Adult presentation of ornithine transcarbamylase deficiency: a possible cause of hyperammonemia after high-dose chemotherapy and stem cell transplantation.

Hyperammonemia is a rare and often fatal complication following the conditioning therapy in autologous and allogeneic stem cell transplant recipients. It is characterized by anorexia, vomiting, lethargy and coma without any other apparent cause. The diagnosis is often delayed because symptoms can be subtle and ammonia is usually not included among the routine analyzes. Previous reports have not identified the molecular mechanisms behind hyperammonemia in stem cell transplant recipients. Urea cycle disorders (UCDs) are inborn errors of metabolism leading to hyperammonemia that usually presents in early childhood, whereas first presentation in adults is less common. Here we describe an adult woman with hyperammonemia following autologous stem cell transplantation for multiple myeloma. No apparent cause of hyperammonemia was identified, including portosystemic shunting, liver dysfunction or recent hyperammonemia-inducing chemotherapy. Hyperammonemia, normal blood glucose as well as anion gap and a previous history of two male newborns that died early after birth, prompted biochemical and genetic investigations for a UCD. A heterozygous variant in the X-linked gene encoding ornithine transcarbamylase (OTC) was identified and was regarded as a cause of UCD. The patient improved after treatment with nitrogen scavengers and high caloric intake according to a UCD protocol. This case report suggests that UCD should be considered as a possible cause of hyperammonemia following stem cell transplantation.

[Molecular basis of hyperammonemia secondary to asparaginase: from therapeutic efficacity to toxicity]. / Bases moléculaires de l'hyperammoniémie sous asparaginase : de l'efficacité thérapeutique à la toxicité.

Asparaginase is a key molecule in the treatment of acute lymphoblastic leukemia. It has improved response rates to chemotherapy. However, this is not without consequences. Therapeutic efficacy is sometimes achieved at the expense of toxicities that can lead to treatment discontinuation. Among them, patients can develop hyperammonemia which can sometimes be symptomatic leading to neurological disorders that can go as far as hyperammonemic coma or even death. Through a review of the current state of the literature, the objective is to understand the disparity of ammonia values as well as the clinical heterogeneity for a given ammonia concentration. A review of the literature including more than eighty publications was performed. The glutaminase activity of asparaginase seems to play an important role in the development of hyperammonia. At present, no risk factors have been identified for the development of hyperammonemia. On the other hand, the question of the impact of pre-analysis phase arises. Indeed, asparaginase continues to exert its activity in vitro, which leads to an artefactual increase in ammonia.

Manejo inicial de la hiperamonemia aguda en pediatría / Initial management of acute hyperammonemia in pediatrics

La hiperamonemia constituye una emergencia médica. No existen publicaciones que hagan referencia a la disponibilidad de recursos, insumos y conocimientos necesarios para el manejo inicial de esta por parte del pediatra en nuestro país, pero, según la experiencia de los autores, los recursos necesarios no se encuentran disponibles los 365 días del año en una gran porción de nuestro territorio. Sobre la base de este estado de situación, de una revisión bibliográfica internacional sobre el tema y de la experiencia de los autores, se elaboraron una serie de recomendaciones para el manejo pediátrico inicial de esta emergencia, que tienen como objetivo poder reducir las deficiencias, permitir una sospecha clínica adecuada que lleve a un diagnóstico y tratamiento de emergencia oportunos, con utilización racional de recursos farmacológicos (algunos de ellos de alto costo), para reducir la morbimortalidad que asocia la patología.

Hyperammonemia is a medical emergency. There are no publications regarding the availability of resources, supplies, and knowledge necessary for the initial management of hyperammonemia by pediatricians in Argentina; however, according to the authors' experience, the necessary resources are not available all year round in a large portion of our territory. Based on such state of affairs, an international bibliographic review on this topic and the authors' experience, we developed a series of recommendations for the initial pediatric management of this emergency, with the objective of reducing deficiencies, allowing adequate clinical suspicion leading to a timely diagnosis and emergency management and a rational use of pharmacological resources (some of which are costly) to reduce the morbidity and mortality associated with hyperammonemia.

Feline hyperammonemia associated with functional cobalamin deficiency: A case report.

