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. 2021 Feb;132(2):146-153.
doi: 10.1016/j.ymgme.2021.01.005. Epub 2021 Jan 14.

TRMU deficiency: A broad clinical spectrum responsive to cysteine supplementation

Chaya N Murali  1 , Claudia Soler-Alfonso  2 , Kathleen M Loomes  3 , Amit A Shah  3 , Danielle Monteil  4 , Carmencita D Padilla  5 , Fernando Scaglia  6 , Rebecca Ganetzky  7
Affiliations

TRMU deficiency: A broad clinical spectrum responsive to cysteine supplementation

Chaya N Murali et al. Mol Genet Metab. 2021 Feb.

Abstract

TRMU is a nuclear gene crucial for mitochondrial DNA translation by encoding tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase, which thiolates mitochondrial tRNA. Biallelic pathogenic variants in TRMU are associated with transient infantile liver failure. Other less common presentations such as Leigh syndrome, myopathy, and cardiomyopathy have been reported. Recent studies suggested that provision of exogenous L-cysteine or N-acetylcysteine may ameliorate the effects of disease-causing variants and improve the natural history of the disease. Here, we report six infants with biallelic TRMU variants, including four previously unpublished patients, all treated with exogenous cysteine. We highlight the first report of an affected patient undergoing orthotopic liver transplantation, the long-term effects of cysteine supplementation, and the ability of the initial presentation to mimic multiple inborn errors of metabolism. We propose that TRMU deficiency should be suspected in all children presenting with persistent lactic acidosis and hypoglycemia, and that combined N-acetylcysteine and L-cysteine supplementation should be considered prior to molecular diagnosis, as this is a low-risk approach that may increase survival and mitigate the severity of the disease course.

Keywords: Cysteine; Liver failure; Mitochondrial disorder; Orthotopic liver transplant; TRMU.

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Conflict of interest statement

Declaration of Competing Interest Dr. Loomes declares consulting relationships with Albireo Pharma, Mirum Pharmaceuticals and Retrophin, and grant funding for clinical trials from Albireo Pharma and Mirum Pharmaceuticals. Dr. Monteil declares that the views expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government. I am a military service member. This work was prepared as part of my official duties. Title 17 U.S.C. 105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person's official duties. Dr. Scaglia declares grant funding for clinical trials from NIH-5 U54-NS078059-09, PTC Therapeutics, Stealth BioTherapeutics, and Entrada Therapeutics, and is an investigator in the North American Mitochondrial Disease Consortium. Dr. Ganetzky declares consulting relationships with Minovia therapeutics.

Figures

Figure 1.
Figure 1.
Liver histology images for Patient 1. A) Portal inflammation with bridging fibrosis and nodularity. B) Foci of oncocytic hepatocytes. C) Parenchymal collapse with steatosis, cholestasis, and hepatocellular multinucleation. D) Numerous mitochondria with loss of cristae and focal densities. E) Fat droplets and increased numbers of mitochondria with dense internal structure.
Figure 2.
Figure 2.
Clinical disease course for Patients 1–6 over the first year of life and beyond. Stabilization – stable laboratory lactate and non-recurrent hospitalizations. NAC – N-acetylcysteine. LC – L-cysteine.
See this image and copyright information in PMC

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