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

Lookup NU author(s): Professor Robert Taylor



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2022 The Authors. 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.

Publication metadata

Author(s): Vogel GF, Mozer-Glassberg Y, Landau YE, Schlieben LD, Prokisch H, Feichtinger RG, Mayr JA, Brennenstuhl H, Schroter J, Pechlaner A, Alkuraya FS, Baker JJ, Barcia G, Baric I, Braverman N, Burnyte B, Christodoulou J, Ciara E, Coman D, Das AM, Darin N, Della Marina A, Distelmaier F, Eklund EA, Ersoy M, Fang W, Gaignard P, Ganetzky RD, Gonzales E, Howard C, Hughes J, Konstantopoulou V, Kose M, Kerr M, Khan A, Lenz D, McFarland R, Margolis MG, Morrison K, Muller T, Murayama K, Nicastro E, Pennisi A, Peters H, Piekutowska-Abramczuk D, Rotig A, Santer R, Scaglia F, Schiff M, Shagrani M, Sharrard M, Soler-Alfonso C, Staufner C, Storey I, Stormon M, Taylor RW, Thorburn DR, Teles EL, Wang J-S, Weghuber D, Wortmann S

Publication type: Article

Publication status: Published

Journal: Genetics in Medicine

Year: 2022

Pages: Epub ahead of print

Online publication date: 28/10/2022

Acceptance date: 28/09/2022

Date deposited: 15/11/2022

ISSN (print): 1098-3600

ISSN (electronic): 1530-0366

Publisher: Elsevier Inc.


DOI: 10.1016/j.gim.2022.09.015

PubMed id: 36305855


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Funder referenceFunder name
203105/Z/16/ZWellcome Trust
MR/S005021/1Medical Research Council (MRC)