Cryptic residual GALT activity is a potential modifier of scholastic outcome in school age children with classic galactosemia

• Authors: Emily L. Ryan, Emory University; Mary Lynch, Emory University; Elles Taddeo, Emory University; Tyler J. Gleason, Emory University; Michael Epstein, Emory University; Judith Fridovich-Keil, Emory University
• Journal Title: Journal of Inherited Metabolic Disease
• Volume: Volume 36, Number 6
• Publisher: Wiley | 2013-11-01, Pages 1049-1061
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1007/s10545-012-9575-x
• Subjects: Health Sciences, Public Health; Biology, Genetics; Education, Educational Psychology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental; Research & Experimental Medicine; HUMAN GALACTOSE-1-PHOSPHATE URIDYLYLTRANSFERASE; DROSOPHILA-MELANOGASTER MODEL; SYSTEM-RATING SCALES; Q188R MUTATION; URIDYLTRANSFERASE GENE; HETERODIMER FORMATION; BEHAVIOR CHECKLIST; PHENOTYPE; GENOTYPE; STRENGTHS

Abstract

Classic galactosemia is a potentially lethal disorder that results from profound deficiency of galactose-1-phosphate uridylyltransferase (GALT), the second enzyme in the Leloir pathway of galactose metabolism. Although early diagnosis and rigorous dietary restriction of galactose prevent or resolve the potentially lethal acute symptoms, patients are at markedly increased risk of long-term complications including significant cognitive, speech, and behavioral difficulties, among other problems. The mechanisms that underlie these long-term complications remain unclear, as do the factors that modify their severity. Here we explored the scholastic and behavioral outcomes experienced by a cohort of 54 school age children with classic galactosemia. Data collected included survey responses from parents and teachers, school records including standardized test scores, and GALT genotype data used to estimate predicted residual GALT activity based on a yeast expression system. As expected, many but not all of the children in our study demonstrated speech, scholastic, and behavioral difficulties. Perhaps most striking, we found that predicted cryptic residual GALT activity, often below the threshold of detection of clinical assays, appeared to modify scholastic outcome. These data raise the intriguing possibility that cryptic GALT activity might also influence the severity of other long-term complications in classic galactosemia.