{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:02:11Z","timestamp":1790704931597,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.pgen.1012276","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000}}],"reference-count":35,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R21HD092785"],"award-info":[{"award-number":["R21HD092785"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    Classic galactosemia (CG) is a potentially lethal disease that results from profound deficiency of galactose-1-P uridylyltransferase (GALT). Prior reports document elevated galactose metabolites beginning\n                    <jats:italic>in utero<\/jats:italic>\n                    in CG, raising concern that long-term complications in CG might also trace their origins to the prenatal period. However, studies document that elevated galactose metabolites in the postnatal period do not predict later developmental complications, challenging the connection. Here, we explored the relationship between elevated galactose metabolites\n                    <jats:italic>in utero<\/jats:italic>\n                    and fetal outcome using a GALT-null rat model of CG. To modify galactose metabolites\n                    <jats:italic>in utero<\/jats:italic>\n                    , we arranged rat crosses to produce GALT-null pups developing within either a GALT-null or heterozygous dam, and with or without heterozygous siblings. We reasoned that GALT activity present\n                    <jats:italic>outside<\/jats:italic>\n                    the fetus, but within the maternal-fetal compartment, might limit metabolic abnormalities in a developing GALT-null fetus -- and it did. Specifically, while galactose metabolites in GALT-null fetal pups from all crosses remained elevated over controls, the levels varied. When the dam and some siblings were heterozygous, amniotic fluid galactitol from GALT-null fetal pups at GD21 was comparable to the levels reported from second trimester human CG amniotic fluid. When the dam was GALT-null, but some siblings were heterozygous, the median galactitol level in amniotic fluid was 2.45-fold higher. When the dam and all siblings were GALT-null, the median amniotic fluid galactitol level was 5.67-fold higher. GALT-null fetal pups also showed significant growth delay\n                    <jats:italic>in utero<\/jats:italic>\n                    , but only when the dam and all siblings were GALT-null. That growth of GALT-null fetal pups was fully rescued by gestation within a heterozygous dam despite the persistence of moderately elevated galactose metabolites raises the possibility that babies with CG developing within a carrier mother might also be at least partially protected\n                    <jats:italic>in utero<\/jats:italic>\n                    from the adverse consequences of their GALT-deficiency.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1012276","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T18:05:20Z","timestamp":1790013920000},"page":"e1012276","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Prenatal consequences of GALT deficiency in a rat model of classic galactosemia"],"prefix":"10.1371","volume":"22","author":[{"given":"Shauna A.","family":"Rasmussen","sequence":"first","affiliation":[{"name":"Emory University School of Medicine","place":["Atlanta, Georgia, United States of America"],"department":["Department of Human Genetics"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7740-5518","authenticated-orcid":true,"given":"Catherine M.","family":"Lemons","sequence":"additional","affiliation":[{"name":"Emory University","place":["Atlanta, Georgia, United States of America"],"department":["Emory College of Arts and Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9492-7573","authenticated-orcid":true,"given":"Madelyn M.","family":"Seemiller","sequence":"additional","affiliation":[{"name":"Emory University","place":["Atlanta, Georgia, United States of America"],"department":["Emory College of Arts and Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5878-6702","authenticated-orcid":true,"given":"Sabrina R.","family":"Dallas","sequence":"additional","affiliation":[{"name":"Emory University","place":["Atlanta, Georgia, United States of America"],"department":["Emory College of Arts and Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milan Cambon","family":"Ledesma","sequence":"additional","affiliation":[{"name":"Emory University","place":["Atlanta, Georgia, United States of America"],"department":["Emory College of Arts and Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5670-6815","authenticated-orcid":true,"given":"Yuhan","family":"Wu","sequence":"additional","affiliation":[{"name":"Emory University","place":["Atlanta, Georgia, United States of America"],"department":["Emory College of Arts and Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren E.","family":"Anshen","sequence":"additional","affiliation":[{"name":"Emory University","place":["Atlanta, Georgia, United States of America"],"department":["Emory College of Arts and Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2290-243X","authenticated-orcid":true,"given":"Ashlyn","family":"Farnham","sequence":"additional","affiliation":[{"name":"Emory University","place":["Atlanta, Georgia, United States of America"],"department":["Emory College of Arts and Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia S.","family":"Garrett","sequence":"additional","affiliation":[{"name":"Emory University School of Medicine","place":["Atlanta, Georgia, United States of America"],"department":["Department of Human Genetics"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7947-5807","authenticated-orcid":true,"given":"Judith L.","family":"Fridovich-Keil","sequence":"additional","affiliation":[{"name":"Emory University School of Medicine","place":["Atlanta, Georgia, United States of America"],"department":["Department of Human Genetics"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"pgen.1012276.ref001","article-title":"Classic Galactosemia and Clinical Variant Galactosemia","volume-title":"GeneReviews","author":"G Berry","year":"2020"},{"issue":"45","key":"pgen.1012276.ref002","doi-asserted-by":"crossref","first-page":"43885","DOI":"10.1074\/jbc.R300025200","article-title":"Structure and function of enzymes of the Leloir pathway for galactose metabolism","volume":"278","author":"HM Holden","year":"2003","journal-title":"J Biol Chem"},{"key":"pgen.1012276.ref003","first-page":"967","article-title":"Disorders of galactose metabolism.","volume-title":"The metabolic and molecular bases of inherited disease","author":"S Segal","year":"1995","edition":"7"},{"issue":"3","key":"pgen.1012276.ref004","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1002\/jcp.20820","article-title":"Galactosemia: the good, the bad, and the unknown","volume":"209","author":"JL Fridovich-Keil","year":"2006","journal-title":"J Cell Physiol"},{"issue":"2","key":"pgen.1012276.ref005","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/S0022-3476(85)80143-8","article-title":"Accumulation of galactose-1-phosphate in the galactosemic fetus despite maternal milk avoidance","volume":"107","author":"M Irons","year":"1985","journal-title":"J Pediatr"},{"key":"pgen.1012276.ref006","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1007\/BF01799295","article-title":"Prenatal diagnosis of disorders of galactose metabolism","author":"JB Holton","year":"1989","journal-title":"J Inherit Metab 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complications in classic galactosemia: What we do and do not know","volume":"137","author":"JL Fridovich-Keil","year":"2022","journal-title":"Mol Genet Metab"},{"issue":"4","key":"pgen.1012276.ref011","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1007\/s10545-006-0382-0","article-title":"Classical galactosaemia revisited","volume":"29","author":"AM Bosch","year":"2006","journal-title":"J Inherit Metab Dis"},{"issue":"9","key":"pgen.1012276.ref012","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.4155\/fmc.14.43","article-title":"GALK inhibitors for classic galactosemia","volume":"6","author":"K Lai","year":"2014","journal-title":"Future Med Chem"},{"issue":"3","key":"pgen.1012276.ref013","doi-asserted-by":"crossref","DOI":"10.1016\/j.gim.2022.01.556","article-title":"OP005: AT-007 significantly reduces toxic galactitol in ACTION-galactosemia kids - the 1st therapeutic interventional clinical trial in children with classic galactosemia","volume":"24","author":"E Bailey","year":"2022","journal-title":"Genetics in Medicine"},{"issue":"4","key":"pgen.1012276.ref014","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.ymgme.2006.06.005","article-title":"Of mice and men: galactosemia","volume":"89","author":"S Segal","year":"2006","journal-title":"Mol Genet Metab"},{"issue":"1","key":"pgen.1012276.ref015","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/s13023-019-1047-z","article-title":"The natural history of classic galactosemia: lessons from the GalNet registry","volume":"14","author":"ME Rubio-Gozalbo","year":"2019","journal-title":"Orphanet J Rare