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Adenosine Deaminase Deficiency

Adenosine Deaminase [ada] Deficiency

Adenosine deaminase deficiency (ADD) is a metabolic, multisystem disorder. In the vast majority of patients, ADD is triggered by mutations of the gene encoding for adenosine deaminase, but iatrogenic causes have been described in isolated cases. ADD patients suffer from severe combined immunodeficiency disease (SCID) as well as skeletal anomalies, sensorineural deafness, and other neurological deficits. If left untreated, ADD is uniformly fatal. Most patients initially receive enzyme replacement therapy to improve their immune status, but this is not a curative approach. By contrast, hematopoeitic stem cell transplantation and gene therapy allow for the full reconstitution of the immune system, for long-term survival and cure.


Presentation

Inherited ADD typically manifests within the first six months of life. However, a late-onset, milder form of the disease has also been described, where symptom onset occurs at any age during the first decade of life [1]. Iatrogenic ADD related to the administration of purine analogs may manifest at any age but is increasingly rare.

The hallmark of ADD is SCID, an immunodeficient condition rendering affected individuals prone to bacterial, viral, and fungal infections. ADD patients suffer from recurrent respiratory, gastrointestinal, and skin infections, and microbiological examinations often reveal the presence of opportunistic pathogens. In pediatric patients, these infections contribute to developmental delays and failure to thrive, but ADD is also related to primary skeletal anomalies and disorders of the nervous system, such as hearing impairment and behavioral disorders [1] [2]. Costochondral abnormalities may be visualized in about half of ADD patients [3]. With regards to neurological disorders, bilateral sensorineural deafness, hyperactivity, attention deficits, and aggression are commonly observed [4] [5].

Furthermore, ADD-associated pulmonary alveolar proteinosis may lead to pulmonary insufficiency [6]. Lung function impairment has been reported as a presenting symptom but is generally aggravated by respiratory infections. Similarly, other organ systems may be involved, but it is increasingly difficult to distinguish between primary lesions and complications of infectious diseases.

