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JIMD Reports Sep 2022N-acetylglutamate synthase (NAGS) deficiency is a rare autosomal recessive disorder, which results in the inability to activate the key urea cycle enzyme,...
N-acetylglutamate synthase (NAGS) deficiency is a rare autosomal recessive disorder, which results in the inability to activate the key urea cycle enzyme, carbamoylphosphate synthetase 1 (CPS1). Patients often suffer life-threatening episodes of hyperammonaemia, both in the neonatal period and also at subsequent times of catabolic stress. Because NAGS generates the cofactor for CPS1, these two disorders are difficult to distinguish biochemically. However, there have now been numerous case reports of 3-methylglutaconic aciduria (3-MGA), a marker seen in mitochondrial disorders, occurring in CPS1 deficiency. Previously, this had not been reported in NAGS deficiency. We report a four-day-old neonate who was noted to have 3-MGA at the time of significant hyperammonaemia and lactic acidosis. Low plasma citrulline and borderline orotic aciduria were additional findings that suggested a proximal urea cycle disorder. Subsequent molecular testing identified bi-allelic pathogenic variants in . The 3-MGA was present at the time of persistent lactic acidosis, but improved with normalization of serum lactate, suggesting that it may reflect secondary mitochondrial dysfunction. NAGS deficiency should therefore also be considered in patients with hyperammonaemia and 3-MGA. Studies in larger numbers of patients are required to determine whether it could be a biomarker for severe decompensations.
PubMed: 36101823
DOI: 10.1002/jmd2.12318 -
The Tohoku Journal of Experimental... Nov 1987A 2 month-old Japanese girl with hereditary orotic aciduria type I was treated with oral uridine supplement. The activities of orotate phosphoribosyltransferase (OPRT)...
Increase of protein synthesis by uridine supplement in lectin-stimulated peripheral blood lymphocytes and EB virus-transformed B cell line of hereditary orotic aciduria type I.
A 2 month-old Japanese girl with hereditary orotic aciduria type I was treated with oral uridine supplement. The activities of orotate phosphoribosyltransferase (OPRT) and orotidine-5'-phosphate decarboxylase (ODC) in erythrocytes were 2.7 and 0.4%, respectively, of those in the controls. Megaloblastic anemia, excessive urinary excretion of orotic acid, lymphopenia and decreased number of OKT3 positive lymphocytes on admission were corrected after the uridine supplement. Peripheral blood lymphocytes (PBL) were cultured for 24 hr in RPMI 1640 medium with 10% heat-inactivated fetal calf serum and further stimulated with PHA-P, ConA or PWM in the presence of 10 to 1000 microM uridine. EB virus-transformed B cell line (LCL) maintained with an optimal concentration of uridine was cultured for 48 hr in uridine free medium and cultured for an additional 48 hr with 1 to 1000 microM uridine. The incorporations of leucine in to PHA-, ConA- and PWM-stimulated PBL and into LCL of the patient increased in the presence of uridine over 10 microM, although they did not increase in controls. These data suggest that low protein synthesis might correlate with an immune deficiency in hereditary orotic aciduria type I.
Topics: Antigens, Surface; Cell Transformation, Viral; Female; Herpesvirus 4, Human; Humans; Infant; Lectins; Lymphocyte Activation; Lymphocytes; Metabolism, Inborn Errors; Orotic Acid; Protein Biosynthesis; Uridine
PubMed: 2829387
DOI: 10.1620/tjem.153.189 -
The FEBS Journal Mar 2010Gut granules are cell type-specific lysosome-related organelles found within the intestinal cells of Caenorhabditis elegans. To investigate the regulation of...
