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

Purpose: The study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and to determine the role of cysteine supplementation in its treatment. Methods: Individuals with biallelic (likely) pathogenic variants in TRMU were studied through an international retrospective collection of de-identified patient data. Results: In 62 individuals, including 30 previously unreported cases, we described 48 (likely) pathogenic TRMU variants, of which, 18 were novel. 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 is a transient, reversible disease and cysteine supplementation improved survival. © 2022 The AuthorsDMB-1805- 0002; 01GM1207; MR/S005021/1; G0800674; National Institutes of Health, NIH: 5U54-NS078059-11, 5U54-NS115198-02; Wellcome Trust, WT: 203105/Z/16/Z; PTC Therapeutics, PTC; Manchester Biomedical Research Centre, BRC; Medical Research Council, MRC: MR/W019027/1; Pathological Society of Great Britain and Ireland; National Health and Medical Research Council, NHMRC: GNT1155244, GNT1164479; Bundesministerium für Bildung und Forschung, BMBF: 01GM1906B, 01KU2016A; Newcastle upon Tyne Hospitals NHS Foundation Trust; State Government of Victoria; Astellas Pharma; Bundesministerium für Bildung und Frauen, BMBF; Medizinische Universität Innsbruck, MUI; King Salman Center for Disability Research, KSCDR: RG-2022-010; Lily FoundationThe Chair in Genomic Medicine awarded to J.C. is generously supported by The Royal Children’s HospitalFoundation The Royal Children's Hospital Foundation . We are grateful to the Crane, Perkins, and Miller families for their generous financial support. We thank the Kinghorn Centre for Clinical Genomics for assistance with production and processing of genome sequencing data. This project was supported by the funding from MitoCanada ( https://mitocanada.org ) as part of the Mitochondrial Functional and Integrative Next Generation Diagnostics (MITO-FIND) study. This work was supported by the European Reference Network for Hereditary Metabolic Disorders (MetabERN). S.W. received funding from ERAPERMED2019-310 Personalized Mitochondrial Medicine (PerMiM): Optimizing diagnostics and treatment for patients with mitochondrial diseases FWF 4704-B. F.S.A. is funded by the National Institutes of Health along with the North American Mitochondrial Disease Consortia (5U54-NS078059-11), the Frontiers of Congenital Disorders of Glycosylation Consortia (FCDGC, 5U54-NS115198-02), Mervar Foundation, Courage for a Cure Foundation , PTC Therapeutics , Astellas Pharma Inc, and Saol Therapeutics. R.M. and R.W.T. are funded by the Wellcome Trust Centre for Mitochondrial Research (203105/Z/16/Z), the Mitochondrial Disease Patient Cohort (United Kingdom) (G0800674), the Medical Research Council International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), the Medical Research Council (MR/W019027/1), the Lily Foundation , the UK NIHR Biomedical Research Centre for Ageing and Age-related Disease award to the Newcastle upon Tyne Hospitals NHS Foundation Trust , and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children. R.W.T. also receives funding from the Pathological Society of Great Britain and Ireland. J.C. is supported by a New South Wales Office of Health and Medical Research Council Sydney Genomics Collaborative grant. We acknowledge funding from the National Health and Medical Research Council ( NHMRC ): project grant GNT1164479 (D.R.T.) and Principal Research Fellowship GNT1155244 (D.R.T.). The research conducted at the Murdoch Children’s Research Institute was supported by the Victorian Government’s Operational Infrastructure Support program. This study was supported by BMBF (German Federal Ministry of Education and Research ) through the German Network for Mitochondrial Diseases ([mitoNET] grant number 01GM1906B), Personalized Mitochondrial Medicine (PerMiM) (grant number 01KU2016A), and E-Rare project GENOMIT (grant number 01GM1207) and the Bavarian State Ministry of Health and Care within its framework of DigiMed Bayern (grant number DMB-1805- 0002). The