Infantile Liver Failure Syndrome 1

A number sign (#) is used with this entry because of evidence that infantile liver failure syndrome-1 (ILFS1) is caused by homozygous mutation in the LARS gene (151350) on chromosome 5q32. One such family has been reported.

Genetic Heterogeneity of Infantile Liver Failure Syndrome

See also ILFS2 (616483), caused by mutation in the NBAS gene (608025) on chromosome 2p24.

A transient form of infantile liver failure (613070) is caused by mutation in the TRMU gene (610230) on chromosome 22q13.

Clinical Features

Casey et al. (2012) reported a 4-generation Irish Traveller family in which 6 individuals in 3 generations were affected with an infantile hepatopathy characterized by acute liver failure in the first year of life. The patients showed signs of intermittent improvement and developed acute symptoms only when their bodies were under physiologic stress due to illness. Earliest age at presentation was 2 months; the oldest affected family member was 33 years old at the time of the report. Liver biopsy performed in 3 family members showed steatosis and fibrosis. Patients also had microcytic anemia. Abnormal liver function tests, elevated lactates, abnormal brain MRIs, failure to thrive, developmental delay, and seizures were suggestive of a mitochondrial disorder. However, known causes of childhood liver failure and mitochondrial disease were excluded by biochemical, metabolic, and genetic analyses.

Population Genetics

Casey et al. (2012) stated that the estimated prevalence of infantile liver failure is less than 1 in 1 million.

Molecular Genetics

Using homozygosity mapping and whole-exome sequencing in a consanguineous Irish Traveller family with acute infantile liver failure, Casey et al. (2012) identified mutations in the LARS gene. All affected individuals were homozygous for 2 missense mutations. One was determined to be a rare nonpathogenic variant (c.245A-G, K82R, rs112954500). The other (Y373C; 151350.0001) was predicted to be highly deleterious, was highly conserved across eukaryotic species (89%), and was not present in 186 control chromosomes or in the dbSNP or 1000 Genomes Project databases. This mutation occurred in the editing domain of LARS, known as connective peptide-1, and was predicted to destabilize the protein structure. LARS knockdown achieved by siRNA in HEK293 cells had no effect on mitochondrial function even when cells were under physiologic stress.