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 15% 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 the second case with ADA deficiency and immunodeficiency, 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.

Patients with adenosine deaminase deficiency have severely reduced numbers of T, B, and natural killer (NK) cells. However, some patients may retain NK cells and even B cells. Patients with ADA-severe combined immunodeficiency (SCID) often have myeloid dysplasia and bone marrow hypocellularity.

Causes

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

Differentiating Adenosine deaminase deficiency 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

The 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

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 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.

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).TRECs, formed during the differentiation of T cells in the thymus. A quantitative real-time polymerase chain reaction (PCR) test can measure T cell receptor excision circles. TRECs serve as a biomarker of naïve T cells, which is a sensitive and specific, as well as cost effective method for ADA deficiency newborn screening.

Natural History, Complications, and Prognosis

Natural History

Infants with adenosine deaminase deficiency are typically healthy at birth, protected by acquired maternal immunoglobulin G (IgG) antibodies in the first few months of life. As this protection diminishes, patients with ADA deficiency may present with multiple recurrent severe infections, chronic diarrhea, and failure to thrive (FTT) in the first few months of life. Infants with adenosine deaminase (ADA) deficiency with severe combined immunodeficiency phenotype without reconstitution of a functioning immune system usually die of overwhelming infection by one year of age. Variability in genetic mutations cause various phenotypes of ADA deficiency, and there are also a few patients with a later onset and relatively milder disease.

Complications

• Patients are at risk for 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 impede stem cell reconstitution.
• Lymphoma is an invariably fatal complication that occurs among patients with a later onset and in patients treated successfully with enzyme replacement therapy.

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).

History and Symptoms

The hallmark of findings among patients affected with adenosine deaminase (ADA) deficiency with severe combined immunodeficiency phenotype are life-threatening infections, chronic persistent diarrhea, and failure to thrive in the first months of life. Some neonates may present with prolonged hyperbilirubinemia and hepatitis.

Physical Examination

Physical findings are multisystemic. The patient may present with the following:

• Fever
• Failure to thrive
• Dehydration due to chronic diarrhea
• Acute otitis media
• Absent lymphatic tissue
• Extensive candidiasis in the mouth and diaper area
• Recurrent skin abscesses and/or other severe skin infections
• Neurologic abnormalities include cognitive deficits, behavioral problems, gait abnormalities, hypo- and hypertonia, and sensorineural hearing loss are prominent in ADA deficiency.

Laboratory Findings

Laboratory findings consistent with the diagnosis of ADA deficiency include :

• Absent ADA levels in lysed erythrocytes
• A significant decrease in ATP concentration in red blood cells
• Absent or extremely low levels of N adenosylhomocysteine hydrolase in red blood cells
• A marked increase in deoxyadenosine triphosphate (dATP) levels in erythrocyte lysates
• 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

The mainstay of treatment for adenosine deaminase (ADA) deficiency with severe combined immunodeficiency phenotype is hematopoietic cell transplantation (HCT) from a human leukocyte antigen (HLA)-identical sibling, or if not available, a matched family donor. If a matched sibling or family donor is not an option, then gene therapy is suggested, if available and not cost prohibitive, for an infant or young child with ADA-deficient SCID. The majority of cases of adenosine deaminase deficiency require enzyme replacement therapy with polyethylene glycol-adenosine deaminase [PEG-ADA].

Primary Prevention

There are no established measures for the primary prevention of adenosine deaminase deficiency.

Secondary Prevention

Effective measures for the secondary prevention of adenosine deaminase deficiency include:

• Mothers with a history of a prior affected child with SCID should receive recommended booster vaccines prior to delivery to provide transplacental antibodies
• Protective isolation for neonates with suspected SCID before receiving definitive treatment
• All blood products must be irradiated, leukodepleted, and cytomegalovirus (CMV) negative

Typical prophylaxis against infection includes:

• Immune globulin replacement therapy
• Prophylaxis for Pneumocystis jirovecii pneumonia with trimethoprim-sulfamethoxazole.
• Antifungal prophylaxis with fluconazole
• Monoclonal antibody against respiratory syncytial virus (RSV) with palivizumab
• Antiviral agent for prophylaxis against HSV, CMV, EBV

External links

• Gene Therapy: A Brief History: [2]