Duarte galactosemia is an inherited condition associated with diminished ability to metabolize galactose due to a partial deficiency of the enzyme galactose-1-phosphate uridylyltransferase.Fridovich-Keil, J., et al., Duarte Variant Galactosemia, in GeneReviews, R. Pagon, et al., Editors. 2014, University of Washington, Seattle. Review. DG differs from classic galactosemia in that patients with Duarte galactosemia have partial GALT deficiency whereas patients with classic galactosemia have complete, or almost complete, GALT deficiency.Berry, G., Classic Galactosemia and Clinical Variant Galactosemia, in GeneReviews, R. Pagon, et al., Editors. 2014, University of Washington, Seattle. Review. Duarte galactosemia (DG) is much more common than classic galactosemia, and is estimated to affect close to one in 4,000 infants born in the United States. Historically, most healthcare professionals have considered DG to be clinically mild based on pilot studies and anecdotal experience, and in 2019 a large study confirmed that children with DG are not at increased risk for developmental problems relative to children who do not have DG.Carlock, G., Fischer, S. T., Lynch, M. E., Potter, N. L., Coles, C. D., Epstein, M. P., ... & Wilson, E., Developmental outcomes in Duarte galactosemia. 2018 Pediatrics, doi: 10.1542/peds.2018-2516. Due to regional variations in newborn screening (NBS) protocols, some infants with DG are identified by NBS but others are not.Pyhtila, B.M., et al., Newborn screening for galactosemia in the United States: looking back, looking around, and looking ahead. JIMD Rep, 2015. 15: p. 79-93. Review.
Symptoms and signs Infants with DG often show biochemical differences from infants who do not have DG, especially if exposed to milk, but may not show any acute or developmental symptoms. Specifically, when exposed to high levels of dietary galactose, a sugar abundant in breast milk, milk formula, and most dairy products,Van Calcar SC, Bernstein LE, Rohr FJ, Scaman CH, Yannicelli S, Berry GT. A re-evaluation of life-long severe galactose restriction for the nutrition management of classic galactosemia. Mol Genet Metab. 2014 Jul;112(3):191-7. doi: 10.1016/j.ymgme.2014.04.004. Epub 2014 May 2. Review. infants with DG may show elevated levels of galactose and galactose metabolites such as galactose-1-phosphate (Gal-1P) and galactitol in blood and urine, respectively. Like many infants who do not have DG, some infants with DG may also show acute symptoms of milk sensitivity, such as Jaundice or vomiting, after exposure to milk but these symptoms may reflect sensitivity of the child to components of milk other than galactose, and typically resolve quickly when the baby is switched to a non-dairy diet, such as soy formula. A large study of developmental outcomes in 6- to 12-year-old children with Duarte galactosemia published in 2019 demonstrated that children with DG do not show increased prevalence of developmental problems relative to children who do not have DG. This suggests that if a child with DG does show developmental problems, other possible causes should be explored.
Cause
Duarte galactosemia is inherited as a Mendelian autosomal recessive trait. A child with DG carries two different types of GALT alleles, one inherited from each parent. One of these GALT alleles, the G allele, carries a mutation that severely inhibits the function of the encoded GALT enzyme. The other GALT allele, called the D or D2 allele, carries mutations that partially compromise the expression and change some biochemical properties of the encoded GALT enzyme. Together, the G and D alleles only produce about 25% of the normal level of GALT enzyme activity found in a person with two normal (N) GALT alleles. Both parents of a child with DG are considered carriers for GALT variant alleles. One parent carries the G allele and the other carries the D allele. The genotypes of these parents would be written GN and DN, respectively. Without follow-up testing of the parents, it is not possible to know which parent contributed which GALT allele to a child with DG. Like other autosomal recessive conditions, the recurrence risk for DG is 1 in 4, meaning that for each successive child born to parents who already have a child with DG there is a 1 in 4 chance the new baby will also have DG (Figure 2). In rare cases, one parent may actually have DG, while the other parent is a carrier for a G allele (GN). For these couples, there is a 1 in 4 recurrence risk for DG and also a 1 in 4 risk with each pregnancy that the new baby will have classic galactosemia (GG). In extremely rare cases a GALT gene mutation may arise de novo, so that only one parent is a carrier; however, only one case of this has been reported in the literature for galactosemia.Tran, T.T., et al., A De Novo Variant in Galactose-1-P Uridylyltransferase (GALT) Leading to Classic Galactosemia. JIMD Rep, 2015. 19: p. 1-6
Diagnosis Infants with DG are generally diagnosed in follow-up to a positive newborn screening (NBS) result for galactosemia. Specifically, dried blood spots collected for NBS from infants with DG may show low (but generally non-zero) GALT enzyme activity, elevated galactose metabolite levels, or both. DG can also be identified by genetic testing.
Of note, not all NBS tests for galactosemia are designed to detect DG so infants with DG born in one jurisdiction may be detected while those born in another may not. For example, all states in the US screen for classic galactosemia in their NBS panel, but some states have lower GALT enzyme activity cut-off levels than others. NBS in states with a low GALT cut off level still detect classic galactosemia, but are likely to miss many infants with DG. In those states, a normal NBS result for galactosemia may not be informative about an infant's DG status.
