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While deficiency of other PPP enzymes, such as transketolase (<jats:italic>TKT<\/jats:italic>), are incompatible with mammalian cell survival, mice lacking TAL are viable and develop progressive liver disease attributed to oxidative stress. Mice with homozygous or heterozygous TAL deficiency are predisposed to cirrhosis, hepatocellular carcinoma (HCC) and acetaminophen (APAP)\u2010induced liver failure. Both mice and humans with complete TAL deficiency accumulate sedoheptulose 7\u2010phosphate (S7P). Previous human studies relied on screening patients with S7P accumulation, thus excluding potentially pathogenic haploinsufficiency. Of note, mice with TAL haploinsufficiency are also predisposed to HCC and APAP\u2010induced liver failure which are preventable with oral N\u2010acetylcysteine (NAC) administration. Based on <jats:italic>TALDO1<\/jats:italic> DNA sequencing, we detected functional TAL deficiency due to novel, heterozygous variations in two of 94 healthy adults and four of 27 subjects with APAP\u2010induced liver failure (<jats:italic>P<\/jats:italic> = .022). The functional consequences of these variations were individually validated by site\u2010directed mutagenesis of normal cDNA and loss of activity by recombinant enzyme. All four patients with TAL haplo\u2010insufficiency with APAP\u2010induced liver failure were successfully treated with NAC. We also document two novel variations in two of 15 children with previously unexplained liver cirrhosis. Examination of the National Center for Biotechnology Information databases revealed 274 coding region variations have been documented in 1125 <jats:italic>TALDO1<\/jats:italic> sequences relative to 25 variations in 2870 <jats:italic>TKT<\/jats:italic> sequences (<jats:italic>P<\/jats:italic>\u2009&lt;\u2009.0001). These findings suggest an unexpected prevalence and variety of genetic changes in human <jats:italic>TALDO1<\/jats:italic> with relevance for liver injury that may be preventable by treatment with NAC.<\/jats:p>","DOI":"10.1002\/jimd.12197","type":"journal-article","created":{"date-parts":[[2019,11,26]],"date-time":"2019-11-26T16:23:23Z","timestamp":1574785403000},"page":"496-506","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Transaldolase haploinsufficiency in subjects with acetaminophen\u2010induced liver failure"],"prefix":"10.1002","volume":"43","author":[{"given":"Zachary","family":"Oaks","sequence":"first","affiliation":[{"name":"Department of Medicine, State University of New York Upstate Medical University  Syracuse New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Jimah","sequence":"additional","affiliation":[{"name":"Department of Medicine, State University of 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