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Author Notes:

E-mail address: jfridov@emory.edu.

JLFK and ELR initiated the project, recruited the study volunteers, gathered the survey and school records data, assembled the Tables and Figures, and wrote the majority of the manuscript; MEL and ET reviewed the school records and provided valuable insight and interpretation; TJG conducted all of the experiments related to patient GALT genotyping and GALT functional analysis using the yeast system; MPE performed the statistical analyses; all co-authors contributed to writing and editing the final manuscript.

First and foremost, we are grateful to the many study volunteers and their families and teachers who participated in this project; without these amazing people this project could never have been completed.

We are also grateful to our colleagues in the Departments of Human Genetics and Psychiatry and Behavioral Sciences at Emory for their many helpful discussions.

Subjects:

Research Funding:

This work was supported in part by funds from the National Institutes of Health grant R01 DK059904 (to JLFK); ELR was also supported in part by NIH Training Grants T32 MH087977, TL1 RR025010 and T32 GM008367.

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

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

Tools:

Journal Title:

Journal of Inherited Metabolic Disease

Volume:

Volume 36, Number 6

Publisher:

, Pages 1049-1061

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2013 SSIEM and Springer Science+Business Media Dordrecht.

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