Dataset Information

Biallelic Mutations in NBAS Cause Recurrent Acute Liver Failure with Onset in Infancy.

ABSTRACT: Acute liver failure (ALF) in infancy and childhood is a life-threatening emergency. Few conditions are known to cause recurrent acute liver failure (RALF), and in about 50% of cases, the underlying molecular cause remains unresolved. Exome sequencing in five unrelated individuals with fever-dependent RALF revealed biallelic mutations in NBAS. Subsequent Sanger sequencing of NBAS in 15 additional unrelated individuals with RALF or ALF identified compound heterozygous mutations in an additional six individuals from five families. Immunoblot analysis of mutant fibroblasts showed reduced protein levels of NBAS and its proposed interaction partner p31, both involved in retrograde transport between endoplasmic reticulum and Golgi. We recommend NBAS analysis in individuals with acute infantile liver failure, especially if triggered by fever.

SUBMITTER: Haack TB

PROVIDER: S-EPMC4572578 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Biallelic Mutations in NBAS Cause Recurrent Acute Liver Failure with Onset in Infancy.

Haack Tobias B TB Staufner Christian C Köpke Marlies G MG Straub Beate K BK Kölker Stefan S Thiel Christian C Freisinger Peter P Baric Ivo I McKiernan Patrick J PJ Dikow Nicola N Harting Inga I Beisse Flemming F Burgard Peter P Kotzaeridou Urania U Kühr Joachim J Himbert Urban U Taylor Robert W RW Distelmaier Felix F Vockley Jerry J Ghaloul-Gonzalez Lina L Zschocke Johannes J Kremer Laura S LS Graf Elisabeth E Schwarzmayr Thomas T Bader Daniel M DM Gagneur Julien J Wieland Thomas T Terrile Caterina C Strom Tim M TM Meitinger Thomas T Hoffmann Georg F GF Prokisch Holger H

American journal of human genetics 20150611 1

Acute liver failure (ALF) in infancy and childhood is a life-threatening emergency. Few conditions are known to cause recurrent acute liver failure (RALF), and in about 50% of cases, the underlying molecular cause remains unresolved. Exome sequencing in five unrelated individuals with fever-dependent RALF revealed biallelic mutations in NBAS. Subsequent Sanger sequencing of NBAS in 15 additional unrelated individuals with RALF or ALF identified compound heterozygous mutations in an additional si ...[more]

PMID: 26073778

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Project description:Pediatric acute-liver-failure due to acetaminophen (APAP) administration at therapeutic dosage is rare, while viral infections and metabolic defects are the prevalent causes. Yet, as acetaminophen is routinely used in febrile illnesses, it may be mistakenly held responsible for the acute liver damage.An 11 month old boy had been on acetaminophen for 10 days (total dose 720 mg = 72 mg/kg) when he developed acute-liver-failure with encephalopathy. As he rapidly improved on N-acetylcysteine (NAC) infusion, it was concluded that chronic acetaminophen administration in an infant had lead to acute-liver-failure even at therapeutic doses, that N-acetylcysteine infusion had been life-saving and should be immediately started in similar circumstances. The child, however, had two further episodes of acute liver damage over a 34-month period, without having been given acetaminophen, as the parents carefully avoided using it. His clinical, laboratory and radiological findings between the acute episodes were unremarkable. His features and skeletal surveys were not suggestive of a syndromic condition. He then went on to suffer another episode of acute-liver-failure with multi-organ failure, necessitating an urgent liver transplant. All efforts to come to a diagnosis for the causes of his recurrent episodes of liver failure had been unsuccessful, until a biallelic mutation in the NBAS gene was reported to be associated with recurrent acute-liver-failure in children. The boy's DNA analysis revealed compound heterozygous pathogenic mutations in the NBAS gene. Liver failure episodes in these patients are triggered and worsened by fever, most likely due to thermal susceptibility of hepatocytes, hence APAP, rather than being a culprit, is part of the supportive treatment.We suggest that, in acute-liver-failure with a history of acetaminophen exposure at therapeutic dosage, clinicians should not be contented with administering NAC, but should consider an alternative etiology, above all if the episodes are recurrent, and actively start supportive and antipyretic treatment while seeking the advice of a specialist unit.

Dataset Information

Biallelic Mutations in NBAS Cause Recurrent Acute Liver Failure with Onset in Infancy.

Publications

Biallelic Mutations in NBAS Cause Recurrent Acute Liver Failure with Onset in Infancy.

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