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At a glance

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

Synonyms

Severe Combined Immunodeficiency Syndrome (SCIDS) due to Adenosine Deaminase Deficiency; ADA Deficiency; ADAD Syndrome.

Incidence

Affects about 1 in 200,00 to 1,000,000 newborns and accounts for approximately 15 to 20% of all patients with severe combined immunodeficiency syndrome (SCIDS).

Genetic inheritance

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

Pathophysiology

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 ADAD symptoms 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 allosteric inhibition of ribonucleotide reductase, an enzyme involved in DNA synthesis. Immature T- (and to a lesser degree B-) lymphocytes show the 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 believe 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.

Diagnosis

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 already present at birth in nearly all patients with ADAD. Since 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, the measurements need to be taken before any transfusions, enzyme replacement therapy, or bone marrow transplant is started.

Clinical aspects

The majority of ADAD patients present with SCIDS in the first 4 to 8 months of life, usually in combination with skeletal and neurologic anomalies. Outcome in these patients is often fatal in the first 2 years of life if immunity cannot be achieved. 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 only little residual ADA activity (approximately 10% of normal) is sufficient to prevent profound immunodeficiency. The suggested classification has four groups:

  • SCID: Diagnosed in the first year of life, presents with failure to thrive and recurrent (most often opportunistic) infections. Lymphopenia is profound ...

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