The goal of this proposal is to develop effective methods of treating infants and children with inborn errors of ureagenesis. We propose to fulfill this goal by: 1) maintaining a national referral center to coordinate the therapeutic protocol, 2) develop a dietary nitrogen intake that will minimize the requirement for waste nitrogen excretion and activate metabolic pathways that enhance waste nitrogen excretion. These pathways include the biosynthesis and excretion of citrulline and argininosuccinic acid in argininosuccinate synthetase and lyase deficiency respectively and hippurate and phenylacetylglutamine in deficiencies of carbamyl phosphate synthetase, ornithine transcarbamylase and arginionosuccinate synthetase. 3) Improve methods of treatment of intercurrent hyperammonemic episodes by similar techniques with efforts to increase the rate of hippurate synthesis. In-vivo residual enzyme activities of patients with these diseases will be examined by studying 15NH4 enrichment of urea. This therapy will be extended to other diseases (Reye's syndrome, portalsystemic encephalopathy, organic acidemias) where hyperammonemia may have a role. It is also planned to perform a study in rats to evaluate the in vivo rate limiting steps of hippurate synthesis. The long term neurodevelopmental consequences of low grade neonatal hyperammonemia in low birth weight children will be studied by developmental and psychological methods.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD011134-09
Application #
3311494
Study Section
Biochemistry Study Section (BIO)
Project Start
1977-02-01
Project End
1986-03-31
Budget Start
1985-02-01
Budget End
1986-03-31
Support Year
9
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Brusilow, Saul W; Cooper, Arthur J L (2011) Encephalopathy in acute liver failure resulting from acetaminophen intoxication: new observations with potential therapy. Crit Care Med 39:2550-3
Brusilow, S W; Maestri, N E (1996) Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr 43:127-70
Maestri, N E; Brusilow, S W; Clissold, D B et al. (1996) Long-term treatment of girls with ornithine transcarbamylase deficiency. N Engl J Med 335:855-9
Brusilow, S W (1995) Urea cycle disorders: clinical paradigm of hyperammonemic encephalopathy. Prog Liver Dis 13:293-309
Maestri, N E; Clissold, D B; Brusilow, S W (1995) Long-term survival of patients with argininosuccinate synthetase deficiency. J Pediatr 127:929-35
Collins, A F; Pearson, H A; Giardina, P et al. (1995) Oral sodium phenylbutyrate therapy in homozygous beta thalassemia: a clinical trial. Blood 85:43-9
Dover, G J; Brusilow, S; Charache, S (1994) Induction of fetal hemoglobin production in subjects with sickle cell anemia by oral sodium phenylbutyrate. Blood 84:339-43
Beliveau Carey, G; Cheung, C W; Cohen, N S et al. (1993) Regulation of urea and citrulline synthesis under physiological conditions. Biochem J 292 ( Pt 1):241-7
Takahashi, H; Koehler, R C; Hirata, T et al. (1992) Restoration of cerebrovascular CO2 responsivity by glutamine synthesis inhibition in hyperammonemic rats. Circ Res 71:1220-30
Maestri, N E; McGowan, K D; Brusilow, S W (1992) Plasma glutamine concentration: a guide in the management of urea cycle disorders. J Pediatr 121:259-61

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