Recurrent elevated liver transaminases and acute liver failure in two siblings with novel bi-allelic mutations of NBAS

Regateiro, Frederico S.; Belkaya, Serkan; Neves, Nélson; Ferreira, Sandra; Silvestre, Paula; Lemos, Sónia; Venâncio, Margarida; Casanova, Jean‐Laurent; Gonçalves, Isabel; Jouanguy, Emmanuelle; Diogo, Luísa

doi:10.1016/j.ejmg.2017.05.005

Cited by 24 publications

(19 citation statements)

References 11 publications

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“…Characteristically, these patients presented with recurrent vomiting and increasing lethargy 1 or 2 days after the onset of fever. Syndromic SOPH-like features and stunted linear growth have been reported in up to 77% of the 22 children with pathological NBAS mutations described to date, while liver cytolytic episodes, which were absent in the original 33 SOPH cases, were present in all 22, but did not necessarily evolve into ALF [ 31 ]. Intermediate phenotypes have recently been described [ 32 ] Antipyretic therapy and anabolic support, including high glucose and parenteral lipids, effectively improve the liver crisis [ 8 , 16 , 28 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…gDNA extraction, WES data collection, and analyses were performed as previously described ( Belkaya et al, 2017 ; Regateiro et al, 2017 ). Briefly, allele frequencies (AFs) were obtained from the National Heart, Lung, and Blood Institute Gene Ontology Exome Sequencing Project (EVS, ESP6500SI-V2 release on http://evs.gs.washington.edu/EVS/ ), 1000 Genomes Project (April 2014 data release on http://grch37.ensembl.org ), and GnomAD (February 2017 data release on http://gnomad.broadinstitute.org/ ).…”

Section: Methodsmentioning

confidence: 99%

Inherited IL-18BP deficiency in human fulminant viral hepatitis

Belkaya

Michailidis

Korol

et al. 2019

Journal of Experimental Medicine

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Fulminant viral hepatitis (FVH) is a devastating and unexplained condition that strikes otherwise healthy individuals during primary infection with common liver-tropic viruses. We report a child who died of FVH upon infection with hepatitis A virus (HAV) at age 11 yr and who was homozygous for a private 40-nucleotide deletion in IL18BP, which encodes the IL-18 binding protein (IL-18BP). This mutation is loss-of-function, unlike the variants found in a homozygous state in public databases. We show that human IL-18 and IL-18BP are both secreted mostly by hepatocytes and macrophages in the liver. Moreover, in the absence of IL-18BP, excessive NK cell activation by IL-18 results in uncontrolled killing of human hepatocytes in vitro. Inherited human IL-18BP deficiency thus underlies fulminant HAV hepatitis by unleashing IL-18. These findings provide proof-of-principle that FVH can be caused by single-gene inborn errors that selectively disrupt liver-specific immunity. They also show that human IL-18 is toxic to the liver and that IL-18BP is its antidote.

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“…NBAS‐associated facial phenotype and genotype–phenotype correlations. (a–d) Composite photos obtained from patients (Balasubramanian et al, ; Capo‐Chichi et al, ; Kortum et al, ; Maksimova et al, ; Megarbane et al, ; Regateiro et al, ; Staufner et al, ) and age‐/gender‐matched controls. Facial features of subjects with biallelic inactivating/hypomorphic NBAS variants include hypotelorism, thin upper lip, pointed chin, and a progeroid appearance.…”

Section: Introductionmentioning

confidence: 99%

“…So far, 47 different pathogenic NBAS variants have been reported in 71 individuals. To explore possible genotype–phenotype correlations, the available clinical data were collected (Table S5; Balasubramanian et al, ; Capo‐Chichi et al, ; Kortum et al, ; Maksimova et al, ; Megarbane et al, ; Regateiro et al, ; Segarra et al, ; Staufner et al, ; E‐P03.292008: European Society of Human Genetics 2018 meeting). A total of 36 patients have been reported to carry the homozygous p.Arg1914His change associated with the SOPH phenotype (Maksimova et al, ; Park & Lee, ), while two patients were reported to have a skeletal phenotype associated with the homozygous c.6237−3C>G splice‐site change (Palagano et al, ; Prontera et al, ).…”

Section: Introductionmentioning

confidence: 99%

NBAS pathogenic variants: Defining the associated clinical and facial phenotype and genotype–phenotype correlations

Carli¹,

Giorgio

Pantaleoni

et al. 2019

Human Mutation

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The pathogenic variants in the neuroblastoma‐amplified sequence (NBAS) are associated with a clinical spectrum involving the hepatic, skeletal, ocular, and immune systems. Here, we report on two unrelated subjects with a complex phenotype solved by whole‐exome sequencing, who shared a synonymous change in NBAS that was documented to affect the transcript processing and co‐occurring with a truncating change. Starting from these two cases, we systematically assessed the clinical information available for all subjects with biallelic NBAS pathogenic variants (73 cases in total). We revealed a recognizable facial profile (hypotelorism, thin lips, pointed chin, and “progeroid” appearance) determined by using DeepGestalt facial recognition technology, and we provide evidence for the occurrence of genotype–phenotype correlations. Notably, severe hepatic involvement was associated with variants affecting the NBAS‐Nter and Sec39 domains, whereas milder liver involvement and immunodeficiency were generally associated with variants located at the N‐terminus and C‐terminus of the protein. Remarkably, no patient was reported to carry two nonsense variants, suggesting lethality of complete NBAS loss‐of‐function.

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Recurrent elevated liver transaminases and acute liver failure in two siblings with novel bi-allelic mutations of NBAS

Cited by 24 publications

References 11 publications

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

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

Inherited IL-18BP deficiency in human fulminant viral hepatitis

NBAS pathogenic variants: Defining the associated clinical and facial phenotype and genotype–phenotype correlations

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