Infantile Liver Failure Syndrome 2

A number sign (#) is used with this entry because of evidence that infantile liver failure syndrome-2 (ILFS2) is caused by homozygous or compound heterozygous mutation in the NBAS gene (608025) on chromosome 2p24.

Description

Infantile liver failure syndrome-2 is an autosomal recessive disorder characterized by recurrent episodes of acute liver failure during intercurrent febrile illness. Patients first present in infancy or early childhood, and there is complete recovery between episodes with conservative treatment (summary by Haack et al., 2015).

For a discussion of genetic heterogeneity of infantile liver failure syndrome, see ILFS1 (615438).

Clinical Features

In 10 unrelated families, most apparently of European descent, Haack et al. (2015) identified 11 patients, aged 3 to 37 years, with onset of recurrent acute liver failure in infancy. Most patients had onset in the first 2 years of life, although 1 had the first episode at age 6 years. Episodic liver failure in these patients was precipitated by intercurrent febrile illness, and liver function recovered completely with conservative management in the interval. Crises were manifest by vomiting, lethargy, increased liver enzymes, jaundice, and coagulopathy. Some patients developed secondary hyperammonemia, hypoglycemia, or encephalopathy. Four patients had comorbid features, such as cardiomyopathy, autoimmune gastrointestinal disease, and epilepsy, but none of these features were present in more than 1 patient. None of the 11 patients died, but 2 had older sibs who died of acute liver failure in early infancy.

Inheritance

The transmission pattern of ILFS2 in the families reported by Haack et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 5 unrelated German patients with ILFS2, Haack et al. (2015) identified homozygous or compound heterozygous mutations in the NBAS gene (see, e.g., 608025.0002-608025.0006). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families with available data. Screening of the NBAS gene in 15 additional unrelated patients with acute liver failure identified biallelic NBAS mutations in 6 patients from 5 families. All 11 affected individuals carried at least 1 missense mutation on 1 allele. Seven of the mutations were predicted to result in a loss of function, and all remaining missense mutations or in-frame deletions were clustered in 2 regions in the first half of the gene: exons 8 to 12 encoding the quinoprotein amine dehydrogenase beta-chain-like domain, and exons 21 to 28 encoding the secretory pathway sec39 domain. Patient fibroblasts showed a reduction of NBAS levels to 18 to 36% of control values, indicating a substantial impairment of protein translation and/or stability. Patient fibroblasts showed normal glycosylation patterns but an increase in expression of genes involved in the ER stress response compared to controls. Haack et al. (2015) suggested that a catabolic state with high energy demands during febrile infections may cause derailment of ER/Golgi vesicular transport.