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The inclusion of ADA-SCID in expanded newborn screening by tandem mass spectrometry
Giancarlo la Marca1, Elisa Giocaliere, Sabrina Malvagia
1Newborn Screening, Biochemistry and Pharmacology Laboratories, Clinic of Pediatric Neurology, Meyer University Children's Hospital, Florence, Italy; Department of Neurosciences, Psychology, Pharmacology and Child Health, University of Florence, Italy.
Insights
Newborn screening for adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) is crucial for early intervention. A new, simple, and cost-effective tandem mass spectrometry method enables reliable diagnosis in infants.
Area of Science:
- Biochemistry
- Genetics
- Immunology
Background:
- Severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID) is a life-threatening genetic disorder.
- Early diagnosis and treatment are critical to prevent severe infections and irreversible damage.
- Current diagnostic methods may not be suitable for widespread newborn screening.
Purpose of the Study:
- To develop and validate a robust, cost-effective tandem mass spectrometry method for diagnosing ADA-SCID in newborns.
- To integrate adenosine and 2-deoxyadenosine testing into an expanded newborn screening program.
- To establish reference values and a confirmatory second-tier test for improved diagnostic accuracy.
Main Methods:
- A revised tandem mass spectrometry protocol was developed for analyzing adenosine and 2-deoxyadenosine in dried blood spots.
- The method was validated using samples from 9 genetically confirmed ADA-SCID patients (4 early-onset, 5 delayed-onset).
- Reference ranges were established from 50,000 healthy newborns, and a second-tier test was created for confirmation.
Main Results:
- The developed method demonstrated simplicity, low cost, and minimal preparation, making it suitable for mass screening.
- Reference values for deoxyadenosine (<0.09 μmol/L) and adenosine (<1.61 μmol/L) were established.
- A pilot project successfully identified one newborn with a confirmed ADA gene defect within 18 months.
Conclusions:
- The new tandem mass spectrometry method is effective for the early detection of ADA-SCID in newborn screening programs.
- Early diagnosis through this screening method allows for timely intervention, improving patient outcomes.
- The method's applicability to mass screening ensures broader access to diagnosis and treatment for ADA-SCID.
Abstract:
Severe combined immunodeficiency due to adenosine-deaminase defect (ADA-SCID) is usually deadly in childhood because of severe recurrent infections. When clinical diagnosis is done, permanent damages due to infections or metabolite accumulation are often present. Gene therapy, bone marrow transplantation or enzyme replacement therapy may be effective if started early. The aim of this study was to set-up a robust method suitable for screening with a minimized preparation process and with inexpensive running costs, for diagnosing ADA-SCID by tandem mass spectrometry. ADA-SCID satisfies all the criteria for inclusion in a newborn screening program. We describe a protocol revised to incorporate adenosine and 2-deoxyadenosine testing into an expanded newborn screening program. We assessed the effectiveness of this approach testing dried blood spots from 4 genetically confirmed early-onset and 5 delayed-onset ADA-SCID patients. Reference values were established on 50,000 healthy newborns (deoxyadenosine <0.09μmol/L, adenosine <1.61μmol/L). We also developed a second tier test to distinguish true positives from false positives and improve the positive predictive value of an initial abnormal result. In the first 18 months, the pilot project has identified a newborn with a genetically confirmed defect in adenosine deaminase (ADA) gene. The results show that the method having great simplicity, low cost and low process preparations can be fully applicable to a mass screening program.
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