Pediat. R e s . 9: 488--497 (1975) Extract Six related subjects with severe feeding problems in infancy, hyperammonemia, hyperornithinenia, and homocitrullinuria are reported. The clinical picture includes episodic motor and mental impairment, seizures, intellectual deficits that vary from severe to very mild and, in two cases, a bleeding tendency early in life. The pedigree indicates autosomal recessive inheritance.C a r b a m y l p h o s p h a t e synthetase I hyperornithinemia hoinocitrulliriuria leukocytes h y p e r a m m o n e m i aIn a liver biopsy in one patient decreased activity of carbamyl phosphate synthetase I ( C P S I, EC. 2.7.2.5) was found. Enzymatic assays on peripheral leukocytes in all six subjects confirmed the liver results. Loading studies with ornithine and citrulline were consistent with a defect early in the urea cycle. Homocitrullinuria appeared to arise from excessive synthesis from lysine, but there was no impairment of the main lysine catabolic pathway.Large and bizarrely shaped hepatic mitochondria with curious periodic (35@400W) membranes were observed ultrastructurally. SpeculationClinical entities in which liver C P S I deficiency has been reported represent a heterogeneous group. This heterogeneity may arise because the assays currently in use do not differentiate between individual steps in the complex synthetic reaction catalyzed by this enzyme. Associated abnormalities in ornithine transport into the hepatic mitochondria in some may also contribute to the varying expression of this group of disorders. It is conceivable that some unusual periodic structures observed just inside the inner mitochondrial membranes are related to altered ornithine mitochondria1 entry.This disorder adds to the evidence from other inborn errors that there are one or more ways in which lysine metabolism and the urea cycle are specifically interrelated, but the details remain obscure.In 1969 Shih et al. (23) described a patient with hyperammonemia who could be differentiated from the growing group of specific inherited hyperammonemias by the presence of markedly elevated blood ornithine and urinary homocitrulline in addition to the high levels of blood ammonia. Wright and Pollitt (28) reported briefly a second patient with these features.During the past several years we have had the opportunity to study six related subjects with this disorder, and carry out assays of the urea cycle enzymes on peripheral leukocytes of all, and on liver biopsy in one of these. In addition, ultrastructural examination was carried out on the biopsied hepatic tissue.It is the purpose of this communication to report on the results of the above study with special reference to clinical manifestations, localization of the metabolic block, possible mechanism of produc-48 tion of homocitrullinuria, and correlation of the biochemical and morphologic data. CLINICAL SUMMARIES CASE IThis severely mentally retarded boy, Figure 1 IV-8, first came to our attention at the age of 7 years when increased excretion of ornithine and lysi...

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WHEN the blood supply to the brain is cut off, function may be maintained for a short time through utilization of the energy reserve. This reserve has only four major components, P-creatine, ATP, glycogen, and glucose. Consequently the rates of change of these four substances during brief periods of complete ischaemia should be a valid measure of metabolic rate. Studies of whole brain (LOWRY, PASSONNEAU, HASSELBERGER and SCHULZ, 1964) and nerve (STEWART, PASSONNEAU and LOWRY, 1965) indicate this to be true. Although this 'closed system' method of measuring metabolic rate is relatively cumbersome it avoids some of the uncertainties of other procedures based on in vitro measurements or blood flow. The closed system method should be particularly useful for application to small areas of the brain for which there are no other methods available. Even single neuronal elements should eventually be accessible to this tool. This is a report of the application of this method to four gross regions of mouse brain and three histologically defined layers of mouse cerebellum. Measurements were made both with normal mice and with mice depressed with phenobarbitone. To provide a background, experiments are also reported with whole brain from mice given different dosages of phenobarbitone. E X P E R I M E N T A LReagents. All enzymes were obtained from Boehringer and Sons through Calbiochem, Berkeley, Calif., except glycogen phosphorylase (Sigma Chemical Co., St. Louis) and ox heart lactate dehydrogenase (Worthington, Freehold, N.J.). The phosphorylase was used as purchased for glycogen determination but was recrystallized three of four times to free it of ATPase and Pi when used for measuring the latter. Glycogen was dialysed against 0.025 M-acetate buffer at pH 4.7 to free it of contaminating Pi.Preparation ofmaterial. Male white mice of a local strain weighing about 20 g were used. These were decapitated, and the heads frozen either immediately or after a measured time interval (20 or 30 sec). Rapid freezing was accomplished by violent agitation in Freon-12 that had been chilled to its freezing point (-150") with liquid N,. Subsequently the tissue was kept at -80" whenever possible until enzymes present had been removed or inactivated. For studies of whole brain, the frozen tissue was powdered and treated with HClO, in such a manner as to avoid thawing and consequent changes in substrate concentrations (LOWRY et al. , 1964). The entire brain rostra1 to the inferior colliculi was used in this case. For the gross regional studies, 5 mg samples were dissected at -15" from four areas of the frozen brain with great care

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