A Novel Mutation of the Ornithine Transcarbamylase Gene Leading to Fatal Hyperammonemia in a Liver Transplant Recipient

Mukhtar, Ahmed; Dabbous, Hany; Sayed, Riham El; Aboulfetouh, Fawzia; Bahaa, Mohamed; Abdelaal, Amr; Fathy, Mohamed; El-Meteini, Mahmoud

doi:10.1111/ajt.12146

Cited by 16 publications

(16 citation statements)

References 16 publications

(18 reference statements)

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“…Data from the patient at Loyola Medical Center suggest that transmission of this organism from the donor is a possible mechanism, because donor BAL before the lung procurement was positive for Ureaplasma species. HS has been described in other immunocompromised states, including heart-lung (9), kidney (13), liver (14), intestinal (15), islet cell (16), and bone marrow (17) transplantation; however, the syndrome has been most frequently reported in lung transplant recipients. This might result from increased recognition of the disorder in this population or reflect increased risks associated with lung transplantation, including the possibility of donor transmission.…”

Section: Discussionmentioning

confidence: 99%

Disseminated Ureaplasma infection as a cause of fatal hyperammonemia in humans

et al. 2015

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Hyperammonemia syndrome is a fatal complication affecting immunosuppressed patients. Frequently refractory to treatment, it is characterized by progressive elevations in serum ammonia of unknown etiology, ultimately leading to cerebral edema and death. In mammals, ammonia produced during amino acid metabolism is primarily cleared through the hepatic production of urea, which is eliminated in the kidney. Ureaplasma species, commensals of the urogenital tract, are Mollicutes dependent on urea hydrolysis to ammonia and carbon dioxide for energy production. We hypothesized that systemic infection with Ureaplasma species might pose a unique challenge to human ammonia metabolism by liberating free ammonia resulting in the hyperammonemia syndrome. We used polymerase chain reaction, specialized culture, and molecular resistance profiling to identify systemic Ureaplasma infection in lung transplant recipients with hyperammonemia syndrome, but did not detect it in any lung transplant recipients with normal ammonia concentrations. Administration of Ureaplasma-directed antimicrobials to patients with hyperammonemia syndrome resulted in biochemical and clinical resolution of the disorder. Relapse in one patient was accompanied by recurrent Ureaplasma bacteremia with antimicrobial resistance. Our results provide evidence supporting a causal relationship between Ureaplasma infection and hyperammonemia, suggesting a need to test for this organism and provide empiric antimicrobial treatment while awaiting microbiological confirmation.

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Section: Discussionmentioning

confidence: 99%

Disseminated Ureaplasma infection as a cause of fatal hyperammonemia in humans

et al. 2015

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“…There are >10 types of defect in the urea cycle, which have been shown to be associated with various metabolic pathways (26)(27)(28)(29)(30). The activities of enzymes including N-acetylglutamate synthetase (NAGs), carbamoyl phosphate synthetase I (CPS-I), argininosuccinate synthetase, argininosuccinate lyase, OTC and argininase are severely lacking in the urea cycle, leading to the accumulation of ammonia and other abnormal metabolites.…”

Section: Discussionmentioning

confidence: 99%

Novel two-step derivation method for the synchronous analysis of inherited metabolic disorders using urine

Sheng

Wang

2017

Experimental and Therapeutic Medicine

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Abstract. The aim of the present study was to conduct preliminary clinical screening and monitoring using a novel two-step derivatization process of urine in five categories of inherited metabolic disease (IMD). Urine samples (100 µl, containing 2.5 mmol/l creatinine) were taken from patients with IMDs. The collected urine was then treated using a two-step derivatization method (with oximation and silylation at room temperature), where urea and protein were removed. In the first step of the derivatization, α-ketoacids and α-aldehyde acids were prepared by oximation using novel oximation reagents. The second-step of the derivatization was that residues were silylated for analysis. Urine samples were examined using gas chromatography/mass spectrometry (GC/MS) and a retention time-locking technique. The simultaneous analysis and identification of >400 metabolites in >130 types of IMD was possible from the GC/MS results, where the IMDs included phenylketonuria, ornithine transcarbamylase deficiency, neonatal intrahepatic cholestasis caused by citrin deficiency, β-ureidopropionase deficiency and mitochondrial metabolic disorders. This method was demonstrated to have good repeatability. Considering α-ketoglutarate (α-KG) as an example, the relative standard deviations (RSDs) of the α-KG retention time and peak area were 0.8 and 3.9%, respectively, the blank spiked recovery rate was between 89.6 and 99.8%, and the RSD was ≤7.5% (n=5). The method facilitates the analysis of thermally non-stable and semi-volatile metabolites in urine, and greatly expands the range of materials that can be synchronously screened by GC/MS. Furthermore, it provides a comprehensive, effective and reliable biochemical analysis platform for the pathological research of IMDs.

