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JIMD Rep. 2018 Jun 20. doi: 10.1007/8904_2018_116. [Epub ahead of print]

Apparent Acetaminophen Toxicity in a Patient with Transaldolase Deficiency.

Author information

1
Department of Pediatrics, The Johns Hopkins University, Baltimore, MD, USA.
2
McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
3
Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
4
Pavilion Pediatrics, Lutherville, MD, USA.
5
Department of Pediatrics, The Johns Hopkins University, Baltimore, MD, USA. hbjorns1@jhmi.edu.
6
McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. hbjorns1@jhmi.edu.
7
Faculty of Medicine, University of Iceland, Reykjavík, Iceland. hbjorns1@jhmi.edu.
8
Landspitali University Hospital, Reykjavík, Iceland. hbjorns1@jhmi.edu.

Abstract

Transaldolase deficiency (MIM#: 606003) is a rare autosomal recessive defect in the pentose phosphate pathway. Affected individuals are at risk for progressive liver failure and hepatocarcinoma. In the transaldolase-deficient mouse model (Taldo1 -/- ), these hepatic complications are accentuated by oxidative stress related to acetaminophen administration. We report a 13-month-old transaldolase-deficient male who developed mild liver failure after receiving standard doses of acetaminophen during a febrile respiratory syncytial virus infection. He was admitted for respiratory distress with neutropenia and thrombocytopenia, but developed an enlarged nodular liver with accompanying splenomegaly and rising alpha-fetoprotein which peaked 2 weeks after acetaminophen exposure. Whole exome sequencing revealed compound heterozygous variants c.512_514delCCT (p.Ser171del) and c.931G > T (p.Gly311Trp) in TALDO1 (HGNC:11559), which encodes transaldolase (EC 2.2.1.2), a key enzyme in ribose metabolism. Urine polyols and plasma metabolomics confirmed the diagnosis of transaldolase deficiency. Studies on the Taldo1 -/- mouse model demonstrate acetaminophen-induced liver failure can be prevented by administration of the antioxidant N-acetylcysteine. Moreover, a published report showed treatment of a transaldolase-deficient patient with N-acetylcysteine was associated with a decrease in alpha-fetoprotein levels. After discontinuation of acetaminophen and prior to initiation of N-acetylcysteine treatment, our patient demonstrated resolving alpha-fetoprotein levels suggesting acetaminophen incited the liver failure.

CONCLUSION:

Our observations support the conclusion from mouse model studies that transaldolase-deficient patients are uniquely sensitive to acetaminophen and should avoid this antipyretic. Recognition of this individualized toxicity and avoidance of acetaminophen are essential for management of these patients.

KEYWORDS:

Acetaminophen; Actionable genetic disorders; Pentose phosphate pathway; Transaldolase deficiency; Treatment of genetic diseases; Whole exome sequencing

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