Adenosine deaminase deficiency

Adenosine deaminase deficiency
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Synonyms	ADA deficiency or ADA-SCID
Pronounce	N/A
Field	N/A
Symptoms
Complications
Onset
Duration
Types
Causes
Risks
Diagnosis
Differential diagnosis
Prevention
Treatment
Medication
Prognosis
Frequency
Deaths

Adenosine deaminase deficiency is an autosomal recessive<ref>,

 Adenosine deaminase deficiency: frequency and comparative pathology in autosomally recessive severe combined immunodeficiency, 
 Clinical Immunology and Immunopathology, 
 
 Vol. 14(Issue: 1),
 pp. 107–20,
 DOI: 10.1016/0090-1229(79)90131-4,
 PMID: 477037,</ref> metabolic disorder that causes immunodeficiency.  It occurs in fewer than one in 100,000 live births worldwide. 

It accounts for about 15% of all cases of severe combined immunodeficiency (SCID).<ref>Hershfield MS,

 Genotype is an important determinant of phenotype in adenosine deaminase deficiency, 
 Current Opinion in Immunology, 
 
 Vol. 15(Issue: 5),
 pp. 571–7,
 DOI: 10.1016/S0952-7915(03)00104-3,
 PMID: 14499267,</ref>

ADA deficiency may be present in infancy, childhood, adolescence, or adulthood. Age of onset and severity is related to some 29 known genotypes associated with the disorder.<ref name=AV1998>,

 Adenosine deaminase deficiency: genotype-phenotype correlations based on expressed activity of 29 mutant alleles, 
 American Journal of Human Genetics, 
 
 Vol. 63(Issue: 4),
 pp. 1049–59,
 DOI: 10.1086/302054,
 PMID: 9758612,
 PMC: 1377486,</ref>

Signs/symptoms

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. Most individuals with ADA deficiency are diagnosed with SCID in the first 6 months of life.

An association with polyarteritis nodosa has been reported.<ref name=Liebowitz2019>Liebowitz J, Hellmann DB1, Schnappauf O (2019) Thirty years of followup in 3 patients with familial polyarteritis nodosa due to adenosine deaminase 2 deficiency. J Rheumatol </ref>

Genetics

Adenosine deaminase deficiency has an autosomal recessive pattern of inheritance.

The enzyme adenosine deaminase is encoded by a gene on chromosome 20. ADA deficiency is inherited in an autosomal recessive manner. This means the defective gene responsible for the disorder is located on an autosome (chromosome 20 is an autosome), and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.

Age of onset and severity is related to some 29 known genotypes associated with the disorder.<ref> name=AV1998>,

 Adenosine deaminase deficiency: genotype-phenotype correlations based on expressed activity of 29 mutant alleles, 
 American Journal of Human Genetics, 
 
 Vol. 63(Issue: 4),
 pp. 1049–59,
 DOI: 10.1086/302054,
 PMID: 9758612,
 PMC: 1377486,</ref>

Pathophysiology

ADA deficiency is due to a lack of the enzyme adenosine deaminase. This deficiency results in an accumulation of deoxyadenosine,<ref name="titleAdenosine Deaminase (ADA) Deficiency">

Adenosine Deaminase (ADA) Deficiency(link). {{{website}}}.

</ref> which, in turn, leads to:

• a buildup of dATP in all cells, which inhibits ribonucleotide reductase and prevents DNA synthesis, so cells are unable to divide. Since developing T cells and B cells are some of the most mitotically active cells, they are highly susceptible to this condition.
• an increase 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.

Because T cells undergo proliferation and development in the thymus, affected individuals typically have a small, underdeveloped thymus.<ref>p347, The Immune System Peter Parham, Garland Science, London and New York, 2009</ref> As a result, the immune system is severely compromised or completely lacking.

Diagnosis

The diagnosis is based on clinical features, with a concomitant decreased blood adenosine deaminase level supporting the diagnosis.

Treatment

Treatments include:<ref name=Booth2006/>

• bone marrow transplant
• ADA enzyme in PEG vehicle <ref name=Booth2006>Booth Claire,

 Management options for adenosine deaminase deficiency; proceedings of the EBMT satellite workshop (Hamburg, March 2006), 
 Clinical Immunology, 
 2007,
 Vol. 123(Issue: 2),
 pp. 139–147,
 DOI: 10.1016/j.clim.2006.12.009,
 PMID: 17300989,</ref>

Gene Therapy

On September 1990, the first gene therapy to combat this disease was performed by Dr. William French Anderson on a four-year-old girl, Ashanti DeSilva, at the National Institutes of Health, Bethesda, Maryland, U.S.A.<ref name="titleMore Than Human - New York Times"> Naam, Ramez,

 'More Than Human' - New York Times Full text, 
 The New York Times, 
  
 2005-07-03,

</ref> In April 2016 the Committee for Medicinal Products for Human Use of the European Medicines Agency endorsed and recommended for approval a stem cell gene therapy called Strimvelis, for children with ADA-SCID for whom no matching bone marrow donor is available.<ref>House, Douglas W., (1 April 2016) European Ad Comm backs Glaxo's stem cell therapy Strimvelis for rare autoimmune disorder, Seeking Alpha, Retrieved 13 April 2016</ref><ref name="Strimvelis">

Summary of opinion1 (initial authorisation) Strimvelis(link). European Medicines Agency.

1 April 2016.

</ref>

History

ADA deficiency was discovered in 1972 by Eloise Giblett, a professor at the University of Washington.<ref name=":0">Motulsky A, Gartler S. "Biographical Memoirs: Eloise R. Giblett". National Academy of Sciences.</ref> The ADA gene was used as a marker for bone marrow transplants. A lack of ADA activity was discovered by Giblett in an immunocompromised transplant candidate. After discovering a second case of ADA deficiency in an immunocompromised patient, ADA deficiency was recognized as the first immunodeficiency disorder.<ref name=":0" />

Further reading

• Adenosine deaminase deficiency - Genetics Home Reference

External links

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