Adenosine deaminase (ADA) deficiency is an inherited disorder that damages the immune system and causes severe combined immunodeficiency (SCID). People with SCID lack virtually all immune protection from bacteria, viruses, and fungi. They are prone to repeated and persistent infections that can be very serious or life-threatening. These infections are often caused by "opportunistic" organisms that ordinarily do not cause illness in people with a normal immune system.

The main symptoms of ADA deficiency are pneumonia, chronic diarrhea, and widespread skin rashes. Affected children also grow much more slowly than healthy children and some have developmental delay.

Most individuals with ADA deficiency are diagnosed with SCID in the first 6 months of life. Without treatment, these babies usually do not survive past age 2. In about 10 percent to 15 percent of cases, onset of immune deficiency is delayed to between 6 and 24 months of age (delayed onset) or even until adulthood (late onset). Immune deficiency in these later-onset cases tends to be less severe, causing primarily recurrent upper respiratory and ear infections. Over time, affected individuals may develop chronic lung damage, malnutrition, and other health problems.

Adenosine deaminase deficiency is caused by mutations in the ADA gene. This gene provides instructions for producing the enzyme adenosine deaminase. This enzyme is found throughout the body but is most active in specialized white blood cells called lymphocytes. These cells protect the body against potentially harmful invaders, such as bacteria and viruses, by making immune proteins called antibodies or by directly attacking infected cells. Lymphocytes are produced in specialized lymphoid tissues including the thymus, which is a gland located behind the breastbone, and lymph nodes, which are found throughout the body. Lymphocytes in the blood and in lymphoid tissues make up the immune system.

The function of the adenosine deaminase enzyme is to eliminate a molecule called deoxyadenosine, which is generated when DNA is broken down. Adenosine deaminase converts deoxyadenosine, which can be toxic to lymphocytes, to another molecule called deoxyinosine that is not harmful. Mutations in the ADA gene reduce or eliminate the activity of adenosine deaminase and allow the buildup of deoxyadenosine to levels that are toxic to lymphocytes.

Immature lymphocytes in the thymus are particularly vulnerable to a toxic buildup of deoxyadenosine. These cells die before they can mature to help fight infection. The number of lymphocytes in other lymphoid tissues is also greatly reduced. The loss of infection-fighting cells results in the signs and symptoms of SCID.

Normal Function

The ADA gene provides instructions for producing the enzyme adenosine deaminase. This enzyme is produced in all cells, but the highest levels of adenosine deaminase occur in immune system cells called lymphocytes, which develop in lymphoid tissues. These lymphoid tissues include the thymus, which is a gland located behind the breastbone, and lymph nodes, which are found throughout the body. Lymphocytes form the immune system, which defends the body against potentially harmful invaders, such as viruses or bacteria.

The function of the adenosine deaminase enzyme is to eliminate a molecule called deoxyadenosine, which is generated when DNA is broken down. Adenosine deaminase converts deoxyadenosine, which is toxic to lymphocytes, to another molecule called deoxyinosine, which is not harmful.

Health Conditions Related to Genetic Changes

Adenosine deaminase deficiency

More than 70 mutations in the ADA gene have been identified. Most of these mutations result in the substitution of one protein building block (amino acid) for another amino acid in the adenosine deaminase enzyme. Other mutations cause the enzyme to be unstable or prevent it from being produced at all.

These mutations result in the absence or deficiency of the adenosine deaminase enzyme in cells, preventing the normal breakdown of deoxyadenosine. A buildup of this toxic compound interferes with the development and maintenance of lymphocytes, resulting in severe combined immunodeficiency (SCID), which is characteristic of adenosine deaminase deficiency.

Other Names for This Gene

• ADA_HUMAN
• adenosine aminohydrolase

Genomic Location

The symptoms of adenosine deaminase deficiency (ADA deficiency) usually begin before 6 months of age. Babies with ADA deficiency usually develop serious lung infections and chronic diarrhea. They have trouble gaining weight and do not grow very well. Other symptoms include skin rashes, absent tonsils and lymph nodes, bone abnormalities, and developmental delay. Approximately 10-15% of people with ADA deficiency do not develop symptoms until later in childhood, often between ages 1 and 10, or even into adulthood. In these cases, people are usually diagnosed with "combined immunodeficiency (CID)", since symptoms are initially milder than those seen in SCID. However, over time, people with the milder form of ADA deficiency may develop chronic lung damage, malnutrition, and other health problems.

There are some people who have partial ADA deficiency. People with this condition have low amount of ADA enzyme in some cells, but have normal immune systems. Partial ADA deficiency is considered a benign condition that does not cause health problems.

Most states in the United States screen newborns for severe combined immune deficiency (SCID). One common cause of SCID is adenosine deaminase deficiency (ADA deficiency). If a newborn screen result is abnormal for SCID, additional blood tests are necessary to confirm the diagnosis of ADA deficiency (and other less common causes for SCID). These blood tests include testing for levels of immunoglobulins and white blood cells (WBCs) including T cells, B cells and natural killer cells. Immunoglobulins and WBCs are important parts of the body’s immune system. Genetic testing to identify mutations in the ADA gene may be used to confirm the diagnosis.

In children and adults with the mild form of ADA deficiency, the diagnosis is made based on symptoms which include frequent unusual infections, low WBCs in the blood, absent tonsils or lymph nodes, and low levels of the adenosine deaminase enzyme. Genetic testing for mutations in the ADA gene can confirm the diagnosis of the mild form of ADA deficiency.

The treatment of severe combined immune deficiency due to adenosine deaminase deficiency (ADA deficiency) may include the following:

• Early diagnosis and treatment of bacterial, viral, and fungal infections
• Preventative medications for certain types of pneumonia
• Intravenous (IV) immunoglobulin to boost the body's natural response to infections
• Bone marrow or stem cell transplant
• Gene therapy

The primary treatment is transplantation of blood-forming stem cells from the bone marrow of a healthy brother or sister (allogenic bone marrow transplant /stem cell transplant or BMT/SCT). This therapy is effective in approximately 70% or more of people with severe combined immunodeficiency (SCID), including SCID caused by ADA deficiency.

If a BMT/SCT is not an option, enzyme replacement therapy (ERT) may be recommended. ERT is a treatment that replaces the enzyme that is missing or not working properly (adenosine deaminase) with a bovine form of the enzyme that has been genetically modified to work in humans.

Gene therapy is also available through clinical trials, and appears to be successful in treating people with SCID due to ADA deficiency. Gene therapy involves replacing a copy of the non-working ADA gene with a working copy, so that a person can make the ADA enzyme on his or her own. Gene therapy for SCID due to ADA deficiency has been approved in Europe , but is still considered experimental in the US.

The long-term outlook (prognosis) for people with adenosine deaminase deficiency (ADA deficiency) varies depending on the severity of the condition, the timing of the diagnosis, and the response to treatment.Newborn screening for SCID has made it possible for more babies to get diagnosed and treated earlier. This may change long-term outcomes.

For babies diagnosed early and treated with a bone marrow transplant/stem cell transplant, the long-term outlook is generally good. At this time, it isn’t clear if these children will still develop developmental or behavioral problems later in life. People with ADA deficiency who have been treated with gene therapy also seem to have a good long-term outlook, although information is still being collected. People with ADA deficiency who are treated with enzyme replacement therapy (ERT) generally do well, but ERT may lose effectiveness over many years.

Without early diagnosis and treatment, babies with ADA deficiency usually do not survive past age 2.