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Biomedical subjects

S D Cederbaum

Publications and source records attributed to S D Cederbaum.

At least 19 recordsLinked to original sources
PubMed1992

The pathobiochemistry of uremia and hyperargininemia further demonstrates a metabolic relationship between urea and guanidinosuccinic acid.

To better understand the biosynthesis of guanidinosuccinic acid, we determined urea, arginine, and guanidinosuccinic acid levels in nondialyzed uremic and hyperargininemic patients. These substances were also determined during several years of therapy in one hyperarginiemic patient. Interrelationships of guanidinosuccinic acid levels with their corresponding urea and arginine levels were assessed by linear correlation studies. In uremic patients, a significant positive linear correlation (r = .821, p less than .001) was found between serum urea and guanidinosuccinic acid levels A significant positive linear correlation was also found between serum urea levels and urinary guanidinosuccinic acid levels (r = .828, P less than .001), but not between serum arginine levels and urinary guanidinosuccinic acid levels in hyperargininemic patients. In the intrahyperargininemic patient study, a similar significant positive correlation was found between serum urea levels and the corresponding urinary guanidinosuccinic acid levels (r = .866, P less than .001); the correlation between serum arginine levels and the corresponding urinary guanidinosuccinic acid levels was smaller. The presented analytical findings in uremic and hyperargininemic patients clearly demonstrate a metabolic relationship between urea and guanidinosuccinic acid.

Adult↗
PubMed1992

Deletion in blood mitochondrial DNA in Kearns-Sayre syndrome.

Mitochondrial DNA deletions have been described in the Kearns-Sayre syndrome (KSS) and the Pearson's marrow-pancreas syndrome. In some cases, the same 4,977-bp deletion has been identified in these two very different diseases. Therefore, it is not currently possible to predict the clinical phenotype from the size or location of the deletion. Instead, differential tissue distribution of the deletion has been implicated as one possible determinant of phenotype. In particular, in KSS the deletions have not been detected by Southern blotting in the blood, whereas in Pearson's syndrome they are easily detectable. We describe here an 11-y-old boy with clinically characteristic KSS and a 7.4-kb mitochondrial DNA deletion between nucleotides 7,194 and 14,595. Southern blotting reveals that 75% of the mitochondrial DNA molecules from his peripheral blood have this deletion. This case blurs further the molecular distinction between the KSS and Pearson's marrow-pancreas syndrome, questioning whether tissue distribution is a sufficient explanation for the very different phenotypes of these disorders.

Anemia, Sideroblastic↗
PubMed1991

Effect of an adjacent base on detection of a point mutation by restriction enzyme digestion.

While routinely mapping point mutations within the arginase locus of a collection of hyperargininemic patients, we discovered that a base immediately outside a restriction endonuclease recognition site (TaqI) can eliminate cleavage of this site by this enzyme. The genetic lesion lay in a base immediately flanking a TaqI recognition site within exon 8 of the arginase locus and abolished cutting by approximately 80%. We wish to emphasize the necessity of heeding subtle cues frequently encountered while generating restriction enzyme data, because neither Southern blot maps nor endonuclease digestion of polymerase chain reaction amplified products of exon 8 accurately predicted where the point mutation lay. To our knowledge, this is the first instance of inhibition of cleavage by flanking bases occurring on natural (nonsynthetic) DNA substrates, i.e., within the clinical setting of characterization of a human genetic disorder.

Base Sequence↗
PubMed1990

Guanidino compound analysis as a complementary diagnostic parameter for hyperargininemia: follow-up of guanidino compound levels during therapy.

The aim of this collaborative study was to investigate whether guanidino compound analyses in the biologic fluids can be used as a complementary diagnostic parameter for hyperargininemia. Guanidino compounds were determined in the biologic fluids of all known living hyperargininemic patients using a cation exchange chromatographic system with a fluorescence detection method. The serum arginine, homoarginine, alpha-keto-delta-guanidino-valeric acid, argininic acid, and N-alpha-acetylarginine levels of all the hyperargininemic patients are higher than the normal range. Similar increases were seen for the urinary excretion of alpha-keto-delta-guanidinovaleric acid and argininic acid. Untreated hyperargininemic patients have the highest guanidino compound levels in cerebrospinal fluid. However, even under therapy, the arginine, homoarginine, alpha-keto-delta-guanidinovaleric acid, and argininic acid levels in cerebrospinal fluid are still increased. Protein restriction alone is not sufficient to normalize the hyperargininemia, but protein restriction together with supplementation of essential amino acids with or without sodium benzoate decreases further the arginine levels. However, whereas the argininemia can be normalized, the catabolites of arginine are still increased. We conclude that the urinary amino acid levels may remain normal in hyperargininemia, whereas consistent increases of the guanidino compounds are observed. Thus, guanidino compound analyses can be used as a complementary biochemical diagnostic parameter for hyperargininemia. Although the argininemia can be normalized by therapy, the levels of the catabolites of arginine are still elevated.