Fever
  • Type II (DAD2), analyze the relationship between CECR1 mutation location and neurological findings, and report a case with a novel CECR1 mutation Background: DAD2 is an autoinflammatory disease caused by mutations in the CECR1 gene yielding recurrent fever[neurology.org]
  • Signs and symptoms that can occur with ADA2 deficiency include fevers that are intermittent, meaning they come and go; areas of net-like, mottled skin discoloration called livedo racemosa; an enlarged liver and spleen (hepatosplenomegaly); and recurrent[ghr.nlm.nih.gov]
  • Patient 3 had fever, a sudden decrease in thrombocyte count, and rising ferritin; thus, a probable diagnosis of macrophage activation syndrome was made.[jrheum.org]
Candidiasis
  • Severe combined immunodeficiency disease with adenosine deaminase deficiency was reported of a 1-year-2-month-old boy, who showed clinical picture of pulmonary candidiasis.[ncbi.nlm.nih.gov]
  • Candidiasis is first observed as "diaper rash" but then progresses to an extensive infection involving the skin, oral and esophogeal mucosa and the vagina.[themedicalbiochemistrypage.org]
  • Five months after diagnosis and while receiving corticosteroid therapy for chronic obstructive pulmonary disease, patient no. 1 developed gastrointestinal candidiasis and progressive hemiplegia.[bloodjournal.org]
Recurrent Bronchitis
  • A three-yr-old Japanese boy was diagnosed with delayed-onset ADA deficiency because of recurrent bronchitis, bronchiectasia, and lymphopenia. In addition, autoimmune thyroiditis and neutropenia were present.[ncbi.nlm.nih.gov]
Sepsis
  • He had no history of recurrent otitis, bronchitis, pneumonia, sepsis, meningitis, or hepatitis.[bloodjournal.org]
Lymphadenopathy
  • CT of chest was negative for lymphadenopathy or granulomatous calcifications but revealed ill-defined nodular opacities within the right upper lobe and left lower.[autoimmunediseases.imedpub.com]
Cough
  • By the time she was walking, she was constantly hacking and dripping with coughs and colds, and just toddling would make her as winded as an elderly chain smoker, recalls her father Raj.[raredr.com]
Diarrhea
  • The main symptoms of ADA deficiency are pneumonia, chronic diarrhea, and widespread skin rashes. Affected children also grow much more slowly than healthy children and some have developmental delay.[en.wikipedia.org]
  • Infants exhibit failure to thrive, growth failure, chronic diarrhea, and absence of tonsils and lymph nodes. If compromised immunity cannot be restored, life expectancy is predicted to be between one to two years.[sema4genomics.com]
  • Infants with SCID typically experience pneumonia, chronic diarrhea, and widespread skin rashes, and grow much more slowly than healthy children. Some also have neurological problems such as developmental delay, movement disorders, and hearing loss.[news-medical.net]
  • Signs and symptoms of ADA include pneumonia, chronic diarrhea, widespread skin rashes, slowed growth and/or developmental delay. ADA is caused by changes (mutations) in the ADA gene and is inherited in an autosomal recessive manner.[diseaseinfosearch.org]
Failure to Thrive
  • A first-born baby boy presented at age 3 months with persistent diarrhoea, failure to thrive, and recurrent bacterial and fungal infections. Severe combined immunodeficiency was demonstrated.[ncbi.nlm.nih.gov]
  • Infants exhibit failure to thrive, growth failure, chronic diarrhea, and absence of tonsils and lymph nodes. If compromised immunity cannot be restored, life expectancy is predicted to be between one to two years.[sema4genomics.com]
  • Abstract A first-born baby boy presented at age 3 months with persistent diarrhoea, failure to thrive, and recurrent bacterial and fungal infections. Severe combined immunodeficiency was demonstrated.[adc.bmj.com]
  • Furthermore, ADD may cause developmental delays and failure to thrive. Skeletal anomalies, neurological deficits, and behavioral disorders have also been reported in ADD patients. These findings are non-specific for ADD.[symptoma.com]
  • Typical patients are infants with lymphocytopenia, failure to thrive and life-threatening opportunistic infections (SCID). Fifteen to 20% are less severely affected and present at 1–8 years of age; several adults have been diagnosed at 15–39 years.[link.springer.com]
Hepatosplenomegaly
  • Signs and symptoms that can occur with ADA2 deficiency include fevers that are intermittent, meaning they come and go; areas of net-like, mottled skin discoloration called livedo racemosa; an enlarged liver and spleen (hepatosplenomegaly); and recurrent[ghr.nlm.nih.gov]
  • At age 38, computerized tomography (CT) showed diffuse pulmonary miliary infiltrates with fibrosis and bronchiectasis, hepatosplenomegaly, and cholelithiasis.[bloodjournal.org]
Hepatomegaly
  • A year later she developed hepatomegaly, cholecystitis, and cholelithiasis. Liver biopsy specimens showed granulomas of undetermined cause. She developed pancytopenia and chronic sinopulmonary infections.[bloodjournal.org]
Behavior Disorder
  • Skeletal anomalies, neurological deficits, and behavioral disorders have also been reported in ADD patients. These findings are non-specific for ADD.[symptoma.com]
Neonate-Onset
  • Genetic deficiency of adenosine deaminase (ADA) results in varying degrees of immunodeficiency, including neonatal onset severe combined immunodeficiency (ADA-SCID), and milder, later onset immunodeficiency.[ncbi.nlm.nih.gov]
  • Due to underlying allelic heterogeneity, the disorder manifests as a spectrum, ranging from neonatal onset severe combined immunodeficiency to apparently normal partial adenosine deaminase deficiency.[nopr.niscair.res.in]

Workup

Despite ongoing infections, lymph nodes cannot be palpated during physical examinations. The patient's tonsils are small or absent [7]. Differential hematology yields high-grade lymphocytopenia with blood counts of B cells, T cells, and natural killer cells being severely decreased. Serum levels of immunoglobulins may only be slightly diminished in neonates, who are still protected by maternal antibodies. However, immunoglobulin levels decline over time, and qualitative analyses of immunoglobulins demonstrate the absence of IgA and IgM, which are unable to cross the placental barrier [2] [8]. In agreement with these findings, radiographic images of the thorax show no thymus shadow.

