Newborn Screening for Classic Galactosemia: Biochemical Testings, Challenges, and Future

Abstract

Galactosemia is a group of hereditary disorders of galactose metabolism. Newborn screening for galactosemia type I is mandatory in all states in the US since timely intervention can prevent life-threatening sequela. The biochemical basis, clinical presentation, and potential treatment options for different types of galactosemia are described. This review has a focus on the screening methodologies, including the principle of the assay, the transition from the initial bacteria inhibition test to the modern fluorometry test, and their respective advantages and disadvantages especially regarding specificity and sensitivity. Diagnosis can be confirmed by biochemical and/or molecular testing. Although newborn screening for classic galactosemia is highly successful, the high false-positive rate and long-term complications in treated galactosemia patients continue to pose some challenges. We are proposing a newborn screening follow-up testing algorithm to assist screening and differentiating four different forms of galactosemia including the most recently described galactosemia type IV. In the near future, we predict that liquid chromatography tandem mass spectrometry may become a new platform for galactosemia screening, due to its multiplexing capability. In-depth parallel sequencing may be integrated in newborn screening algorithm to confirm diagnoses and further reduce false-positive rate.