Galactosemias are disorders of carbohydrate metabolism caused by a deficiency of one of three enzymes involved in galactose metabolism (galactose-1-phosphate uridyltransferase [GALT], galactokinase [GALK], or uridine diphosphate galactose-4'-epimerase [GALE]). Classic galactosemia, caused by a deficiency in GALT due to GALT gene variants, is the most common and most severe form and can lead to liver disease, sepsis, or death if not diagnosed and treated soon after birth. Newborn screening for classic galactosemia, which affects approximately one in 53,500 neonates in the United States, is required in all 50 states. Early diet-based interventions can prevent neonatal complications and irreversible end-organ damage, but even with such interventions, long-term effects such as infertility and neurologic complications may occur. Although not all forms of galactosemia require treatment, classic galactosemia requires early and lifelong lactose and galactose restriction. Diagnosis is based on testing for GALT enzyme activity, which is absent or nearly undetectable in patients with the disorder, and often involves DNA analysis of the GALT gene to determine if pathogenic variants are present. Other forms of galactosemia include type II and III, which are caused by GALK and GALE deficiencies, respectively.
Quick Answers for Clinicians
Following a diagnosis of classic galactosemia, monitoring typically involves testing for galactose-1-phosphate concentrations in red blood cells, and may involve urinary galactitol measurement. Patients with classic galactosemia should also be monitored for long-term complications (see Monitoring below).
Indications for Testing
Testing for classic galactosemia is included in mandated newborn screening panels throughout the U.S. Newborns with abnormal screening test results for galactosemia should undergo further testing. Individuals with a family history of galactosemia or patients with symptoms of galactosemia (see Quick Answers above) also warrant testing. Carrier testing is indicated in parents and family members of affected children.
Testing of GALT enzyme activity in red blood cells is indicated in patients with newborn screening results that suggest classic galactosemia (and in those with family history or symptoms of the disease). GALT activity is absent or greatly reduced in affected patients (<0.20 U/Hb in red blood cells); a GALT activity of ≤3% of normal is diagnostic for classic galactosemia.
Measurement of GALT activity in red blood cells after blood transfusion can cause false-negative results because GALT activity in donor blood is detectable for up to 4 months after a transfusion. DNA analysis, measurement of galactose metabolites, or parental testing can be useful to confirm or rule out the possibility of galactosemia in patients who have had transfusions. (See Molecular Tests and Metabolite Assays below.)
DNA analysis to detect common pathogenic variants in GALT is often used to evaluate patients with suspected classic galactosemia. Other molecular tests that may be useful include GALT gene sequencing or targeted deletion/duplication tests, particularly if the results of biochemical tests are equivocal. Follow-up molecular testing of the parents of an affected child can help assess risk associated with future pregnancies.
For more information on GALT variants and polymorphisms, refer to ARUP's GALT gene database. Genotype/phenotype correlations aid in prognostication. Test options for genotype/phenotype determination include targeted mutation panels and full gene sequencing (see the Galactosemia (GALT) Enzyme Activity and 9 Mutations Test Fact Sheet).
Galactose-1-phosphate is a galactose metabolite that can be measured in patients with suspected galactosemia. Patients with classic galactosemia who have not yet received treatment (ie, removal of dietary galactose) will have high concentrations of galactose-1-phosphate in red blood cells.
Galactitol, another metabolite, can be measured in urine or in red blood cells (testing not performed at ARUP Laboratories). Urinary galactitol is increased in individuals with classic galactosemia, although baseline values may vary widely among patients.
Concentrations of galactose-1-phosphate in red blood cells are typically monitored in patients with galactosemia, and a correlation exists between these concentrations and long-term outcomes. Urinary galactitol concentrations may also be helpful for monitoring.
Patients with classic galactosemia should be monitored for long-term complications, including cognitive, psychosocial, neurologic, and speech and language complications, and changes in bone health and fertility in girls and women. In girls and women, follicle-stimulating hormone, luteinizing hormone, estradiol, and anti-Müllerian hormone tests are useful to assess reproductive function.
ARUP Laboratory Tests
Enzymatic Assay/Polymerase Chain Reaction (PCR)/Single Nucleotide Extensions
Enzymatic Assay/Liquid Chromatography-Tandem Mass Spectrometry
Massively Parallel Sequencing
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