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Heterogeneous systemic disorder caused by the deficiency of adenosine deaminase (ADA) resulting primarily in severe combined (cellular and humoral) immunodeficiency but also systemic abnormalities.

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Severe Combined Immunodeficiency Syndrome due to Adenosine Deaminase Deficiency; ADA Deficiency.

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Estimated to be approximately 1:1,000,000. Adenosine deaminase deficiency (ADAD) accounts for approximately 20% of all patients with severe combined immunodeficiency syndrome (SCID).

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Autosomal recessive. More than 50 mutations of ADA have been found. The genetic defect has been mapped to gene locus 20q13.11.

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ADA catalyzes the irreversible conversion of adenosine and 2′-deoxyadenosine to inosine and 2′-deoxyinosine. Because of alternate bypass routes in the purine catabolic pathway, ADAD patients have normal concentrations of inosine and 2′-deoxyinosine. However, the concentrations of adenosine and 2′-deoxyadenosine are elevated, and accumulation of 2′-deoxyadenosine seems to be the main culprit in the development of ADA deficiency because its phosphorylation leads to deoxyadenosine triphosphate (dATP). The excessive amount of dATP (up to 200-fold increased concentrations have been reported) results in toxicity and leads to allosteric inhibition of ribonucleotide reductase, an enzyme involved in DNA synthesis. Immature T (and to a lesser degree B) lymphocytes show highest sensitivity to this toxicity (most likely as a consequence of their high turnover), which results in impaired cellular immunity and decreased synthesis of immunoglobulins. Some researchers are convinced that the neurologic abnormalities are caused by the same mechanism. Elevated levels of dATP also induce apoptosis in thymic lymphocytes and affect normal methylation processes.

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Early diagnosis is crucial so that severe and potentially fatal infections can be prevented. The absolute lymphocyte count is a useful diagnostic test for screening because lymphopenia is present at birth in nearly all patients with SCID. Because the enzyme defect is found in all body cells, dATP concentration in erythrocytes is considered a sensitive marker for the metabolic severity of ADAD; however, measurements are needed before any transfusions, enzyme replacement therapy, or bone marrow transplant is started.

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The majority of ADAD patients present with SCID in the first 4 to 8 months of life, usually in combination with skeletal and neurologic anomalies. These patients often have a fatal outcome. However, up to 20% are diagnosed later in life, either in childhood or as adults with an immunodeficiency that evolves insidiously and mainly involves cellular immunity. It seems that little residual ADA activity (approximately 10% of normal) is sufficient to prevent profound immunodeficiency. The suggested classification has four groups:

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  1. 1. SCID, which is diagnosed in the first year of life, presents with failure to thrive and recurrent (most often opportunistic) infections. Lymphopenia is profound (most severe of all forms of SCID), with absent cellular and humeral immune function.

  2. 2. Delayed onset, for which the diagnosis usually is made between 1 and several years of age. Patients present with clinical deterioration secondary to the combined immunodeficiency.

  3. 3. Late onset, for which diagnosis is made ...

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