ADA – Autosomal Recessive Severe Combined Immunodeficiency due to Adenosine Deaminase Deficiency

Adenosine deaminase (ADA) deficiency is an autosomal recessive disorder resulting in profound T-, B-, and NK-cell lymphopenia and toxic accumulation of deoxyadenosine nucleotides, manifesting as severe combined immunodeficiency (SCID).

Biallelic ADA variants have been identified in numerous unrelated patients, with evidence of disease in consanguineous families and compound heterozygotes, supporting autosomal recessive inheritance and complete penetrance ([PMID:9758612]). Segregation in sibships and parental carrier status further confirm the AR mode.

Genetic studies report over 50 distinct pathogenic alleles, including missense, splicing, and frameshift mutations. A recurrent pathogenic variant is c.632G>A (p.Arg211His), demonstrated to cause ADA deficiency yet paradoxically retain normal enzyme kinetics in selected T-cell cultures ([PMID:1974554]).

Mechanistically, ADA deficiency leads to toxic deoxyadenosine triphosphate accumulation, impairing lymphoid proliferation via ribonucleotide reductase inhibition, SAH hydrolase inactivation, and DNA strand breaks. Mosaicism and reversion studies reveal somatic rescue can transiently restore enzyme activity in lymphoid subsets ([PMID:2078332]).

Functional assays in bacterial and mammalian expression systems quantify residual ADA activity across >29 alleles, correlating <0.05% activity with SCID and 5–28% with delayed-onset phenotypes ([PMID:9758612]). Tissue-specific splicing variability also modulates severity in siblings carrying identical splice-site mutations.

Experimental gene therapy and enzyme replacement trials demonstrate restoration of ADA activity in T cells and partial immunologic reconstitution, underscoring the therapeutic potential of hematopoietic stem cell gene transfer and PEG-ADA replacement ([PMID:8227344]).

Integration of genetic and functional data establishes a definitive gene–disease relationship for ADA deficiency SCID, guiding molecular diagnosis, family counseling, and personalized treatment selection. Key take-home: early ADA mutation screening and prompt therapeutic intervention are critical for survival in ADA-SCID.

References

• The Journal of Clinical Investigation • 1990 • Paradoxical expression of adenosine deaminase in T cells cultured from a patient with adenosine deaminase deficiency and combine immunodeficiency. PMID:1974554
• American Journal of Human Genetics • 1998 • Adenosine deaminase deficiency: genotype-phenotype correlations based on expressed activity of 29 mutant alleles. PMID:9758612
• Immunodeficiency Reviews • 1990 • Adenosine deaminase deficiency. PMID:2078332
• The Journal of Clinical Investigation • 1993 • Novel splicing, missense, and deletion mutations in seven adenosine deaminase-deficient patients with late/delayed onset of combined immunodeficiency disease. Contribution of genotype to phenotype. PMID:8227344

Evidence Based Scoring (AI generated)