Dis"},{"issue":"1","key":"pgen.1012276.ref016","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1007\/BF02072514","article-title":"Long-term outcome in 134 patients with galactosaemia","volume":"152","author":"S Schweitzer","year":"1993","journal-title":"Eur J Pediatr"},{"issue":"6","key":"pgen.1012276.ref017","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1007\/BF01800204","article-title":"Long-term prognosis in galactosaemia: results of a survey of 350 cases","volume":"13","author":"DD Waggoner","year":"1990","journal-title":"J Inherit Metab Dis"},{"key":"pgen.1012276.ref018","article-title":"Duarte variant galactosemia.","volume-title":"GeneReviews","author":"JL Fridovich-Keil","year":"2020"},{"issue":"1","key":"pgen.1012276.ref019","doi-asserted-by":"crossref","DOI":"10.1542\/peds.2018-2516","article-title":"Developmental Outcomes in Duarte Galactosemia","volume":"143","author":"G Carlock","year":"2019","journal-title":"Pediatrics"},{"issue":"3","key":"pgen.1012276.ref020","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1002\/jimd.12205","article-title":"A galactose-1-phosphate uridylyltransferase-null rat model of classic galactosemia mimics relevant patient outcomes and reveals tissue-specific and longitudinal differences in galactose metabolism","volume":"43","author":"SA Rasmussen","year":"2020","journal-title":"J Inherit Metab Dis"},{"key":"pgen.1012276.ref021","doi-asserted-by":"crossref","DOI":"10.1007\/BF02143800","article-title":"Prenatal diagnosis of galactosemia","volume":"154","author":"C Jakobs","year":"1995","journal-title":"Eur J Pediatr"},{"key":"pgen.1012276.ref022","doi-asserted-by":"crossref","DOI":"10.1007\/BF02143809","article-title":"Effects of galactosemia in utero","volume":"154","author":"JB Holton","year":"1995","journal-title":"Eur J Pediatr"},{"issue":"6","key":"pgen.1012276.ref023","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1002\/jimd.12684","article-title":"Grip strength in patients with galactosemia and in a galactose-1-phosphate uridylyltransferase (GALT)-null rat model","volume":"46","author":"JJ Druss","year":"2023","journal-title":"J Inherit Metab 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Res"},{"issue":"1","key":"pgen.1012276.ref030","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.ymgme.2003.08.026","article-title":"The rate of de novo galactose synthesis in patients with galactose-1-phosphate uridyltransferase deficiency","volume":"81","author":"GT Berry","year":"2004","journal-title":"Mol Genet Metab"},{"issue":"1","key":"pgen.1012276.ref031","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.ymgme.2003.10.007","article-title":"Age dependence of endogenous galactose formation in Q188R homozygous galactosemic patients","volume":"81","author":"P Schadewaldt","year":"2004","journal-title":"Mol Genet Metab"},{"issue":"6","key":"pgen.1012276.ref032","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1177\/0192623315570339","article-title":"Vaginal Cytology of the Laboratory Rat and Mouse: Review and Criteria for the Staging of the Estrous Cycle Using Stained Vaginal Smears","volume":"43","author":"MC Cora","year":"2015","journal-title":"Toxicol Pathol"},{"key":"pgen.1012276.ref033","volume-title":"R: A language and environment for statistical computing","author":"Team R","year":"2023"},{"key":"pgen.1012276.ref034","volume-title":"RStudio: Integrated Development Environment for R","author":"Team P","year":"2023"},{"key":"pgen.1012276.ref035","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1093\/biomet\/52.3-4.591","article-title":"An Analysis of Variance Test for Normality (Complete Samples)","volume":"52","author":"SS Shapiro","year":"1965","journal-title":"Biometrika"}],"updated-by":[{"DOI":"10.1371\/journal.pgen.1012276","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000}}],"container-title":["PLOS Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1012276","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:41:47Z","timestamp":1790703707000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1012276"}},"subtitle":[],"editor":[{"given":"Marisa S","family":"Bartolomei","sequence":"first","affiliation":[{"name":"University of Pennsylvania","place":["UNITED STATES OF AMERICA"]}],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,9,21]]},"references-count":35,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9,21]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pgen.1012276","relation":{},"ISSN":["1553-7404"],"issn-type":[{"value":"1553-7404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,21]]}}}