The aim of newborn screening (NBS) is to identify infants who present as healthy at birth but have an underlying condition associated with severe morbidity and mortality. In many countries, population-wide NBS is used as a successful technique for diagnosing a wide range of clinical conditions. However, with the exception of the majority of US states, testing for SCID is not included as part of NBS programmes in the vast majority of other countries.
The clinical severity and associated economic burden of a delayed SCID diagnosis, as well as the potentially fatal outcome if not treated promptly, emphasise the importance of early identification of affected newborns. The potential benefits of SCID NBS are made clear by comparing families with multiple cases of the disease. A study from 2011 by Brown et al. found overall survival to be ~90% for siblings who were diagnosed, antenatally or at birth, on the basis of family history compared with around 40% for the first sibling to present with SCID. The same study also reported for the first sibling an approximate mortality rate of 35% between diagnosis and receiving treatment.
Early diagnosis allows clinicians to employ a range of preventive measures to improve patient outcomes. These include ADA enzyme-replacement therapy, prophylactic antimicrobials and not administering routine infant live vaccines. Additionally, the search for an HLA-matched donor can occur earlier in the course of the disease, shortening the time before curative therapy can be administered, and consequently reducing the mortality rate. In the absence of a matched donor, preparation for gene therapy can be initiated and undertaken at an earlier time point.
The most common validated assay for SCID is the T-cell receptor excision circles (TREC) test. This test uses DNA extracted from the dried blood spots collected routinely at birth to identify by-products (the TRECs) of T-cell receptor gene splicing and rearrangement. The TRECs act as a proxy for a newborn’s ability to produce T cells, which is severely deficient in SCID patients.
Following a positive TREC test, further tests are required to establish the diagnosis of SCID. These include diagnostic tests to exclude other diseases and immunological phenotyping of peripheral blood lymphocytes. To confirm ADA-SCID, testing for genetic defects of the ADA gene or for elevated metabolite levels must be performed. Data reporting the cost effectiveness of SCID NBS using the TREC assay have now been conducted in a number of different healthcare systems and show that it reduces overall healthcare costs.
Recently, a method using tandem mass spectrometry (TMS) to perform SCID NBS has been developed. It analyses dried blood spots for two metabolites, adenosine and deoxyadenosine, which accumulate in infants with ADA enzyme deficiency. Testing samples from patients with both early- and delayed-onset ADA deficiency, la Marca et al demonstrated that metabolites are significantly increased at birth, and can be easily detected using TMS. This is in contrast with the TREC assay which can only detect the early-onset phenotype of ADA-SCID (refer to the other portal article).
During this Italian pilot study, TMS showed a very high specificity with no false-positives reported in over 50,000 performed tests. Given that TMS uses the same operators, procedures and instruments already used in routine NBS for other conditions, and can be performed at the same time, the cost is approximately $0.01 per test compared with $4.22 for TREC analysis. Although the technique is still to be fully validated, it represents an exciting potential addition to aid the early diagnosis of ADA-SCID.
Written by Paul Taylor, Senior Medical Education Writer at Springer Healthcare IME, and reviewed and approved by all Editorial Board Members, Andrew Gennery, Bobby Gaspar and Robbert Bredius.
TREC Based Newborn Screening for Severe Combined Immunodeficiency Disease: A Systematic Review.
van der Spek J, Groenwold RH, van der Burg M, van Montfrans JM.
J Clin Immunol. 2015 May;35: 416-30.
The inclusion of ADA-SCID in expanded newborn screening by tandem mass spectrometry.
la Marca G, Giocaliere E, Malvagia S, Funghini S, Ombrone D, Della Bona ML, Canessa C, Lippi F, Romano F, Guerrini R, Resti M, Azzari C.
J Pharm Biomed Anal. 2014 Jan;88: 201-6