ADA – Adenosine Deaminase Deficiency–related Severe Combined Immunodeficiency

Adenosine deaminase (ADA) deficiency is an autosomal recessive inborn error of purine metabolism that accounts for approximately 20% of severe combined immunodeficiency (SCID) cases. The ADA gene encodes a 40-kDa homodimeric enzyme responsible for deamination of adenosine and deoxyadenosine; loss of ADA activity leads to toxic accumulation of deoxyadenosine nucleotides, resulting in profound T−B−NK− lymphopenia and failure of lymphopoiesis [PMID:9758612].

Genetic evidence for ADA-SCID is definitive, with over 50 distinct disease-associated alleles described in more than 50 unrelated patients, including missense, nonsense, splicing, and large Alu-mediated deletions [PMID:9758612]. In Newfoundland, homozygosity for c.58G>A (p.Gly20Arg) was associated with neonatal-onset fatal SCID in an inbred community [PMID:8299233], and a cohort of 45 ADA− chromosomes revealed that five recurrent missense mutations accounted for one-third of alleles in ADA-SCID patients [PMID:1346349].

Segregation analyses across consanguineous and non-consanguineous families demonstrate autosomal recessive inheritance, with parental carrier status confirmed in multiplex sibships and two affected siblings showing divergent clinical courses [PMID:8120281]. Unaffected heterozygous carriers lack immunodeficiency, supporting a recessive mechanism.

Functional assays of mutant ADA cDNAs expressed in E. coli and mammalian cells correlate residual enzymatic activity with clinical phenotype. The c.58G>A (p.Gly20Arg) and c.646G>A (p.Gly216Arg) alleles abolish enzyme activity in vitro, causing classic SCID [PMID:1680289], whereas hypomorphic variants retaining 1–2% activity (e.g., p.Arg253Gln) manifest delayed-onset or partial immunodeficiency [PMID:8258146].

Therapeutic interventions underscore functional concordance: pegylated ADA enzyme replacement therapy (ERT) increases peripheral T cells, corrects lymphopenia, and reduces infection frequency [PMID:8433875], and retroviral-mediated gene therapy of autologous T lymphocytes achieves sustained immune reconstitution [PMID:9414266]. Somatic reversion of ADA mutations in T cells has been observed to restore ADA activity and improve immunologic function [PMID:21671975].

In summary, biallelic ADA mutations underlie autosomal recessive ADA-SCID (MONDO:0015974). Genetic testing of ADA is indicated in infants presenting with profound lymphopenia (HP:0001888), failure to thrive (HP:0001508), and recurrent infections (HP:0002719). Early diagnosis enables prompt ERT or curative hematopoietic stem cell transplantation and informs prognosis based on residual enzyme activity.

References

• American journal of human genetics • 1998 • Adenosine deaminase deficiency: genotype-phenotype correlations based on expressed activity of 29 mutant alleles PMID:9758612
• Clinical immunology and immunopathology • 1994 • Homozygosity for a missense mutation (G20R) associated with neonatal onset adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) PMID:8299233
• American journal of medical genetics • 1992 • Five missense mutations at the adenosine deaminase locus (ADA) detected by altered restriction fragments and their frequency in ADA--patients with severe combined immunodeficiency (ADA-SCID). PMID:1346349
• The Journal of allergy and clinical immunology • 1994 • Heterogeneity of phenotype in two siblings with adenosine deaminase deficiency. PMID:8120281
• Journal of immunology (Baltimore, Md. : 1950) • 1991 • Homozygosity for a newly identified missense mutation in a patient with very severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID). PMID:1680289
• Pediatric research • 1993 • Development of gene therapy for immunodeficiency: adenosine deaminase deficiency. PMID:8433875
• Blood • 1998 • Successful peripheral T-lymphocyte-directed gene transfer for a patient with severe combined immune deficiency caused by adenosine deaminase deficiency. PMID:9414266
• Scandinavian journal of immunology • 2011 • Somatic mosaicism caused by monoallelic reversion of a mutation in T cells of a patient with ADA-SCID and the effects of enzyme replacement therapy on the revertant phenotype. PMID:21671975
• Journal of cellular biochemistry • 1991 • Adenosine deaminase deficiency due to heterozygous abnormality consisting of a deletion of exon 7 and the absence of enzyme mRNA. PMID:1939366

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