Neonatal screening for severe combined immunodeficiency caused by an adenosine deaminase defect: A reliable and inexpensive method using tandem mass spectrometry

BackgroundAdenosine deaminase (ADA)–severe combined immunodeficiency (SCID) is an SCID caused by a defect in the enzyme adenosine deaminase. It is usually fatal in infancy because of severe recurrent infections. When diagnosis is made, permanent damage caused by infections or by metabolites is often present. Gene therapy, bone marrow transplantation, or enzyme therapy might be effective if performed early. ADA-SCID complies with all the criteria for inclusion in a newborn screening program. However, screening methods are still expensive or provide a non-negligible number of indeterminate results.ObjectiveThe aim of the present study was to develop a simple, reliable, and inexpensive method for diagnosis of ADA-SCID by using dried blood spot (DBS) samples taken at birth. Cost per test was calculated, including the cost for reagents, equipment, and operators.MethodsDBS samples from 4 patients with genetically confirmed ADA-SCID and 12,020 DBS samples from healthy newborns were examined. Adenosine and 2′-deoxyadenosine were tested by using tandem mass spectrometry (PCT EP2010/070517).ResultsThe mean levels of adenosine and 2′-deoxyadenosine were 7.8 ± 3.1 and 8.5 ± 6.0 μmol/L, respectively, in affected children; adenosine was found at 0.23 ± 0.09 μmol/L, whereas 2′-deoxyadenosine was never detected in healthy control subjects (adenosine: P < 10−6 [95% confidence limit, 7.59-7.78] and 2′-deoxyadenosine: P < 10−6 [95% confidence limit, 8.65-8.82] for control subjects vs patients with ADA-SCID). No indeterminate or false-positive results were found. Cost per test was €0.01 ($0.013). A pilot population-based newborn screening for ADA-SCID has started in Tuscany, Italy.ConclusionTandem mass spectrometry can be used for diagnosis of one of the most frequent form of SCID at a negligible cost.