DISORDERS OF GALACTOSE METABOLISM
Galactosemia denotes the elevated level of galactose in the blood and, among other reasons, is found in 3 distinct inborn errors of galactose metabolism involving 1 of the following enzymes that comprise the Leloir pathway: galactose-1-phosphate uridyl transferase (GALT), galactokinase (GALK), and uridine diphosphate galactose-4-epimerase (GALE). The term galactosemia, although adequate for the deficiencies of any of these three disorders, generally designates the transferase deficiency that is by far the most prevalent form, and when completely deficient the disorder is called classical galactosemia.
GALACTOSE-1-PHOSPHATE URIDYL TRANSFERASE (GALT) DEFICIENCY GALACTOSEMIA
Galactose is a disaccharide made up of glucose and galactose. Classical galactosemia due to a complete GALT deficiency is a serious disease, with an incidence of approximately 1 in 30,000 to 60,000. Symptoms typically appear by the second half of the first week of life, when the newborn receives high amounts of lactose (up to 40% of calories in breast milk and certain formulas). Without the transferase activity, the infant is unable to metabolize galactose-1-phosphate (see Chapter 149, Fig. 149-1), the accumulation of which is associated with injury to parenchymal cells of the kidney, liver, and brain.
The diagnosis of GALT deficiency should be considered in newborns, older infants, or children with any of the following clinical manifestations: jaundice, hepatomegaly, vomiting, hypoglycemia, convulsions, lethargy, irritability, feeding difficulties, poor weight gain, amino aciduria, nuclear cataracts, vitreous hemorrhage, hepatic cirrhosis, ascites, splenomegaly, or intellectual disability. Patients with galactosemia are at an increased risk of Escherichia coli neonatal sepsis. Importantly, the onset of sepsis often precedes the diagnosis of galactosemia. Pseudotumor cerebri may occur and may cause a bulging fontanel.
When the diagnosis is not made at birth, damage to the liver (cirrhosis) and brain (intellectual disability) becomes increasingly severe and may be irreversible. Symptoms are milder and improve when milk is temporarily withdrawn and replaced by lactose-free nutrition.
Partial transferase deficiency may be due to the Duarte variant and is generally asymptomatic. It is more frequent than classical galactosemia and is often diagnosed by newborn screening because of moderately elevated blood galactose or low transferase activity.
GALT deficiency galactosemia (Online Mendelian Inheritance in Man [MIM] 230400) is inherited as an autosomal recessive disorder and leads to accumulation of galactose-1-phosphate. The gene for GALT is located on chromosome 9p13. There are several enzymatic variants of galactosemia depending on the residual enzyme activity. Duarte variant is the most common abnormal allele and has a carrier frequency of 12% in the general population, with the allele being designated D. Individuals who are homozygous for the Duarte variant have diminished red cell enzyme activity (50% of normal) but no clinical manifestations. The most common complete loss of function variant leading to classical galactosemia is Q188R, and the allele ...