Galactosemia screening with low false-positive recall rate: the Swedish experience

Abstract

Newborn screening was implemented in the 1960s with screening for phenylketonuria (PKU). In the same decade, it became possible to screen for classical galactosemia, a rare autosomal recessive inherited disorder, which is potentially life threatening if not treated. While newborn screening for PKU has become almost universal, galactosemia is included only in a minority of European newborn screening programs. The major arguments why galactosemia is excluded from newborn screening programs are that the disease can be diagnosed clinically, there is a high rate of false positives and long-term complications are common despite early diagnosis.Here, we report how we have decreased the number of false-positive galactosemia recalls to less than 0.01%, using a two-tier test strategy. All samples are tested with the Beutler blood spot test, a method that measures galactose-1-phosphate uridyltransferase activity. Samples with less than ≤15% activity are tested for galactose with a galactose dehydrogenase test (the rapid GAL-DH test), which catalyzes the oxidation of galactose and the reduction of NAD(+) to NADH that is estimated visually by fluorescence under UV-light. Both tests are semiquantitative.With this strategy, screening for galactosemia is inexpensive, does not demand a heavy workload, and has a low false-positive re-call rate. The incidence of classical galactosemia in Sweden is 1/100,000, which is lower than the reported incidence in other European countries. Despite this, newborn screening for galactosemia has never been questioned. Concise sentence: Screening for galactosemia using well-established methods to reduce the false-positive rate.

Fig. 1

Determination of GALT-activity according to Beutler. GALT galactose-1-phosphate uridyltransferase, PGM phosphoglucomutase, G6P-DH glucose-6-phosphate dehydrogenase

Fig. 2

Principle for rapid GAL-DH. GAL-DH galactose dehydrogenase

Fig. 3

Rapid GAL-DH test. First line: samples containing 0, 2, 4 mM galactose. Second line: sample containing 8 mM galactose, number 9 healthy child, number 184 and 185 twins with classical galactosemia. Number 184 had 7.3 mmol/l galactose and number 185 had 5.3 mmol/l galactose when determined quantitatively

Fig. 4

Algorithm for newborn screening for galactosemia using the two-tier approach with Beutler screening and the rapid GAL-DH on the initial screening sample. Positive Beutler test ≤15% activity. Positive rapid Gal-DH test approximately ≥2 mM galactose