Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants

Georg F Vogel; Yael Mozer-Glassberg; Yuval E Landau; Lea D Schlieben; Holger Prokisch; René G Feichtinger; Johannes A Mayr; Heiko Brennenstuhl; Julian Schröter; Agnes Pechlaner; Fowzan S Alkuraya; Joshua J Baker; Giulia Barcia; Ivo Baric; Nancy Braverman; Birute Burnyte; John Christodoulou; Elzbieta Ciara; David Coman; Anibh M Das; Niklas Darin; Adela Della Marina; Felix Distelmaier; Erik A Eklund; Melike Ersoy; Weiyan Fang; Pauline Gaignard; Rebecca D Ganetzky; Emmanuel Gonzales; Caoimhe Howard; Joanne Hughes; Vassiliki Konstantopoulou; Melis Kose; Marina Kerr; Aneal Khan; Dominic Lenz; Robert McFarland; Merav Gil Margolis; Kevin Morrison; Thomas Müller; Kei Murayama; Emanuele Nicastro; Alessandra Pennisi; Heidi Peters; Dorota Piekutowska-Abramczuk; Agnès Rötig; René Santer; Fernando Scaglia; Manuel Schiff; Mohmmad Shagrani; Mark Sharrard; Claudia Soler-Alfonso; Christian Staufner; Imogen Storey; Michael Stormon; Robert W Taylor; David R Thorburn; Elisa Leao Teles; Jian-She Wang; Daniel Weghuber; Saskia Wortmann

doi:10.1016/j.gim.2022.09.015

Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants

Genet Med. 2023 Jun;25(6):100314. doi: 10.1016/j.gim.2022.09.015. Epub 2022 Oct 29.

Authors

Georg F Vogel¹, Yael Mozer-Glassberg², Yuval E Landau³, Lea D Schlieben⁴, Holger Prokisch⁴, René G Feichtinger⁵, Johannes A Mayr⁵, Heiko Brennenstuhl⁶, Julian Schröter⁷, Agnes Pechlaner⁸, Fowzan S Alkuraya⁹, Joshua J Baker¹⁰, Giulia Barcia¹¹, Ivo Baric¹², Nancy Braverman¹³, Birute Burnyte¹⁴, John Christodoulou¹⁵, Elzbieta Ciara¹⁶, David Coman¹⁷, Anibh M Das¹⁸, Niklas Darin¹⁹, Adela Della Marina²⁰, Felix Distelmaier²¹, Erik A Eklund²², Melike Ersoy²³, Weiyan Fang²⁴, Pauline Gaignard²⁵, Rebecca D Ganetzky²⁶, Emmanuel Gonzales²⁷, Caoimhe Howard²⁸, Joanne Hughes²⁸, Vassiliki Konstantopoulou²⁹, Melis Kose³⁰, Marina Kerr³¹, Aneal Khan³¹, Dominic Lenz³², Robert McFarland³³, Merav Gil Margolis³⁴, Kevin Morrison³⁵, Thomas Müller⁸, Kei Murayama³⁶, Emanuele Nicastro³⁷, Alessandra Pennisi¹¹, Heidi Peters³⁸, Dorota Piekutowska-Abramczuk¹⁶, Agnès Rötig³⁹, René Santer⁴⁰, Fernando Scaglia⁴¹, Manuel Schiff⁴², Mohmmad Shagrani⁴³, Mark Sharrard⁴⁴, Claudia Soler-Alfonso⁴⁵, Christian Staufner³², Imogen Storey⁴⁶, Michael Stormon⁴⁷, Robert W Taylor³³, David R Thorburn¹⁵, Elisa Leao Teles⁴⁸, Jian-She Wang²⁴, Daniel Weghuber⁵, Saskia Wortmann⁴⁹