authors extend their appreciation to the King Salman Center For Disability Research for funding this work through research group number RG-2022-010 (to F.S.A.)The Chair in Genomic Medicine awarded to J.C. is generously supported by The Royal Children's HospitalFoundationThe Royal Children's Hospital Foundation. We are grateful to the Crane, Perkins, and Miller families for their generous financial support. We thank the Kinghorn Centre for Clinical Genomics for assistance with production and processing of genome sequencing data. This project was supported by the funding from MitoCanada (https://mitocanada.org) as part of the Mitochondrial Functional and Integrative Next Generation Diagnostics (MITO-FIND) study. This work was supported by the European Reference Network for Hereditary Metabolic Disorders (MetabERN). S.W. received funding from ERAPERMED2019-310 Personalized Mitochondrial Medicine (PerMiM): Optimizing diagnostics and treatment for patients with mitochondrial diseases FWF 4704-B. F.S.A. is funded by the National Institutes of Health along with the North American Mitochondrial Disease Consortia (5U54-NS078059-11), the Frontiers of Congenital Disorders of Glycosylation Consortia (FCDGC, 5U54-NS115198-02), Mervar Foundation, Courage for a CureFoundation, PTC Therapeutics, Astellas Pharma Inc, and Saol Therapeutics. R.M. and R.W.T. are funded by the Wellcome Trust Centre for Mitochondrial Research (203105/Z/16/Z), the Mitochondrial Disease Patient Cohort (United Kingdom) (G0800674), the Medical Research Council International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), the Medical Research Council (MR/W019027/1), the LilyFoundation, the UK NIHR Biomedical Research Centre for Ageing and Age-related Disease award to the Newcastle upon Tyne Hospitals NHS Foundation Trust, and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children. R.W.T. also receives funding from the Pathological Society of Great Britain and Ireland. J.C. is supported by a New South Wales Office of Health and Medical Research Council Sydney Genomics Collaborative grant. We acknowledge funding from the National Health and Medical Research Council (NHMRC): project grant GNT1164479 (D.R.T.) and Principal Research Fellowship GNT1155244 (D.R.T.). The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support program. This study was supported by BMBF (German Federal Ministry of Education and Research) through the German Network for Mitochondrial Diseases ([mitoNET] grant number 01GM1906B), Personalized Mitochondrial Medicine (PerMiM) (grant number 01KU2016A), and E-Rare project GENOMIT (grant number 01GM1207) and the Bavarian State Ministry of Health and Care within its framework of DigiMed Bayern (grant number DMB-1805- 0002). The authors extend their appreciation to the King Salman Center For Disability Research for funding this work through research group number RG-2022-010 (to F.S.A.), Conceptualization: G.F.V. S.W.; Data Curation: G.F.V. S.W. Y.M.-G. Y.E.L. R.G.F. J.A.M. H.B. L.D.S. H.Pr. A.Pec. F.S.A. J.J.B. G.B. I.B. N.B. B.B. J.C. E.C. D.C. A.M.D. N.D. A.D.M. F.D. E.A.E. M.E. W.F. P.G. R.D.G. E.G. C.H. J.H. V.K. M.Ko. M.Ke. A.K. D.L. R.M. M.G.M. K.Mo. T.M. K.Mu. E.N. A.Pen. H.Pe. D.P.-A. A.R. R.S. F.S. M.Sc. M.Shag. M.Shar. C.S.-A. C.S. I.S. M.St. R.W.T. D.R.T. E.L.T. J.-S.W. D.W.; Methodology: G.F.V. S.W. R.G.F. J.A.M.; Visualization: G.F.V. S.W. H.B. J.S.; Writing-original draft: G.F.V. S.W.; Writing-review and editing: G.F.V. S.W. Y.M.-G. Y.E.L. R.G.F. J.A.M. H.B. L.D.S. H.Pr. A.Pec. F.S.A. J.J.B. G.B. I.B. N.B. B.B. J.C. E.C. D.C. A.M.D. N.D. A.D.M. F.D. E.A.E. M.E. W.F. P.G. R.D.G. E.G. C.H. J.H. V.K. M.Ko. M.Ke. A.K. D.L. R.M. M.G.M. K.Mo. T.M. K.Mu. E.N. A.Pen. H.Pe. D.P.-A. A.R. R.S. F.S. M.Sc. M.Shag. M.Shar. C.S.-A. C.S. I.S. M.St. R.W.T. D.R.T. E.L.T. J.-S.W. D.W. This study was conducted in accordance with the guidelines of the Institutional Review Board of the Medical University of Innsbruck and the 1975 Declaration of Helsinki.29 Participants gave written informed consent for genetic investigations according to local regulations