Gut granules are cell type-specific lysosome-related organelles found within the intestinal cells of Caenorhabditis elegans. To investigate the regulation of lysosome-related organelle size, we screened for C. elegans mutants with substantially enlarged gut granules, identifying alleles of the vacuolar-type H(+)-ATPase and uridine-5'-monophosphate synthase (UMPS)-1. UMPS-1 catalyzes the conversion of orotic acid to UMP; this comprises the two terminal steps in de novo pyrimidine biosynthesis. Mutations in the orthologous human gene UMPS result in the rare genetic disease orotic aciduria. The umps-1(-) mutation promoted the enlargement of gut granules to 250 times their normal size, whereas other endolysosomal organelles were not similarly affected. UMPS-1::green fluorescent protein was expressed in embryonic and adult intestinal cells, where it was cytoplasmically localized and not obviously associated with gut granules. Whereas the umps-1(-) mutant is viable, combination of umps-1(-) with mutations disrupting gut granule biogenesis resulted in synthetic lethality. The effects of mutations in pyr-1, which encodes the enzyme catalyzing the first three steps of de novo pyrimidine biosynthesis, did not phenotypically resemble those of umps-1(-); instead, the synthetic lethality and enlargement of gut granules exhibited by the umps-1(-) mutant was suppressed by pyr-1(-). In a search for factors that mediate the enlargement of gut granules in the umps-1(-) mutant, we identified WHT-2, an ABCG transporter previously implicated in gut granule function. Our data suggest that umps-1(-) leads to enlargement of gut granules through a build-up of orotic acid. WHT-2 possibly facilitates the increase in gut granule size of the umps-1(-) mutant by transporting orotic acid into the gut granule and promoting osmotically induced swelling of the compartment.
Topics: Animals; Base Sequence; Caenorhabditis elegans; Cytoplasmic Granules; Gene Expression Regulation, Developmental; Gene Knockout Techniques; Humans; Larva; Lysosomes; Molecular Sequence Data; Multienzyme Complexes; Mutation; Orotate Phosphoribosyltransferase; Orotic Acid; Orotidine-5'-Phosphate Decarboxylase; Particle Size; Phenotype
PubMed: 20148972
DOI: 10.1111/j.1742-4658.2010.07573.x -
Journal of Cellular and Molecular... Apr 2021Urea cycle disorders (UCDs) are a group of rare metabolic conditions characterized by hyperammonemia and a broad spectrum of phenotypic severity. They are caused by the...
Urea cycle disorders (UCDs) are a group of rare metabolic conditions characterized by hyperammonemia and a broad spectrum of phenotypic severity. They are caused by the congenital deficiency in the eight biomolecules involved in urea cycle. In the present study, five cases of UCD were recruited and submitted to a series of clinical, biochemical, and genetic analysis with a combination of high throughput techniques. Moreover, in silico analysis was conducted on the identified missense genetic variants. Various clinical and biochemical indications (including profiles of amino acids and urinary orotic acids) of UCD were manifested by the five probands. Sequence analysis revealed nine diagnostic variants, including three novel ones, which caused Argininosuccinic aciduria (ASA) in one case, Carbamoyl phosphate synthetase 1deficiency (CPS1D) in two cases, Ornithine transcarbamylase deficiency (OTCD) in one case, and Citrin deficiency in 1case. Results of in silico biophysical analysis strongly suggested the pathogenicity of each the five missense variants and provided insight into their intramolecular impacts. In conclusion, this study expanded the genetic variation spectrum of UCD, gave solid evidence for counselling to the affected families, and should facilitate the functional study on the proteins in urea cycle.
Topics: Computer Simulation; DNA Mutational Analysis; Female; Humans; Infant; Infant, Newborn; Male; Mutation, Missense; Ornithine Carbamoyltransferase; Pedigree; Prognosis; Urea Cycle Disorders, Inborn
PubMed: 33611823
DOI: 10.1111/jcmm.16379 -
American Journal of Human Genetics May 1979Enzyme assays of skin fibroblasts from five children with familial hyperlysinemia from unrelated families are added to the previous report of three children from two...
Enzyme assays of skin fibroblasts from five children with familial hyperlysinemia from unrelated families are added to the previous report of three children from two unrelated families. In all instances there was a deficiency in lysine-ketoglutarate reductase, saccharopine dehydrogenase, and saccharopine oxidoreductase activities. To complete the studies on the enzymes associated with familial hyperlysinemia, saccharopine oxidoreductase was partially purified from human liver and characterized. The activity did not separate from that of lysine-ketoglutarate reductase or saccharopine dehydrogenase. A simple screening test for familial hyperlysinemia is described based on the evolution of 14CO2 from lysine-14C by skin fibroblasts. The test differentiated, without overlap, seven patients with familial hyperlysinemia from control subjects. The relation of the two genetic entities involving lysine degradation, familial hyperlysinemia and saccharopinuria, is discussed. It is suggested that familial hyperlysinemia, type I, be applied to patients with major defects in lysine-ketoglutarate reductase and saccharopine dehydrogenase, and that familial hyperlysinemia, type II, to be used to designate patients in whom significant amounts of lysine-ketoglutarate reductase are retained. The nomenclature would be consistent with that of an analogous disease, orotic aciduria.