The aforementioned findings warrant a tentative diagnosis of ADD, which may be confirmed by demonstrating reduced activity of adenosine deaminase or elevated levels of its substrates in erythrocytes, leukocytes, or fibroblasts [1]. Residual enzyme activity is associated with lower concentrations of 2′-deoxyadenosine and has been reported to correlate with milder ADD [3]. However, no threshold has been defined for severe ADD with SCID. Because 2′-deoxyadenosine inhibits S-adenosylhomocysteine hydrolase, the activity of this enzyme is also decreased [1].

Finally, genetic studies may be carried out to identify the causal mutations of the ADA gene [1]. Sequence analysis and gene-targeted deletion/duplication analysis yield positive results in >90% of ADD patients [7].

Platelet Aggregation Abnormal
  • Despite the in vitro platelet aggregation abnormality, the patient had no clinical evidence of impaired hemostasis.[ncbi.nlm.nih.gov]

Treatment

Treatment options comprise enzyme replacement therapy, hematopoeitic stem cell transplantation, and gene therapy.

  • Enzyme replacement therapy is often chosen to alleviate acute symptoms and to partially reconstitute lymphocyte function. Unless patients are referred for stem cell transplantation or gene therapy, life-long treatment with polyethylene glycol-conjugated bovine adenosine deaminase is required. It is important to note that enzyme replacement is not curative of ADD. Furthermore, patients may develop antibodies against bovine adenosine deaminase, which render it ineffective [2].
  • Hematopoeitic stem cell transplantation has long since been the treatment of choice, especially if a matched donor is available. It allows for a full reconstitution of the immune system and long-term survival if complications related to the procedure can be avoided. Due to superior overall survival, non-conditioned transplantations are preferred over myeloablative preconditioning regimens [9].
  • Autologous hematopoeitic stem cell gene therapy has been shown an effective alternative to stem cell transplantation [10]. The sustained engraftment of transduced cells doesn't require intense preconditioning and eventually obviates the need for enzyme replacement therapy. In fact, gene therapy of ADD has become a milestone in the history of medicine when Strimvelis has been approved in the European Union as the first ex vivo stem cell retroviral vector [11].

Beyond that, symptomatic treatment of ADD-related infections should be offered. Patients should be administered antibiotic, antiviral, and antimycotic drugs according to their current needs. The application of intravenous immunoglobulin may also be helpful [7].

Prognosis

If left untreated, ADD-related infections lead to death within short periods of time. Infants suffering from ADD rarely live beyond the age of 2 unless they are provided adequate treatment [7]. Late-onset ADD follows a milder, but progressive course. Early infections tend to be less severe than those observed in infants, but these patients are likely to develop autoimmune disorders like hemolytic anemia, thrombocytopenia, autoimmune thyroiditis, and diabetes mellitus [2]. The pathogenetic mechanisms underlying the loss self-tolerance and onset of autoimmunity is poorly understood and is currently not possible to predict. Besides immunological symptoms, neurological sequelae of ADD may affect the patients' quality of life. In this context, a negative correlation between residual enzyme activity and intelligence has been observed [7].

Data regarding the long-term outcome of ADD are scarce. According to current knowledge, best prognoses are for those who undergo non-conditioned hematopoeitic stem cell transplantation from a matched donor or gene therapy [1].

Etiology

Adenosine deaminase is encoded by the ADA gene, which is located on the long arm of chromosome 20. Most ADD patients carry mutations of the ADA gene that interfere with the activity of the enzyme. Here, ADD is inherited in an autosomal recessive manner, and >70 pathogenic mutations have been identified to date. Private mutations are common, and most patients are heteroallelic, which hinders the establishment of genotype-phenotype correlations. Nevertheless, certain mutations have been related to total or partial deficiency of adenosine deaminase [3]. While the activity of adenosine deaminase is typically reduced in heterozygous carriers, these individuals don't develop clinical ADD [1].

