Duarte Variant Galactosemia

Excerpt

Clinical characteristics: Infants with Duarte variant galactosemia who receive breast milk or a high galactose-containing formula (dairy milk-based formula) are typically asymptomatic and show the same prevalence of acute issues seen in the general newborn population. For decades it has been unclear whether Duarte variant galactosemia results in long-term developmental problems either with or without dietary intervention. However, a recent study of 350 children ages six to 12 years reported no detectable differences in developmental outcomes tested between children with Duarte variant galactosemia and controls, or among children with Duarte variant galactosemia as a function of galactose exposure in infancy. Premature ovarian insufficiency, which is common in classic galactosemia, also has not been reported for girls or women with Duarte variant galactosemia.

Diagnosis/testing: Duarte variant galactosemia is diagnosed by a combination of biochemical and genetic testing. Specifically, erythrocyte galactose-1-phosphate uridylyltransferase (GALT) enzyme activity is typically about 25% of control activity, and GALT genotyping reveals the presence of one heterozygous pathogenic GALT variant together with either a heterozygous or homozygous Duarte (D₂) GALT variant.

Management: Treatment of manifestations: Currently, there is no uniform standard of care regarding restriction of dietary galactose for infants with Duarte variant galactosemia. Thus, some health care providers, or parents, may choose to restrict dietary galactose in the first year of life, while others may not. When dietary galactose is restricted in infancy, centers often perform a galactose challenge around age one year followed by measurement of the erythrocyte galactose-1-phosphate level. If the level is within the normal range (<1.0 mg/dL), dietary restriction of galactose is generally discontinued. When dietary galactose is not restricted in infancy, some health care providers may still choose to check the erythrocyte galactose-1-phosphate level at age one year to confirm that the level is approaching the normal range.

Surveillance: For infants on dietary restriction of galactose: if the erythrocyte galactose-1-phosphate level is >1.0 mg/dL following a galactose challenge at age one year, galactose restriction may be resumed. In this case, the galactose challenge and measurement of erythrocyte galactose-1-phosphate level may be repeated every four to six months until the erythrocyte galactose-1-phosphate level stabilizes at <1.0 mg/dL.

Agents/circumstances to avoid: Opinion varies as to whether avoidance of all dairy products (including breast milk and dairy milk-based formula) until age one year is warranted.

Evaluation of relatives at risk: If families with one child with Duarte variant galactosemia wish to evaluate their other children for Duarte variant galactosemia, molecular genetic testing for the GALT variants identified in the family can be performed.

Genetic counseling: Duarte variant galactosemia is inherited in an autosomal recessive manner. When one parent is heterozygous for the GALT D₂ allele and the other parent is heterozygous for a GALT pathogenic variant, each child has a 25% chance of having Duarte variant galactosemia, a 25% chance of being an asymptomatic carrier of the D₂ allele, a 25% chance of being an asymptomatic carrier of the GALT pathogenic variant, and a 25% chance of being unaffected and also not a carrier of either GALT variant. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk requires prior identification of the GALT variants in the family and determination of the parental origin of each allele.