Study of Acute Liver Failure in Children Using Next Generation Sequencing Technology

Hegarty, Robert; Gibson, Philippa; Sambrotta, Melissa; Strautnieks, Sandra; Foskett, Pierre; Ellard, Sian; Baptista, Júlia; Lillis, Suzanne; Bansal, Sanjay; Vara, Roshni; Dhawan, Anil; Grammatikopoulos, Tassos; Thompson, Richard J.

doi:10.1016/j.jpeds.2021.05.041

Cited by 15 publications

(26 citation statements)

References 29 publications

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“…Although not generally considered as part of the first-line workup for acute liver failure, molecular testing is essential to confirm certain diagnoses in the pediatric population. 8,9 DNA sequencing technology (e.g., clinical exome sequencing and next generation sequencing) is increasingly effective in detecting inherited metabolic disorders and monogenic diseases. 4 In their cohort of 45 children with indeterminate PALF, Hegarty et al 9 reported that next generation sequencing helped identifying specific etiologies in 20% of the cases.…”

Section: Clinical Evaluationmentioning

confidence: 99%

“…1,4 Potential causes for indeterminate PALF include occult acetaminophen toxicity, unrecognized viral infection, undiagnosed autoimmune hepatitis and metabolic disorders. 5,9 Alonso et al 85 reported the presence of acetaminophen protein adducts in 11% of patients with indeterminate PALF. 85 Recent studies suggest that many of patients with indeterminate PALF develop hepatic injury due to hyperinflammatory responses and immune dysregulation.…”

Section: Non-hepatotropic Virus Infectionmentioning

confidence: 99%

“…8,9 DNA sequencing technology (e.g., clinical exome sequencing and next generation sequencing) is increasingly effective in detecting inherited metabolic disorders and monogenic diseases. 4 In their cohort of 45 children with indeterminate PALF, Hegarty et al 9 reported that next generation sequencing helped identifying specific etiologies in 20% of the cases. The most common findings were variants involving neuroblastoma amplified sequence ( NBAS ) and mitochondrial DNA maintenance genes.…”

Section: Clinical Evaluationmentioning

confidence: 99%

“…The most common findings were variants involving neuroblastoma amplified sequence ( NBAS ) and mitochondrial DNA maintenance genes. 9…”

Section: Clinical Evaluationmentioning

confidence: 99%

Section: Pediatric Acute Liver Failure In Other Age Groupsmentioning

confidence: 99%

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Pediatric Acute Liver Failure: A Clinicopathological Perspective

Putra

Perez‐Atayde

2022

Pediatr Dev Pathol

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Pediatric acute liver failure (PALF) is a life-threatening disorder characterized by acute hepatocellular injury occurring in children without recognized underlying liver disease. The clinicopathologic evaluation of PALF requires a different approach from that in adults. The diagnostic considerations differ depending on the age, personal and family history, geographical region, and clinical presentation. Distinct entities such as gestational alloimmune liver disease, herpes simplex virus infection, and metabolic disorders should be considered in neonates with acute liver failure, while acetaminophen toxicity and autoimmune hepatitis are more frequently seen in older children and adolescents. An identified cause for PALF despite a negative complete evaluation (indeterminate) is lacking in 30 to 50% of cases. Although not routinely performed in the setting of PALF, liver biopsy may be helpful in assessing the etiology, potential mechanisms of injury, determining the appropriateness of liver transplantation, and prognostication of the patients. In this article, we review the clinicopathologic characteristics of PALF with an emphasis on general approach of pathologic evaluation and histopathologic characteristic of selected entities.

