Galactosemia

Galactosemia, first described in the early 1900s by von Reuss, is an autosomal recessive inborn error of carbohydrate metabolism characterized by the inability to convert galactose to glucose. In 1970, Louis Leloir won the Nobel Prize in Chemistry for defining the pathway of galactose catabolism. Three galactose-metabolizing enzymes are active in the Leloir pathway: galactokinase (GALK), galactose-1-phoshate uridyltransferase (GALT), and uridine diphosphate (UDP)-galactose 4-epimerase (GALE). When any of these enzymes is deficient, galactose accumulates and galactosemia is the consequence.

Classic galactosemia, resulting from any of more than 250 mutations in the GALT gene, initially presents in the newborn period with subtle, nonspecific clinical signs, such as feeding intolerance, jaundice, lethargy, hypotonia, vomiting, and poor weight gain. If left untreated, it advances to a severe life-threatening event progressing to hepatomegaly, hepatic failure, bleeding diatheses, renal dysfunction, encephalopathy, Escherichia coli sepsis, shock, and, ultimately, death. Galactosemia occurs throughout the world, but its incidence varies widely: in the United States and Europe it affects approximately 1:40,000 to 1:60,000 newborns; Ireland has the highest reported frequency (1:20,000) and Japan the lowest (1:1,000,000).

The primary sources of galactose in the human diet are milk and milk-containing products: galactose and glucose together form the disaccharide lactose, which is present in both human and bovine milk. Galactose is an important carbohydrate for infants because it is a source of energy and is used for the synthesis of glucoconjugates such as galactoproteins, galactolipids, and mucopolysaccharides (Fig).

Galactose is first phosphorylated and converted to galactose-1-phosphate (Gal-1-P) by the enzyme GALK. GALT then converts Gal-1-P and UDP into glucose-1-phosphate and UDP-galactose. The …