infants showed greater functional residual capacity during the disease than after clinical recovery. The results suggest that gas mixing efficiency is impaired in infants with PMA and that this might be due to effects on the small airway function in the lungs.

Low Apgar score as a risk factor for respiratory disturbances in the newborn infant.

The value of the Apgar score as a risk factor for all neonatal respiratory disturbances (RD) was evaluated in a prospective study of an unselected population. All liveborn infants (n = 4656) of mothers living in Gothenburg were screened over one year for signs of respiratory disease. This unselected population could be obtained since virtually all infants in Gothenburg are born in two maternity hospitals, with similar treatment principles, the same equipment standard and neonatal care. A low one minute Apgar score (less than 7) was found to be a powerful risk factor for RD in full term newborns and infants of 33-36 weeks gestation provided that the delivery had been vaginal. In these infants a low Apgar score at five minutes further increased the risk of RD. In immature infants less than 32 weeks and after cesarean section in all gestational ages a low Apgar score did not mean any additional risk of RD. The respiratory component in the Apgar score was not more predictive of RD than any of the others. In most infants with RD, irrespective of Apgar score, there was a few hours interval free from respiratory signs after birth. It has been well shown in other studies that Apgar score is not a reliable index of intrauterine or birth asphyxia. Nevertheless the one-minute score is a powerful predictor of neonatal respiratory difficulties. One explanation might be that Apgar score is correlated with sympathoadrenal activity at birth.(ABSTRACT TRUNCATED AT 250 WORDS)

Lung function in newborn infants with tachypnea of unknown cause.

Twenty-one infants with tachypnea (f greater than 60/min) lasting more than 2 h and diagnosed as mild respiratory disease or pulmonary maladaptation according to previously presented criteria were studied during the course of the disease and after clinical recovery. Lung physiology (total and alveolar ventilation, efficiency and distribution of ventilation, functional residual capacity, and lung mechanics) was studied in combination with clinical data. The pathophysiological findings were characterized by increased total ventilation but normal alveolar ventilation, reduced efficiency of ventilation but more even distribution of ventilation (nitrogen elimination pattern) during disease than after clinical recovery, hyperinflation, reduced dynamic lung compliance but unaffected specific lung conductance. Infants with low gestational ages were most severely affected and had longer duration of disease than full-term infants. Our findings suggest that this condition is caused by small airway disease. Disturbances in normal pulmonary adaptation with abnormal retention of lung fluid is the most probable cause.

Interval from rupture of the membranes to delivery and neonatal respiratory adaptation.

The influence of the time interval from rupture of the membranes to delivery on neonatal respiratory adaptation was analysed in a prospective study of all infants born in Göteborg, Sweden in one year. The correlation between the incidence of respiratory disorders and the rupture-delivery interval was analysed in all preterm infants (less than or equal to 36 weeks, n = 240) and in all term infants born by caesarean section (n = 452). A uniform pattern was found for all preterm infants, irrespective of mode of delivery, and for the term infants born by caesarean section. The curve was 'U-shaped' with higher incidence of respiratory diseases in infants born immediately after rupture of the membranes than in those born 3-36 h after membrane rupture. The incidence increased again in infants born greater than 36 h after membrane rupture. The same pattern was found for all kinds of respiratory diseases including idiopathic respiratory distress syndrome. Therefore, there seems to be no advantage in postponing delivery greater than 36 h after rupture of the membranes.

Effects of delivery by caesarean section on lung function in healthy newborn infants.

With the aim of extending previous studies showing differences in lung function after birth between infants delivered vaginally (VD) and by Caesarean section (CS) we investigated lung volumes, ventilation, efficiency of ventilation, and lung mechanics in 24 healthy, full term infants with no clinical signs of respiratory disease, 12 after VD and 12 after CS. Measurements were made on two occasions: 2 and 26 hours after birth. At 2 hours no differences in any measured quantity were found between the groups. The only difference found 24 hours later was that the average thoracic gas volume (TGV), was lower in infants after CS than after VD. The difference in functional residual capacity was, however, not significant. This means that the difference in TGV, previously also found by other workers, did not affect the ventilated air space. Our results do not support the theory of general inferiority in lung performance after birth in healthy, full term infants without respiratory disease delivered by CS.