Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins (ORPHA:217371)
A rare mitochondrial respiratory chain deficiency due to TRMU deficiency leading to mitochondrial tRNA synthesis defect and characterized clinically by transient, but life-threatening acute liver failure episodes.
Epidemiology
To date, more than 30 cases have been reported.
Clinical description
Clinical presentation is typically with acute liver failure (hepatomegaly, jaundice, irritability, feeding difficulties, vomiting, coagulopathy) occurring between 1 and 6 months of age. Patients present with hypoglycemia and hyperlactatemia, consistent with a defect in mitochondrial respiratory chain function. Uncommon clinical features including muscular involvement, mainly cardiac, have also been reported.
Etiology
This disease is due to biallelic pathogenic variants in the (TRMU, 22q13.31) gene. This gene encodes for the tRNA mitochondrial 2-thiouridylase that is responsible for the 2-thiolation of uridine at the first anticodon position of the mitochondrial tRNALys, tRNAGlu, and tRNAGln. Mutations in this gene impair the translation of mtDNA-dependent complexes and cause combined respiratory chain defects.
Diagnostic methods
Diagnosis is based on the clinical evaluation of liver failure symptoms and on metabolic tests evaluating the mitochondrial function. Abdominal ultrasound usually disclosed hyperechogenic liver. When performed, liver biopsy analysis showed microvesicular steatosis and oncocytic hepatocytes, suggesting mitochondrial disease. Molecular genetic analysis searching for mitochondrial diseases establishes the diagnosis by identifying pathogenic TRMU variants.
Differential diagnosis
Differential diagnoses include mainly: other mitochondrial respiratory chain diseases involving the liver, especially hepatocerebral depletion syndromes (POLG, DGUOK, MPV17); adenosine kinase deficiency; recurrent acute liver failure triggered by infections or hyperthermia (NBAS, SCYL1, RINT1); aminoacyl-tRNA synthetase deficiencies (LARS, MARS, IARS). Molecular genetic testing rules out the diagnosis of these diseases.
Antenatal diagnosis
Prenatal testing is possible if pathogenic variants have been previously identified in the family.
Genetic counseling
The disorder follows an autosomal recessive inheritance pattern. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Non-specific supportive care including treatment and prevention of hypoglycemia is provided to patients undergoing an episode of acute liver failure. While cysteine supplementation efficacy is not demonstrated, supplementation with N-acetylcysteine or L-cysteine should be considered. Given the absence of significant neurological involvement reported so far, when indicated, a liver transplantation could be considered in these patients.
Prognosis
According to published data, 8 out of 32 patients (25%) died during the first year of life. In patients who survive the acute liver failure episodes, a full recovery occurs within months. Currently, no prognostic factor has been identified.

                            Last update: 
                            December 2021


                            - Expert reviewer(s): 
                            Dr Pauline GAIGNARD  - Pr Emmanuel GONZALES | RARE-LIVER*


                                * European Reference Network