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

Adolescent Child Child, Preschool Humans Infant Young Adult Acetylcysteine / therapeutic use Liver Failure / drug therapy Liver Failure, Acute / drug therapy Mitochondrial Proteins / genetics Mutation Retrospective Studies tRNA Methyltransferases / genetics
Acute liver failure Cysteine Liver transplantation Mitochondrial disease Reversible

Journal

Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831

Informations de publication

Date de publication:
06 2023
Historique:
received: 01 07 2022
revised: 27 09 2022
accepted: 28 09 2022
medline: 7 6 2023
pubmed: 29 10 2022
entrez: 28 10 2022
Statut: ppublish

Résumé

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. Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data. 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. In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.

Identifiants

DOI: 10.1016/j.gim.2022.09.015 PMID: 36305855
pubmed: 36305855
pii: S1098-3600(22)00953-4
doi: 10.1016/j.gim.2022.09.015
pii:
doi:

Substances chimiques

Acetylcysteine WYQ7N0BPYC
Mitochondrial Proteins 0
TRMU protein, human EC 2.1.1.61
tRNA Methyltransferases EC 2.1.1.-

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

100314

Subventions

Organisme : NINDS NIH HHS
ID : U54 NS078059
Pays : United States
Organisme : NINDS NIH HHS
ID : U54 NS115198
Pays : United States
Organisme : Wellcome Trust
ID : 203105/Z/16/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S005021/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/W019027/1
Pays : United Kingdom

Commentaires et corrections

Type : ErratumIn

Informations de copyright

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Conflict of Interest The authors declare no conflicts of interest.

Auteurs

Georg F 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.

Yael Mozer-Glassberg (Y)

Institute for Gastroenterology, Nutrition and Liver diseases, Schneider Children's Medical Center of Israel, Petah Tiqwa, Israel.

Yuval E Landau (YE)

Metabolism Service, Schneider Children's Medical Center of Israel, Petah Tiqwa, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Lea D 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.

Holger 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.

René G Feichtinger (RG)

University Children's Hospital, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg, Austria.

Johannes A Mayr (JA)

University Children's Hospital, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg, Austria.

Heiko 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.

Julian Schröter (J)

Division of Paediatric Epileptology, Center for Paediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.

Agnes Pechlaner (A)

Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria.

Fowzan S Alkuraya (FS)

Department of Genetics, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.

Joshua J Baker (JJ)

Division of Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.

Giulia 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.

Ivo Baric (I)

Department of Pediatrics, School of Medicine, University Hospital Center Zagreb and University of Zagreb, Zagreb, Croatia.

Nancy Braverman (N)

Division of Medical Genetics, Department of Pediatrics and Human Genetics, McGill University, Montreal, Quebec, Canada.

Birute Burnyte (B)

Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.

John 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.

Elzbieta Ciara (E)

Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland.

David Coman (D)

Faculty of Medicine, Queensland Children's Hospital, University of Queensland, Herston, Brisbane, Queensland, Australia.

Anibh M Das (AM)

Department of Paediatrics, Paediatric Metabolic Medicine, Hannover Medical School, Hannover, Germany.

Niklas Darin (N)

Department of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden.

Adela Della Marina (A)

Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- und Behavioral Sciences, University Duisburg-Essen, Essen, Germany.

Felix Distelmaier (F)

Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich-Heine-University Dusseldorf, Dusseldorf, Germany.

Erik A Eklund (EA)

Section for Pediatrics, Department of Clinical Sciences, Lund University, Lund, Sweden.

Melike Ersoy (M)

Department of Pediatrics, Division of Pediatric Metabolism, University of Health Sciences, Bakırkoy Dr. Sadi Konuk Training and Research, Istanbul, Turkey.

Weiyan Fang (W)

The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.

Pauline 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.

Rebecca D 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.

Emmanuel 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, Orsay, Paris, France.

Caoimhe Howard (C)

Children's Health Ireland, Temple Street Hospital, Dublin, Ireland.

Joanne Hughes (J)

Children's Health Ireland, Temple Street Hospital, Dublin, Ireland.

Vassiliki Konstantopoulou (V)

Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

Melis Kose (M)

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.

Marina 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.

Aneal 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.

Dominic Lenz (D)

Division of Neuropaediatrics and Metabolic Medicine, Center for Paediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.

Robert 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, Newcastle upon Tyne, United Kingdom.

Merav Gil Margolis (MG)

Institute of Endocrinology and Diabetes, National Center of Childhood Diabetes Schneider Children's Medical Center of Israel, Petah Tiqwa, Israel.

Kevin Morrison (K)

Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.

Thomas Müller (T)

Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria.

Kei Murayama (K)

Department of Metabolism, Chiba Children's Hospital, Midori-ku, Chiba, Japan.

Emanuele Nicastro (E)

Pediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Bergamo, Italy.

Alessandra 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.

Heidi Peters (H)

Department of Metabolic Medicine, Royal Children's Hospital, Melbourne, Victoria, Australia.

Dorota Piekutowska-Abramczuk (D)

Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland.

Agnès Rötig (A)

Institut Imagine, INSERM UMR 1163, Paris, France.

René Santer (R)

Department of Pediatrics, University Medical Center Hamburg Eppendorf, Hamburg, Germany.

Fernando 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.

Manuel 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.

Mohmmad 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.

Mark Sharrard (M)

Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom.

Claudia Soler-Alfonso (C)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.

Christian Staufner (C)

Division of Neuropaediatrics and Metabolic Medicine, Center for Paediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.

Imogen Storey (I)

University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom.

Michael Stormon (M)

Department of Gastroenterology, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.

Robert W Taylor (RW)

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.

David R Thorburn (DR)

Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Melbourne, Victoria, Australia; Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia.

Elisa Leao Teles (EL)

Inherited Metabolic Diseases Reference Centre, São João Hospital University Centre, EPE, Porto, Portugal.

Jian-She Wang (JS)

The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.

Daniel Weghuber (D)

University Children's Hospital, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg, Austria.

Saskia Wortmann (S)

University Children's Hospital, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg, Austria; Amalia Children's Hospital, Radboudumc, Nijmegen, The Netherlands.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adolescent › Genotypic and phenotypic spectrum of infantile...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Genotypic and phenotypic spectrum of infantile...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Enfant d'âge préscolaire › Genotypic and phenotypic spectrum of infantile...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Genotypic and phenotypic spectrum of infantile...
questionsmedicales.fr › Personnes › Tranches d'âge › Nourrisson › Genotypic and phenotypic spectrum of infantile...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Jeune adulte › Genotypic and phenotypic spectrum of infantile...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Acides aminés soufrés › Cystéine › Acétylcystéine › Genotypic and phenotypic spectrum of infantile...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Insuffisance hépatique › Défaillance hépatique › Genotypic and phenotypic spectrum of infantile...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Insuffisance hépatique › Défaillance hépatique › Défaillance hépatique aigüe › Genotypic and phenotypic spectrum of infantile...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines mitochondriales › Genotypic and phenotypic spectrum of infantile...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Genotypic and phenotypic spectrum of infantile...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Études rétrospectives › Genotypic and phenotypic spectrum of infantile...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › One-carbon group transferases › Methyltransferases › T-RNA methyltransferases › Genotypic and phenotypic spectrum of infantile...