Abstract: Objective To explore the genotype and clinical characteristics of the leukoencephalopathy with thalamus and brainstem involvement and high lactste (LTBL) caused by the mutation of EARS2 gene, and to improve the understanding of the disease. Methods The clinical characteristics, laboratory examination and genetic testing of one case of LTBL were presented，analyzed and discussed. The related literatures were reviewed. Results The male case presented jaundice from the second day after birth. Liver failure (severe cholestasis, hypoglycemia and dysfunction of blood coagulation), typical LTBL clinical features including severe lactic acidosis, growth and mental retarration besides hypoglycemia were found after the age of 42 days. Brain MR revealed multiple brain injury. Genetic sequencing from the child and his parents revealed compound heterozygous variants in EARS2 gene: c.1355T>G（p.L452R）and c.813C>A（p.F271L）. At the age of 15 months old, biochemical markers (including liver enzymes, bilirubin, blood glucose and lactic acid ) were completely normal and delayed psychomotor development was obvious. Brain MR showed severe hydrocephalus. Hydrocephalus and delyed motor development improved greatly after 6 months of ventriculo-peritoneal drainage. Conclusion Liver failure is one of the early major manifestations of LTBL caused by gene mutation in EARS2. With age, hydrocephalus may be one of the clinical features of this disease. EARS2 gene mutations of c.1355T>G (p.L452R) and c.813C>A (p.F271L) are the pathogenic gene mutations of LTBL. The clinical features and genotypes of LTBL should be further studied.