Grant Morrow

Respiratory Distress Syndrome of Newborn Infants I. New Clinical Scoring System (RDS Score) with Acid-Base and Blood- Gas Correlations

From the Section on 1~’ecvborn Pediatrics, Pennsylvania Hospital, and the Departments of Anesthesia and Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pa. 19104. Supported in part by grants NB 04828, NB 02367, and PA 43684 from the U. S. Public Health Service, National Institutes of Health. P-r-AJL 0 assess objectively the severity of idiopathic respiratory distress syndrome of the newborn (RDS) and the effects of therapy requires serial measurements of arterial pH and blood-gas tensions., The pediatrician for whom these measurements are not available

Deranged B12 metabolism: Effects on sulfur amino acid metabolism

Abstract Several enzymes have been studied in the tissues of a patient who had a combination of increased homocystine and cystathionine and decreased methionine in plasma, tissues, and urine. This patient specifically lacked activity of N 5 -methyltetrahydrofolate-homocysteine methyltransferase. In addition, the patient excreted an increased amount of methylmalonic acid. His liver had an abnormally low methylmalonyl-CoA isomerase activity unless supplemented with deoxyadenosyl-B 12 . These findings, as well as others presented elsewhere (3, 4), indicate that the deficient enzyme activities were due to lack of the suitable B 12 -containing coenzymes rather than to primary lack of the apoenzymes. Deficient activity of cystathionine synthase or cystathionase, which often cause homocystinuria and cystathioninuria, respectively, are ruled out in this patient. Amino acid concentrations and enzyme activities have been measured also in the tissues of a second patient with many biochemical abnormalities similar to those found in the first patient. The findings indicate that remethylation of homocysteine by N 5 -methyltetrahydrofolate methyltransferase, under at least some conditions, may be a physiologically important reaction.

Observations on the coexistence of methylmalonic acidemia and glycinemia

Methylmalonic acidemia and ketotic glycinemia are clinically indistinguishable. Both disorders if untreated are characterized by vomiting, lethargy, failure to thrive, hepatomegaly, ketoacidosis, osteoporosis, neutropenia, and thrombocytopenia. Biochemically, however, they are distinct entities. Glycinemia patients do not excrete methylmalonate, whereas in methylmalonic acidemia massive urinary methylamalonate is an essential finding. Some patients with methylmalonic acidemia are responsive to massive doses of vitamin B 12 .

Prenatal detection of methylmalonic acidemia

Summary The case report of a pregnant woman heterozygous for methylmalonic acidemia is presented. The fetus was suspected of having the disease prenatally because of increasing amounts of methylmalonate in the maternal urine and in amniotic fluid during the third trimester. After birth the diagnosis of methylmalonic acidemia was confirmed in the child. Neither mother nor child had evidence of vitamin B 12 deficiency. This demonstration appears to be the first example of an inborn error of metabolism identified by measuring maternal secretions for an inappropriate metabolite.

Exchange transfusion in the newborn infant with fresh and “old” blood: The role of storage on 2,3-diphosphoglycerate, hemoglobin-oxygen affinity, and oxygen release

The hemoglobin-oxygen equilibrium curve and red cell 2,3-diphosphoglycerate values were measured in 29 infants before and after exchange transfusions for hyperbilirubinemia. In 12 infants the blood used for exchange was 4 to 5 days old (Group 1), while in the other 10 the blood was used within 24 hours of collection in acid-citrate-dextrose. The mean P 50 and the mean red cell 2,3-diphosphoglycerate were similar in both groups prior to exchange transfusion and averaged 20.0 mm. Hg and 4,250 mμm per milliliter of red blood cells, respectively. In the infants in Group 1 the mean postexchange P 50 fell to 17.1, rose to 23.0 at 24 hours, and was 27.9 mm. Hg 5 days later. The 2,3-diphosphoglycerate values at these times averaged 1.6, 3.1, and 6.5 mmoles per milliliter of red blood cells. In contrast, in the infants in Group 2, the P 50 immediately after exchange transfusion had risen to 23.1, was 25.9 at 24 hours, and was 28.1 five days after exchange. The 2,3-diphosphoglycerate values at these times averaged 3.5, 4.9, and 6.5 mmoles per milliliter of red blood cells. These studies illustrate that while blood less than 5 days of age is generally considered to be suitable for exchange transfusions, considerable differences exist between blood of one and 5 days of age with respect to oxygen affinity. It is suggested that only truly fresh blood be employed for exchange transfusion in any severely ill infant.

Studies in a patient with methylmalonic acidemia

The biochemical and therapeutic responses in a patient with methylmalonic acidemia unresponsive to vitamin B 12 are discussed. Hypooxaluria, hypoglycemia, hyperammonemia, and aberrant amino acid patterns were components of this patients disorder. A decrease in methylmalonyl isomerase activity appears to be the most likely site for the defect. Various therapeutic measures to lower methylmalonate excretion were of only limited effectiveness.

