The ADA gene provides instructions for an enzyme found in all human cells. This enzyme plays a role in metabolic processes and is particularly active in immune cells.
Function of the ADA Gene
The ADA gene creates adenosine deaminase. This enzyme is key in purine metabolism, processing purines, DNA and RNA components. It breaks down adenosine and 2′-deoxyadenosine. This prevents the harmful buildup of deoxyadenosine.
Deoxyadenosine breakdown is crucial in lymphocytes, immune cells. High ADA levels are found in these cells. If deoxyadenosine is not broken down, its accumulation can lead to early cell death, especially in rapidly dividing immune cells. This ensures toxic byproducts are removed, supporting normal immune cell function.
ADA Deficiency and Its Impact
A faulty ADA gene leads to adenosine deaminase deficiency. This causes a harmful buildup of deoxyadenosine and metabolites, primarily in lymphocytes. This accumulation interferes with DNA synthesis, induces chromosome breaks, and impairs immune cell development.
The most severe form of ADA deficiency is Severe Combined Immunodeficiency (ADA-SCID). This inherited, autosomal recessive condition results in a profound lack of functional T and B lymphocytes, leaving individuals with little immune protection. Children with ADA-SCID are highly susceptible to severe, recurrent infections from bacteria, viruses, and fungi.
Symptoms of ADA-SCID appear within the first six months of life, including persistent pneumonia, chronic diarrhea, skin rashes, and failure to thrive. Without treatment, infants with ADA-SCID often do not survive past two years due to overwhelming infections. Beyond immune issues, ADA deficiency can also cause neurodevelopmental deficits, behavioral disorders, sensorineural deafness, and skeletal or hepatic abnormalities.
Diagnosis and Treatment Approaches
Diagnosis of ADA deficiency involves several laboratory tests. Newborn screening can indicate a low number of T cells, a sign of SCID. Laboratory tests measure ADA enzyme activity in blood cells, detecting very low or undetectable levels. Genetic testing identifies specific mutations within the ADA gene, confirming the diagnosis. Elevated deoxyadenosine in urine and increased deoxy ATP in red blood cells further support the diagnosis.
Enzyme Replacement Therapy (ERT) for ADA-SCID involves regular injections of a modified ADA enzyme, such as PEG-ADA. This therapy metabolizes toxic byproducts, reducing their accumulation, providing temporary immune function improvement and minimizing infections. While ERT can be life-saving and restore some immune function, it is not a permanent cure and may not achieve complete, long-term immune reconstitution.
Hematopoietic Stem Cell Transplantation (HSCT) is a primary option for a lasting cure. This procedure replaces the patient’s faulty immune cells with healthy stem cells from a donor. Successful outcomes are often achieved with a matched sibling donor. Matched unrelated or haploidentical donors can also be used, though these may require more intensive conditioning regimens. Early transplantation, before severe infections begin, is associated with better survival rates.
Gene therapy offers another curative approach for ADA-SCID, especially for patients without a suitable HSCT donor. This treatment involves collecting the patient’s own hematopoietic stem cells, introducing a functional ADA gene copy via a viral vector and reinfusing the corrected cells. This enables the patient to produce their own functional ADA enzyme and develop a healthy immune system. Gene therapy for ADA-SCID has shown promising results, with high rates of immune reconstitution and survival in clinical trials.