Published Online: January 2, 2013
Adenosine deaminase (ADA) deficiency is a severe combined immunodeficiency (SCID), characterized by recurrent serious or often fatal infections. Early diagnosis and treatment are mandatory to cure the affected infants. Tandem mass spectrometry (TMS) and T-cell-receptor excision circles (TRECs) can identify early-onset ADA deficiency at birth, on dried blood spot (DBS) taken within the routine newborn screening procedure. However ADA deficiency may present with delayed-onset or late-onset phenotypes, usually diagnosed in the first decade of life and associated with severe asthma, recurrent infections, permanent lung damage such as bronchiectasis, autoimmunity, immune dysregulation, and organ damage associated with metabolite accumulation. The incidence of those phenotypes is largely underestimated, while early diagnosis of the disease would allow prompt resolving treatment and avoid permanent damage. Up to now it had not been clarified whether delayed or late-onset ADA deficiency could be identified at birth, in the pre-symptomatic period.
In a recent article in The Journal of Allergy & Clinical Immunology (JACI), LaMarca et al evaluated four patients with delayed-onset ADA deficiency and three patients with early onset phenotype with the aim to understand whether TMS and TREC assay could identify those patients at birth. Actually, TMS is routinely used all over the world for newborn screening of metabolic diseases such as hypothyroidism and over 20 million children are screened every year by that method. TREC assay is used in the USA and other Western countries for newborn screening of SCID and seems to be, at present, the best candidate for that application. The authors measured by TMS, the two metabolites accumulating in ADA enzyme deficiency, adenosine and 2’-deoxyadenosine, in DBS taken at birth from early-onset and delayed-onset patients. In the same DBS, TRECs were measured, using Real time PCR.
Results obtained by LaMarca et al demonstrated that both adenosine and 2’-deoxyadenosine are significantly increased at birth, and can be easily detected using TMS. In contrast, TRECs, which are reflective of thymic function, are still normal at birth, since thymic involution occurs during the following months. Therefore TMS can identify at birth both patients with early onset and late-onset ADA deficiency using DBS, while TRECs assay fail in identifying patients with delayed- or late-onset phenotypes. TMS is currently used in a pilot study for newborn screening of SCID in Tuscany, Italy. TMS showed a very high specificity (no false positive result in over 50,000 test performed) and a very low cost. Actually, since TMS uses the same operators, the same procedures, the same instruments already used for routine TMS screenings, and can be performed at the same time, the cost is about $0.01.
Identification of delayed- or late-onset ADA phenotypes at birth is extremely important, because it allows the start of curative treatment in the pre-symptomatic period, before severe lung and other organ damages occur, due to increased levels of toxic metabolites. TMS can identify, at a very low cost, all phenotypes of ADA deficiency at birth, including the delayed and the late-onset phenotypes. TREC assay can only identify early-onset ADA deficiency but fails in identifying other phenotypes. The inclusion of TMS analysis of adenosine and 2’-deoxyadenosine in the routine newborn screening is recommended, so that all variants of ADA deficiency could be diagnosed at birth. Moreover, given the very low cost of the test, TMS can be useful in countries that cannot afford TREC analysis but are already using TMS to screen for other metabolic diseases.
The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.