Topics: Amino Acid Metabolism, Inborn Errors; Humans; Liver; Lysine; Oxidoreductases Acting on CH-NH Group Donors; Saccharopine Dehydrogenases; Terminology as Topic
PubMed: 463877
DOI: No ID Found -
Gene Therapy Apr 2012Ornithine transcarbamylase deficiency (OTCD) is the most common inborn error of urea synthesis. Complete OTCD can result in hyperammonemic coma in the neonatal period,...
Ornithine transcarbamylase deficiency (OTCD) is the most common inborn error of urea synthesis. Complete OTCD can result in hyperammonemic coma in the neonatal period, which can rapidly become fatal. Current acute therapy involves dialysis; chronic therapy involves the stimulation of alternate nitrogen clearance pathways; and the only curative approach is liver transplantation. Adeno-associated virus (AAV) vector-based gene therapy would add to current treatment options provided the vector delivers high level and stable transgene expression in liver without dose-limiting toxicity. In this study, we employed an AAV2/8-based self-complementary (sc) vector expressing the murine OTC (mOTC) gene under a liver-specific thyroxine-binding globulin promoter and examined the therapeutic effects in a mouse model of OTCD, the spf (ash) mouse. Seven days after a single intravenous injection of vector, treated mice showed complete normalization of urinary orotic acid, a measure of OTC activity. We further improved vector efficacy by incorporating a Kozak or Kozak-like sequence into mOTC complementary DNA, which increased the OTC activity by five or twofold and achieved sustained correction of orotic aciduria for up to 7 months. Our results demonstrate that vector optimizations can significantly improve the efficacy of gene therapy.
Topics: Animals; Base Sequence; Conserved Sequence; Dependovirus; Disease Models, Animal; Genetic Therapy; Genetic Vectors; Injections, Intravenous; Mice; Ornithine Carbamoyltransferase; Ornithine Carbamoyltransferase Deficiency Disease; Orotic Acid; Specific Pathogen-Free Organisms; Thyroxine-Binding Globulin
PubMed: 21850052
DOI: 10.1038/gt.2011.111 -
Proceedings of the National Academy of... Jan 1983Several dairy cows have been identified as partially deficient in UMP synthase. Although erythrocytes of normal cows contained 2.54 units of enzyme per ml, four cows...
Several dairy cows have been identified as partially deficient in UMP synthase. Although erythrocytes of normal cows contained 2.54 units of enzyme per ml, four cows were discovered with only 1.08 units per ml. Cows deficient in UMP synthase secreted milk with abnormally high levels of orotate, 300-1,000 micrograms of orotate per ml compared to 80 micrograms/ml for normal cows. The deficiency also was accompanied by a lactation-induced orotic aciduria. Although bovine urinary orotate was generally less than 10 micrograms/ml, the urine of the deficient cows, when lactating, contained 20-200 micrograms/ml. Their plasma orotate also was elevated. Genetic transmission of the condition was suggested by a common bull in the pedigrees of all deficient animals. Indeed, these cows, with half the normal level of UMP synthase, are probably heterozygotes with a 50% chance of passing the deficient allele to their progeny. For these putative heterozygotes, the condition is apparently benign because longevity and production were unaffected. However, the existence of a gene for UMP synthase deficiency in the dairy cow population poses a hazard with respect to the conception of homozygotic, deficient animals. These, in analogy with a comparable human condition, would be expected to exhibit high perinatal morbidity and mortality.
Topics: Aging; Animals; Animals, Newborn; Carboxy-Lyases; Cattle; Female; Male; Milk; Multienzyme Complexes; Orotate Phosphoribosyltransferase; Orotic Acid; Orotidine-5'-Phosphate Decarboxylase; Pedigree; Pentosyltransferases
PubMed: 6572893
DOI: 10.1073/pnas.80.2.321 -
The Tohoku Journal of Experimental... May 1998We report a family with hereditary orotic aciduria heterozygotes. A 3-year-old boy who had been diagnosed as having cerebral palsy and mental retardation presented...
