ABSTRACT
The liver ultrastructural findings in two girls with partial carbamyl phosphate synthetase I (CPS) deficiency and their heterozygote parents and two siblings with ornithine transcarbamylase (OTC) deficiency are described. Liver ultrastructure in the four patients with inherited deficiencies of urea cycle enzymes showed minimal alterations with essentially normal mitochondria when biopsy was performed during periods of good control of their hyperammonemia. Mitochondrial ultrastructure was also essentially normal in the heterozygotes for carbamyl phosphate synthetase I deficiency. These findings are in contrast to the marked alterations in mitochondrial ultrastructure found in the study of two cases of Reye's syndrome in which severe depression of ornithine transcarbamylase and carbamyl phosphate synthetase I activities was noted.
Subject(s)
Amino Acid Metabolism, Inborn Errors/pathology , Ammonia/blood , Mitochondria, Liver/ultrastructure , Reye Syndrome/pathology , Adolescent , Adult , Amino Acid Metabolism, Inborn Errors/enzymology , Carbamoyl-Phosphate Synthase (Ammonia)/deficiency , Child , Female , Humans , Male , Microbodies/ultrastructure , Microscopy, Electron , Mitochondrial Swelling , Ornithine Carbamoyltransferase Deficiency Disease , Reye Syndrome/enzymologyABSTRACT
All individuals receiving valproic acid therapy in an institution for the mentally retarded were evaluated for hyperammonemia. Of these 19 adults, 6 had persistent and 5 others had intermittent hyperammonemia. The hyperammonemic patients were asymptomatic, except that 2 had occasional lethargy. Hyperammonemia was detected more often in younger adults and in those treated with multiple anticonvulsants, especially phenytoin. Valproate-induced hyperammonemia is probably the result of depletion of mitochondrial acetyl CoA and decreased production of N-acetylglutamate, the obligatory activator of the first enzyme of the urea cycle, carbamyl phosphate synthetase I. Anticonvulsant-mediated microsomal enzyme induction may also contribute.
Subject(s)
Ammonia/blood , Intellectual Disability/drug therapy , Valproic Acid/adverse effects , Adolescent , Adult , Aged , Female , Humans , Intellectual Disability/blood , Male , Middle AgedABSTRACT
Two unrelated newborn infants with multiple malformations were found to have complete trisomy 9 in all cells examined. In both, the phenotype was similar, consisting of characteristic facial appearance (microphthalmia, bulbous nose, micrognathia, cleft palate, low set ears), skeletal abnormalities (dislocated joints, flexion contractures of the fingers), cardiovascular malformations (persistent left superior vena cava, ventricular septal defect), hypoplastic genitalia, renal anomalies, and central nervous system malformations. Both died during the first few hours of life. Comparison of these two infants with the previously reported cases reveals a consistent pattern of malformations and very short survival associated with trisomy 9. These cases illustrate the importance of doing chromosome studies on infants with congenital malformations dying in the newborn period and the usefulness of such studies in counselling parents regarding the risk of recurrence.
Subject(s)
Abnormalities, Multiple/genetics , Chromosomes, Human, 6-12 and X/ultrastructure , Infant, Newborn, Diseases/genetics , Trisomy , Female , Genetic Counseling , Humans , Infant, Newborn , Male , Phenotype , RiskABSTRACT
The mode of inheritance of hepatic mitochondrial carbamyl phosphate synthetase (CPS I) deficiency has not been established conclusively in the past. In this study, hepatic tissue obtained by percutaneous biopsy from all members of the immediate family of two girls affected with partial CPS I deficiency was assayed for CPS I, ornithine transcarbamylase (OTC), and arginase activities. Only values for CPS I activity differed significantly from those in controls. The two affected girls each had markedly reduced CPS I activities of about 6% of the control mean. Their brother had activity well within the normal range. Of greatest significance was the finding that both parents had activities below the 95% confidence limits in controls, and intermediate between the deficient values of the two girls and the control range. The father and mother had, respectively, 32% and 54% of mean control activity. These data indicate that CPS I deficiency is inherited as an autosomal recessive trait and that the two affected girls are homozygous for the mutant gene, their brother is homozygous for the normal allele, and the parents are heterozygous.
Subject(s)
Amino Acid Metabolism, Inborn Errors/genetics , Ammonia/blood , Carbamoyl-Phosphate Synthase (Ammonia)/deficiency , Genes, Recessive , Ligases/deficiency , Adolescent , Adult , Amino Acid Metabolism, Inborn Errors/enzymology , Arginase/analysis , Child , Female , Homozygote , Humans , Male , Mitochondria, Liver/enzymology , Ornithine Carbamoyltransferase/analysisABSTRACT
A male infant with complete hereditary deficiency of hepatic ornithine transcarbamylase was fed a low-protein diet (1 gm/kg/day) supplemented with nitrogen-free analogues of essential amino acids from the age of 2 days until his death at 5 months. Blood ammonia and plasma acid concentrations were maintained in the near normal range during most of his lifetime. Growth and development were entirely normal. Abrupt, unprecipitated hyperammonemia, which could not be reversed by intensive treatment, led to his death. To our knowledge, this child lived longer than any previously reported infant with OTC deficiency of this severity.