Treatment of Chronic Hepatitis C Virus Infection in Children: A Position Paper by the Hepatology Committee of European Society of Paediatric Gastroenterology, Hepatology and Nutrition

Objectives: In 2017, the European Medicines Agency and the Food and Drug Administration approved the use of the fixed-dose combination of ledipasvir/sofosbuvir and of the combination of sofosbuvir and ribavirin for treatment of adolescents (12-17 years or weighing > 35 kg) with chronic hepatitis C virus (HCV) genotype 1, 4, 5, and 6 and genotype 2 and 3 infections, respectively. Although trials with direct-acting antivirals are ongoing for younger children, the only available treatment in the United States and Europe for those <12 years is still the dual therapy of pegylated interferon and ribavirin. There is currently a lack of a systematic approach to the care of these patients. The Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition developed an evidence-based position paper for the management of chronic HCV infection in children. Methods: A systematic literature search and meta-analysis were performed using MEDLINE and Embase from June 1, 2007 to June 1, 2017. The approach of the Grading of Recommendations Assessment, Development and Evaluation was applied to evaluate outcomes. European Society of Pediatric Gastroenterology, Hepatology and Nutrition Committee members voted on each recommendation, using the nominal voting technique. Results: The efficacy of the different direct-acting antivirals combinations tested was higher, the relapse and the treatment discontinuation rates lower when compared to pegylated interferon and ribavirin. Conclusions: This position paper addresses therapeutic management issues including goals, endpoints, indications, contraindications, and the optimal treatment regimen in children with chronic HCV infection

Simultaneous liver-pancreas transplantation for cystic fibrosis-related liver disease: A multicenter experience

Background: Diabetes is associated with increased morbidity and mortality in patients with cystic fibrosis (CF). While liver transplantation is well established for CF-related liver disease (CFLD), the role of simultaneous liver pancreas transplantation is less understood. Methods: We polled 81 pediatric transplantation centers to identify and characterize subjects who had undergone simultaneous liver pancreas transplantation and obtain opinions about this procedure in CFLD. Results: Fifty (61.7%) polled transplant centers responded and 94% reported that they would consider simultaneous liver pancreas transplantation for CFLD and diabetes. A total of 8 patients with simultaneous liver pancreas transplantation were identified with median follow up of 38 months. All patients had pre-existing diabetes. Exocrine and endocrine pancreatic function was initially restored in all patients with later functional loss in one patient. Body mass index Z-score increased between one year pre-transplantation and one year post-transplantation (P = 0.029). Conclusions: Patients with CFLD undergoing initial assessment for liver transplantation may benefit from consideration of simultaneous liver pancreas transplantation. (C) 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved

Congenital porto-systemic shunts in children: preliminary results from the IRCPSS

Background: • Congenital portosystemic shunts (CPSS) are increasingly diagnosed in children and adults owing to high resolution imaging. • Their natural history is incompletely understood. • CPSS may be associated with life-threatening complications. • There are no established predictors of spontaneous closure. •Among patients in whom CPSS does not close spontaneously, is unclear which patients will develop complications, consequently which shunts require closure. Aim: To use preliminary data from 15/28 centers participating in the International Registry for Congenital Porto-Systemic Shunts (IRCPSS) to identify trends that might inform management decision

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

Purpose: The study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and to determine the role of cysteine supplementation in its treatment. Methods: Individuals with biallelic (likely) pathogenic variants in TRMU were studied through an international retrospective collection of de-identified patient data. Results: In 62 individuals, including 30 previously unreported cases, we described 48 (likely) pathogenic TRMU variants, of which, 18 were novel. 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 is a transient, reversible disease and cysteine supplementation improved survival