Ammonia is a major neurotoxic substance associated with the complex pathogenesis of hepatic encephalopathy. Although several primary and secondary conditions have been reported to cause hyperammonemia, in veterinary medicine this condition is considered primarily associated with hepatic disease or portosystemic shunting. Only a few cases of inherited urea cycle enzyme deficiency and organic acid metabolic disorders have been reported in cats with hyperammonemia. To the best of our knowledge, this is the first report of hyperammonemia in a cat caused by accumulation of methylmalonic acid (MMA) secondary to functional cobalamin deficiency. A 2-year-old spayed female Turkish Angora cat exhibited postprandial depression with a 3-month history of hyperammonemia. Serum protein C and bile acid concentrations were normal. Plasma amino acid analysis revealed a deficiency of urea cycle amino acids. Although the serum cobalamin concentration was markedly high, there was no evidence of inflammatory, hepatic, or renal disease or neoplasia on blood, ultrasonographic, and computed tomographic examination. Gas chromatography-mass spectrometry revealed a high MMA concentration in the urine. Based on the results, functional cobalamin deficiency was diagnosed. Following oral amino acid supplementation and initiation of a low-protein diet, the serum ammonia level returned to normal and the postprandial depression improved. Urea cycle amino acid deficiency secondary to functional cobalamin deficiency presumably caused hyperammonemia due to MMA accumulation in this case.

Hyperammoniémie féline associée à un déficit fonctionnel en cobalamine : rapport de cas. L'ammoniac est une substance neurotoxique majeure associée à la pathogenèse complexe de l'encéphalopathie hépatique. Bien que plusieurs affections primaires et secondaires aient été signalées comme étant à l'origine d'une hyperammoniémie, en médecine vétérinaire, cette affection est considérée comme principalement associée à une maladie hépatique ou à un shunt porto-systémique. Seuls quelques cas de déficit héréditaire en enzymes du cycle de l'urée et de troubles métaboliques des acides organiques ont été signalés chez des chats atteints d'hyperammoniémie. À notre connaissance, il s'agit du premier rapport d'hyperammoniémie chez un chat causée par une accumulation d'acide méthylmalonique (MMA) secondaire à un déficit fonctionnel en cobalamine.Une chatte angora turque stérilisée âgée de 2 ans a présenté une dépression postprandiale avec une histoire d'hyperammoniémie depuis 3 mois. Les concentrations sériques de protéine C et d'acides biliaires étaient normales. L'analyse plasmatique des acides aminés a révélé une déficience en acides aminés du cycle de l'urée. Bien que la concentration sérique de cobalamine ait été nettement élevée, il n'y avait aucun signe de maladie inflammatoire, hépatique ou rénale ou de néoplasie à l'examen sanguin, échographique et tomodensitométrique. La chromatographie en phase gazeuse-spectrométrie de masse a révélé une forte concentration de MMA dans l'urine. Sur la base des résultats, un déficit fonctionnel en cobalamine a été diagnostiqué. Après une supplémentation orale en acides aminés et la mise en place d'un régime pauvre en protéines, le taux sérique d'ammoniac est revenu à la normale et la dépression postprandiale s'est améliorée. Une carence en acides aminés du cycle de l'urée secondaire à une carence en cobalamine fonctionnelle a vraisemblablement causé une hyperammoniémie due à l'accumulation de MMA dans ce cas.(Traduit par Dr Serge Messier).

Acute onset of ornithine transcarbamylase deficiency after total anomalous pulmonary venous connection repair to a 2-day-old neonate.

Ornithine transcarbamylase deficiency is an X-linked disorder which results in the accumulation of ammonia causing irritability and vomiting. Acute hyperammonemia requires rapid and intensive intervention. However, as those clinical features are non-specific and commonly seen in peri-operative situation, ornithine transcarbamylase deficiency could be difficult to diagnose prior to and post-emergency cardiac surgery. We report a 2-day-old male neonate who was diagnosed with ornithine transcarbamylase deficiency presenting hyperammonemia and severe heart failure after total anomalous pulmonary venous connection repair.

Aggressive Plasmablastic Myeloma With Extramedullary Cord Compression and Hyperammonemic Encephalopathy: Case Report and Literature Review.

