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Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants.
Vogel, Georg F; Mozer-Glassberg, Yael; Landau, Yuval E; Schlieben, Lea D; Prokisch, Holger; Feichtinger, René G; Mayr, Johannes A; Brennenstuhl, Heiko; Schröter, Julian; Pechlaner, Agnes; Alkuraya, Fowzan S; Baker, Joshua J; Barcia, Giulia; Baric, Ivo; Braverman, Nancy; Burnyte, Birute; Christodoulou, John; Ciara, Elzbieta; Coman, David; Das, Anibh M; Darin, Niklas; Della Marina, Adela; Distelmaier, Felix; Eklund, Erik A; Ersoy, Melike; Fang, Weiyan; Gaignard, Pauline; Ganetzky, Rebecca D; Gonzales, Emmanuel; Howard, Caoimhe; Hughes, Joanne; Konstantopoulou, Vassiliki; Kose, Melis; Kerr, Marina; Khan, Aneal; Lenz, Dominic; McFarland, Robert; Margolis, Merav Gil; Morrison, Kevin; Müller, Thomas; Murayama, Kei; Nicastro, Emanuele; Pennisi, Alessandra; Peters, Heidi; Piekutowska-Abramczuk, Dorota; Rötig, Agnès; Santer, René; Scaglia, Fernando; Schiff, Manuel; Shagrani, Mohmmad.
Affiliation
  • Vogel GF; Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria; Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria. Electronic address: georg.vogel@i-med.ac.at.
  • Mozer-Glassberg Y; Institute for Gastroenterology, Nutrition and Liver diseases, Schneider Children's Medical Center of Israel, Petah Tiqwa, Israel.
  • Landau YE; Metabolism Service, Schneider Children's Medical Center of Israel, Petah Tiqwa, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • Schlieben LD; Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany; Institute of Neurogenomics, Computational Health Center, Helmholtz Zentrum München, Neuherberg, Germany.
  • Prokisch H; Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany; Institute of Neurogenomics, Computational Health Center, Helmholtz Zentrum München, Neuherberg, Germany.
  • Feichtinger RG; University Children's Hospital, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg, Austria.
  • Mayr JA; University Children's Hospital, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg, Austria.
  • Brennenstuhl H; Division of Neuropaediatrics and Metabolic Medicine, Center for Paediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
  • Schröter J; Division of Paediatric Epileptology, Center for Paediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
  • Pechlaner A; Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
  • Alkuraya FS; Department of Genetics, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.
  • Baker JJ; Division of Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.
  • Barcia G; Department of Medical Genetics and Reference Center for Mitochondrial Diseases (CARAMMEL), Necker Hospital, Université Paris Cité, Paris, France; Institut Imagine, INSERM UMR 1163, Paris, France.
  • Baric I; Department of Pediatrics, School of Medicine, University Hospital Center Zagreb and University of Zagreb, Zagreb, Croatia.
  • Braverman N; Division of Medical Genetics, Department of Pediatrics and Human Genetics, McGill University, Montreal, Quebec, Canada.
  • Burnyte B; Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
  • Christodoulou J; Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Melbourne, Victoria, Australia; Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia.
  • Ciara E; Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland.
  • Coman D; Faculty of Medicine, Queensland Children's Hospital, University of Queensland, Herston, Brisbane, Queensland, Australia.
  • Das AM; Department of Paediatrics, Paediatric Metabolic Medicine, Hannover Medical School, Hannover, Germany.
  • Darin N; Department of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden.
  • Della Marina A; Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- und Behavioral Sciences, University Duisburg-Essen, Essen, Germany.
  • Distelmaier F; Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich-Heine-University Dusseldorf, Dusseldorf, Germany.
  • Eklund EA; Section for Pediatrics, Department of Clinical Sciences, Lund University, Lund, Sweden.
  • Ersoy M; Department of Pediatrics, Division of Pediatric Metabolism, University of Health Sciences, Bakirkoy Dr. Sadi Konuk Training and Research, Istanbul, Turkey.
