Philip J. Snodgrass

Evidence for X-Linked Dominant Inheritance of Ornithine Transcarbamylase Deficiency

Abstract The mode of Inheritance of ornithine transcarbamylase deficiency was studied in four kindreds, each containing one or more affected children with ammonia intoxication. In two families a to...

Ornithine Transcarbamylase Deficiency — A Cause of Bizarre Behavior in a Man

THE most commonly reported deficiency of the urea-cycle enzymes is that of ornithine transcarbamylase (E.C.2.1.3.3).1 It is inherited as an X-linked defect.2 , 3 In the usual forms of this disease,...

Urea cycle enzyme adaptation to dietary protein in primates

Activities of the five hepatic enzymes of the urea cycle increased two- to threefold in monkeys on a 60 percent protein diet compared with levels in monkeys on an isocaloric 6 percent protein diet. Equal adaptation occurred in rats on the same diets. These enzyme activities in adult humans approximate those of monkeys on a similar protein intake.

Methylmalonyl Coenzyme A Racemase Defect: Another Cause of Methylmalonic Aciduria

Extract: Metabolism of 14C-propionate and methylmalonate was severely curtailed in fibro-blasts cultured from an infant with massive transient hyperammonemia (1370

Ornitbine transcarbamylase deficiency in the newborn infant

mUg/100 ml), severe metabolic acidosis, and excretion of large amounts of methylmalonic acid (580 mg at 24°). Metabolism of succinate was normal.Metabolism of methylmalonate was not enhanced by the addition of excessive amounts of the cofactor, 5′-deoxyadenosylcobalamin (DBCC). The DBCG content of the liver was within normal limits.Homogenates of liver and fibroblasts metabolized methylmalonate approximately one-half as well as control samples when tritiated racemic methylmalonyl coenzyme A (CoA) was added. Inasmuch as L-methylmalonyl-CoA and not D-methylmalonyl-CoA is the substrate for the enzyme, methylmalonyl-CoA mutase, which converts L-methylmalonyl-CoA to succinyl-CoA, this indicates that the mutase was intact.Mitochondrial homogenate from liver, in contrast to normal samples, did not incorporate tritium during the metabolism of synthetic methylmalonyl-CoA, which indicates that activity of racemase was deficient.Activities of the urea cycle enzymes were low but not rate limiting.Speculation: A diet low in isoleucine, threonine, methionine, and valine may offer a rational therapeutic approach to other affected patients. The hyperammonemia observed resembles that reported in propionyl-CoA carboxylase deficiency and Reyes syndrome, which raises the possibility of a common denominator in these several disorders.

Letter to the Editor: White Cell Ornithine Transcarbamylase Activity Cannot Detect the Liver Enzyme Deficiency

Two newborn infants who were brothers had a rapidly fatal, fulminant disorder characterized by coma, convulsions, and metabolic acidosis. The disorder was due to deficiency of ornithine transcarbamylase activity.

Effect of a maternal fast on the urea cycle enzymes of the ovine fetus.

Letter to the Editor: White Cell Ornithine Transcarbamylase Activity Cannot Detect the Liver Enzyme Deficiency

Complete ornithine transcarbamylase deficiency: A cause of lethal neonatal hyperammonemia

Summary Activities of five urea cycle enzymes were measured in maternal and fetal sheep liver during the normal fed state and following 5 days of fasting. Six ewes and 10 fetuses were studied in both the fed and fasted periods at 132 days gestation (term: 147 days) for liver protein and enzyme levels. Results indicated that protein content increased during fasting in both the maternal and fetal liver. Fetal liver weight was decreased during fasting from 108 ± 8.5 to 71 ± 8.2 g (mean ± SD) (p < 0.001). Fed state fetal enzyme activities per gram liver were 50–125% of maternal values. After fasting, four of the five fetal enzymes increased approximately twofold to fivefold (per gram tissue) (ornithine transcarbamylase did not change). Only one enzyme (argininosuccinase) increased significantly in maternal liver. Total liver activities gave similar results. These data indicate that the in vivo studies that demonstrate a doubling in fetal urea production in the fasted sheep in later gestation are associated with parallel increases in the fetal hepatic activities of several enzymes that are responsible for urea synthesis.

Establishment of a clonal strain of hepatoma cells which maintain in culture the five enzymes of the urea cycle.

Hyperammonemia secondary to deficiency of one of the enzymes of the urea cycle causes infantile somatic and mental retardation, but has not, bitherto, been noted to cause death in the newborn period. A term infant, born to healthy parents after an uneventful pregnancy and delivery, thrived for three days, then lapsed rapidly into deep coma. Becuase a previous sibling had died under identical circumstances, an inherited metabolic derangement was sought. The blood ammonia concentration was 1208 μg% (normal <150 μg%). The blood urea nitrogen was 7 mg% and numerous other studies of plasma and urinary amino or organic acids were unrevealing. Despite a protein free diet, enemas, antibiotic therapy and an exchange transfusion, the blood ammonia remained about 1200 μg% and the child expired on the fifth day of life. Hepatic assays of the five enzymes of the urea cycle revealed absence of ornithine transcarbamylase (OCT) activity. No OCT acitivity was restored by changes in substrte concentration, enzyme concentration or pH, and mixing experiments excluded the presence of an inhibitor of OCT in the patients cells. Activity of the other four urea cycle enzymes was int he range noted in other age-matche, autopsy-control livers. These findings document complete OCT deficiency for the first time and emphasize the lethality of this enzymatic defect. Hyperammonemia must be considered in a newborn with coma, particularly if there is a family history of neonatal death. In such situations, unrestricted dietary protein ingestion will have disastrous consequences.