Adenosine Deaminase Deficiency

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

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

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).

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

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.

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.

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:

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 after the first decade of life, secondary to major immunologic and clinical deterioration (initially chronic chest infections, oral and vaginal candidiasis, viral warts, recurrent dermatomal zoster).

4. 4. Partial ADAD, in which the patient is ADA deficient but otherwise healthy, with normal immune function.

In all patients with SCID, the thymus is severely hypoplastic, with a lack of corticomedullary distinction and thymocytes. Hassall corpuscles are either abortive or absent. Symptoms pointing to the diagnosis include recurrent and/or opportunistic infections with candida (oral candidiasis), respiratory syncytial virus, adenovirus, parainfluenza virus, cytomegalovirus, or pneumonia secondary to Pneumocystis carinii. Bacterial pneumonia, Gram-negative sepsis, and persistent diarrhea with failure to thrive are common and often the cause of death. Behavioral and neurologic problems (with severity proportional to dATP levels) are common in ADAD patients and may include hyperactivity/attention deficit disorders, aggressivity, sensorineural hearing loss, seizures, spasticity, athetosis, head lag, tremor, nystagmus, and decreased cognitive function and IQ. Renal problems have been reported in a number of patients and include proteinuria and transient proximal renal tubular acidosis. The kidneys often are enlarged, and histologic examination reveals mesangial sclerosis with thickening of the subendothelial layer of capillary walls, particularly in the juxtamesangial region. Some degree of (most likely progressive) glomerulosclerosis may be seen. Adenosine, which is elevated in ADAD, has significant effects on arteriolar resistance and renin secretion. Fibrosis of the adrenal cortex (especially in the subcapsular region) and the pituitary gland is a common finding. Adrenal insufficiency with a high risk of hypoglycemia, hyponatremia, and hypokalemia has been reported. Hypocalcemia is common. Osseous anomalies are characterized by prominent costochondral junctions, and microscopic examination shows chondroosseous dysplasia with disordered chondrocyte columns, hypertrophic chondrocytes in resting cartilage, ballooned lacunae, and abrupt transition of cartilage to bone. The skin often is edematous and appears hyperpigmented. Pulmonary alveolar proteinosis has been found in a few patients. Transfusion of normal erythrocytes leads to a temporary decrease in the serum adenosine concentration and an increase in lymphocyte count; however, retransfusions are required every few weeks to maintain ADA activity above a certain level. Covalent binding of modified bovine intestinal ADA to polyethylene glycol (polyethylene glycol-modified adenosine deaminase [PEG-ADA]) has been used successfully to partially correct the enzyme defect and thereby allow immune function to recover to a degree at least sufficient to prevent opportunistic infections. The risks and side effects are lower than with bone marrow transplantation; however, the costs reportedly are excessive. Gene therapy with viral vectors has been used with some success in a number of patients. Hemosiderosis with marked iron depositions in hepatocytes, Kupffer cells, and spleen is seen after chronic transfusions. The most prominent ADAD patient probably was the “Bubble Boy,” a boy who lived in a germ-proof plastic enclosure to prevent infections until he died at age 12 years.

Obtain a complete blood count (especially after recent bone marrow transplant) and check blood glucose and electrolyte levels (hypocalcemia, hypokalemia). Assess liver and kidney function and obtain a chest radiograph. Cooperation may be difficult because of hyperactivity, aggressivity, and/or cognitive impairment; sedative premedication may be advantageous. A recent transfusion leads to increased ADA-levels and provides at least some protection from infections. Alternatively, injection of PEG-ADA provides the same degree of protection. However, to ensure an optimal effect, the timing of the transfusion or injection should be correlated to the date of surgery.

Strict aseptic technique is mandatory to prevent infections. Vascular access may be difficult because of edematous skin. Graft-versus-host reaction after transfusion of nonirradiated blood has been described in these patients, so ensure the blood has been irradiated prior to administration. This step also applies to patients after bone marrow transplantation until full engrafting has been established. Check blood glucose concentration on a regular basis during the perioperative period.

Vaccination with attenuated, living viruses must be avoided because patients may otherwise suffer from a severe infection.

Omenn Syndrome: Inherited form of SCID secondary to defective T lymphocytes and lack of B lymphocytes.

Purine Nucleoside Phosphorylase Deficiency: Inherited disease of purine catabolism resulting in deficient T cell immunity and, frequently, neurologic symptoms.

Nezelof Syndrome: Genetic form of thymus hypoplasia resulting in lack of competent T cells.

DiGeorge Syndrome: Genetic defect leading to a wide range of phenotypic presentations, mainly developmental defects in the outflow tract of the heart, hypoparathyroidism with hypocalcemia, and thymic hypoplasia/aplasia with immune defects.