BACKGROUND: Plasmablastic myeloma is an aggressive subtype of multiple myeloma with overall poor prognosis. Spinal cord compression and hyperammonemic encephalopathy are two grave complications of multiple myeloma with significantly poor survival outcomes. CASE REPORT: A 49-year-old male presented with a 5-day history of worsening abdominal distention with inability to walk, urinate or defecate. Imaging findings of innumerable spinal osteolytic lesions with paraspinal masses coupled with a bone marrow biopsy of ≥70% plasmablasts confirmed the diagnosis of plasmablastic myeloma. Despite spinal decompression surgery, the patient remained paraplegic. Three myeloma-directed chemotherapies failed, eventually leading to him developing hyperammonemic encephalopathy culminating in his death. CONCLUSION: Plasmablastic myeloma is a rare entity which poses therapeutic challenges especially in patients with negative prognosticators, including high-risk cytogenetic markers, extraosseous involvement with cord compression and hyperammonemic encephalopathy. Early aggressive management with consideration of novel therapeutic alternatives, especially in treatment refractory disease, can be worthwhile.

[A case of hyperammonemia presented in a patient with multiple myeloma]. / Hyperammonemi ­ en sällsynt komplikation av multipelt myelom.

Hyperammonemia-induced encephalopathy is a rare complication of untreated multiple myeloma. This case report illustrates a 78-year-old woman with multiple myeloma who developed acute delirium due to elevated level of serum ammonia in the absence of hepatic failure. One should suspect the condition when common management is ineffective. The adequate treatment of underlaying multiple myeloma is necessary.

Hyperammonemia-induced impaired consciousness following mFOLFOX6 therapy in a patient with recurrent rectal cancer.

OBJECTIVES: FOLFOX is a standard chemotherapy regimen used to treat colorectal cancer. Adverse events associated with FOLFOX treatment include peripheral neuropathy and myelosuppression. This report discusses the case of a 64-year-old man with rectal cancer who developed hyperammonemia and impaired consciousness following initiation of mFOLFOX6 as a postoperative adjuvant therapy. METHODS: This case study reports on the clinical disease progression of the aforementioned patient. RESULTS: Following preoperative chemoradiotherapy, the patient underwent low anterior resection for rectal cancer. mFOLFOX6 was then initiated as postoperative adjuvant therapy. During the 5th cycle of mFOLFOX6 treatment, the patient presented with impaired consciousness and upper extremity convulsions. Blood testing revealed marked hyperammonemia (349 µg/dL (normal range: 12 - 66 µg/dL)). Imaging did not reveal any intracranial lesions that could cause impaired consciousness. The patient recovered within a day after rehydration and BCAA substitution. CONCLUSION: Although impaired consciousness is a rare adverse reaction of FOLFOX, it has a major psychological impact on the patient and his/her family. Hyperammonemia should therefore be considered a potential cause of impaired consciousness during FOLFOX therapy and should be appropriately diagnosed and treated.

[Hyperammonaemic encephalopathy in adults without liver diseases].

Hyperammonaemic encephalopathy (HAE) in adults in the absence of acute or chronic liver disease is a severe condition caused by inborn errors of metabolism or acquired conditions like bariatric surgery, medications or malignancy as summarised in this review. Metabolic defects are most often caused by partial defects in the urea cycle enzymes demasked by stressors, whereas mechanisms underlying the acquired causes are complex and often multifactorial. Awareness of HAE and knowledge of the causes can help the clinician to deal appropriately with patients presenting with symptoms suggesting HAE and no signs of liver disease.

Transient hyperammonaemia following epileptic seizures in cats.

OBJECTIVES: The aim of this study was to determine whether transient postictal hyperammonaemia exists in cats. METHODS: The medical records of all feline patients that presented at a Swedish veterinary hospital between 2008 and 2018 were retrospectively reviewed to find those that had a recent or ongoing epileptic seizure. To qualify for inclusion, the medical record had to include information on at least one ammonia value taken in close proximity to, or during, an active seizure, the cat must have exceeded the normal upper limit of blood ammonia concentration on initial testing (reference interval 0-95 µmol/l), and there needed to be a follow-up ammonia value available within a maximum of 3 days. RESULTS: Five cats were included in the study, and they had blood ammonia concentrations on initial testing ranging from 146 to 195 µmol/l. They were all retested within a period of 2 h to 3 days of the original reading. All five cats had a spontaneous decrease in ammonia levels without any specific treatment for hyperammonaemia. CONCLUSIONS AND RELEVANCE: Pursuant to the findings of this retrospective study, transient hyperammonaemia may be noted after epileptic seizure in cats. Consequently, a differential diagnostic list in feline patients with hyperammonaemia could, depending on the context, include non-hepatic-related pathologies, such as epileptic seizures.

