Abstract
The Leloir pathway, which consists of highly conserved enzymes, metabolizes galactose. Deficits in three enzymes in this pathway, namely galactose-1-phosphate uridylyltransferase (GALT), galactokinase (GALK1), and UDP-galactose-4′-epimerase (GALE), are associated with genetic galactosemia. We recently identified patients with galactosemia and biallelic variants in GALM, encoding galactose epimerase (GALM), an enzyme that is directly upstream of GALK1. GALM deficiency was subsequently designated as type IV galactosemia. Currently, all the published patients with biallelic GALM variants were found through newborn screening in Japan. Here, we review GALM deficiency and describe how we discovered this relatively mild but not rare disease through the newborn screening system in Japan.
Highlights
galactose epimerase (GALM) catalyzes the equilibrium between β-D-galactose and α-D-galactose, GALM predominantly promotes the conversion from β-D-galactose, which is primarily derived from dietary lactose, to α-D-galactose in vivo
Among 67 variants that were prevalent in the ExAC database, we considered 30 variants to be pathogenic based on in vitro expression and enzymatic assays to estimate the incidence of GALM deficiency [28]
It may be possible to incorporate screening for GALM deficiency by measuring galactose or total galactose levels in newborn screening (NBS) for classic galactosemia
Summary
The main energy source for human babies, is hydrolyzed into β-D-galactose and D-glucose on the intestinal microvilli by β-D-galactosidase and is absorbed into the blood. The Leloir pathway was named after its discovery by Dr Louis Leloir in the 1940s [2,3,4] It consists of highly conserved enzymes, including galactose-1-phosphate uridylyltransferase (GALT, EC 2.7.7.12), galactokinase (GALK1, EC 2.7.1.6), and UDP-galactose-40 -epimerase (GALE, EC 5.1.3.2). Since the 1950s, mutarotase, an enzyme that catalyzes the conversion between α and β-anomers of D-glucose, D-galactose, and some structurally related sugars, has been identified in various organisms [5,6,7]. The four enzymes are encoded by a gene cluster in some organisms including S. cerevisiae, Lactococcus lactis [13], and E. coli, wherein these genes are cistrons of the gal operon [14].
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