Propionic Acidemia and Hyperlysinemia in a Case With Ornithine Transcarbamylase (OTC) Deficiency

Krieger, Ingeborg; Bachmann, C.; Gronemeyer, W; Čejka, Jan

doi:10.1210/jcem-43-4-796

Cited by 12 publications

(6 citation statements)

References 16 publications

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“…[32][33][34] An inherited deficiency of the activity of these enzymes or mutations of genes cause hyperammonemia clinically. [35][36][37][38][39][40][41] In addition, glutamate dehydrogenase (GDH) and glutaminase (GL) bring ammonia into the urea cycle from certain amino acids. 32,[42][43][44][45] as schematically shown in Figure 1.…”

Section: Introductionmentioning

confidence: 99%

In vitro excess ammonia production in human myeloma cell lines

et al. 1998

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It is well known that cases with multiple myeloma reveal various clinical manifestations such as pancytopenia, hyperproteinemia, renal dysfunction, bone lesions, hypercalcemia and immunodeficiency. Recently, a few more clinical features associated with myeloma, such as salivary type hyperamylasemia and elevated serum C-reactive protein (CRP) concentration, have been reported. The elevation of CRP is thought to be related to interleukin-6 (IL-6) production by myeloma cells, because of identification of IL-6 as an autocrine and/or paracrine growth factor for myeloma cells. More recently, there have been several reports of cases with myeloma associated with hyperammonemia. This hyperammonemia is not considered to be due to liver dysfunction, because in most of these cases tests revealed normal hepatic function, and some cases showed different patterns of serum amino acid distribution than that associated with hepatic failure. However, there have been no apparent observations of ammonia production by myeloma cells. In this study, we used six human myeloma cell lines including KMS-18, which was recently established from a myeloma case associated with hyperammonemia. These lines were treated with MRA (mycoplasma removal agent) to observe ammonia production in vitro. They produced and released significantly higher levels of ammonia into culture medium than non-myeloma hematological cell lines or the HepG2 human hepatic carcinoma cell line. Although attempts to analyze the relative expression levels of the enzymes related to ammonia biosynthesis using the reverse transcriptase-polymerase chain reaction assay failed to detect any differences between these myeloma lines and other cell lines, in vitro excess ammonia production by the myeloma cells was confirmed and the relevance to clinical manifestations is discussed.

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Section: Introductionmentioning

confidence: 99%

In vitro excess ammonia production in human myeloma cell lines

et al. 1998

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“…A variant form of the disease was therefore diagnosed (12). A link between hyperammonemia and abnormal lysine catabolism has been documented in congenital lysine intolerance (4), as well as in in some urea cycle disorders (2,10,16,17,20), and in hyperornithinemia (6). Several explanations for the elevated serum ammonia after lysine loading may be offered: I) because competition between lysine and ammonia for a-ketoglutarate is possible (10).…”

Section: Discussionmentioning

confidence: 99%

“…A link between hyperammonemia and abnormal lysine catabolism has been documented in congenital lysine intolerance (4), as well as in in some urea cycle disorders (2,10,16,17,20), and in hyperornithinemia (6). Several explanations for the elevated serum ammonia after lysine loading may be offered: I) because competition between lysine and ammonia for a-ketoglutarate is possible (10). further loading with lysine may induce a decrease of the tr-ketoglutarate reserve which subsequently results in an increase of serum ammonia, 2) lysine is an inhibitor of arginase and, therefore, may induce hype~ammonemia (4, S), 3) a relations hi^ seemes to be exist between Krebs-Henseleit urea cvcle and the alternate urea cycle, as discussed later in this paper.…”

Section: Discussionmentioning

confidence: 99%

“…Hyperlysinemia and homocitrullinemia are well documented in cases of hereditary urea cycle disorders, such as ornithine transcarbamylase (OCT) deficiency (10) and argininosuccinate synthetase (AS) deficiency (2,16,20), suggesting abnormal lysine metabolism. In a variant form of AS deficiency, it was found that serum citrulline elevation was milder than in the classical form and serum lysine was normal (8,13).…”

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Lysine Intolerance in a Variant Form of Citrullinemia

et al. 1979

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Summary MATERIALS AND METHODSAn oral loading of lysine (100 mg of lysine-HCL/kg) was performed in two patients, I&and 23-yr-old, with a variant form of citrullinemia.Serum citrulline levels were approximately 10 times higher than control level and lysine levels were within the normal range, in contrast to the classical form of the disease in which serum citrulline is approximately 100 times normal levels and hyperlysinemia is usually present.After lysine loading, lysine levels rose sharply and clearance was decreased. Blood ammonia rose approximately 2.5 times. Lysine, citrulline, and arginine were markedly elevated in urine, collected 90-210 min after the lysine loading. Baseline homocitrulline and homoarginine excretion was elevated and increased further after the load. SpeculationLysine tolerance was impaired in two patients with citrullinemia, although baseline lysine levels were normal. Lysine seemed to be catabolized along the alternate urea cycle: lysine-homocitrullinehomoarginine-urea. Hyperammpnemia was aggravated, suggesting competition between lysine and ammonia for a-ketoglutarate and inability to remove ammonia completely by these two alternate pathways.

