Adenosine Deaminase Deficiency

Overview

Plain-Language Overview

Adenosine Deaminase Deficiency is a rare genetic disorder that affects the immune system. It causes a lack of a crucial enzyme called adenosine deaminase, which leads to problems in the development and function of immune cells. People with this condition often have frequent and severe infections because their bodies cannot fight off germs effectively. Symptoms usually appear in early infancy and can include failure to thrive, chronic diarrhea, and respiratory infections. Without treatment, this condition can be life-threatening, but advances in medical care have improved outcomes for many patients.

Clinical Definition

Adenosine Deaminase Deficiency is an autosomal recessive primary immunodeficiency characterized by a profound deficiency of the enzyme adenosine deaminase (ADA), which is critical for purine metabolism. The absence or severe reduction of ADA activity leads to the accumulation of toxic metabolites such as deoxyadenosine and deoxy-ATP, which are particularly harmful to lymphocytes. This results in severe lymphopenia, especially affecting T, B, and natural killer (NK) cells, causing a combined immunodeficiency phenotype. Clinically, patients present in infancy with recurrent, severe infections, failure to thrive, and chronic diarrhea. The disease is a major cause of severe combined immunodeficiency (SCID). Diagnosis is confirmed by measuring ADA enzyme activity in red blood cells or genetic testing identifying mutations in the ADA gene. Without intervention, the condition is fatal due to overwhelming infections. Treatment options include enzyme replacement therapy, hematopoietic stem cell transplantation, and gene therapy. Early diagnosis and management are critical to improve survival and quality of life.

Inciting Event

No external inciting event; disease results from inherited genetic mutation causing enzyme deficiency.

Latency Period

Symptoms typically develop within the first 3 to 6 months of life as toxic metabolites accumulate.

Diagnostic Delay

Nonspecific early symptoms such as failure to thrive and recurrent infections may delay suspicion of immunodeficiency.
Lack of newborn screening in some regions contributes to delayed diagnosis.
Misdiagnosis as common infections or other immunodeficiencies can postpone definitive testing.

Clinical Presentation

Signs & Symptoms

Severe combined immunodeficiency presenting in infancy.
Recurrent, severe bacterial, viral, and fungal infections.
Chronic diarrhea and failure to thrive.
Persistent oral thrush and skin infections.
Respiratory distress due to pneumonia.

History of Present Illness

Recurrent, severe bacterial, viral, and fungal infections starting in early infancy.
Failure to thrive and chronic diarrhea are common presenting features.
Persistent oral candidiasis and pneumonia are frequently reported.
Lymphopenia-related symptoms such as skin rashes and opportunistic infections may be present.

Past Medical History

No significant past medical history prior to symptom onset in infancy.
May have history of recurrent infections or hospitalizations if symptoms began earlier.
No prior immunizations with live vaccines due to risk of severe infection.

Family History

Positive family history of severe combined immunodeficiency (SCID) or early infant deaths from infections.
Consanguinity or known carrier status in parents increases risk.
Siblings may have similar symptoms or confirmed diagnosis of ADA deficiency.

Physical Exam Findings

Presence of lymphopenia may be inferred from recurrent infections.
Possible failure to thrive and poor growth in infants.
Signs of oral thrush or other opportunistic infections.
Absence or underdevelopment of lymphoid tissue such as tonsils.

Diagnostic Workup

Diagnostic Criteria

Diagnosis of Adenosine Deaminase Deficiency is established by demonstrating markedly reduced or absent ADA enzyme activity in red blood cells or other tissues, combined with clinical features of severe combined immunodeficiency such as profound lymphopenia affecting T, B, and NK cells. Genetic testing confirming pathogenic mutations in the ADA gene supports the diagnosis. Additional laboratory findings include elevated levels of toxic purine metabolites in blood or urine. The clinical presentation typically involves recurrent severe infections in early infancy, failure to thrive, and absence of thymic shadow on chest imaging. These criteria together confirm the diagnosis and guide appropriate treatment.

Pathophysiology

Key Mechanisms

Adenosine deaminase (ADA) deficiency leads to accumulation of toxic metabolites such as deoxyadenosine and deoxy-ATP, which cause lymphocyte apoptosis and severe immunodeficiency.
The lack of ADA enzyme activity impairs purine metabolism, resulting in defective development and function of T, B, and NK cells.
The immunodeficiency primarily affects the adaptive immune system, leading to severe combined immunodeficiency (SCID).

