Galactose-1-phosphate uridylyltransferase deficiency

Galactose-1-phosphate uridylyltransferase deficiency
Other names	Galactosemia type 1, Classic galactosemia or GALT deficiency
Galactose
Specialty	Endocrinology

Galactose-1-phosphate uridylyltransferase deficiency (classic galactosemia) is the most common type of galactosemia, an inborn error of galactose metabolism, caused by a deficiency of the enzyme galactose-1-phosphate uridylyltransferase.^[1] It is an autosomal recessive metabolic disorder that can cause liver disease and death if untreated. Treatment of galactosemia is most successful if initiated early and includes dietary restriction of lactose intake. Because early intervention is key, galactosemia is included in newborn screening programs in many areas. On initial screening, which often involves measuring the concentration of galactose in blood, classic galactosemia may be indistinguishable from other inborn errors of galactose metabolism, including galactokinase deficiency and galactose epimerase deficiency. Further analysis of metabolites and enzyme activities are needed to identify the specific metabolic error.

Symptoms and signs

In undiagnosed and untreated children, the accumulation of precursor metabolites due to the deficient activity of galactose 1-phosphate uridylyltransferase (GALT) can lead to feeding problems,

In classic galactosemia, galactose-1-phosphate uridylyltransferase activity is reduced or absent; leading to an accumulation of the precursors, galactose, galactitol, and Gal-1-P.^[3] The elevation of precursors can be used to differentiate GALT deficiency from galactokinase deficiency, as Gal-1-P is typically not elevated in galactokinase deficiency.

Genetics

All forms of galactosemia are inherited in an

There are several variants in the GALT gene, which have different levels of residual enzyme activity. A patient homozygous for one of the severe mutations in the GALT gene (commonly referred to as G/G) will typically have less than 5% of the enzyme activity expected in an unaffected patient.[2] Duarte galactosemia is caused by mutations that produce an unstable form of the GALT enzyme, with reduced promoter expression. Patients who are homozygous for Duarte mutations (D/D) will have reduced levels of enzyme activity compared to normal controls, but can often maintain a normal diet. Compound heterozygotes (D/G) will often be detected by newborn screening and treatment is based on the extent of residual enzyme activity.^[2]

Diagnosis

In most regions, galactosemia is diagnosed as a result of

There is no cure for GALT deficiency, in the most severely affected patients, treatment involves a galactose free diet for life. Early identification and implementation of a modified diet greatly improves the outcome for patients. The extent of residual GALT enzyme activity determines the degree of dietary restriction. Patients with higher levels of residual enzyme activity can typically tolerate higher levels of galactose in their diets. As patients get older, dietary restriction is often relaxed.[2] With the increased identification of patients and their improving outcomes, the management of patients with galactosemia in adulthood is still being understood.^{[citation needed]}

After diagnosis, patients are often supplemented with

Gal-1-P is assumed as to be a toxic agent, since the inhibition of the Galactokinase prevents toxicity in disease's models,^[5][6] although this is controversial for Drosophila models.^[7] Phosphate depletion as a consequence of Gal-1-P is also proposed as a mechanism of toxicity in yeast models.^[8]

References