Fatal hyperammonemia and carbamoyl phosphate synthetase 1 (CPS1) deficiency following high-dose chemotherapy and autologous hematopoietic stem cell transplantation

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.

"Alexander von Humboldt als internationaler Publizist. Zur Edition seiner sämtlichen Schriften"

Alexander von Humboldt veröffentlichte rund 800 Aufsätze, Artikel und Essays in zahlreichen Wissensgebieten und diversen Sprachen. Die Verteilung ihrer Publikati-onsorte entspricht der Reichweite seiner Reisen und der globalen Perspektive seiner Forschungen. Die Vielfalt seiner Co-Autoren und Kooperationspartner spiegelt seine Multidisziplinarität. Humboldts umfangreiches publizistisches Werk dokumentiert sei-ne internationale Bedeutung als Wissenschaftler, Reiseschriftsteller und Kulturver-mittler. An der Universität Bern entsteht die erste Gesamtedition dieses Humboldt-schen Œuvres, die 2019 zum 250. Geburtstag des Autors vorliegen soll. Ihr Ziel ist Systematisierung, Dokumentation und Erschließung des Corpus – in einer Buchausgabe mit Text- und Apparatbänden und in einer digitalen Edition mit computerphilo-logischen Werkzeugen. Alexander von Humboldt (1769–1859), Aufsätze und Essays, internationale Publizistik, Wissenschaftsgeschichte, Editionsphilologie.