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Inborn error of metabolism with the inability to metabolize galactose appropriately. This results in toxic effects on brain, liver, kidney, and eyes. Early diagnosis and galactose-free diet are key.

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Galactose-1-Phosphate Uridyltransferase Deficiency; GALT Deficiency.

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The incidence in the general population is estimated between 1:30,000 and 1:70,000, with the highest incidence in Ireland. It occurs in all races, but the incidence is lower among Asian people. Both genders are equally affected.

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Transmission is autosomal recessive. The responsible gene encoding galactose-1-phosphate uridyltransferase (GALT) has been mapped to 9p13.

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Lactose is a disaccharide consisting of galactose and glucose that is metabolized to glucose-6-phosphate via uridine diphosphate (UDP)-glucose in the Leloir pathway. Three different enzyme defects within the Leloir pathway can lead to galactosemia. Classic galactosemia, the most common form, is caused by GALT deficiency. The inability to metabolize galactose-1-phosphate to UDP-galactose results in accumulation of the former in brain, kidney, and liver, where it exerts a toxic effect. Galactosemia also can be caused by a deficiency in galactokinase, the enzyme responsible for the initial phosphorylation of galactose to galactose-1-phosphate. Erythrocytic galactokinase activity (used for diagnostic purposes) is significantly diminished in homozygous patients, whereas intermediate activities are measured in heterozygous children. Increased galactose levels are found in blood and urine samples after ingestion of lactose. In general, the prognosis is better than observed for the classic form. Finally, UDP-galactose-4-epimerase is necessary for the conversion of UDP-galactose to UDP-glucose. The deficiency of this enzyme comes in two different clinical forms. The benign form usually is detected during newborn screening tests with increased levels of erythrocytic galactose-1-phosphate concentrations, whereas galactokinase and uridyltransferase activities are normal. In this benign form, the defect affects only blood cells, so no treatment is required. In the generalized form, however, the clinical course is indistinguishable from classic galactosemia. In patients with black ethnic background, the most frequent mutation (S135L, which was previously called “Negro” or “African American” variant) accounts for approximately 45% of the mutant alleles. Homozygosity for the S135L allele and for two other mutant alleles (Duarte and Los Angeles variants) results in approximately 50% of normal GALT activity and a mild clinical course. A certain amount of free galactose may be reduced to galactitol through aldose reductase; however, this is a dead-end pathway and the poorly diffusable galactitol accumulates in the cells. It is partly responsible for the toxic effects seen in galactosemia.

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Most often galactosemia is detected by standard newborn screening tests for inborn errors of metabolism. The test requires that the child be fed with human or cow's milk or a lactose-containing formula. A galactose breath test with orally administered stable isotope-labeled galactose can be used to determine whole-body galactose oxidation to CO2. The absence of a marked CO2 peak after 2 to 5 hours is found in patients with a severe clinical course or in affected neonates exposed to galactose.

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