Tandem mass spectrometry, but not T-cell receptor excision circle analysis, identifies newborns with late-onset adenosine deaminase deficiency

Abstract

Background: Adenosine deaminase (ADA)-severe combined immunodeficiency (SCID) is caused by genetic variants that disrupt the function of ADA. In its early-onset form, it is rapidly fatal to infants. Delayed or late-onset ADA-SCID is characterized by insidious progressive immunodeficiency that leads to permanent organ damage or death. Quantification of T-cell receptor excision circles (TRECs) or tandem mass spectrometry (tandem-MS) analysis of dried blood spots (DBSs) collected at birth can identify newborns with early-onset ADA-SCID and are used in screening programs. However, it is not clear whether these analyses can identify newborns who will have delayed or late-onset ADA-SCID before symptoms appear. Objective: We performed a retrospective study to evaluate whether tandem-MS and quantitative TREC analyses of DBSs could identify newborns who had delayed-onset ADA-SCID later in life. Methods: We tested stored DBSs collected at birth from 3 patients with delayed-onset ADA-SCID using tandem-MS (PCT EP2010/070517) to evaluate levels of adenosine and 29-deoxyadenosine and real-time PCR to quantify TREC levels. We also analyzed DBSs from 3 newborns with early-onset ADA-SCID and 2 healthy newborn carriers of ADA deficiency. Results: The DBSs taken at birth from the 3 patients with delayed-onset ADA-SCID had adenosine levels of 10, 25,

The inclusion of ADA-SCID in expanded newborn screening by tandem mass spectrometry

“…Up to now no later onset ADA-SCID patients have been identified at birth, so no data are present in literature on the natural history of a later phenotype [23]. The present method offers, for the first time, the possibility to get the diagnosis of ADA-SCID at birth, before onset of infectious disease.…”

“…ADA enzymatic activity, immunoglobulin levels, lymphocyte subsets and proliferation as well as ADA gene sequence were performed. Data obtained from all the biochemical and molecular analysis let to include our first patient as possible late onset ADA-SCID [23].…”

“…Moreover, delayed ADA-SCID false negative cases by TREC test have been recently described [23][24][25] Within the last 7 years (2004-2011) approximately 250,000 births occurred in Tuscany, among them four ADA-SCID patients were diagnosed. These preliminary data show the incidence in our catchment area seems to be greater than about 1:500,000 as reported in literature [26].…”

“…Three were born in Tuscany before ADA-SCID was included in the newborn screening panel and six were from other screening laboratories. Clinical and genetics details on ADA-SCID patients and the correlation of enzyme residual activity and metabolite' levels have been described by la Marca et al [23].…”

Newborn Screening for Severe Combined Immunodeficiency in Taiwan

“…Since the TREC assay may not reliably detect patients with ADA deficiency [34], we also tested the newborns for ADA deficiency by determining the concentrations of two purine metabolites, Ado and dAdo, using NeoBase2 Non-derivatized MSMS kit (PerkinElmer, Turku, Finland). After we had screened 21,591 newborns, there were no cases showing elevation of Ado and dAdo.…”