Adolescent↗
PubMed1989

Parenteral nutrition in propionic and methylmalonic acidemia.

Although propionic acidemia and methylmalonic acidemia, two disorders of branched-chain amino acid metabolism often complicated by chronic anorexia and vomiting, are not usually treated with parenteral nutrition for fear of amino acid overload and exacerbation of biochemical derangements, we gave long-term parenteral nutrition to two critically ill patients with these disorders. Health and growth were restored, and there was minimal production of abnormal metabolites. The dramatic clinical and biochemical improvement of these patients bolsters the concept that most of the toxic metabolites produced in these diseases are not related to the administered load of nutrient precursors, but rather to endogenous turnover of amino acids, particularly during a chronic catabolic state. Suppression of catabolism can produce striking biochemical and clinical improvement. With appropriate monitoring, parenteral nutrition can be used safely in the management of patients with these disorders.

Amino Acid Metabolism, Inborn Errors↗
PubMed1989

Differential expression of the two human arginase genes in hyperargininemia. Enzymatic, pathologic, and molecular analysis.

Previous studies in our laboratory and others have demonstrated in humans and other mammals two isozymes of arginase (AI and AII) that differ both electrophoretically and antigenically. AI, a cytosolic protein found predominantly in liver and red blood cells, is believed to be chiefly responsible for ureagenesis and is the one missing in hyperargininemic patients. Much less is known about AII because it is present in far smaller amounts and localized in less accessible deep tissues, primarily kidney. We now report the application of enzymatic and immunologic methods to assess the independent expression and regulation of these two gene products in normal tissue extracts, two cultured cell lines, and multiple organ samples from a hyperargininemic patient who came to autopsy after an unusually severe clinical course characterized by rapidly progressive hepatic cirrhosis. AI was totally absent (less than 0.1%) in the patient's tissues, whereas marked enhancement of AII activity (four times normal) was seen in the kidney by immunoprecipitation and biochemical inhibition studies. Immunoprecipitation-competition and Western blot analysis failed to reveal presence of even an enzymatically inactive cross-reacting AI protein, whereas Southern blot analysis showed no evidence of a substantial deletion in the AI gene. Induction studies in cell lines that similarly express only the AII isozyme indicated that its activity could be enhanced severalfold by exposure to elevated arginine levels. Our findings suggest that the same induction mechanism may well be operative in hyperargininemic patients, and that the heightened AII activity may be responsible for the persistent ureagenesis seen in this disorder. These data lend further support to the existence of two separate arginase gene loci in humans, and raise possibilities for novel therapeutic approaches based on their independent manipulation.

Arginase↗
PubMed1988

Effects of deletions in mouse chromosome 7 on expression of genes encoding the urea-cycle enzymes and phosphoenolpyruvate carboxykinase (GTP) in liver, kidney, and intestine.

Chromosomal deletions at and around the albino locus on chromosome 7 of the mouse affect the enzyme activities and steady-state levels of mRNAs for five urea-cycle enzymes in liver. In newborn c3H homozygotes, activities of these enzymes were 43-62% of normal, while corresponding mRNA levels were 14-29% of normal. c14CoS deletion homozygotes expressed mRNA levels for these enzymes which were 32-48% of normal. However, transcription rates of these genes in hepatic nuclei of c3H/c3H mice were reduced only to 57-84% of normal. Since effects of the deletions had previously been noted in the kidney, mRNA levels for three enzymes expressed also in the kidney were examined. Mice homozygous for the c3H deletion, shown previously to have drastically reduced mRNA levels for phosphoenolpyruvate carboxykinase in the liver, expressed the same deficiency in the kidney, while mRNA levels for argininosuccinate synthetase and argininosuccinate lyase were reduced in the liver but remained unaffected in the kidney. However, mRNA levels for phosphoenolpyruvate carboxykinase, carbamyl phosphate synthetase I, and ornithine transcarbamylase were unaffected in the intestine of c3H homozygotes. The results suggest that a regulatory factor(s) encoded in the DNA encompassed by the deletion is involved in the normal developmental maturation of hepatocytes and certain cells in the kidney.

