Lee-Barber Jasmine, English Taylor E, Britton Jacquelyn F, Sobreira Nara, Goldstein Jason, Valle David, Bjornsson Hans Tomas
Department of Pediatrics, The Johns Hopkins University, Baltimore, MD, USA.
McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
JIMD Rep. 2019;44:9-15. doi: 10.1007/8904_2018_116. Epub 2018 Jun 20.
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.
转醛醇酶缺乏症（MIM#：606003）是磷酸戊糖途径中一种罕见的常染色体隐性缺陷。受影响的个体有发生进行性肝衰竭和肝癌的风险。在转醛醇酶缺陷小鼠模型（Taldo1）中，对乙酰氨基酚给药引起的氧化应激会加剧这些肝脏并发症。我们报告了一名13个月大的转醛醇酶缺乏男性，他在发热性呼吸道合胞病毒感染期间接受标准剂量的对乙酰氨基酚后出现了轻度肝衰竭。他因呼吸窘迫伴中性粒细胞减少和血小板减少入院，但出现肝脏肿大结节，伴有脾肿大和甲胎蛋白升高，在接触对乙酰氨基酚2周后达到峰值。全外显子组测序显示TALDO1（HGNC：11559）中存在复合杂合变异c.512_514delCCT（p.Ser171del）和c.931G>T（p.Gly311Trp），该基因编码转醛醇酶（EC 2.2.1.2），是核糖代谢中的关键酶。尿多元醇和血浆代谢组学证实了转醛醇酶缺乏症的诊断。对Taldo1小鼠模型的研究表明，给予抗氧化剂N-乙酰半胱氨酸可预防对乙酰氨基酚引起肝衰竭。此外，一份已发表的报告显示，用N-乙酰半胱氨酸治疗一名转醛醇酶缺乏症患者与甲胎蛋白水平降低有关。在停用对乙酰氨基酚并开始N-乙酰半胱氨酸治疗之前，我们的患者甲胎蛋白水平有所下降，表明对乙酰氨基酚引发了肝衰竭。结论：我们的观察结果支持小鼠模型研究得出的结论，即转醛醇酶缺乏症患者对对乙酰氨基酚具有独特的敏感性，应避免使用这种退烧药。认识到这种个体毒性并避免使用对乙酰氨基酚对这些患者的管理至关重要。