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“…Wolfe and Gatfield (17) recently demonstrated the presence of ornithine transcarbamylase [EC 2.1.3.31 (OTC) as well as other urea cycle enzymes in peripheral white blood cells from normal subjects. OTC deficiency was diagnosed by using peripheral blood white cells from the patients with OTC deficiency (7,17). On the other hand, Snodgrass et al (15) recently reported that OTC deficiency in the liver can not be inferred from the measurements of the enzyme's activity in peripheral white blood cells because the latter parameter was normal in their patients.…”

Section: Speculationmentioning

confidence: 99%

Ornithine Transcarbamylase (OTC) in White Blood Cells

et al. 1980

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Summarythe OTC activity is low in the verivheral white blood cells and A radiochemical assay method of ornithine transcarbamylase (OTC) was developed using labeled carbamyl phosphate as a substrate. The enzyme activities determined by this method in peripheral white blood cells from ten normal subjects were 1.32 A 0.95 nmoles/mg/hr and the apparent Km9s, when assayed at pH 8.5. were 6.4 mM for ornithine and 0.6 mM for carbamvl ~h o sphate. On the contrary, the apparent Km9s of human livk OTC were 0.6 mM for ornithine and 0.12 mM for carbamyl phosphate. The average OTC activity of granulocytes was 1.0 nmoles/mg/hr, whereas that of mononuclear cells was 0.4 nmoles/mg/hr.Lymphoid cell lines were established from three normal subjects and an OTCdeficient infant. All these cell lines demonstrated no OTC activity. When arginine was removed from the medium and replaced by ornithine, the lymphoid cells were unable to grow in culture. On autoradiography, the lymphoid cells showed labeling at incubation in the presence of "C-citrulline, but not with "Cornithine. SpeculationThe wide range of OTC activities observed in white blood cells from normal subjects might be due to a difference of the enzyme activities between granulocytes and mononuclear cells and in turn due to an individual difference of the two cell population.OTC is either absent or inactivated in lymphoid cell lines, when grown in a culture medium with arginine. The enzyme of the peripheral white blood cells might be of a different genetic origin from that of the liver.The diagnosis of inherited hyperamrnonemia has been made by measuring urea cycle enzymes in the liver (3, 4, 10) and other organs. Wolfe and Gatfield (17) recently demonstrated the presence of ornithine transcarbamylase [EC 2.1.3.31 (OTC) as well as other urea cycle enzymes in peripheral white blood cells from normal subjects. OTC deficiency was diagnosed by using peripheral blood white cells from the patients with OTC deficiency (7,17). On the other hand, Snodgrass et al. (15) recently reported that OTC deficiency in the liver can not be inferred from the measurements of the enzyme's activity in peripheral white blood cells because the latter parameter was normal in their patients.All these studies were carried out using a colorime&c method that is designed to measure the amount of citrulline produced in the assay system. The colorimetric method has several disadvantages: (1) the color complex formed is relatively light sensitive; (2) diacetylmonoxime reacts with carbamide compounds other than citrulline which give a color reaction; (3) the narrow range of optical density, which is from 0.01 to 0.03 according to Wolfe and Gatfield (17), is another problem in measuring OTC activity in white blood cells.The use of radiochemical assay method as suggested by Wolfe and Gatfield (17), appears to be preferable in view of the fact that that the sensiti4ty of the radidcheinical method is higher than that of the colorimetric method.We would like to describe a radiochemical assay method using I4C-carba...

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Propionic Acidemia and Hyperlysinemia in a Case With Ornithine Transcarbamylase (OTC) Deficiency

Cited by 12 publications

References 16 publications

In vitro excess ammonia production in human myeloma cell lines

In vitro excess ammonia production in human myeloma cell lines

Lysine Intolerance in a Variant Form of Citrullinemia

Ornithine Transcarbamylase (OTC) in White Blood Cells

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