On the other hand, an inhibition of adenosine deaminase may have iatrogenic causes. Purine analogs like pentostatin - which are administered to those suffering from hairy cell leukemia or graft-versus-host disease, among others - compete with adenosine and 2′-deoxyadenosine for the binding site of the enzyme. It thus seems feasible that patients who receive such drugs may eventually develop signs and symptoms of ADD, but there is next to no literature on acquired ADD in men. In animal-based research, ADD is generally induced with purine analogs.

Epidemiology

ADD accounts for about 15% of cases of SCID [1]. In Europe, its incidence has been estimated to be <3 per 1,000,000 live births [2]. An actualization of these data is expected in the scope of newborn screens for primary immunodeficiency, which have been implemented in several countries [12] [13].

Sex distribution
Age distribution

Pathophysiology

Adenosine deaminase catalyzes the conversion of adenosine and 2′-deoxyadenosine to inosine and 2′-deoxyinosine, respectively. These reactions are part of the purine salvage pathway, where purine nucleotides are synthesized from purine degradation by-products [5]. It may be understood as a form of recycling and serves to avoid the accumulation of cytotoxic intermediates of purine degradation. In patients suffering from ADD, adenosine, 2′-deoxyadenosine, and deoxyadenosine triphosphate are insufficiently degraded and pile up in all types of cells [2].

The expression of the ADA gene is highest in the thymus and bone marrow, where large numbers of cells undergo apoptosis during differentiation and selection, which yields vast amounts of DNA to be degraded. Accordingly, the accumulation of cytotoxic 2′-deoxyadenosine most severely affects B and T and natural killer cells. What's more, adenosine has been suggested to inhibit the differentiation of precursor cells, thereby aggravating lymphocytopenia [2].

Non-immunological manifestations of ADD may also be attributed to the accumulation of cytotoxic metabolites. However, adenosine itself is more than a substrate for DNA synthesis. It also binds to adenosine receptors in the central nervous system and periphery, which are implicated in distinct signaling cascades. It may be speculated that dysfunctional adenosine receptor signaling contributes to the onset of neurological symptoms in ADD patients [5].

Prevention

Affected families may benefit from genetic counseling. The prenatal diagnosis of ADD is feasible and allows for an early treatment of the disease, which may significantly improve the outcome [3] [14]. Alternatively, newborn screening programs bear the chance to identify homozygous carriers of pathogenic ADA mutations [3]. Newborn screens are based on the quantification of T-cell receptor excision circles or tandem mass spectrometry analysis of dried blood spots collected at birth [12].

Summary

ADD is a metabolic disorder, usually of genetic origin, that interferes with the function of all types of lymphocytes. Thus, ADD is generally classified as a type of SCID [5]. It should also be noted, though, that adenosine deaminase is physiologically expressed by a broad spectrum of cells, so symptoms of ADD are not limited to the immune system. ADD patients suffer from a decreased production of immunoglobulins and impaired cellular immunity, but they also show skeletal abnormalities, neurological deficits, and developmental disorders.

Still, life-threatening infections are major complications of ADD and the most common cause of persistent disability and early death. In order to improve the outcome, patients should receive adequate treatment as early as possible. Enzyme replacement therapy plays a key role in the acute management of the disease, but best long-term results are achieved by hematopoeitic stem cell transplantation and gene therapy. Adequate treatment requires a reliable diagnosis of the disease, which is based on the results of laboratory analyses of blood samples, enzyme activity measurements, and sequencing of the gene encoding for adenosine deaminase.

Patient Information

Adenosine deaminase is an enzyme involved in the degradation of building blocks of DNA, and it is encoded by the ADA gene. Pathogenic mutations of the ADA gene are associated with significantly reduced or even absent activity of adenosine deaminase, which leads to the accumulation of toxic metabolites in distinct types of cells. Large quantities of DNA are degraded in immune cells, so they are most severely affected by this process. In detail, patients suffering from adenosine deaminase deficiency (ADD) have very low counts of B cells, T cells, and natural killer cells, which fulfill a myriad of functions in the immune system. ADD is thus related to severe immunodeficiency and susceptibility to all kinds of infections.