Most infants with DG who are flagged by a positive NBS result for galactosemia have their diagnosis confirmed in a follow-up evaluation. The differential diagnosis for a positive newborn screening result for galactosemia, especially if based on galactose metabolite levels, includes: classic galactosemia, clinical variant galactosemia, DG, GALE (epimerase) deficiency, GALK (galactokinase) deficiency, or a false positive result. There are also other rare conditions, such as portosystemic venous shunting and hepatic arteriovenous malformations, or Fanconi-Bickel Syndrome (GSDXI) that can lead to elevated blood galactose or urinary galactitol, potentially triggering an initial suspicion of galactosemia.Nishimura Y, Tajima G, Dwi Bahagia A, Sakamoto A, Ono H, Sakura N, Naito K, Hamakawa M, Yoshii C, Kubota M, Kobayashi K, Saheki T. Differential diagnosis of neonatal mild hypergalactosaemia detected by mass screening: clinical significance of portal vein imaging. J Inherit Metab Dis. 2004;27(1):11-8. If the NBS result is based only on GALT activity and not on metabolite levels then the differential diagnosis would include classic galactosemia, clinical variant galactosemia, DG, and false positive.
Management Historically, there has been no broadly accepted standard of care for infants with DG.Fernhoff, P.M., Duarte galactosemia: how sweet is it? Clin Chem, 2010. 56(7): p. 1045-6. At present, some healthcare providers recommend partial to complete restriction of milk and other high galactose foods for infants with DG; others do not. Because children with DG develop increased tolerance for dietary galactose as they grow, few healthcare providers recommend dietary restriction of galactose beyond early childhood. A revised perspective on clinical care for infants with Duarte galactosemia was published in 2019.McCandless, S. E., 2019. Answering a Question Older Than Most Pediatricians: What to Do About Duarte Variant Galactosemia. Pediatrics, 143(1). doi: 10.1542/peds.2018-3292
The rationale for NOT restricting milk exposure of infants with DG: Healthcare providers who do not recommend dietary restriction of milk for infants with DG generally consider DG to be of no clinical significance—meaning most infants and children with DG seem to be doing clinically well. A large study reported in 2019 supported this conclusion. Further, these providers may be opposed to interrupting or reducing breastfeeding when there is no clear evidence it is contraindicated. These providers may argue that the recognized health benefits of breastfeeding outweigh the potential risks of as yet unknown negative effects of continued milk exposure for these infants. For infants with DG who continue to drink milk, some doctors recommend that blood galactose-1-phosphate (Gal-1P) or urinary galactitol be rechecked by age 12 months to ensure that these metabolite levels are normalizing.
The rationale FOR restricting milk exposure of infants with DG: Healthcare providers who recommend partial or complete dietary restriction of milk for infants with DG generally cite concern about the unknown long-term consequences of abnormally elevated galactose metabolites in a young child's blood and tissues. Infants with DG who continue to drink milk accumulate the same set of abnormal galactose metabolites seen in babies with classic galactosemia – e.g. galactose, Gal-1P, galactonate, and galactitolFicicioglu, C., et al., Monitoring of biochemical status in children with Duarte galactosemia: utility of galactose, galactitol, galactonate, and galactose 1-phosphate. Clin Chem, 2010. 56(7): p. 1177-82. – but to a lesser extent. While it remains unclear whether any of these metabolites contribute to the long-term developmental complications experienced by so many older children with classic galactosemia, the theoretical possibility that they might cause problems in children with DG serves to motivate some healthcare providers to recommend dietary galactose restriction for infants with DG. Switching an infant with DG from milk or milk formula (high galactose) to a low-galactose formula rapidly normalizes their galactose metabolites. This approach is considered potentially preventative rather than responsive to symptoms. Of course, if a baby with DG, like any other baby, shows acute signs of milk sensitivity then switching the baby to a non-dairy formula would be responsive to those acute symptoms.
If a baby with DG is switched to a low-galactose diet due to concern about elevated galactose metabolites, the healthcare provider may recommend a galactose challenge to re-evaluate galactose tolerance before the restrictive diet is discontinued. Most infants or young children with DG who are followed by a metabolic specialist are discharged from follow up after a successful galactose challenge.
The goal of a galactose challenge is to learn whether a child is able to metabolize dietary galactose sufficiently to prevent the abnormal accumulation of galactose metabolites, generally measured as Gal-1P in the blood or galactitol in the urine. For infants with DG who showed elevated galactose metabolites at diagnosis, this test can be used to see if the child's ability to process galactose has improved.
For example, to test galactose metabolism, a baseline Gal-1P level is measured while the child is on a galactose-restricted diet. If the level is within the normal range (e.g. <1.0 mg/dL), the parent/guardian is advised to challenge their child with dietary galactose—meaning feed the child a diet that includes normal levels of milk and dairy for 2–4 weeks. Immediately after that time, another blood sample is collected and analyzed for Gal-1P level. If this second result is still in the normal range, the child is said to have passed their galactose challenge, and dietary galactose restrictions are typically relaxed or discontinued. If the second test shows elevated Gal-1P levels, the parent/guardian may be advised to resume galactose restriction for the child, and the challenge may be repeated after a few months.
Prognosis