Epimerase deficiency galactosemia is an autosomal recessive disorder that results from partial impairment of UDP-galactose 4'-epimerase (GALE), the third enzyme in the Leloir pathway of galactose metabolism. Clinical severity of epimerase deficiency ranges from potentially lethal to apparently benign, likely reflecting the extent of GALE enzyme impairment, among other factors. We report here a case study of monozygotic twins identified by newborn screening with elevated total galactose and normal galactose-1P uridylyltransferase (GALT). Follow-up testing revealed partial impairment of GALE in hemolysates but near-normal activity in lymphoblasts; molecular testing identified a missense substitution, R220W, apparently in the homozygous state. The twins were treated with dietary galactose restriction for the first 18 months of life. During this time, independent testing revealed concurrent diagnoses of Williams Syndrome in both twins, and cytomegalovirus (CMV) infection in one. Expression studies of R220W-hGALE in a null-background strain of Saccharomyces cerevisiae demonstrated a very limited impairment of V (max) for UDP-galactose (UDP-Gal) and K (m) for UDP-N-acetylgalactosamine (UDP-GalNAc), but a galactose challenge in vivo failed to uncover any evidence of impaired Leloir function. Similarly, both twins demonstrated normal hemolysate galactose-1-phosphate (Gal-1P) levels following normalization of their diets at 18 months of age. While these studies cannot rule out a negative consequence from some cryptic GALE impairment in a specific tissue or developmental stage, they suggest that the substitution, R220W, is mild to neutral, so that any GALE impairment in these twins is likely to be peripheral and therefore unlikely to be the cause of the negative outcomes observed.

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Journal Article

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Liu Y, Bentler K, Coffee B, Chhay JS, Sarafoglou K, Fridovich-Keil JL

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