Clinical Information

Galactosemia is an autosomal recessive disorder that results from a deficiency of 1 of the 3 enzymes catalyzing the conversion of galactose to glucose: galactose-1-phosphate uridyltransferase (GALT), galactokinase (GALK), and uridine diphosphate galactose-4-epimerase (GALE). GALT deficiency is the most common cause of galactosemia and is often referred to as classic galactosemia. The complete or near-complete deficiency of GALT enzyme is life threatening if left untreated. Complications in the neonatal period include failure to thrive, liver failure, sepsis, and death; even with survival, long-term intellectual disability can occur.

Galactosemia is treated by a galactose-restricted diet, which allows for rapid recovery from the acute symptoms and a generally good prognosis. Despite adequate treatment from an early age, individuals with galactosemia remain at increased risk for developmental delays, speech problems, and abnormalities of motor function. Females with galactosemia are at increased risk for premature ovarian failure. Based upon reports by newborn screening programs, the frequency of classic galactosemia in the United States is approximately 1 in 30,000, although literature reports range from 1 in 10,000 to 1 in 60,000 live births.

Galactose-1-phosphate (Gal-1-P) accumulates in the erythrocytes of patients with galactosemia. The quantitative measurement of Gal-1-P is useful for monitoring compliance with dietary therapy. Gal-1-P is thought to be the causative factor for development of liver disease in these patients and, because of this, patients should maintain low levels and be monitored on a regular basis.

Duarte-variant galactosemia (compound heterozygosity for the Duarte mutation, N314D, and a classic mutation) is generally associated with higher levels of enzyme activity (5%-20%) than classic galactosemia (<5%); however, this may be indistinguishable by newborn screening assays. Typically, individuals with Duarte-variant galactosemia have a milder phenotype, but are also often treated with a low galactose diet during infancy. The Los Angeles variant, which consists of N314D and a second mutation, L218L, is associated with higher levels of GALT enzyme activity than the Duarte-variant allele.

Newborn screening for galactosemia is performed in all 50 US states, though the method by which potentially affected individuals are detected varies from state to state and may include the measurement of total galactose (galactose and Gal-1-P) and/or determining the activity of the GALT enzyme. The diagnosis of galactosemia is established by follow-up quantitative measurement of GALT enzyme activity. If enzyme levels are indicative of carrier or affected status, molecular testing for common GALT mutations may be performed. If 1 or both disease-causing mutations are not detected by targeted mutation analysis and biochemical testing has confirmed the diagnosis of galactosemia, sequencing of the GALT gene is available to identify private mutations.

See Galactosemia Testing Algorithm in Special Instructions for additional information.