title: Fatal hyperammonemia and carbamoyl phosphate synthetase 1 (CPS1) deficiency following high-dose chemotherapy and autologous hematopoietic stem cell transplantation.
abstract: Fatal hyperammonemia secondary to chemotherapy for hematological malignancies or following bone marrow transplantation has been described in few patients so far. In these, the pathogenesis of hyperammonemia remained unclear and was suggested to be multifactorial. We observed severe hyperammonemia (maximum 475 μmol/L) in a 2-year-old male patient, who underwent high-dose chemotherapy with carboplatin, etoposide and melphalan, and autologous hematopoietic stem cell transplantation for a neuroblastoma stage IV. Despite intensive care treatment, hyperammonemia persisted and the patient died due to cerebral edema. The biochemical profile with elevations of ammonia and glutamine (maximum 1757 μmol/L) suggested urea cycle dysfunction. In liver homogenates, enzymatic activity and protein expression of the urea cycle enzyme carbamoyl phosphate synthetase 1 (CPS1) were virtually absent. However, no mutation was found in CPS1 cDNA from liver and CPS1 mRNA expression was only slightly decreased. We therefore hypothesized that the acute onset of hyperammonemia was due to an acquired, chemotherapy-induced (posttranscriptional) CPS1 deficiency. This was further supported by in vitro experiments in HepG2 cells treated with carboplatin and etoposide showing a dose-dependent decrease in CPS1 protein expression. Due to severe hyperlactatemia, we analysed oxidative phosphorylation complexes in liver tissue and found reduced activities of complexes I and V, which suggested a more general mitochondrial dysfunction. This study adds to the understanding of chemotherapy-induced hyperammonemia as drug-induced CPS1 deficiency is suggested. Moreover, we highlight the need for urgent diagnostic and therapeutic strategies addressing a possible secondary urea cycle failure in future patients with hyperammonemia during chemotherapy and stem cell transplantation.
authors: Division of Metabolism and Children's Research Center (CRC), University Children's Hospital, Zurich, Switzerland; Department of Pediatrics, University Children's Hospital, Bern, Switzerland. Electronic address: Alexander.Laemmle@kispi.uzh.ch.
authors: Alexander
authors: A
authors: Laemmle
authors: University Institute of Clinical Chemistry, University of Bern, Switzerland. Electronic address: Dagmar.Hahn@insel.ch.
authors: Dagmar
authors: D
authors: Hahn
authors: Division of Metabolism and Children's Research Center (CRC), University Children's Hospital, Zurich, Switzerland. Electronic address: Liyan.Hu@gmx.ch.
authors: Liyan
authors: L
authors: Hu
authors: Division of Metabolism and Children's Research Center (CRC), University Children's Hospital, Zurich, Switzerland. Electronic address: Veronique.Ruefenacht@kispi.uzh.ch.
authors: Véronique
authors: V
authors: Rüfenacht
authors: Department of Pediatrics, University Children's Hospital, Bern, Switzerland; University Institute of Clinical Chemistry, University of Bern, Switzerland. Electronic address: Matthias.Gautschi@insel.ch.
authors: Matthias
authors: M
authors: Gautschi
authors: Department of Pediatrics, University Children's Hospital, Bern, Switzerland. Electronic address: Kurt.Leibundgut@insel.ch.
authors: Kurt
authors: K
authors: Leibundgut
authors: Department of Pediatrics, University Children's Hospital, Bern, Switzerland; University Institute of Clinical Chemistry, University of Bern, Switzerland. Electronic address: Jean-Marc.Nuoffer@insel.ch.
authors: Jean-Marc
authors: JM
authors: Nuoffer
authors: Division of Metabolism and Children's Research Center (CRC), University Children's Hospital, Zurich, Switzerland. Electronic address: Johannes.Haeberle@kispi.uzh.ch.
authors: Johannes
authors: J
authors: Häberle
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D001929:Brain Edema / Q000209:etiology; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D002221:Carbamyl Phosphate / Q000378:metabolism; D016190:Carboplatin / Q000009:adverse effects / Q000494:pharmacology; D002675:Child, Preschool; D003131:Combined Modality Therapy; D005047:Etoposide / Q000009:adverse effects / Q000494:pharmacology; D017809:Fatal Outcome; D005973:Glutamine / Q000097:blood; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D056945:Hep G2 Cells; D006801:Humans; D022124:Hyperammonemia / Q000139:chemically induced / Q000209:etiology*; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009447:Neuroblastoma / Q000188:drug therapy; D009954:Ornithine Carbamoyltransferase / Q000235:genetics; D010085:Oxidative Phosphorylation
chemical_list: D005973:Glutamine; D002221:Carbamyl Phosphate; D005047:Etoposide; D016190:Carboplatin; D009954:Ornithine Carbamoyltransferase; D002222:Carbamoyl-Phosphate Synthase (Ammonia)
keywords: Acquired urea cycle disorder; Carbamoyl phosphate synthetase 1; Chemotherapy; Hematopoietic stem cell transplantation; Hyperammonemia