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. J Inherit Metab Dis 2020 May;43(3):518-528
Date
12/18/2019Pubmed ID
31845342Pubmed Central ID
PMC7318568DOI
10.1002/jimd.12205Scopus ID
2-s2.0-85077897416 (requires institutional sign-in at Scopus site) 8 CitationsAbstract
Classic galactosemia (CG) is a potentially lethal inborn error of metabolism, if untreated, that results from profound deficiency of galactose-1-phosphate uridylyltransferase (GALT), the middle enzyme of the Leloir pathway of galactose metabolism. While newborn screening and rapid dietary restriction of galactose prevent or resolve the potentially lethal acute symptoms of CG, by mid-childhood, most treated patients experience significant complications. The mechanisms underlying these long-term deficits remain unclear. Here we introduce a new GALT-null rat model of CG and demonstrate that these rats display cataracts, cognitive, motor, and growth phenotypes reminiscent of patients outcomes. We further apply the GALT-null rats to test how well blood biomarkers, typically followed in patients, reflect metabolic perturbations in other, more relevant tissues. Our results document that the relative levels of galactose metabolites seen in GALT deficiency differ widely by tissue and age, and that red blood cell Gal-1P, the marker most commonly followed in patients, shows no significant association with Gal-1P in other tissues. The work reported here establishes our outbred GALT-null rats as an effective model for at least four complications characteristic of CG, and sets the stage for future studies addressing mechanism and testing the efficacy of novel candidate interventions.
Author List
Rasmussen SA, Daenzer JMI, MacWilliams JA, Head ST, Williams MB, Geurts AM, Schroeder JP, Weinshenker D, Fridovich-Keil JLAuthor
Aron Geurts PhD Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAnimals, Newborn
Disease Models, Animal
Female
Galactose
Galactosemias
Galactosephosphates
Male
Phenotype
Rats
Rats, Sprague-Dawley
UTP-Hexose-1-Phosphate Uridylyltransferase