Involvement	Details
Organs	Lymph nodes are depleted of lymphocytes, leading to impaired immune responses.
Organs	Spleen is often small and lacks normal lymphoid architecture due to immune cell loss.
Tissues	Thymic tissue is hypoplastic due to lymphocyte depletion, impairing T cell maturation.
Tissues	Bone marrow shows reduced lymphoid precursors affecting immune cell development.
Cells	T lymphocytes are severely reduced due to toxic metabolite accumulation causing immunodeficiency.
	B lymphocytes are also affected, leading to impaired humoral immunity.
	Natural killer cells may be decreased, contributing to susceptibility to viral infections.
Chemical Mediators	Deoxyadenosine accumulates due to ADA deficiency and is toxic to lymphocytes.
Chemical Mediators	dATP levels increase, inhibiting ribonucleotide reductase and impairing DNA synthesis in immune cells.

Treatment

Pharmacological Treatments

Enzyme replacement therapy (PEG-ADA)
- Mechanism: Provides functional adenosine deaminase enzyme to reduce toxic metabolite accumulation
- Side effects: Injection site reactions, hypersensitivity, immune response
Hematopoietic stem cell transplantation (HSCT)
- Mechanism: Replaces defective immune system with healthy donor stem cells
- Side effects: Graft-versus-host disease, infection, transplant rejection

Non-pharmacological Treatments

Isolation and infection control measures to prevent opportunistic infections.
Supportive care including nutritional support and respiratory therapy as needed.

Prevention

Pharmacological Prevention

Enzyme replacement therapy with pegademase bovine to provide ADA activity.
Prophylactic antimicrobial agents to prevent infections.
Immunoglobulin replacement therapy to support humoral immunity.

Non-pharmacological Prevention

Avoidance of exposure to infectious agents through strict hygiene.
Protective isolation or sterile environment for affected infants.
Early hematopoietic stem cell transplantation as curative therapy.

Outcome & Complications

Complications

Severe infections leading to sepsis and death if untreated.
Failure to thrive and developmental delay.
Chronic lung disease from recurrent infections.
Neurological impairment due to toxic metabolite accumulation.

Short-term Sequelae	Long-term Sequelae
Acute respiratory infections requiring hospitalization. Severe opportunistic infections. Electrolyte imbalances and dehydration from diarrhea.	Chronic pulmonary disease due to repeated infections. Persistent immune deficiency without treatment. Neurological deficits from toxic metabolite accumulation. Growth retardation and developmental delays.

Differential Diagnoses

Adenosine Deaminase Deficiency versus Omenn Syndrome

Adenosine Deaminase Deficiency	Omenn Syndrome
Absence of autoimmune skin manifestations and no oligoclonal T cell expansion.	Presence of erythroderma, lymphadenopathy, and hepatosplenomegaly with oligoclonal T cells causing autoimmune-like symptoms.
Profound ADA deficiency with markedly reduced enzyme activity.	Elevated IgE levels and eosinophilia are common laboratory findings.
Severe lymphopenia affecting T, B, and NK cells without eosinophilia or elevated IgE.	Normal or near-normal ADA enzyme activity.

Adenosine Deaminase Deficiency versus Purine Nucleoside Phosphorylase (PNP) Deficiency

Adenosine Deaminase Deficiency	Purine Nucleoside Phosphorylase (PNP) Deficiency
Deficient ADA enzyme activity causing toxic accumulation of deoxyadenosine metabolites affecting all lymphocyte lineages.	Deficiency of PNP enzyme leading to accumulation of deoxyguanosine and selective T cell immunodeficiency with relatively preserved B cells.
Profound combined immunodeficiency with severe lymphopenia involving T, B, and NK cells.	Presence of normal ADA enzyme activity in blood or lymphocytes.
Less prominent or absent neurological manifestations compared to PNP deficiency.	Clinical features include neurological symptoms such as developmental delay and hypotonia, which are less prominent in ADA deficiency.

Adenosine Deaminase Deficiency versus X-linked Severe Combined Immunodeficiency (SCID)

Adenosine Deaminase Deficiency	X-linked Severe Combined Immunodeficiency (SCID)
Autosomal recessive inheritance with mutations in the ADA gene leading to absent or deficient adenosine deaminase activity.	Mutation in the IL2RG gene causing defective T cell and NK cell development with normal or elevated B cells.
Markedly reduced ADA enzyme activity in red blood cells or lymphocytes.	Presence of normal or increased ADA enzyme activity in blood or lymphocytes.
Characteristic T-B-NK- immunophenotype with profound lymphopenia affecting all lymphocyte subsets.	Predominantly T-B+NK- immunophenotype on lymphocyte subset analysis.