We report a family with hereditary orotic aciduria heterozygotes. A 3-year-old boy who had been diagnosed as having cerebral palsy and mental retardation presented himself with an increase in excretion of urinary orotic acid. Enzymatic studies revealed that the boy and his healthy mother were hereditary orotic aciduria heterozygote carriers. We can not prove that this pyrimidine disorder caused his neurological symptoms, but his pyrimidine nucleoside supply may have been insufficient in his neonatal period.
Topics: Cerebral Palsy; Child, Preschool; Humans; Intellectual Disability; Male; Orotate Phosphoribosyltransferase; Orotic Acid; Orotidine-5'-Phosphate Decarboxylase; Purine-Pyrimidine Metabolism, Inborn Errors
PubMed: 9710947
DOI: 10.1620/tjem.185.67 -
Orotate in milk and urine of dairy cows with a partial deficiency of uridine monophosphate synthase.Journal of Dairy Science May 1984Cows with a partial deficiency of uridine monophosphate synthase have elevated orotate in their milk and urine. Variability of orotate was assessed in two such cows...
Cows with a partial deficiency of uridine monophosphate synthase have elevated orotate in their milk and urine. Variability of orotate was assessed in two such cows monitored biweekly for two complete lactations. Concentrations of milk and urinary orotate showed extensive variation during lactation, but coefficients of variation were similar for deficient and normal cows. Orotate averaged 500 micrograms/ml milk for deficient cows (versus a normal of 80 micrograms/ml), and a threshold of 200 micrograms/ml distinguished normal from deficient cows. Deficient cows had low milk orotate upon initiation of lactation and exhibited a latency of 1 to 7 wk to attain that threshold. The deficiency also resulted in a lactation-induced orotic aciduria. Orotate averaged 32.2 micrograms/ml urine for deficient cows (versus a normal of 7.3 micrograms/ml), and a threshold of 15 micrograms/ml urine differentiated the animals. Latency was 3 to 18 wk for deficient cows to exceed that threshold. Total orotate output and orotate concentration were elevated in milk and urine of lactating cows deficient for uridine monophosphate synthase. The output of orotate was predominantly in milk rather than urine for both deficient and normal cows. Additionally, orotate was elevated in blood of deficient cows when they were lactating.
Topics: Animals; Carboxy-Lyases; Cattle; Cattle Diseases; Colostrum; Female; Lactation; Milk; Multienzyme Complexes; Orotate Phosphoribosyltransferase; Orotic Acid; Orotidine-5'-Phosphate Decarboxylase; Pentosyltransferases; Pregnancy
PubMed: 6547459
DOI: 10.3168/jds.S0022-0302(84)81401-0 -
The Journal of Clinical Investigation Dec 1984The role of arginine as an essential amino was evaluated in four children with one of the deficiencies of carbamyl phosphate synthetase, ornithine transcarbamylase,...
The role of arginine as an essential amino was evaluated in four children with one of the deficiencies of carbamyl phosphate synthetase, ornithine transcarbamylase, argininosuccinate synthetase, and argininosuccinase. Within 15-68 h after arginine deprivation nitrogen accumulated as ammonium or glutamine or both, but glutamine was quantitatively the largest nitrogen accumulation product. Concomitantly plasma and urinary urea levels decreased. Resumption of arginine intake (or citrulline in the case of ornithine transcarbamylase deficiency) promptly led to correction of the hyperammonemia, hyperglutaminemia and hypoargininemia. Ornithine was an unsatisfactory substitute for arginine. Arginine deprivation did not interfere with carbamyl phosphate synthesis as manifested by orotic aciduria. It is concluded that arginine is an indispensable amino acid for children with inborn errors of ureagenesis and its absence results in the rapid onset of symptomatic hyperammonemia.
Topics: Amino Acid Metabolism, Inborn Errors; Ammonia; Arginine; Argininosuccinate Synthase; Argininosuccinic Aciduria; Blood Urea Nitrogen; Carbamoyl-Phosphate Synthase (Ammonia); Child, Preschool; Female; Glutamine; Humans; Infant; Infant, Newborn; Male; Ornithine; Ornithine Carbamoyltransferase Deficiency Disease; Urea
PubMed: 6511918
DOI: 10.1172/JCI111640