Adenosine deaminase 2 deficiency (ADA2); Sneddon syndrome - CECR1 gene
Adenosine deaminase 2 (ADA2) deficiency, also known as Sneddon syndrome, is an alteration characterized by abnormal inflammation of various tissues, especially blood vessels. Signs and symptoms can start at any time from early childhood to adulthood. The severity of the disease also varies, even among people affected in the same family.
Inflammation is a normal response of the immune system to the injury and foreign invaders (such as bacteria). However, the uncontrolled inflammation that occurs in ADA2 deficiency can damage many of the tissues and organs of the body, including the skin, gastrointestinal tract, kidneys and nervous system. Depending on the severity and location of the inflammation, this disease can cause disability or be life-threatening. The characteristics that have been described in people with ADA2 deficiency include intermittent fevers, livedo racemosa, hepatosplenomegaly and recurrent cerebrovascular accidents that affect the deep structures of the brain that can begin in the first years of life. ADA2 deficiency causes mild abnormalities of the immune system in some people, but it is usually not associated with a significantly increased risk of bacterial and viral infections. This disease is sometimes described as a form of polyarteritis nodosa (PAN), a condition that causes systemic vasculitis.
This process is due to mutations in the CECR1 gene (adenosine deaminase 2), located on the long arm of chromosome 22 (22q11.1). This gene encodes the enzyme called adenosine deaminase 2. This enzyme breaks down the adenosine and 2'-deoxyadenosine molecules. Because this enzyme performs functions in the intercellular spaces, it is considered extracellular. Another form of adenosine deaminase, called adenosine deaminase 1, breaks down the same molecules inside cells. This last version of the enzyme is encoded from the ADA gene. Work is underway to determine what functions the extracellular form of adenosine deaminase plays in the body. It is likely to act as a cell growth factor. In particular, the enzyme appears to be involved in the growth and development of certain cells of the immune system, including macrophages, which play a critical role in inflammation. Some macrophages are pro-inflammatory, while others are anti-inflammatory. Adenosine deaminase 2 also appears to be essential to keep the lining of blood vessel walls intact.
More than 60 mutations in the CECR1 gene have been identified in people with adenosine deaminase 2 deficiency. These mutations strongly reduce or eliminate the function of adenosine deaminase 2. Although it is not clear how a loss of function of this enzyme leads to characteristics of ADA2 deficiency, it is likely that the deficiency of this enzyme may alter the balance between proinflammatory and anti-inflammatory macrophages in various tissues, leading to abnormal inflammation. The role of the enzyme in maintaining the structural integrity of blood vessels could help explain why blood vessels are most affected by inflammation in this disease.
This disease is inherited with an autosomal recessive pattern, that is, both copies of the gene in each cell must have the mutations so that the alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease.
Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with adenosine deaminase 2 deficiency, by means of complete PCR amplification of the exons of the CECR1 gene, and its subsequent sequencing.
Recommended samples: blood drawn with EDTA for separation of blood leukocytes, or card impregnated with dried blood sample (IVAMI can mail the card to deposit the blood sample).