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