REPORT Acute Infantile Liver Failure Due to Mutations in the TRMU Gene Avraham Zeharia, 1,4,9 Avraham Shaag, 1,9 Orit Pappo, 2 Anne-Marie Mager-Heckel, 5 Ann Saada, 1 Marine Beinat, 6 Olga Karicheva, 5 Hanna Mandel, 7 Noa Ofek, 3 Reeval Segel, 8 Daphna Marom, 4 Agnes Ro ¨tig, 6 Ivan Tarassov, 5 and Orly Elpeleg 1, * Acute liver failure in infancy accompanied by lactic acidemia was previously shown to result from mtDNA depletion. We report on 13 unrelated infants who presented with acute liver failure and lactic acidemia with normal mtDNA content. Four died during the acute episodes, and the survivors never had a recurrence. The longest follow-up period was 14 years. Using homozygosity mapping, we iden- tified mutations in the TRMU gene, which encodes a mitochondria-specific tRNA-modifying enzyme, tRNA 5-methylaminomethyl-2- thiouridylate methyltransferase. Accordingly, the 2-thiouridylation levels of the mitochondrial tRNAs were markedly reduced. Given that sulfur is a TRMU substrate and its availability is limited during the neonatal period, we propose that there is a window of time whereby patients with TRMU mutations are at increased risk of developing liver failure. Acute liver failure in infancy is a life-threatening condition manifested by poor feeding, vomiting, jaundice, distended abdomen, hemorrhagic diathesis, irritability, and hypoac- tivity. Routine laboratory investigations reveal elevated liver transaminases, hypoglycemia, coagulopathy, hyper- ammonemia, and direct hyperbilirubinemia. The differen- tial diagnosis includes viral infections, intoxications, and inborn errors of metabolism. The finding of hyperlactate- mia directs the diagnosis toward mitochondrial respiratory chain disorders, and in about half of the patients there is a defect in the mtDNA synthesis machinery, resulting in mtDNA depletion (MIM 251880). This was heretofore attributed to mutations in three genes: DGUOK (MIM 601465), POLG (MIM 174763), and MPV17 (MIM 137960). 1–3 In the past 14 years, we have encountered eight patients in seven unrelated families of Yemenite Jewish origin, who presented in infancy with acute liver failure. All were born at term, had birth weights appropriate for gestational age, and had physiologic hyperbilirubinemia that resolved in a normal manner. All were reportedly healthy during the early neonatal period but were admitted at 2–4 months because of irritability, poor feeding, and vomiting. On physical examination, all were found to be well-nourished but lethargic, with pale-gray skin color, jaundiced sclerae, distended abdomen, and hepatomegaly. All of the patients required intensive care for several weeks, with supportive nutrition and blood products given as compensation for coagulopathy and active GIT bleeding. Liver transplanta- tion was considered but was not performed in any of the patients. Laboratory investigation disclosed acute liver failure (clinical and biochemical data presented in Table 1) with severe coagulopathy that included low factor 5 and 11 and was not corrected by vitamin K supplementation, low albumin, direct hyperbilirubinemia, metabolic acidosis, hy- perlactatemia, and high alpha-fetoprotein. Blood ammonia level was normal or slightly elevated, and plasma amino acid profile was noted for high phenylalanine, tyrosine, methionine, glutamine, and alanine. Urinary organic acid analysis revealed massive excretion of lactate, phenylala- nine and tyrosine metabolites, and ketotic dicarboxylic and 3-hydroxydicarboxylic aciduria. Serology for hepatitis viruses and body fluid cultures failed to detect an infectious etiology. Abdominal ultrasound disclosed enlarged homog- enous liver with normal diameter of the bile ducts and the portal vein. Clinical and biochemical improvement started after 2–3 weeks, and liver functions returned to normal within 3-4 months. Nonetheless, liver size had normalized only after 3 months to 3 years. Seven patients survived the acute episode, were observed on a long term follow-up (the old- est currently 14 years of age) to be developing normally, and never experienced a similar episode. One patient (2859) died of intractable lactic acidosis and multiple organ failure. During the acute phase, there was usually no indication of extrahepatic involvement, as evidenced by normal electrolytes, creatinine and renal function, blood count, bone marrow aspiration, creatine phosphoki- nase (CPK), electromyography (EMG), echocardiogram, ophthalmologic examination, brain magnetic resonance imaging (MRI), electroencephalogram (EEG), and nerve 1 Department of Human Genetics and Metabolic Diseases, 2 Department of Pathology, 3 Department of Neonatology, Hadassah, the Hebrew University Medical Center, Jerusalem, Israel; 4 Day Hospitalization Unit and Department of Pediatrics A, Schneider Children’s Medical Center and Sackler School of Medicine, Tel Aviv University, Israel; 5 UMR 7156 Centre National de la Recherche Scientifique - Universite ´ de Strasbourg, Genetique Moleculaire, Genomi- que, Microbiologie, Strasbourg, France; 6 INSERM U781 and Department of Genetics, Ho ˆpital Necker-Enfants Malades, Universite ´ Rene ´ Descartes Paris V, 149 rue de Se `vres, 75015 Paris, France; 7 Metabolic Disease Unit, Rambam and the Rappaport Faculty of Medicine, Technion, Haifa, Israel; 8 Institute of Medical Genetics, Shaare-Zedek Medical Center, Jerusalem, Israel 9 These authors contributed equally to this work *Correspondence: elpeleg@cc.huji.ac.il DOI 10.1016/j.ajhg.2009.08.004. ª2009 by The American Society of Human Genetics. All rights reserved. The American Journal of Human Genetics 85, 401–407, September 11, 2009 401