Severe Combined Immunodeficiency, Autosomal Recessive, T Cell-Negative, B Cell-Negative, Nk Cell-Negative, due to Adenosine Deaminase Deficiency

Alternative Names

  • SCID due to ADA Deficiency
  • ADA-SCID
  • SCID due to ADA Deficiency, Early-Onset

Associated Genes

Adenosine Deaminase
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WHO-ICD-10 version:2010

Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism

Certain disorders involving the immune mechanism

OMIM Number

102700

Mode of Inheritance

Autosomal recessive; Somatic mosaicism

Gene Map Locus

20q13.12

Description

Severe Combined Immunodeficiency (SCID) describes a range of clinically and genetically diverse immune system disorders, characterized by compromised T-Cell development, and further classification is based on the presence or absence of B lymphocytes and natural killer (NK) cells.  SCID due to Adenosine Deaminase (ADA) deficiency is the second most common SCID disorder, representing 15% of all SCID cases, with an incidence ranging between 1:200,000 and 1:1,000,000 births.  Low or aberrant ADA enzyme activity in developing white blood cells leads to dysfunctional T-cell, B-cell, and NK cell, resulting in compromised humoral and cellular immunity.  The weakened immune system becomes particularly vulnerable to opportunistic organisms, consequently, prominent clinical symptoms involve various recurring infections- including pneumonia, meningitis, and sepsis, as well as chronic skin infections, yeast infections, and gastrointestinal infections. Cases usually exhibit an abnormally small thymus due to the effect of ADA deficiency on developing T-cells.  Spleen abnormalities, a lack of tonsils and lymph nodes, thrombocytopenia, as well as skeletal and neurological abnormalities, are among the clinical features of ADA deficiency.  

Severe lymphopenia is the diagnostic hallmark of all SCID disorders, and is detected through complete blood count and flow cytometry analysis of white blood cell subsets. Early diagnosis of ADA-SCID involves prenatal testing of ADA enzyme activity through chorionic villus sampling or amniocentesis, as well as assessing enzyme levels in fetal blood samples. ADA-SCID can present in infancy and is fatal within one year if left untreated.  Non-curative treatment of ADA-SCID involves enzyme replacement therapy (ERT). ERT can temporarily ameliorate infections; however restoring immune system function requires bone marrow transplantation (BMT) or gene therapy (GT). BMT performed during the first three months of infancy have a high success rate, offering post-transplantation survival that can extend to several years. GT studies are currently ongoing, and involve the transduction of host hematopoietic stem cells with the wild type ADA gene using retroviral vectors.

ADA-SCID is an autosomal recessive condition originating from mutations in the Adenosine Deaminase (ADA) gene. The Adenosine deaminase enzyme functions in the purine metabolism and salvage pathways, specifically catalyzing the deamination of adenosine and deoxyadenosine.  Due to the high mitotic and apoptotic activity of lymphocytes undergoing development and selection, ADA is essential for the metabolic maintenance of the immune system.  Loss of ADA function leads to the abnormal buildup of deoxyadenosine, and consequently dATP buildup, which is cytotoxic to developing lymphocytes. Adenosine toxicity has been shown to interfere with mature T-cell receptor signaling and activation. Absent ADA activity leads to early-onset ADA-SCID, whereas cases retaining some immune function can present after a delay from childhood to adulthood.

Epidemiology in the Arab World

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Other Reports

Saudi Arabia

Arredondo-Vega et al. (2002) described four cases of delayed-onset combined immunodeficiency due to ADA deficiency in three Saudi Arabian families. Genotype analysis of all cases identified homozygosity for a novel splicing mutation in ADA.  In family 1, the 4 year old female proband presented with multiple infections and lymphopenia leading to testing and confirmation for ADA deficiency.  Her 16-year old brother was subsequently tested and determined ADA deficient.  In addition to multiple infections, he had developed restrictive lung disease, kyphoscoliosis, and muscle weakness.  He also presented with rales, bronchiectasis, and digital clubbing.  Being risky candidates for BMT, both siblings underwent successful ERT management.  Blood dAXP levels were significantly lower in the older sibling relative to his sister, indicating substantial ADA activity in non-erythroid cells.  In the male patient; 75% ADA activity was detected in T-cells before ERT, and in an in vitro B lymphoblastoid cell line derived from him after ERT.  Based on these findings, genotype analysis described somatic mosaicism due to second site reversion in these cells.  7 months of ERT had resulted in a significant decrease of revertant lymphoid cells in the male patient, with T-cells exhibiting 8.5% of ADA activity.  The two patients, aged 5.5 and 1 years, from families 2 and 3 respectively, were born to second degree parents, distantly related to family 1.  Suggestive symptoms including lymphopenia lead to the diagnosis of combined immunodeficiency.  With the presence of HLA-identical siblings, both patients underwent BMT soon after diagnosis, and were not studied further.

Hellani et al. (2009) described a case of severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency in a 14 month old Saudi Arabian boy born to first-degree consanguineous parents.  He exhibited 2% of the normal white blood count, which constituted 88% T-cells, 5% B-cells, and 7% NK-cells.  Multiple recurrent infections and lymphopenia exhibiting a T-, NK-, and B- phenotype, lead to diagnosis of ADA-SCID.  He presented with mycobacterium intracellulare infection, gastroenteritis, sepsis, irritability, and skin rash.  He had a history of chest infections, lower respiratory tract infections with bronchospasm, and diarrhea.  DNA sequencing identified homozygosity for a novel missense mutation in ADA.  The boy underwent successful bone marrow transplantation using his HLA-identical sister as a donor. 

Somalia

Sanchez et al. (2007) reported on 5 Somali cases with ADA-SCID, from 4 unrelated families in London, who were homozygous for a nonsense (Q3X) mutation in ADA.  Due to the established rarity of ADA-SCID, these cases prompted a study into the genetics of ADA in Somalis.  Based on a population of 207 unrelated Somali immigrants in Denmark, the estimated frequency of the Q3X mutation was 1.2%; as none were homozygous for this mutation, 2.4% of individuals in this group were observed as carriers. The expected incidence of ADA-SCID due to the Q3X mutation in Somalis was estimated at 1 in 5000-10,000 births. All individuals were part of the Hawiye clan -one of two largest clans- suggesting a higher incidence of ADA-SCID and a higher carrier frequency of Q3X in this subgroup.  The 5 reported patients have all underwent successful therapies. 

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