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Section: Clinical Evaluationmentioning

confidence: 99%

Section: Non-hepatotropic Virus Infectionmentioning

confidence: 99%

Section: Clinical Evaluationmentioning

confidence: 99%

“…The most common findings were variants involving neuroblastoma amplified sequence ( NBAS ) and mitochondrial DNA maintenance genes. 9…”

Section: Clinical Evaluationmentioning

confidence: 99%

Section: Pediatric Acute Liver Failure In Other Age Groupsmentioning

confidence: 99%

See 3 more Smart Citations

Pediatric Acute Liver Failure: A Clinicopathological Perspective

Putra

Perez‐Atayde

2022

Pediatr Dev Pathol

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Two siblings with acute necrotizing encephalopathy associated with variants of LARS1

Uehara,

Seki,

Nonoda

et al. 2024

American J of Med Genetics Pt A

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Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy of unknown etiology. The underlying mechanisms are highly heterogeneous, often including genetic backgrounds. Variants of LARS1, encoding the leucyl‐tRNA synthetase 1, are responsible for infantile liver failure syndrome 1. We describe two siblings with ANE caused by compound heterozygous variants of LARS1. Patient 1 was a 17‐month‐old girl. She presented with generalized seizure and liver dysfunction due to influenza type A infection. Brain magnetic resonance imaging on day 4 of onset showed diffuse high‐intensity signals consistent with ANE. She died on day 10. Patient 2, a younger male sibling of patient 1, had mild to moderate developmental delay and growth failure at the age of 18 months. He showed a markedly elevated level of transaminases triggered by infection with human herpesvirus 6. On day 4 of onset, he had generalized seizures. Brain computed tomography showed a diffuse symmetrical hypodensity consistent with ANE. He died on day 7. Whole exome sequencing identified the compound heterozygous variants in LARS1 (NM_020117.11) as c.83_88delinsAATGGGATA, p.(Arg28_Phe30delinsLysTryAspIle) and c.1283C>T, p.(Pro428Leu) in both siblings. The severe neurologic phenotype, found in our patients, reflects the complicated pathogenesis of LARS1‐related disorder.

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Hepatic presentations of mitochondrial DNA depletion syndrome in children: A single tertiary liver centre experience

Vara

Pinon

Fratter

et al. 2023

J of Inher Metab Disea

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Mitochondrial DNA depletion syndromes (MDDS) are a heterogeneous group and the hepato‐cerebral phenotype is highly variable. A single centre retrospective study of all patients with MDDS presenting between January 2002 and September 2019. In total, 24 (13 male) children were identified: 7 POLG, 7 DGUOK, and 10 MPV17. Median age at presentation was 3 months (0.06–189). Sixteen had acute liver failure (ALF) and eight chronic cholestasis and/or raised transaminases. Four POLG patients developed liver injury after starting sodium valproate; Six DGUOK patients had neonatal ALF (median age 12 days), liver involvement developed at a median age of 2.5 and 11 months with MPV17 and POLG patients, respectively. Eighteen patients showed neurological involvement. Liver histology from 10 patients showed variable degrees of necrosis, steatosis, cholestasis, and fibrosis. Mitochondrial respiratory chain enzymology was abnormal in 5. Seventeen patients died at a median age of 8 months (range, 1–312) after a median time of 5.6 months from presentation: 5/7 POLG at 53 months, 7/7 DGUOK at 8 months and 5/10 MPV17 at 8 months. Three patients with MPV17 mutations received liver transplant (LT) at a median age of 24 months (range 5–132): all alive at 19, 18 and 3 years post‐LT. Mutations in DGUOK and MPV17 genes are associated with a severe clinical phenotype characterised by early‐onset/neonatal ALF or rapidly progressive cholestasis and death before 12 months of age. A subset of MPV17 patients was amenable to LT. Consideration for LT in infantile ALF remains difficult and rapid genetic testing is advised.

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Study of Acute Liver Failure in Children Using Next Generation Sequencing Technology

Cited by 15 publications

References 29 publications

Pediatric Acute Liver Failure: A Clinicopathological Perspective

Pediatric Acute Liver Failure: A Clinicopathological Perspective

Two siblings with acute necrotizing encephalopathy associated with variants of LARS1

Hepatic presentations of mitochondrial DNA depletion syndrome in children: A single tertiary liver centre experience

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