Duarte galactosemia: how sweet is it?

The pathologic consequences of various inborn errors of metabolism in the conversion of dietary and endogenously produced galactose through the Leloir pathway have recently been reviewed (1, 2 ). In this issue of the Journal, Ficicioglu and colleagues (3 ) report that children (ages 1– 6 years) who have Duarte galactosemia (DG), a variant form of galactosemia, and are on a standard diet have typical concentrations of red blood cell (RBC) galactose 1-phosphate but increased concentrations of other galactose metabolites. The increased concentrations of galactose metabolites in these patients correlated with their dietary intake of galactose but not with any observable developmental or clinical pathology at this young age. Why is this observation important? For more than 30 years in the US and many industrialized countries, most newborns have been routinely screened within 48 h after birth for classic galactosemia, along with multiple other genetic disorders, with a filter paper card containing a sample of dried blood (4 ). The primary purpose of the screen has been to detect newborns with classic galactosemia before they rapidly become symptomatic (severe liver failure, coagulopathy, sepsis, and death). If a screening result is consistent with classic galactosemia, the newborn is immediately switched from either breast milk or a cow’s milk formula to a galactose-restricted formula. If the diagnosis of classic galactosemia is confirmed by enzymatic and/or molecular testing, the affected child must maintain a lifelong diet that is severely restricted in galactose. Classic galactosemia is caused by the near total absence of galactose-1-phosphate uridyltransferase (GALT) activity and the resulting accumulation of markedly increased concentrations of galactose and its metabolites. Depending on the population screened, classic galactosemia is found in approximately 1 in every 30 000 to 60 000 newborns (1, 2 ). There are, however, many milder or variant forms of GALT deficiency. One of the more common forms detected in newborn screening is DG, which is caused by the inheritance of 1 Duarte gene and 1 classic galactosemia gene. The Duarte variant consists of the substitution of Asp for Asn at residue 314 (p.Asn314Asp), which causes bioinstability of the GALT enzyme. This variant leaves the child with about 25% of the wild-type GALT activity (2 ). Infants with DG are found much more frequently during newborn screening than those with classic galactosemia. During the last 3 years in the state of Georgia, we screened approximately 405 000 newborns and detected 8 children with classic galactosemia, but we detected 83 children with DG. Infants with DG remain asymptomatic but can have mildly to moderately increased concentrations of galactose metabolites while ingesting lactose from either breast milk or a cow’s milk formula. Early studies found many healthy adults with DG who had never been restricted in their lactose intake (5, 6 ). Since the beginning of newborn screening for galactosemia, the metabolicand newborn-screening communities have been split over whether newborns with DG require any dietary restriction of lactose or whether galactose intake during the first 6 –12 months of life should be limited. Because of this controversy, several newborn-screening programs do not recommend any restriction of dietary galactose, whereas others recommend full or partial restriction of dietary galactose for at least the first year of life. This situation has caused confusion and consternation for parents and metabolism specialists. For those newborn-screening programs that recommend initial limitation of dietary galactose, substantial numbers of parents and their DG newborns must be located and brought to a metabolism center to receive nutritional and genetic counseling about the distinction between classic galactosemia and DG. These programs usually recommend that children with DG limit their feeding with breast milk or cow’s milk formula and replace it with a soya-based or a galactose-free infant formula. This counseling is done at considerable investment of time and expense by the public health system and metabolism clinics. There is also the concern that despite family counseling, infants with DG are mistakenly labeled with “galactosemia” and subjected to many years of unnecessary galactose restriction and testing. 1 Division of Medical Genetics, Department of Human Genetics, Emory University School of Medicine, Atlanta, GA. * Address correspondence to this author at: Emory University School of Medicine, Medical Genetics, 2065 N. Decatur Rd., Decatur, GA 30033. Fax 404-778-8562; e-mail [email protected]. Received April 26, 2010; accepted April 27, 2010. Previously published online at DOI: 10.1373/clinchem.2010.147371 2 Nonstandard abbreviations: DG, Duarte galactosemia; RBC, red blood cell; GALT, galactose-1-phosphate uridyltransferase. Clinical Chemistry 56:7 1045–1046 (2010) Editorials