Most patients develop first symptoms of ADD during their first few months of life: Recurrent respiratory infections, persistent diarrhea, and dermatitis are most commonly observed. Furthermore, ADD may cause developmental delays and failure to thrive. Skeletal anomalies, neurological deficits, and behavioral disorders have also been reported in ADD patients.

These findings are non-specific for ADD. In order to diagnose this type of severe combined immunodeficiency disease, laboratory analyses of blood samples and genetic studies have to be carried out. Characteristic findings comprise low counts of lymphocytes, low levels of antibodies, reduced activity of adenosine deaminase, increased concentrations of this enzyme's substrates, and mutations of the ADA gene.

Patients who have been diagnosed with ADD may receive bovine adenosine deaminase to strengthen their immune system. However, enzyme replacement therapy is not curative and is required life-long. Cure may be achieved by hematopoeitic stem cell transplantation and gene therapy, whereby success of the former is related to the availability of a matched donor. Gene therapy is not yet widely available but has been proven to be effective and is constantly gaining importance.

References

Article

  1. Flinn AM, Gennery AR. Adenosine deaminase deficiency: a review. Orphanet J Rare Dis. 2018; 13(1):65.
  2. Sauer AV, Brigida I, Carriglio N, Aiuti A. Autoimmune dysregulation and purine metabolism in adenosine deaminase deficiency. Front Immunol. 2012; 3:265.
  3. Hershfield MS. Genotype is an important determinant of phenotype in adenosine deaminase deficiency. Curr Opin Immunol. 2003; 15(5):571-577.
  4. Rogers MH, Lwin R, Fairbanks L, Gerritsen B, Gaspar HB. Cognitive and behavioral abnormalities in adenosine deaminase deficient severe combined immunodeficiency. J Pediatr. 2001; 139(1):44-50.
  5. Whitmore KV, Gaspar HB. Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency. Front Immunol. 2016; 7:314.
  6. Grunebaum E, Cutz E, Roifman CM. Pulmonary alveolar proteinosis in patients with adenosine deaminase deficiency. J Allergy Clin Immunol. 2012; 129(6):1588-1593.
  7. Hershfield M. Adenosine Deaminase Deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews® u8i23Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
  8. Geelen J, Pfundt R, Meijer J, et al. Severe phenotype of severe combined immunodeficiency caused by adenosine deaminase deficiency in a patient with a homozygous mutation due to uniparental disomy. J Allergy Clin Immunol. 2013; 132(1):222-223.
  9. Hassan A, Booth C, Brightwell A, et al. Outcome of hematopoietic stem cell transplantation for adenosine deaminase-deficient severe combined immunodeficiency. Blood. 2012; 120(17):3615-3624; quiz 3626.
  10. Cicalese MP, Ferrua F, Castagnaro L, et al. Gene Therapy for Adenosine Deaminase Deficiency: A Comprehensive Evaluation of Short- and Medium-Term Safety. Mol Ther. 2018; 26(3):917-931.
  11. Gardner J. Standing on the Shoulders of Stem Cell Gene Therapists: History, Hyperbole, and Hope for the Future. Hum Gene Ther Clin Dev. 2016; 27(4):140-144.
  12. la Marca G, Canessa C, Giocaliere E, et al. Tandem mass spectrometry, but not T-cell receptor excision circle analysis, identifies newborns with late-onset adenosine deaminase deficiency. J Allergy Clin Immunol. 2013; 131(6):1604-1610.
  13. Vogel BH, Bonagura V, Weinberg GA, et al. Newborn screening for SCID in New York State: experience from the first two years. J Clin Immunol. 2014; 34(3):289-303.
  14. Dooley T, Fairbanks LD, Simmonds HA, et al. First trimester diagnosis of adenosine deaminase deficiency. Prenat Diagn. 1987; 7(8):561-565.

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Last updated: 2019-07-11 20:12