Better diagnostic testing for newborns with galactosemia

Babies with galactosemia cannot properly break down the sugar galactose.

For babies born with galactosemia, the simple act of feeding can be deadly. In this rare inherited disease, infants are deficient in an enzyme known as GALT, leaving them unable to metabolize galactose, a sugary byproduct of lactose found in milk and other dairy foods. Instead, galactose builds up and wreaks havoc. If the condition isn’t caught at birth and treated with a lactose-free diet, infants can develop cataracts, brain swelling and organ failure and die within the first few weeks of life.

However, some babies do have enough enzyme to keep the levels of this sugar down, and have a much milder ”variant” form of the disease. The trouble is, the existing newborn screening test cannot always distinguish these children from those with the more severe form of the disease.  This is because this test cannot differentiate between the absence of GALT and low levels of GALT activity — levels that are still sufficient to spare children from developing speech deficits , intellectual disability and ovarian insufficiency, which despite dietary interventions are characteristic of the severe form of the disease.

Berry and postdoctoral fellow Yijun Li at their liquid chromatograph–tandem mass spectrometer.

Now, Gerard Berry, director of the Metabolism Program at Children’s Hospital Boston, hopes to change that with a more sensitive follow-up test relieving unnecessary distress on families.

“If we can find that there is residual enzyme activity in their newborn, we can counsel the family right away,” says Berry, “so that they realize that their baby might not be as severely affected.”

The liquid chromatography–tandem mass spectrometry based test, pioneered by Berry’s team, can detect as little as 0.2 percent of the normal level of GALT activity with at least 92 percent accuracy, sufficient to distinguish the mild “variant” form from the severe form of the disease.

Now, the Berry team is using this test to classify the over 200 mutations associated with galactosemia. They have launched a large observational study in which patients will be genotyped, their GALT activity measured and their health monitored long-term – so that genetic counselors and physicians can begin to predict a galactosemic baby’s outcome based on his or her genotype.

In the future, the Berry team, in collaboration with George Daleydirector of the Stem Cell Transplantation Program at Children’s, hopes to develop a gene therapy-based treatment for galactosemia and use the GALT test to monitor its effectiveness.

“Even treatment on the first day of life does not cure the disease or prevent complications,” notes Berry. “What is really needed is a prenatal therapy if we are going to make a difference in these children’s lives.”