A Case Study of Monozygotic Twins Apparently Homozygous for a Novel Variant of UDP-Galactose 4′-epimerase (GALE)

Abstract

Epimerase deficiency galactosemia is an autosomal recessive disorder that results from partial impairment of UDP-galactose 4 0 -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

Genetic and functional studies reveal a novel noncoding variant in GALT associated with a false positive newborn screening result for galactosemia

“…Samples prepared from lymphoblasts representing three unrelated controls (FKT936, FKT937, and FKT939), and two unrelated patients with classic galactosemia (FKT218 and FKT221, both Q188R homozygotes) were evaluated in parallel. As expected, GALT activity in the three controls was strong and comparable to levels we have reported previously [8], while in the two classic galactosemia samples GALT activity was essentially undetectable. Consistent with the clinical red blood cell GALT activities presented in Table 1, lymphoblasts from FKT395 and FKT395P2 both exhibited GALT activities below the controls, but clearly well above the classic galactosemics (Figure 1A).…”

“…Lymphoblast cell cultures were harvested and lysates prepared and analyzed for GALT and GALE activities as described previously [8]. Enzyme activity was defined in units of pmol product produced per minute per microgram of soluble protein.…”