Liver Failure, Infantile, Transient

A number sign (#) is used with this entry because transient infantile liver failure (LFIT) can be caused by homozygous or compound heterozygous mutation in the TRMU gene (610230), which is involved in mitochondrial protein translation, on chromosome 22q13.

Description

Acute infantile liver failure resulting from TRMU mutation is a transient disorder of hepatic function. In addition to elevated liver enzymes, jaundice, vomiting, coagulopathy, and hyperbilirubinemia, the presence of increased serum lactate is consistent with a defect in mitochondrial respiratory function. With supportive care, patients who survive the initial acute episode can recover and show normal development (Zeharia et al., 2009).

See also transient infantile mitochondrial myopathy (MMIT; 500009), which is a similar disorder.

A more severe, permanent disorder with some overlapping features is associated with mitochondrial DNA depletion (251880).

See ILFS1 (615438) for information on syndromic infantile liver failure.

Clinical Features

Lev et al. (2002) reported an infant, born of unrelated Yemenite Jewish parents, who had fulminant lactic acidosis in the neonatal period. She presented at age 9 weeks with vomiting and metabolic acidosis and was found to have an enlarged liver. During the second week of her illness, she developed progressive hepatic insufficiency, jaundice, ascites, hypersplenism, coagulopathy, increased transaminases, and pancreatic failure. Liver transplant was suggested. Over the next few weeks, the liver abnormalities and lactic acidosis improved. Neurologic status remained intact throughout the illness. Studies of muscle and liver biopsies showed decreased mitochondrial complex IV activity (12% residual activity) in the liver only. Lev et al. (2002) commented on the unusual spontaneous recovery in this patient.

Zeharia et al. (2009) reported 7 unrelated families of Yemenite Jewish origin in which at least 1 family member had acute liver failure in early infancy. 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 to 4 months of age with irritability, poor feeding, and vomiting. Physical examination showed pale-gray skin color, jaundiced sclerae, distended abdomen, hepatomegaly, and coagulopathy requiring intensive care. Laboratory studies indicated acute liver failure, with low albumin, direct hyperbilirubinemia, metabolic acidosis, hyperlactatemia, lactic aciduria, and high alpha-fetoprotein. Clinical and biochemical improvement began after 2 to 3 weeks of supportive care, and liver functions returned to normal within 3 to 4 months; however, liver size normalized only after 3 months to 3 years. One patient died of multiple organ failure. Of the 7 patients that survived the acute episode, all were alive and well up to age 14 years. During the acute phase, liver biopsy of 2 patients showed minimal chronic inflammation and mild focal proliferation of bile ductules, with variable portal and sinusoidal fibrosis. There were extensive oncocytic changes in the hepatocytes, as well as focal macrovesicular steatosis and focal ballooning of their cytoplasm. Following identification of the molecular defect in the TRMU gene, the authors identified 5 additional non-Yemenite-Jewish patients with the same disorder. These additional patients were of Algerian, Ashkenazi Jewish, and Arab origin. The presentation was the same, but 3 patients died at ages 2 to 4 months. Zeharia et al. (2009) noted that Lev et al. (2002) may have reported the first case of TRMU deficiency in an Israeli infant of Yemenite-Jewish origin who presented with transient liver failure during infancy.

Uusimaa et al. (2011) reported a 4-year-old Irish girl with transient acute infantile liver failure associated with lactic acidosis and profound cytochrome c oxidase deficiency in muscle and liver samples. Brain MRI showed abnormal high signals in the right thalamus, which disappeared by age 1 year. She also had feeding difficulties and hypotonia in early infancy. Although she recovered, she had mildly delayed walking, axial weakness, and bulbar involvement. Molecular analysis identified compound heterozygous mutations in the TRMU gene (610230.0006 and 610230.0007).

Biochemical Features

Zeharia et al. (2009) found markedly reduced activities of mitochondrial respiratory chain complexes I, III, and IV in patients with infantile acute liver failure. There was relatively normal activity of complex II, suggesting a defect in the synthesis of mtDNA-encoded proteins. Notably, mtDNA depletion was not observed, and muscle studies were normal. Further studies indicated a defect in a nuclear-encoded mitochondrial translation factor. A study of tRNAs in cells derived from 3 of the patients showed a severe reduction of thio-modified mitochondrial tRNAs, whereas the pattern of hybridization obtained for the cytosolic tRNA-lys, modified by another enzyme, was similar to controls. The findings suggested that the mitochondrial translation defect resulted from reduced modification of several mitochondrial tRNAs. Noting that the availability of cysteine in the neonatal period is limited, Zeharia et al. (2009) proposed that there is a window of time during 1 to 4 months of age during which patients with TRMU mutations are at an increased risk of developing liver failure.

Molecular Genetics

By linkage analysis, followed by candidate gene sequencing, Zeharia et al. (2009) identified homozygous and compound heterozygous mutations in the TRMU gene (see, e.g., 610230.0002-610230.0005) in patients with infantile acute liver failure. Seven patients of Yemenite Jewish origin had the same Y77H mutation (610230.0002), indicating a founder effect. Overall, 9 mutations were identified in 13 patients.