Chapter 72

## Abstract

1. The main sources of galactose are milk and milk products. Galactose is present as the disaccharide lactose, but lactose is hydrolyzed to its constituent monosaccharides prior to absorption from the intestine. Galactose is an essential energy source in infants but it is necessary that it first be metabolized to glucose. The principal pathway for the metabolism of galactose involves three enzymes: galactokinase, galactose-1-phosphate uridyl transferase, and uridine diphosphate galactose 4′-epimerase. There are genetic diseases due to disorders of all these enzymes.

2. The biochemical consequences of the genetic disorders of galactose metabolism are abnormally high concentrations of galactose and its metabolites in body tissues and fluids. The clinical consequences range from life-threatening crises in the neonatal period and severe long-term complications to complete normality.

3. The first enzyme in the galactose pathway is galactokinase. The gene encoding galactokinase has been mapped to chromosome 17p24. It consists of 8 exons spanning about 7.3 kb of genomic DNA and shows many of the features of a housekeeping gene. The enzyme is a monomer containing 392 amino acids with a molecular weight of 42.

4. The main clinical feature of galactokinase deficiency is cataracts that are usually bilateral and detectable in the early weeks of life, although they have been observed at birth and in a fetus at 20 weeks' gestation. Pseudotumor cerebri has been described in several cases of galactokinase deficiency and is considered to be a true consequence of the disorder. These features resolve when a galactose-restricted diet is introduced.

5. The gene encoding galactose-1-phosphate uridyltransferase is located on the short arm of chromosome 9 in the p13 region and consists of 11 exons. The cDNA is 1295 bases in length and codes a polypeptide of 379 amino acids and an estimated molecular weight of 44. The active enzyme is a dimer of the polypeptide. More than 200 base changes have been characterized at the gene. A few are common, but most are rare; the distribution of several mutations has been studied in a number of major human groups. Q188R is the most common in Europe and in individuals of European descent. S135L is found almost exclusively in individuals of African descent. In vitro functional assays demonstrate that not all mutations at the GALT locus are null. In vivo assays using whole body galactose oxidation substantiate these findings.

6. Severe galactose-1-phosphate uridyltransferase deficiency (classic galactosemia) presents in the first weeks of life with poor feeding and weight loss, vomiting, diarrhea, lethargy, and hypotonia. Liver dysfunction, bleeding tendencies, cataracts, and septicemia may be found on examination. These features usually resolve dramatically, provided treatment is started early; however, it is now recognized that a number of affected individuals will have serious long-term complications, possibly as a result of continued endogenous galactose production.

7. The human uridine diphosphate galactose 4′-epimerase gene has been mapped to the short arm of chromosome 1 at 1p36. The gene spans 4 kb of genomic DNA and consists of 11 exons encoding a polypeptide of 348 amino acids and has a molecular weight of 38. The active enzyme is a dimer. Several mutations have been described at the GALE locus in affected individuals. High-resolution x-ray crystallography of both Escherichia coli and human epimerase enzymes has revealed details of the molecular interactions between substrates and enzymes as well as the mechanism of impact of the V94M mutation on enzyme activity.

8. The majority of patients described with uridine diphosphate galactose 4′-epimerase deficiency have an enzyme defect principally in their erythrocytes and have normal growth and development. A generalized severe form of enzyme deficiency has also been described and is considerably rarer. Patients with this form present similarly to those with classic galactosemia and respond to the removal of galactose from their diet. However, long-term complications may also be associated with this disorder.

9. Neonatal screening for classic galactosemia has been introduced in some areas in order to promote early treatment, although the efficacy of this practice has been questioned. Prenatal diagnosis has been possible for all three enzyme disorders for a number of years.

10. There has been a large volume of research into the pathogenesis of the galactose disorders. Cataract formation is almost certainly caused by galactitol accumulation in the eye lens, but the mechanisms of other multi-organ features of these disorders are undoubtedly multifactorial and will include genomic and environmental influences.

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