Studies of methylmalonyl coenzyme A carbonylmutase activity in methylmalonic acidemia. I. Correlation of clinical, hepatic, and fibroblast data.

Extract: Methylmalonyl-CoA carbonylmutase (mutase) activity was measured in fibroblast extracts from 15 patients with methylmalonic acidemia and in extracts of postmortem tissues from 6 of these children. Propionate oxidation and synthesis of 5′-deoxyadenosylcobalamin (AdoCbl, the vitamin B12 coenzyme that is part of the mutase holoenzyme) were measured in intact fibroblasts. Mutase activity was low in the absence of added AdoCbl in fibroblast extracts from both control subjects and patients. When the assay included supplemental AdoCbl, mutase activity increased in the control subjects (to 24.0 pmol succinate/mg protein/mini and in extracts from eight of the patients (20.8 pmol/mg protein/min), but showed almost no change in extracts from the other seven patients (0.16 pmol/mg protein/min). We have defined the eight fibroblast lines that showed normal mutase activity in the presence of AdoCbl as “responsive lines” and the other seven lines as “nonresponsive.” In the liver or kidney extracts of postmortem tissues, mutase activity responded to AdoCbl supplementation if fibroblast mutase activity from that patient had responded, and failed to respond if fibroblast activity failed to respond. Mean propionate oxidation in intact fibroblasts was much higher in control lines than in either responsive or nonresponsive lines (0.728 vs 0.097 vs 0.080 nmol CO2/106 cells/hr, respectively). AdoCbl synthesis was normal (0.27 pg AdoChl/mg cells wet weight) in nonresponsive fibroblasts but was undetectable (<0.005 pg/mg cells) in the responsive lines. Thus, the deficiency of mutase activity in responsive fibroblast lines is due to the failure to synthesize significant amounts of AdoCbl, whereas the deficiency in nonresponsive lines is due to some other abnormality, presumably a defect in the mutase apoenzyme.Speculation: Fibroblasts can be used to define whether patients with methylmalonic acidemia have an error of vitamin B12 metabolism if both mutase activity and AdoCbl synthesis are measured. The response of fibroblast mutase activity to the addition of AdoCbl reflects accurately the responsiveness of the enzyme in other tissues of the body. If an error of vitamin B12 metabolism is diagnosed with cultured fibroblasts, a prolonged trial of vitamin B12 therapy is warranted in the patient to seek evidence of in vivo responsiveness and clinical benefit from vitamin therapy.

Propionate metabolism in cells cultured from a patient with methylmalonic acidemia

Extract: Propionate metabolism in human skin fibroblasts was studied in cells from three controls and one patient with methylmalonic acidemia. In the control cells, propionate-2-14C was metabolized to succinate and thence into the citric acid cycle, as indicated by the appearance of the C label in CO2, succinate, aspartate, and glutamate. The patients fibroblasts accumulated methylmalonate and failed to convert the C label as readily into CO2, aspartate, and glutamate.Speculation: Human skin fibroblasts cultured from a patient with methylmalonic acidemia offer an in vitro technique of pinpointing the defective site in this disorder. Furthermore, the kinetic properties of the mutant enzyme can be readily investigated.

Pneumomediastinum, a silent lesion in the newborn

During a six year period, the diagnosis of pneumomediastinum was maderadiologically in 21 newborn infants. Fifteen of these patients had an isolated pneumomediastinum and all survived with conservative management. Most of the infants were not resuscitated. Male infants were affected more frequently, as were dysmature infants. The incidence of 25 per 10,000 live births is greater than that previously reported, but is probably below the actual incidence since many of the infants with pneumomediastinum had minimal symptoms.

715 THYMIC APLASIA IN SIBLINGS

DiGeorge syndrome is usually reported as having occurred sporadically. This is the first report of the syndrome occurring in twins and only the second in family members.Black male twins were delivered at 33 weeks gestation. They were dizygotic as proven by different blood types. Each developed hypocalcemic seizures at 9 days. The diagnosis of DiGeorge syndrome was made in each on the basis of refractory hypocalcemia, typical facial features, absent thymic shadow, congenital heart disease and repeatedly low T-cell rosettes with normal immunoglobulins. One died at 58 days of age of aspiration and congestive heart failure. He was found at autopsy to lack thymic tissue and parathyroids. His heart disease consisted of a hypoplastic ascending aorta with the right subclavan artery arising from the right pulmonary artery. The other twin, now 3 yrs. old, has serially low T-cell rosettes, normal PHA stimulation and normal immunoglobulins. He does not suffer from recurrent infections nor does he require calcium or parathormone supplementation. Clinically, he has a small VSD. He is now less than the 3rd percentile in both height and weight and is developmentally delayed. Maternal evaluation revealed normal calcium, phosphorus and parathormone levels. Antilymphocyte antibodies were absent. Although DiGeorge syndrome is usually sporadic, the occurrance in nonidentical twins suggests a genetic etiology in this family.