Clinical Information

Classical galactosemia is an autosomal recessive disorder of galactose metabolism caused by genetic variants 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, intellectual disability, 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. Women 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 variant, N314D and -119_-116delGTCA in cis [on the same chromosome], and a classic variant 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 variants may be performed. If one or both disease-causing variants are not detected by targeted variant analysis and biochemical testing has confirmed the diagnosis of galactosemia, sequencing of the GALT gene is available to identify private variants.

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

These variants, in addition to the LA variant, are included in this test and in GCT / Galactosemia Reflex, Blood. For more information see Galactosemia Testing Algorithm.

Table. Targeted Variants

*Previously detected in a known positive sample