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“…Patients with defects such as citrullinemia and otc deficiency can have characteristic biochemical findings, but nags and cps1 deficiency require dna testing for diagnosis. Molecular and biochemical testing was chosen over liver enzyme testing, because the former approach is preferred in testing for nags and for cps1 and otc deficiency, all of which can result in false negative results on liver biopsy because of heterogeneous liver expression [18][19][20] . This practice accords with recent guidelines 1 .…”

Section: Discussionmentioning

confidence: 99%

Hyperammonemic Encephalopathy in An Adenocarcinoma Patient Managed with Carglumic Acid

et al. 2014

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The cause of he is unclear. In cases of chemotherapy-induced he, suggested mechanisms include a catabolic state induced by chemotherapeutic agents that overwhelms the capacity of the urea cycle; intrahepatic shunting that bypasses the liver; or tumour replacement of normal liver cells, leading to decreased expression of the ornithine transcarbamylase (OTC) gene and insufficient otc enzyme production 3,5,8,9 . Reports in which he has been treated with l-arginine suggest the possibility of a functional arginine deficiency secondary to chemotherapyinduced catabolism.Arginine has multiple metabolic fates: not only does it serve as a precursor for synthesis of proteins, nitric oxide, creatine, polyamines, agmatine, and urea, but it is also an activator of N-acetylglutamate synthase (nags), an enzyme that catalyzes the synthesis of N-acetylglutamate (nag) 10 . N-Acetylglutamate activates carbamoyl phosphate synthase 1 (cps1), the rate-limiting step in the urea cycle. Genetic metabolic deficiencies in either of the foregoing enzymes leads to severe hyperammonemia in the newborn period 5 . Hyperammonemic encephalopathy can manifest with acute neurologic deterioration, and the clinical presentation can be similar to that seen in patients with genetic mutations in the urea cycle enzymes causing activation of nags and cps1, and otc deficiency, thus suggesting a proximal block in the urea cycle 3,5,9 .To date, treatment for he has consisted of standard therapy for hyperammonemia secondary to urea cycle decompensation. The primary objective of standard therapy is to remove ammonia through salvage pathways. The typical approach includes high-rate glucose infusion (to reverse catabolism), hemodialysis to directly remove ammonia, limitations on ammonia sources through dietary protein restriction, and use of ammonia scavengers 2,3,5,11-13 . The combination of scavenger medications is often called the "urea cycle cocktail." Treatment carries with it a high fluid load and a combination of medications that can cause not only gastrointestinal upset, but also electrolyte imbalances such as hypernatremia and ABSTRACTHyperammonemic encephalopathy (he) is a rare complication of malignancy and chemotherapy. Although the cause of he is unclear, a functional arginine deficiency secondary to increased catabolism has been suggested as a possible mechanism. Either that deficiency or an undetermined metabolite could lead to inhibition of N-acetylglutamate synthase (nags), a urea cycle enzyme, resulting in hyperammonemia.We present a case of chemotherapy-induced he in a patient with no underlying primary urea cycle disorder. The patient had a successful trial of carglumic acid (a synthetic analog of the product of nags), which suggests that, at least in some cases, he can be treated by overcoming proximal inhibition of the urea cycle. Further, our case is the first in the literature to exclude genetic defects and disorders of the proximal urea cycle, suggesting that hyperammonemia in these patients is probably secondary to chemotherapy. KEY WOR...

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A Novel Mutation of the Ornithine Transcarbamylase Gene Leading to Fatal Hyperammonemia in a Liver Transplant Recipient

Cited by 16 publications

References 16 publications

Disseminated Ureaplasma infection as a cause of fatal hyperammonemia in humans

Disseminated Ureaplasma infection as a cause of fatal hyperammonemia in humans

Novel two-step derivation method for the synchronous analysis of inherited metabolic disorders using urine

Hyperammonemic Encephalopathy in An Adenocarcinoma Patient Managed with Carglumic Acid

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