ATP synthase deficiency due to m.8528T>C mutation - a novel cause of severe neonatal hyperammonemia requiring hemodialysis.

OBJECTIVES: Hyperammonemia in a newborn is a serious condition, which requires prompt intervention as it can lead to severe neurological impairment and death if left untreated. The most common causes of hyperammonemia in a newborn are acute liver failure and inherited metabolic disorders. Several mitochondrial disorders have been described as a cause of severe neonatal hyperammonemia. CASE PRESENTATION: Here we describe a new case of adenosine-triphosphate (ATP) synthase deficiency due to m.8528T>C mutation as a novel cause of severe neonatal hyperammonemia. So far six patients with this mutation have been described but none of them was reported to need hemodialysis in the first days of life. CONCLUSION: This broadens the so far known differential diagnosis of severe neonatal hyperammonemia requiring hemodialysis.

Successful management of hyperammonemia with hemodialysis on day 2 during 5-fluorouracil treatment in a patient with gastric cancer: a case report with 5-fluorouracil metabolite analyses.

PURPOSE: Hyperammonemia is an important adverse event associated with 5-fluorouracil (5FU) from 5FU metabolite accumulation. We present a case of an advanced gastric cancer patient with chronic renal failure, who was treated with 5FU/leucovorin (LV) infusion chemotherapy (2-h infusion of LV and 5FU bolus followed by 46-h 5FU continuous infusion on day 1; repeated every 2 weeks) and developed hyperammonemia, with the aim of exploring an appropriate hemodialysis (HD) schedule to resolve its symptoms. METHODS: The blood concentrations of 5FU and its metabolites, α-fluoro-ß-alanine (FBAL), and monofluoroacetate (FA) of a patient who had hyperammonemia from seven courses of palliative 5FU/LV therapy for gastric cancer were measured by liquid chromatography-mass spectrometry. RESULTS: On the third day of the first cycle, the patient presented with symptomatic hyperammonemia relieved by emergency HD. Thereafter, the 5FU dose was reduced; however, in cycles 2-4, the patient developed symptomatic hyperammonemia and underwent HD on day 3 for hyperammonemia management. In cycles 5-7, the timing of scheduled HD administration was changed from day 3 to day 2, preventing symptomatic hyperammonemia. The maximum ammonia and 5FU metabolite levels were significantly lower in cycles 5-7 than in cycles 2-4 (NH3 75 ± 38 vs 303 ± 119 µg/dL, FBAL 13.7 ± 2.5 vs 19.7 ± 2.0 µg/mL, FA 204.0 ± 91.6 vs 395.9 ± 12.6 ng/mL, mean ± standard deviation, all p < 0.05). After seven cycles, partial response was confirmed. CONCLUSION: HD on day 2 instead of 3 may prevent hyperammonemia in 5FU/LV therapy.

Metabolic Serendipities of Expanded Newborn Screening.

Incidental findings on newborn screening (NBS) are results that are not the target of screening within a given NBS program, but rather are found as a result of the screening and resulting diagnostic workup for that target. These findings may not have an immediate clinical impact on the newborn, but are sometimes an additional benefit of NBS programs and may be considered secondary targets of NBS programs. This work describes four case reports that had incidental findings on the NBS, which eventually led to the diagnosis of another metabolic disease instead of the one that was initially suspected. The first case was a new defect in the cationic amino acid transporter-2 (CAT-2), which was oriented as an arginase-1 deficiency in the newborn. The second case was a maternal glutaric aciduria type 1 (GA-1) that mimicked a carnitine transporter deficiency in the newborn. The third report was a case of lysinuric protein intolerance (LPI), which appeared as high levels of citrulline on the NBS. The fourth case was a mother with homocystinuria that was diagnosed during the biochemical study of vitamin B12 status. All cases provide new or interesting data that will help guide differential diagnosis in the future.

