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