Clinical characteristics: Infants with untreated TRMU deficiency, a mitochondrial disorder, typically become symptomatic between ages two and four months with transient acute liver dysfunction (including elevated transaminases, abnormal synthetic functions, and/or hepatomegaly), metabolic derangements (severe persistent lactic acidosis, hypoglycemia, hyperammonemia), and poor weight gain. With proper supportive treatment (but not disease-targeted therapy), abnormal liver findings (including coagulopathy) improve or normalize. Likewise, metabolic derangements improve. However, other manifestations typical of a mitochondrial disorder such as persistent lactic acidosis, neurologic dysfunction (including developmental delay / intellectual disability and seizures), cardiomyopathy, and respiratory failure may persist or develop or over time.

Diagnosis/testing: The diagnosis of TRMU deficiency is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in TRMU identified by molecular genetic testing.

Management: Targeted therapies: L-cysteine, with or without N-acetylcysteine (NAC), should be initiated as soon as a diagnosis of TRMU deficiency is suspected. Because the endogenous supply of cysteine is normally low in the first few months of life and because the enzyme TRMU requires adequate amounts of cysteine to enable the essential function of thiolating mitochondrial transfer RNAs, the initial manifestations of TRMU deficiency (primarily hepatopathy) may be reversed, ameliorated, or in some cases prevented by exogenous oral cysteine supplementation in infants with TRMU deficiency. To date, two infants treated presymptomatically overall had a milder clinical course than their affected relatives.

Liver transplantation: Liver transplantation is indicated when hepatopathy does not respond to medical interventions.

Supportive care: Supportive care by a multidisciplinary team of clinicians, including a hepatologist, neurologist, and medical geneticist, is recommended to manage the commonly reported complications of developmental delay / intellectual disability, cardiomyopathy, seizures, and/or respiratory failure.

Surveillance: Routine follow up is recommended to monitor response to L-cysteine and NAC supplementation, to evaluate response to supportive interventions, and to identify emergence of new findings or concerns regarding developmental/educational progress such as persistent neurodevelopmental delay or new onset of seizures that may develop over time.

Agents/circumstances to avoid: Avoid medications that increase metabolic demand (such as corticosteroids) or inhibit mitochondrial activity (such as valproic acid and prolonged propofol infusion) and fasting, as it increases metabolic demand and may exacerbate hypoglycemia. Consider avoiding acetaminophen (paracetamol) during episodes of liver dysfunction based on theoretical concerns for oxidative stress.

Evaluation of relatives at risk: Molecular genetic prenatal testing of fetuses at risk may be performed via amniocentesis or chorionic villus sampling to inform maternal cysteine supplementation (reported in one pregnancy) and to facilitate institution of exogenous cysteine supplementation (as L-cysteine, N-acetylcysteine, or both) at birth. If prenatal testing has not been performed on a pregnancy at risk, supplementation with L-cysteine (and possibly N-acetylcysteine) of an at-risk newborn sib should be offered until molecular genetic testing for the family-specific TRMU pathogenic variants has been completed.

Genetic counseling: TRMU deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a TRMU pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial TRMU pathogenic variants. Once the TRMU pathogenic variants have been identified in an affected family member, molecular genetic carrier testing and prenatal/preimplantation genetic testing are possible.