Adenosine deaminase severe combined immunodeficiency (ADA-SCID) is a rare, inherited, pediatric disorder that is often fatal when left untreated. The disorder stems from a deficiency in adenosine deaminase (ADA), an enzyme found throughout the body. ADA-SCID is characterized by severe and recurrent opportunistic infections, failure to thrive, profound lymphopenia (reduced number of lymphocytes in the blood) with absent or severely impaired immune function, and metabolic abnormalities. Patients with ADA-SCID are also susceptible to recurrent illnesses caused by bacteria, viruses and fungi that often begin within the first few weeks of life.1,2

The average age of diagnosis for patients with ADA-SCID is 4.4 months.3 Left untreated, babies with ADA-SCID usually die before they reach age 2 unless they are diagnosed early and effective treatment is started.4

ADA-SCID is estimated to occur in approximately one in 200,000 to one in 1,000,000 newborns around the world.2,5 The disorder is responsible for approximately 15% of SCID cases.6

What Causes ADA-SCID?

ADA-SCID results from mutations in the ADA gene, which provides instructions for producing the ADA enxyme. This enzyme is found throughout the body but is most active in lymphocytes, which are specialized white blood cells that protect the body from potentially harmful invaders by making immune proteins called antibodies or by directly attacking infected cells. When functioning properly, the adenosine deaminase enzyme eliminates molecules called adenosine and deoxyadenosine, which are toxic to lymphocytes.6

ADA converts adenosine to inosine and deoxyadenosine to deoxyinosine, molecules that do not harm lymphocytes. However, mutations in the ADA gene reduce or eliminate the protective activity of adenosine deaminase, allowing the buildup of adenosine and deoxyadenosine to toxic levels. These toxic levels cause specialized lymphocytes called T-cells and B-cells to accumulate biologic chemicals that would normally be processed by ADA. The buildup of these biologic products in excess of normal causes the T-cells and B-cells to die, leaving affected individuals with no significant immune defense and increasing their risk of infection.7

Newborn Screening for SCID

SCID can be caused by mutations in at least 15 different genes. If the mutation leading to SCID in a family is known, an at-risk fetus can be tested using DNA sequencing.7

A new test known as T-cell Receptor Excision Circles (TREC) can be done at birth to identify babies with SCID and intervene with supportive care. Babies found to screen positive for SCID can have assays (enzyme tests) and genetic testing for ADA to determine whether they have ADA deficiency before symptoms or illness develop.8

Today, all 50 states, the District of Columbia, and Puerto Rico are currently screening or committed to newborn screening for SCID within the next few years.9

References:

Booth C, Gaspar HB. Pegademase bovine (PEG-ADA) for the treatment of infants and children with severe combined immunodeficiency (SCID). Biologics Targets Ther. 2009;3:349-358.

2 Gaspar HB, Aiuti A, Porta F, Candotti F, Hershfield MS, Notarangelo LD. How I treat ADA deficiency. Blood. 2009;114:3524-3532.

3 Arredondo-Vega FX, Santisteban I, Daniels S, Toutain S, Hershfield MS. Adenosine deaminase deficiency: genotype-phenotype correlations based on expressed activity of 29 mutant alleles. Am J Hum Genet. 1998;63:1049-1059.

Hershfield MS. Adenosine deaminase deficiency. GeneReviews [Internet]. Initially posted October 2006. https://www.ncbi.nlm.nih.gov/books/NBK1483/. Accessed August 26, 2017.

5 Hershfield MS. Immunodeficiency caused by adenosine deaminase deficiency. Immunol Allergy Clin North Am. 2000;20:161-175.

6 Adenosine deaminase deficiency. Genetics Home Reference. Bethesda, MD: U.S. Department of Health and Human Services, National Institutes of Health, National Library of Medicine, Lister Hill National Center for Biomedical Communications; 2016. Available at: https://ghr.nlm.nih.gov/condition/adenosine-deaminase-deficiency. Accessed September 15, 2017.

7 Hershfield MS, Mitchell BS. Immunodeficiency diseases caused by adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. In: Valle D, Beaudet AL, Vogelstein B, et al, eds. The Online Metabolic and Molecular Basis of Inherited Disease. The McGraw-Hill Companies; 2017. Ch. 109.

Puck J. Neonatal screening for severe combined immunodeficiency. Curr Opin Pediatr. 2011; 23(6): 667–673. doi:10.1097/MOP.0b013e32834cb9b0.

Newborn screening. Jeffrey Modell Foundation, 2017. Available at: http://www.info4pi.org/town-hall/newborn-screening. Accessed December 5, 2017.