Clinical Information

Classical galactosemia is an autosomal recessive disorder of galactose metabolism caused by mutations in the galactose-1-phosphate uridyltransferase (GALT) gene. The complete or near complete deficiency of the GALT enzyme is life threatening. If left untreated, complications include liver failure, sepsis, mental retardation, and death. Galactosemia is treated by a galactose-free diet, which allows for rapid recovery from the acute symptoms and a generally good prognosis. Despite adequate treatment from an early age, children 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. The prevalence of classic galactosemia is approximately 1 in 30,000.

Duarte variant galactosemia (compound heterozygosity for the Duarte mutation, N314D and -119_-116delGTCA in cis [on the same chromosome], and a classic mutation in trans [on the opposite chromosome]) 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 (LA) variant, which consists of N314D without the presence of -119_-116delGTCA, is associated with normal levels of GALT enzyme activity.

Newborn screening, which identifies potentially affected individuals by measuring total galactose (galactose and galactose-1-phosphate) and/or determining the activity of the GALT enzyme, varies from state to state. 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.

The GALT gene maps to 9p13. Several disease-causing mutations are common in patients with classic galactosemia (G/G genotype). The most frequently observed is the Q188R classic mutation. This mutation accounts for 60% to 70% of classical galactosemia alleles. The S135L mutation is the most frequently observed mutation in African Americans and accounts for approximately 50% of the mutant alleles in this population. The K285N mutation is common in those of eastern European descent and accounts for 25% to 40% of the alleles in this population. The L195P mutation is observed in 5% to 7% of classical galactosemia. The 5 kb deletion is common in individuals of Ashkenazi Jewish descent. The Duarte mutation (N314D and -119_-116delGTCA) is observed in 5% of the general United States population. The rest of the mutations detected by this method (ie, D98N, S135L, T138M, M142K, F171S, Y209C, and Q344K) are all uncommon, but known to be recurrent in the general population.

These mutations, in addition to the LA variant, are included in GAL14 / Galactosemia Gene Analysis (14-Mutation Panel) and in GCT / Galactosemia Reflex, Blood. See Galactosemia Testing Algorithm in Special Instructions for additional information. Refer to Galactosemia: Current Testing Strategy and Aids for Test Selection, Mayo Clinic Laboratories Communique 2005 May;30(5) for more information regarding diagnostic strategy.