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.
Original language | English (US) |
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Article number | 100314 |
Journal | Genetics in Medicine |
Volume | 25 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2023 |
Funding
The 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 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 MITO-FIND study. This work was supported by the European Reference Network for Hereditary Metabolic Disorders (MetabERN). S.W. 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. 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 mitoNET German Network for Mitochondrial Diseases (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.Pe. A.Pen. 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. M.Ke. M.Ko. A.K. D.L. R.M. M.G.M. K.Mo. T.M. K.Mu. E.N. A.Pec. H.Pr. 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.Pe. H.Pr. A.Pen. 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. M.Ke. M.Ko. A.K. D.L. R.M. M.G.M. K.Mo. T.M. K.Mu. E.N. A.Pec. H.Pe. H.Pr. 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.31 Participants gave written informed consent for genetic investigations according to local regulations.
Keywords
- Acute liver failure
- Cysteine
- Liver transplantation
- Mitochondrial disease
- Reversible
ASJC Scopus subject areas
- Genetics(clinical)