Animals↗
PubMed1987

Regulation of mRNA levels for five urea cycle enzymes in rat liver by diet, cyclic AMP, and glucocorticoids.

Adaptive changes in levels of urea cycle enzymes are largely coordinate in both direction and magnitude. In order to determine the extent to which these adaptive responses reflect coordinate regulatory events at the pretranslational level, measurements of hybridizable mRNA levels for all five urea cycle enzymes were carried out for rats subjected to various dietary regimens and hormone treatments. Changes in relative abundance of the mRNAs in rats with varying dietary protein intakes are comparable to reported changes in enzyme activities, indicating that the major response to diet occurs at the pretranslational level for all five enzymes and that this response is largely coordinate. In contrast to the dietary changes, variable responses of mRNA levels were observed following intraperitoneal injections of dibutyryl cAMP and dexamethasone. mRNAs for only three urea cycle enzymes increased in response to dexamethasone. Levels of all five mRNAs increased severalfold in response to dibutyryl cAMP at both 1 and 5 h after injection, except for ornithine transcarbamylase mRNA which showed a response at 1 h but no response at 5 h. Combined effects of dexamethasone and dibutyryl cAMP were additive for only two urea cycle enzyme mRNAs, suggesting independent regulatory pathways for these two hormones. Transcription run-on assays revealed that transcription of at least two of the urea cycle enzyme genes--carbamylphosphate synthetase I and argininosuccinate synthetase--is stimulated approximately four- to fivefold by dibutyryl cAMP within 30 min. The varied hormonal responses indicate that regulatory mechanisms for modulating enzyme concentration are not identical for each of the enzymes in the pathway.

Animals↗
PubMed1986

Cloning of rat liver arginase cDNA and elucidation of regulation of arginase gene expression in H4 rat hepatoma cells.

In order to study the regulation of expression of the two arginase genes in mammalian tissues, we undertook to clone cDNA specific for rat liver arginase. mRNA was isolated from rat liver polysomes enriched for the arginase message by immunopurification and was used to produce an 800-member cDNA library carried in pBR322. Four arginase clones were identified by hybrid selection, and one was used to find two others following colony hybridization. Clonal identity was verified by its enrichment in the cDNA made from immunopurified mRNA; by hybrid selection, immunoprecipitation, and competition by purified arginase; hybridization on Northern analysis with liver-derived RNA (high in arginase) and its absence with mRNA from tissues low in arginase; and independent identification by hybrid selection and colony hybridization. Northern analysis of mRNA from H4-II-E-C3 (H4) rat hepatoma cells in which arginase activity was induced by hydrocortisone demonstrated equal, eightfold augmentation of both arginase activity and arginase mRNA levels. Southern blot analysis of DNA from these cells indicated that no change in arrangement or copy number accompanied induction. Southern analysis also suggested that the gene for rat liver arginase is present in a single copy, without pseudogenes, and that a high degree of homology exists between it and its mouse counterpart.

Animals↗
PubMed1979

Hyperlysinemia with saccharopinuria due to combined lysine-ketoglutarate reductase and saccharopine dehydrogenase deficiencies presenting as cystinuria.

A 7-year-old boy with speech delay, hyperactive behavior, and minor neurologic abnormalities had been found in the past to have "intermittent cystinuria." A more detailed investigation revealed hyperlysinemia and hyperlysinuria, with lesser increases in urinary excretion of arginine and cystine. The plasma and urine abnormalities increased on a diet of 3 gm of protein/kg body weight/day. Saccharopine, a normal metabolite of lysine not found in the body fluids of normal people, was present in plasma, cerebrospinal fluid, and urine of the patient. Lysine-ketoglutarate reductase and saccharopine dehydrogenase activities were not detectable in extracts of cultured skin fibroblasts. Re-examination of the urine of previously studied cases of this double enzyme deficiency suggests that saccharopinuria of variable degree is the rule and not the exception.

Cells, Cultured↗