Affiliations

¹ Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria; Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria. Electronic address: [email protected].
² Institute for Gastroenterology, Nutrition and Liver diseases, Schneider Children's Medical Center of Israel, Petah Tiqwa, Israel.
³ Metabolism Service, Schneider Children's Medical Center of Israel, Petah Tiqwa, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
⁴ Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany; Institute of Neurogenomics, Computational Health Center, Helmholtz Zentrum München, Neuherberg, Germany.
⁵ University Children's Hospital, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg, Austria.
⁶ 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.
⁷ Division of Paediatric Epileptology, Center for Paediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
⁸ Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
⁹ Department of Genetics, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.
¹⁰ Division of Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.
¹¹ 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.
¹² Department of Pediatrics, School of Medicine, University Hospital Center Zagreb and University of Zagreb, Zagreb, Croatia.
¹³ Division of Medical Genetics, Department of Pediatrics and Human Genetics, McGill University, Montreal, Quebec, Canada.
¹⁴ Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
¹⁵ Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Melbourne, Victoria, Australia; Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁶ Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland.
¹⁷ Faculty of Medicine, Queensland Children's Hospital, University of Queensland, Herston, Brisbane, Queensland, Australia.
¹⁸ Department of Paediatrics, Paediatric Metabolic Medicine, Hannover Medical School, Hannover, Germany.
¹⁹ Department of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden.
²⁰ Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- und Behavioral Sciences, University Duisburg-Essen, Essen, Germany.
²¹ Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich-Heine-University Dusseldorf, Dusseldorf, Germany.
²² Section for Pediatrics, Department of Clinical Sciences, Lund University, Lund, Sweden.
²³ Department of Pediatrics, Division of Pediatric Metabolism, University of Health Sciences, Bakırkoy Dr. Sadi Konuk Training and Research, Istanbul, Turkey.
²⁴ The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
²⁵ 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.
²⁶ 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.
²⁷ 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, Orsay, Paris, France.
²⁸ Children's Health Ireland, Temple Street Hospital, Dublin, Ireland.
²⁹ Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
³⁰ Division of Inborn Errors of Metabolism, Department of Pediatrics, İzmir Katip Çelebi University, Izmir, Turkey; Division of Genetics, Department of Pediatrics, Ege University, Izmir, Turkey.
³¹ 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.
³² Division of Neuropaediatrics and Metabolic Medicine, Center for Paediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
³³ 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, Newcastle upon Tyne, United Kingdom.
³⁴ Institute of Endocrinology and Diabetes, National Center of Childhood Diabetes Schneider Children's Medical Center of Israel, Petah Tiqwa, Israel.
³⁵ Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.
³⁶ Department of Metabolism, Chiba Children's Hospital, Midori-ku, Chiba, Japan.
³⁷ Pediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Bergamo, Italy.
³⁸ Department of Metabolic Medicine, Royal Children's Hospital, Melbourne, Victoria, Australia.
³⁹ Institut Imagine, INSERM UMR 1163, Paris, France.
⁴⁰ Department of Pediatrics, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
⁴¹ 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.
⁴² 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.
⁴³ Department of Liver & Small Bowel Health Centre King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
⁴⁴ Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom.
⁴⁵ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
⁴⁶ University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom.
⁴⁷ Department of Gastroenterology, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
⁴⁸ Inherited Metabolic Diseases Reference Centre, São João Hospital University Centre, EPE, Porto, Portugal.
⁴⁹ University Children's Hospital, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg, Austria; Amalia Children's Hospital, Radboudumc, Nijmegen, The Netherlands.

PMID: 36305855
DOI: 10.1016/j.gim.2022.09.015

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.

Keywords: Acute liver failure; Cysteine; Liver transplantation; Mitochondrial disease; Reversible.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetylcysteine / therapeutic use
Adolescent
Child
Child, Preschool
Humans
Infant
Liver Failure* / drug therapy
Liver Failure* / genetics
Liver Failure, Acute* / drug therapy
Liver Failure, Acute* / genetics
Mitochondrial Proteins / genetics
Mutation
Retrospective Studies
Young Adult
tRNA Methyltransferases / genetics

Substances

Acetylcysteine
Mitochondrial Proteins
TRMU protein, human
tRNA Methyltransferases

Abstract

Publication types

MeSH terms

Substances

Grants and funding