  • Fang W; The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
  • Gaignard P; Department of Biochemistry, Reference Center for Mitochondrial Disease, FILNEMUS, Bicêtre University Hospital, University of Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, Paris, France.
  • Ganetzky RD; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA.
  • Gonzales E; Pediatric Hepatology and Pediatric Liver Transplantation Unit, Reference Center for Mitochondrial Disease, FILNEMUS, Bicêtre University Hospital, University of Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, Paris, France; Inserm U1193, Hepatinov, University Paris-Saclay, Or
  • Howard C; Children's Health Ireland, Temple Street Hospital, Dublin, Ireland.
  • Hughes J; Children's Health Ireland, Temple Street Hospital, Dublin, Ireland.
  • Konstantopoulou V; Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
  • Kose M; Division of Inborn Errors of Metabolism, Department of Pediatrics, Izmir Katip Çelebi University, Izmir, Turkey; Division of Genetics, Department of Pediatrics, Ege University, Izmir, Turkey.
  • Kerr M; Discovery DNA, Metabolics and Genetics in Canada (M.A.G.I.C.) Clinic Ltd, Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
  • Khan A; Discovery DNA, Metabolics and Genetics in Canada (M.A.G.I.C.) Clinic Ltd, Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
  • Lenz D; Division of Neuropaediatrics and Metabolic Medicine, Center for Paediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
  • McFarland R; Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newc
  • Margolis MG; Institute of Endocrinology and Diabetes, National Center of Childhood Diabetes Schneider Children's Medical Center of Israel, Petah Tiqwa, Israel.
  • Morrison K; Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.
  • Müller T; Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
  • Murayama K; Department of Metabolism, Chiba Children's Hospital, Midori-ku, Chiba, Japan.
  • Nicastro E; Pediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Bergamo, Italy.
  • Pennisi A; Department of Medical Genetics and Reference Center for Mitochondrial Diseases (CARAMMEL), Necker Hospital, Université Paris Cité, Paris, France; Institut Imagine, INSERM UMR 1163, Paris, France.
  • Peters H; Department of Metabolic Medicine, Royal Children's Hospital, Melbourne, Victoria, Australia.
  • Piekutowska-Abramczuk D; Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland.
  • Rötig A; Institut Imagine, INSERM UMR 1163, Paris, France.
  • Santer R; Department of Pediatrics, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
  • Scaglia F; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Texas Children's Hospital, Houston, TX; Joint BCM-CUHK Center of Medical Genetics, Prince of Wales Hospital, Shatin, Hong Kong SAR.
  • Schiff M; Department of Medical Genetics and Reference Center for Mitochondrial Diseases (CARAMMEL), Necker Hospital, Université Paris Cité, Paris, France; Institut Imagine, INSERM UMR 1163, Paris, France; Reference Center of Inherited Metabolic Disorders, Necker Hospital, Université Paris Cité, Paris, France
  • Shagrani M; Department of Liver & Small Bowel Health Centre King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
Genet Med ; 25(6): 100314, 2023 06.
Article in En | MEDLINE | ID: mdl-36305855
ABSTRACT

PURPOSE:

This study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and determine the role of cysteine supplementation in its treatment.

METHODS:

Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data.

RESULTS:

In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency.

CONCLUSION:

In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.
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Full text: 1 Database: MEDLINE Main subject: Liver Failure, Acute / Liver Failure Type of study: Prognostic_studies Limits: Adolescent / Adult / Child / Child, preschool / Humans / Infant Language: En Year: 2023 Type: Article
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Full text: 1 Database: MEDLINE Main subject: Liver Failure, Acute / Liver Failure Type of study: Prognostic_studies Limits: Adolescent / Adult / Child / Child, preschool / Humans / Infant Language: En Year: 2023 Type: Article