Adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) is a rare, inherited disorder that profoundly impacts the immune system. As a specific form of Severe Combined Immunodeficiency (SCID), it leaves infants extremely vulnerable to recurrent and severe illnesses from bacteria, viruses, and fungi. Affecting an estimated one in 200,000 to one million newborns globally, the condition is often fatal within the first two years of life without prompt diagnosis and intervention.
The Genetic and Biological Basis of ADA-SCID
ADA-SCID is inherited in an autosomal recessive pattern, which means an affected child must inherit two copies of a mutated gene, one from each parent. These parents are carriers who have one normal and one mutated gene copy and do not show signs of the disorder themselves. For each pregnancy, carrier parents have a 25% chance of having a child with ADA-SCID.
The disorder is caused by mutations in the ADA gene, which holds the instructions for making the adenosine deaminase (ADA) enzyme. The ADA enzyme’s job is to break down a substance called deoxyadenosine. When the enzyme is missing or non-functional, deoxyadenosine accumulates to toxic levels within lymphocytes, a type of white blood cell. This toxic buildup prevents T-cells and B-cells from developing and functioning, leading to their death and leaving the body without a significant immune defense.
Signs and Symptoms in Infants
The initial signs of ADA-SCID appear within the first few months of life, with most infants becoming symptomatic before six months of age. A defining characteristic is the onset of severe and persistent infections, often caused by opportunistic organisms that do not sicken healthy individuals. These can include:
- Pneumonia
- Chronic diarrhea
- Widespread skin rashes
- Oral thrush
Beyond infections, infants with ADA-SCID commonly exhibit “failure to thrive,” which describes poor physical growth and insufficient weight gain. A physical examination might reveal the absence of tonsils or lymph nodes, and some infants experience breathing difficulties even without a detectable infection.
Diagnosis Through Newborn Screening
In many regions, including all 50 U.S. states, ADA-SCID is identified through routine newborn screening. The process uses a heel prick blood test to measure T-cell receptor excision circles (TRECs). TRECs are small DNA circles created during normal T-cell development, so their absence or low number indicates a potential T-cell deficiency, a hallmark of SCID.
An abnormal TREC result prompts further confirmatory testing. These follow-up tests involve a detailed blood analysis to count T-cells, B-cells, and Natural Killer (NK) cells; in ADA-SCID, all three are very low. To confirm the diagnosis, doctors measure the ADA enzyme’s activity level in red blood cells, which will be absent or less than 1% of normal. Genetic testing can then be used to identify the specific mutations in the ADA gene.
Treatment Approaches
When a diagnosis of ADA-SCID is confirmed, treatment must begin promptly. One frontline approach is enzyme replacement therapy (ERT), involving regular injections of a manufactured ADA enzyme, PEG-ADA. ERT works by temporarily replacing the missing enzyme, which helps reduce toxic substances and improve immune function. While not a cure, ERT can serve as a bridge to stabilize the patient until a more definitive treatment is arranged.
A potentially curative option is a hematopoietic stem cell transplant (HSCT). This procedure replaces the child’s defective immune system with a healthy one from a donor, ideally a tissue-matched sibling. If a matched sibling is not available, stem cells may come from a matched, unrelated donor or a half-matched parent.
Gene therapy represents another potentially curative treatment. A patient’s own hematopoietic stem cells are collected and modified in a laboratory with a correct, functional copy of the ADA gene. These corrected stem cells are then infused back into the body, where they can produce a continuous supply of healthy immune cells.
Long-Term Outlook and Management
With early diagnosis and successful treatment, the long-term outlook for children with ADA-SCID has improved significantly. Successful HSCT or gene therapy can result in a durable and functional immune system, allowing individuals to live healthier lives. These treatments enable children to fight off infections, attend school, and participate in normal childhood activities.
Despite the success of immune system restoration, lifelong monitoring is necessary as the absence of the ADA enzyme can have systemic effects. Some individuals may experience non-immune issues that require ongoing management, including skeletal abnormalities, hearing loss, and neurodevelopmental challenges. Regular follow-up with a team of specialists helps to monitor for these potential complications.