Factors Raising Serum Ammonia Level During Lenvatinib Treatment of Patients With Hepatocellular Carcinoma.

BACKGROUND/AIM: Hepatic encephalopathy is an adverse event resulting from lenvatinib use in patients with hepatocellular carcinoma (HCC). We analyzed the influence of lenvatinib on portal venous flow velocity (PVV) and serum ammonia concentration. PATIENTS AND METHODS: Eleven patients with unresectable HCC were enrolled, including three with modified albumin-bilirubin (mALBI) grade 1, three with grade 2a, and five with grade 2b. PVV was measured by Doppler ultrasound sonography before and on day 2 of administration. RESULTS: Out of 11 patients, one developed hepatic encephalopathy. PVV was reduced in 10 patients, and the change from baseline was significantly correlated with lenvatinib dosage. The increase in serum ammonia concentration was affected by lenvatinib dose and baseline hepatic function as a threshold between mALBI grade 2a and 2b statistically. There was no correlation between changes in PVV and serum ammonia concentration. CONCLUSION: Lenvatinib might directly disturb hepatocyte metabolism to result in increased serum ammonia concentration.

Hyperammonemic encephalopathy during XELOX regimen. Is it capecitabine or oxaliplatin responsible?

Hyperammonemic encephalopathy represents a rare adverse effect of several chemotherapeutic agents, occurring in about 0.7% of patients treated with fluoropyrimidines, and it is independent from dihydropyrimidine dehydrogenase deficiency. Instead, its physiopathology is linked to the inhibition of Krebs cycle by fluoroacetate, leading to decreased ATP production, and to the inhibition of the urea cycle. Oxaliplatin seems to induce hyperammonemic encephalopathy in a similar way, acting on mitochondria. Here, we report the intriguing case of acute hyperammonemic encephalopathy in a 65-year-old patient with preserved liver function, who was treated with oxaliplatin and capecitabine for a metastatic, G1, atypical lung carcinoid. We reviewed the literature and found very few reports of oxaliplatin or capecitabine-induced hyperammonemic encephalopathy. Out of five cases of capecitabine-related hyperammonemic encephalopathy analyzed (four plus our case), median time to hyperammonemic encephalopathy onset was 6 days, with median serum ammonia levels of 213 µmol/L. Oxaliplatin-related hyperammonemic encephalopathy analyzed cases were three (two plus ours), with a median time to hyperammonemic encephalopathy of 11 days and median serum ammonia levels of 167 µmol/L. Identified predisposing factors for chemotherapy-induced hyperammonemia, such as dehydration, liver and renal impairment, infections, and sarcopenia were absent in our case. We hypothesize that the combination of a platinum-derivative and a fluoropyrimidine multiplies the risk of hyperammonemic encephalopathy, even in the absence of predisposing factors nor impaired liver function. We therefore suggest to always consider the risk of hyperammonemia when starting fluoropyrimidines-based chemotherapy, especially combined with platinum-derivatives, and to timely investigate neurologic symptoms monitoring ammonia serum levels.

Point-of-Care Analysis of Blood Ammonia with a Gas-Phase Sensor.

Elevated blood ammonia (hyperammonemia) may cause delirium, brain damage, and even death. Effective treatments exist, but preventing permanent neurological sequelae requires rapid, accurate, and serial measurements of blood ammonia. Standard methods require volumes of 1 to 3 mL, centrifugation to isolate plasma, and a turn-around time of 2 h. Collection, handling, and processing requirements mean that community clinics, particularly those in low resource settings, cannot provide reliable measurements. We describe a method to measure ammonia from small-volume whole blood samples in 2 min. The method alkalizes blood to release gas-phase ammonia for detection by a fuel cell. When an inexpensive first-generation instrument designed for 100 µL of blood was tested on adults and children in a clinical study, the method showed a strong correlation (R2 = 0.97) with an academic clinical laboratory for plasma ammonia concentrations up to 500 µM (16 times higher than the upper limit of normal). A second-generation hand-held instrument designed for 10-20 µL of blood showed a near-perfect correlation (R2 = 0.99) with healthy donor blood samples containing known amounts of added ammonium chloride up to 1000 µM. Our method can enable rapid and inexpensive measurement of blood ammonia, transforming diagnosis and management of hyperammonemia.