Abstract
BackgroundUnderlying causes in Chinese children with recurrent acute liver failure (RALF), including liver crises less than full acute liver failure, are incompletely understood. We sought to address this by searching for genes mutated in such children.MethodsFive unrelated Chinese boys presenting between 2012 and 2015 with RALF of unexplained etiology were studied. Results of whole exome sequencing were screened for mutations in candidate genes. Mutations were verified in patients and their family members by Sanger sequencing. All 5 boys underwent liver biopsy.ResultsNBAS was the only candidate gene mutated in more than one patient (biallelic mutations, 3 of 5 patients; 5 separate mutations). All NBAS mutations were novel and predictedly pathogenic (frameshift insertion mutation c.6611_6612insCA, missense mutations c.2407G > A and c.3596G > A, nonsense mutation c.586C > T, and splicing-site mutation c.5389 + 1G > T). Of these mutations, 3 lay in distal (C-terminal) regions of NBAS, a novel distribution.Unlike the 2 patients without NBAS mutations, the 3 patients with confirmed NBAS mutations all suffered from a febrile illness before each episode of liver crisis (fever-related RALF), with markedly elevated alanine aminotransferase and aspartate aminotransferase activities 24-72 h after elevation of body temperature, succeeded by severe coagulopathy and mild to moderate jaundice.ConclusionsAs in other countries, so too in China; NBAS disease is a major cause of fever-related RALF in children. The mutation spectrum of NBAS in Chinese children seems different from that described in other populations.
Highlights
Underlying causes in Chinese children with recurrent acute liver failure (RALF), including liver crises less than full acute liver failure, are incompletely understood
Clinical-biochemistry evidence of hepatobiliary injury was seen in none between liver crises or bouts of Acute liver failure (ALF)
Two predictedly pathogenic variations of NBAS were detected in patient 1, patient 2, and patient 3, while no NBAS variant was detected in either patient 4 or patient 5
Summary
Underlying causes in Chinese children with recurrent acute liver failure (RALF), including liver crises less than full acute liver failure, are incompletely understood. Acute liver failure (ALF) is a rare but often fatal emergency for children, especially infants. Recent work in Europe has implicated several genes in recurrent ALF (RALF) in infancy [6,7,8,9,10], the etiology of some instances of pediatric RALF remains unexplained. Biallelic mutations in NBAS (NM_015909) were first identified as causing fever-related RALF (infantile liver failure syndrome 2; MIM616483) by Haack et al [8]. NBAS was previously linked to SOPH (short stature, optic nerve atrophy, and Pelger–Huët anomaly of granulocytes; MIM614800) syndrome in an isolated Russian Yakut population, but without liver failure [11]. Further observations expanded the phenotype spectrum of NBAS disease to involve brain, connective tissues other than bone, and the immune system as well [12,13,14,15]
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