Open AccessA Case of UDP-Galactose 4′-Epimerase Deficiency Associated with Dyshematopoiesis and Atrioventricular Valve Malformations: An Exceptional Clinical Phenotype Explained by Altered N-Glycosylation with Relative Preservation of the Leloir Pathway
Author(s) -
Christopher A. FebresAldana,
Lisét Pelaez,
Meredith S. Wright,
Ossama M. Maher,
Anthony J Febres-Aldana,
Jun Sasaki,
Parul Jayakar,
Anuj Jayakar,
Magaly Diaz-Barbosa,
Michelin Janvier,
Bala R Totapally,
Daria Salyakina,
Jorge Galvez-Silva
Publication year - 2020
Publication title -
molecular syndromology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.609
H-Index - 36
eISSN - 1661-8777
pISSN - 1661-8769
DOI - 10.1159/000511343
Subject(s) - failure to thrive , medicine , phenotype , endocrinology , biology , gene , genetics
The generalized form of UDP-galactose-4′-epimerase (GALE) deficiency causes hypotonia, failure to thrive, cataracts, and liver failure. Individuals with non-generalized forms may remain asymptomatic with uncertain long-term outcomes. We report a 2-year-old child compound heterozygous for GALE p.R51W/p.G237D who never developed symptoms of classic galactosemia but has a history of congenital combined mitral and tricuspid valve malformation and pyloric stenosis, and presented with pancytopenia. Variant pathogenicity was supported by predictive computational tools and decreased GALE activity measured in erythrocytes. GALE function extends to the biosynthesis of glycans by epimerization of UDP- N -acetyl-galactosamine and -glucosamine. Interrogation of the Gene Ontology consortium database revealed several putative proteins involved in normal hematopoiesis and atrioventricular valve morphogenesis, requiring N -glycosylation for adequate functionality. We hypothesize that by limiting substrate supply due to GALE deficiency, alterations in N -linked protein glycosylation can explain the patient’s phenotype.