Online Mendelian Inheritance in Man (OMIM) (original) (raw)

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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 (ILFS2) 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.

Rius et al. (2019) reported a patient who had episodes of fulminant liver failure from the age of 13 months. The episodes were triggered by intercurrent viral infections, and resulted in severe transaminase elevations and abnormal liver synthetic function manifesting as coagulopathy. The episodes were also associated with lactic acidosis, and sometimes with hypoketotic hypoglycemia and elevated ammonia. The patient recovered from the episodes with supportive care, including dextrose-containing IV fluids. In between episodes, the liver size and function were normal, and blood lactate ranged from normal to mildly elevated. The patient had normal growth and development. A liver biopsy during an acute episode showed microvesicular steatosis. Muscle and liver biopsies taken when the patient was well showed mild lipid accumulation. Liver respiratory chain enzymology was normal, but muscle respiratory chain enzymology showed possible complex II + III deficiency. At 9 years of age, the patient was growing and developing normally without any other medical issues, and her last episode of acute liver failure was 3 years earlier.

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.

In an indigenous Australian girl with ILFS2, Rius et al. (2019) identified compound heterozygous mutations in the NBAS gene, a missense mutation (608025.0007) and a deep intronic mutation (608025.0008). Each parent was heterozygous for one of the mutations. The mutations were identified by a combination of whole-exome sequencing, whole-genome sequencing, and RT-PCR.

Genotype/Phenotype Correlations

Hammann et al. (2024) discussed genotype/phenotype correlations in a population of 60 patients with NBAS-associated mutations. They reviewed the suggestion that missense or in-frame deletions in the C-terminal region of the NBAS gene are associated with the multisystem SOPH syndrome (614800), missense or in-frame deletions in the Sec30 domain of NBAS are associated with infantile liver failure syndrome type 2, and missense or in-frame deletions in the beta-propeller domain of NBAS are associated with a combined phenotype of multisystem involvement with acute liver failure. Patients with compound heterozygous mutations in different domains could not be assigned to any subgroup. When comparing patients with the same genotypes, clinical features were most concordant between patients in the ILFS2 cohort (96.7%) and least concordant between patients in the combined multisystem/acute liver failure group (77.8%).