Galactosemia diagnosis gets an upgrade.

Classic galactosemia, a defect of the metabolism of galactose, was one of the earliest defects of intermediary metabolism to be recognized in the mid 20th century (1, 2 ). The disease is caused by a defect of galactose-1phosphate uridyltransferase (GALT), an enzyme central to the Leloir pathway in which galactose is converted into glucose. Galactose is primarily derived from the lactose content of milk that a newborn receives. The well-described and frequently taught clinical phenotype of an untreated newborn with classic galactosemia begins shortly after the onset of regular milk feeding and includes feeding intolerance with vomiting and diarrhea caused by galactose fermentation in the gut; hepatic failure leading to jaundice; bleeding manifestations; hypoalbuminemia and hypoglycemia; a renal Fanconi syndrome with loss of phosphate, glucose, and amino acids; congenital bilateral cataracts; and susceptibility to fatal gram-negative sepsis (primarily Escherichia coli). The hepatic and renal manifestations are caused by intracellular accumulation of galactose 1-phosphate, the substrate for GALT. Cataracts are due to an alternative metabolic pathway of galactose in the lens that leads to galactitol accumulation. Treatment is relatively simple. Once the diagnosis is suspected or confirmed, lactose and lactose-containing products are removed from the diet to reduce the metabolic burden, and most of the neonatal toxicities are alleviated. Subsequent to the recognition of GALT deficiency, 2 additional enzymatic defects of galactose metabolism that also caused galactose accumulation were identified. Galactokinase (GALK) converts galactose to galactose 1-phosphate. GALK deficiency leads to failure to generate the cytotoxic galactose 1-phosphate and therefore does not have the potentially fatal hepatic and renal manifestations. GALK-deficient patients are still at high risk for developing cataracts, which may be congenital or may develop later in life (3 ). The third enzyme is UDP-galactose 4-epimerase (GALE), which converts UDP-galactose to UDP-glucose, which subsequently is converted to glucose or glycogen as a source of energy. Patients with GALE deficiency do accumulate intracellular galactose 1-phosphate, and they may have hepatic and renal disease but typically not to the extent of that seen in GALT deficiency (4 ). The diagnosis of GALT deficiency became even more complex when the mild Duarte GALT variant was identified. Individuals who are homozygous for the Duarte variant are without symptoms and do not require treatment (5 ). Individuals who are compound heterozygotes for classic galactosemia and the Duarte variant have also been identified. Whether treatment helps patients with these variants despite quite low GALT activities and galactosemia has not conclusively been demonstrated, and there is some debate as to whether the restrictive treatment required for classic GALT deficiency is necessary. Most newborn-screening programs for galactosemia in the US monitor blood spot galactose concentrations with a fluorescence assay as a first-line screen and follow up with a fluorometric blood spot enzyme assay for GALT, known as the Beutler test (6 ). The Beutler test is essentially a screening procedure with the potential for false-positive results, particularly when it is used to attempt to differentiate the variant forms of galactosemia. Because of the urgent need to initiate dietary treatment in patients with classic galactosemia and a lesser degree of urgency or perhaps no need for treatment in the case of the compound heterozygotes, it is very important to be able to quickly and accurately distinguish between the 2 groups. A recent review of cutoff values for total galactose concentrations revealed that the fraction of false-positive cases may be high as 89% in some screening programs (7 ). The importance of any delay in getting a confirmatory result cannot be overemphasized, in terms of parental stress induced by waiting for an absolute diagnosis. It is also important to consider that a positive galactose screening result with a typical GALT screen does not exclude the possibility of GALK or GALE deficiencies or other genetic or infectious causes of hepatic dysfunction. The metabolic clinical laboratory has long been involved in confirmatory testing for all 3 enzyme defects to determine the clinical importance of a positive 1 Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA. * Address correspondence to the author at: Metabolic Disease Laboratory, Department of Pathology and Laboratory Medicine, 5NW58, The Children’s Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA 19104. Fax 215-590-1998; e-mail [email protected]. Received February 26, 2010; accepted March 1, 2010. Previously published online at DOI: 10.1373/clinchem.2010.145359 2 Nonstandard abbreviations: GALT, galactose-1-phosphate uridyltransferase; GALK, galactokinase; GALE, UDP-galactose 4-epimerase; UPLC-MS/MS, ultraperformance liquid chromatography–tandem mass spectrometry. Clinical Chemistry 56:5 690–692 (2010) Editorials