Adenosine deaminase deficiency

Adenosine deaminase deficiency
ICD-10	D81.3
ICD-9	279.2
OMIM	102700
DiseasesDB	260

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Adenosine deaminase deficiency, or ADA deficiency, is an inherited immunodeficiency syndrome accounting for about 25% of all cases of severe combined immunodeficiency (SCID).

This disease is due to a lack of the enzyme adenosine deaminase coded for by a gene on chromosome 20. There is an accumulation of dATP, which causes an increase in S-adenosylhomocysteine; both substances are toxic to immature lymphoid cells, so fail to reach maturity. As a result, the immune system of the afflicted person is severely compromised or completely lacking.

The enzyme adenosine deaminase is important for purine metabolism.

Historical Perspective

Adenosine deaminase (ADA) deficiency was first discovered by Dr. Eloise Giblett in 1972, when she received samples from a patient with severe combined immunodeficiency (SCID) that was a candidate for bone marrow transplantation; examination of blood samples presented that the patients have no ADA activity. With discovering a second case with ADA deficiency and immunedeficiency, ADA deficiency was the first immunodeficiency in which the specific molecular defect was described.

Classification

There is no established system for the classification of adenosine deaminase deficiency.

Pathophysiology

Adenosine deaminase (ADA) is an ubiquitous enzyme found in all cells, It catalyzes the deamination of adenosine and deoxyadenosine to inosine and deoxyinosine. ADA deficiency is caused by mutations in the ADA1 gene at 20q13.11. In the absence of functional ADA, there is an intracellular accumulation of adenosine and deoxyadenosine which leads a buildup of dATP and prevent de novo synthesis of nucleotides and deoxynucleotides in all cells, and inhibits ribonucleotide reductase and prevents DNA synthesis.

In addition, deoxyadenosine irreversibly binds to and inhibits S-adenosylhomocysteine hydrolase, a rise in S-adenosylhomocysteine since the enzyme adenosine deaminase is important in the purine salvage pathway; both substances are toxic to immature lymphocytes, which thus fail to mature. which also contributes to abnormal DNA synthesis.

ADA-deficient individuals typically have severely reduced numbers of T, B, and natural killer (NK) cells.

Causes

Adenosine deaminase deficiency is a disorder arising from mutation in the ADA1 gene at 20q13.11.

Differentiating [Disease] from Other Diseases

Adenosine deaminase deficiency must be differentiated from other diseases that cause clinical features of severe combined immunodeficiency , and complete DiGeorge syndrome. Although DiGeorge syndrome is associated with facial and cardiac anomalies which are not seen with ADA deficiency.

Epidemiology and Demographics

TThe incidence of ADA deficiency is approximately 1 per 200,000 livebirths worldwide. It accounts for nearly one-third of all cases of autosomal recessive severe combined immunodeficiency (SCID) and approximately 15 percent of all cases of SCID.

Risk Factors

There are no established risk factors for adenosine deaminase deficiency.

Screening

preferably, ADA deficiency can be diagnosed in a newborn before the beginning of infections, with one well-documented example by screening of T-cell–receptor excision circles(TRECs). Since the goal of newborn screening is to detect treatable disorders that are threatening to life or long-term health before they become symptomatic and prompt treatment of SCID may notably reduce mortality and morbidity among patients. Infants with ADA deficiency without reconstitution of a functioning immune system generally die of overwhelming infection by one year of age.

T cell receptor excision circles (TRECs) as a biomarker of naïve T cells, is a sensitive and specific, as well as cost effective, method for ADA deficiency newborn screening.

Natural History, Complications, and Prognosis

Natural History

Patients with ADA deficiency may present with multiple recurrent severe infections, chronic diarrhea, and failure to thrive (FTT) In the past, ADA deficiency was often diagnosed after children acquired serious infections, such as pneumonia due to Pneumocystis jiroveci.

Complications

Patients are at risk for infections from opportunistic infections usually follow more common infections. P. jiroveci and fungal pneumonias cause death in classic cases. CMV, VZV, and HSV infections typically occur in infants who have already had treatable infections. Neurologic compromise from polio and other enteroviruses impedes stem cell reconstitution.

Prognosis

ADA deficiency is fatal, generally within the first year of life, unless the underlying defect is corrected.Early diagnosis through population-wide newborn screening and early transplantation in the absence of infectious complications may improve hematopoietic cell transplantation (HCT) outcomes. Among patients transplanted under 3.5 months of age without infection, survival post-transplant is about 95 percent, and overall survival is 90 percent.

Diagnosis

Diagnostic Criteria

The diagnosis of adenosine deaminase deficiency is made by finding lymphopenia, with low numbers of CD3+ and CD4+ cells, poor in vitro lymphocyte mitogenic and antigenic responses, and absent mixed lymphocyte reactions (MLRs).

Laboratory Findings

The major diagnostic metabolic laboratory findings specific for ADA deficiency, which are also used to monitor treatment results, are the following:

• Absent ADA levels in lysed erythrocytes
• A marked increase in deoxyadenosine triphosphate (dATP) levels in erythrocyte lysates (with levels that vary by laboratory)
• A significant decrease in ATP concentration in red blood cells
• Absent or extremely low levels of N adenosylhomocysteine hydrolase in red blood cells
• Increase in 2'-deoxyadenosine in urine and plasma

Imaging Findings

A chest x-ray may be helpful in the diagnosis of adenosine deaminase deficiency . The thymic shadow is absent on chest radiography among the majority of patients with adenosine deaminase deficiency, thus, a chest x-ray may be helpful in the newborn suspected of adenosine deaminase deficiency. chest x-ray reveals the flaring of the anterior ribs, pelvic dysplasia, and shortening of the transverse vertebral processes with flattening of their ends and thick growth arrest lines. In addition, obtaining a chest x-ray may be helpful to assess pneumonia secondary to adenosine deaminase deficiency.

Treatment

Medical Therapy

• bone marrow transplant
• gene therapy (efforts halted due to increased incidence of leukemia)
• ADA enzyme in PEG vehicle
• Stem Cell Therapy(still in the experimental stage)

The first gene therapy to combat this disease was performed by Dr. W. French Anderson on a 4yr old girl, Ashanti DeSilva, in 14 September 1990 at the National Institute of Health, Bethesda, Maryland, U.S.A.

The therapy performed was the first successful case of gene therapy.

Primary Prevention

===Secondary Prevention

External links

• Gene Therapy: A Brief History: [2]