TRMU deficiency: A broad clinical spectrum responsive to cysteine supplementation.

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 Here, we report six infants with biallelic TRMU variants, including four previously unpublished patients, all treated with exogenous cysteine.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.

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Déclaration de conflit d'intérêts

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.