NBAS mutations cause acute liver failure: when acetaminophen is not a culprit

Abstract

BackgroundPediatric 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.Case presentationAn 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.ConclusionsWe 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.

Complex Multisystem Phenotype With Immunodeficiency Associated With NBAS Mutations: Reports of Three Patients and Review of the Literature

“…Progressive reduction in NK cells numbers has been described by Garcia Segarra et al (15) and then by Ricci et al (10). As Figure 2 demonstrates, the patients who had immunodeficiency and bone disease had mutations distributed along the gene, with no particular domain predominance (10,(14)(15)(16)(17)(18)(19)(20)(21)(22)(27)(28)(29)(30)(31)(32)(33)(34)(35), current study).…”

“…mortality. Although some degree of liver disease has been associated with most NBAS variants, the mutations associated with severe liver phenotype were either loss-offunction or missense mutations predominantly located in the N-terminal and in the middle part of the NBAS gene (c.409C>T identified in 5 patients: c.680A>C;1749G>A, c.809G>C;2926del, c.1018G>C;2674G>T, c.2819A>C, and c.2819A>C) (15,18,(27)(28)(29)(30)(31).…”

Recurrent acute liver failure associated with novel SCYL1 mutation: A case report

“…Starting in infancy, episodes of hepatic insufficiency recur. These episodes may be preceded by fever (and thus be ascribed to antipyretics, in particular paracetamol)[1-3]. They may not be restricted to childhood[4,5] and may be fatal[6].…”

Severe SOPH syndrome due to a novel NBAS mutation in a 27‐year‐old woman—Review of this pleiotropic, autosomal recessive disorder: Mystery solved after two decades

“…Importantly, as in the case of our proposita, individuals harboring the p.Arg1914His variant did not present with RALF or severe hepatic disease manifestations (Park et al, 2017). In contrast, most NBAS truncating variants reported to date have been found in patients affected with early‐onset fever‐triggered RALF (Calvo et al, 2017; Haack et al, 2015; Li et al, 2017; Regateiro et al, 2017; Sunwoo et al, 2018). The p.Arg1914His variant is located in exon 45 but its effect on the NBAS protein is unclear because it lies within the C‐terminal domain of as yet unknown function.…”

“…Park et al, 2017 reported on a brother and sister with short stature, progeroid face, normal intelligence, and Pelger‐Hüet anomaly but also frequent upper respiratory infections, elevated serum liver enzymes levels and optic atrophy with foveal hypoplasia not previously reported. Several recent reports have emphasized the occurrence in individuals diagnosed with SOPH syndrome of: RALF (Calvo et al, 2017; Cardenas, DiPaola, Adams, Holtz, & Ahmad, 2017; Lenz et al, 2019; Ono et al, 2019; Regateiro et al, 2017; Rius et al, 2018; Staufner et al, 2015; Wang et al, 2018), ocular manifestations (Nucci et al, 2019), growth hormone deficiency (Li et al, 2018), short stature or severe skeletal involvement (Balasubramanian et al, 2017; Kim et al, 2017; Palagano et al, 2018), and early onset of recurrent or severe infections due to abnormalities in both antibody and cell‐mediated immunity documenting a combined immunodeficiency (Balasubramanian et al, 2017; Capo‐Chichi et al, 2015; Li et al, 2018; Regateiro et al, 2017; Segarra et al, 2015). These individuals required frequent antibiotic treatments, and a few were successfully treated with long‐term IgG replacement therapy (Kim et al, 2017).…”