Adenosine deaminase deficiency
Synonyms and Keywords: ADA Deficiency; SCID Due to ADA Deficiency; ADA-SCID

# 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 which finally prevents DNA synthesis.
- In addition, deoxyadenosine irreversibly binds to and inhibits S-adenosylhomocysteine hydrolase and causes rise in S-adenosylhomocysteine. Since S-adenosylhomocysteine is a toxic substance, thus immature lymphocytes fail to mature.
- 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 a 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-cellreceptor 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 naive 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 following finding:
- Lymphopenia, with low numbers of CD3+ and CD4+ cells
Poor in vitro lymphocyte mitogenic and antigenic responses
Absent mixed lymphocyte reactions (MLRs)
- Lymphopenia, with low numbers of CD3+ and CD4+ cells
- Poor in vitro lymphocyte mitogenic and antigenic responses
- 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
- Failure to thrive in the first months of life
- Recurrent skin abscesses and/or other severe skin infections
- 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
- Signs of 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
Sensorineural hearing loss
- Cognitive deficits
- Behavioral problems
- Gait abnormalities
- Hypo- and hypertonia
- Sensorineural hearing loss

## 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 .

## 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