Newborn screening strategy identifies otherwise missed adenosine deaminase deficiencies

Key takeaways:

• Tandem mass spectroscopy can identify partial or delayed adenosine deaminase deficiencies.
• Early identification and treatment of these deficiencies can prevent potentially fatal complications .
• Tandem mass spectroscopy screenings only add 0.013 cents to the cost of current newborn screening practices.

Including tandem mass spectroscopy in newborn screenings to identify adenosine deaminase deficiencies could save lives while adding negligible costs, according to a study published in Annals of Allergy, Asthma & Immunology.

In fact, three recent cases demonstrate the value of these screenings, Nicholas L. Hartog, MD, an allergy and immunology specialist with Spectrum Health, and colleagues wrote in the study.

Providers in Michigan currently screen newborns for 58 independent conditions. This includes 56 conditions screened through dried blood spot (DBS) testing, such as severe combined immunodeficiency (SCID), identified via quantitation of T-receptor excision circles (TRECs).

Deficiencies in adenosine deaminase (ADA), which occur in one in every 200,000 to 1 million live births, account for 12% to 15% of all SCID cases. Also, approximately 15% to 20% of ADA deficiencies have late or adult onset of combined immunodeficiency.

According to the researchers, DBS testing of TRECs can miss delayed and late-onset ADA deficiencies. Meanwhile, biomarkers observable via tandem mass spectroscopy (TMS) are available to diagnose and provide prognoses for immunodeficient patients with ADA deficiency.

Further, the researchers wrote, enzyme replacement therapy (ERT) and gene therapy can be used to treat ADA-SCID in addition to hematopoietic stem cell transplants. Early diagnosis and treatment can improve odds for survival.

In 2019, Michigan began using TMS to screen for ADA deficiency as part of routine newborn screenings. The researchers identified one case of ADA deficiency in the 18 months prior to these screenings and two cases during the 2 years that followed their initiation.

Case studies

The first case involved a boy aged 9 months who presented to a local ED with fever, respiratory failure, bilateral diffuse reticular opacities and a significantly subnormal absolute lymphocyte count of 300 cells/µL, among other irregularities.

Newborn screening revealed the infant had a TREC value of 36.14 cycle threshold (Ct), which was considered normal at the time. But when the infant was transferred from the ED to a pediatric tertiary care center, TREC levels were below the analytical limit of detection.

Genetic testing revealed heterozygous pathogenic variants in ADA. Also, erythrocyte ADA enzymatic activity was about 60% of normal. Treatment included ERT with PEGylated purified bovine ADA, but complications including severe pulmonary hemorrhage followed. The infant died at age 12 months.

In the second case, a boy aged 6 days had a TREC newborn screening result of 31.64 Ct, which was considered normal. But TMS testing for ADA found a borderline deoxyadenosine nucleotide (dAXP) level of 0.2 µmol/L.

Further testing found markedly reduced ADA activity in the infant’s erythrocytes without any dAXP elevation, which the providers considered consistent with partial ADA deficiency, as well as a homozygous missense variant in ADA.

Now aged 15 months, the infant is not getting any specific therapy for ADA deficiency, although he has continued to thrive with no medical issues or infections and an absolute lymphocyte count of 3,500 cells/µL, which is considered normal. Providers plan on yearly immune monitoring depending on the clinical course of the case.

The third case involved a boy aged 4 days with strong positive TREC and ADA test results. However, flow cytometry indicated pan-lymphopenia. Also, providers could barely detect erythrocyte ADA activity, and dAXP levels were markedly elevated, which the researchers called consistent with ADA-SCID.

As subsequent genetic testing revealed compound heterozygous variants in ADA, the infant began weekly subcutaneous IgG replacement, prophylactic treatment and ERT with elapegademase-lvlr (Revcovi, Chiesi), a PEGylated recombinant bovine ADA enzyme.

When aged 24 days, lymphocyte proliferation was considered normal. When aged 6 months, erythrocyte dAXP were undetectable and lymphocyte subsets were normal. IgG replacement and prophylactic treatment were halted, and at age 24 months, the patient remains on ERT monotherapy without significant infections.

Conclusions

Despite normal neonatal TREC numbers, one patient who did not have the benefit of universal TMS ADA screenings died. These screenings, however, identified two patients with ADA deficiencies, including one patient who would not have been identified without the addition of ADA to the screening protocol.

According to the researchers, adding ADA to existing TMS screenings costs 0.013 cents per patient. The researchers also noted that they have developed a workflow for evaluating ADA newborn screening results.

Identifying delayed or partial ADA deficiency during infancy, the researchers concluded, enables early monitoring and treatment that can prevent complications, end-organ damage and other catastrophic results.