ADA2 – Sneddon's Syndrome

Adenosine deaminase 2 (ADA2), encoded by CECR1 (HGNC:1839), is critical for vascular integrity and immune regulation. Sneddon's syndrome (SnS) is characterized by livedo reticularis and recurrent strokes, classically of unknown etiology. Adult presentations of SnS with CECR1 mutations define a genetically distinct subset overlapping deficiency of adenosine deaminase 2 (DADA2). Genetic testing for ADA2 mutations and functional enzymatic assays are emerging as diagnostic cornerstones in this population.

Biallelic loss-of-function variants in CECR1 have been identified in six unrelated adult SnS patients, consistent with autosomal recessive inheritance (PMID:30645994). All DADA2 patients in this cohort exhibited stroke and livedoid vascular pathology. First-degree heterozygous carriers displayed intermediate enzymatic activity but no clinical SnS features, supporting recessive segregation without dominant penetrance. No affected relatives beyond probands were reported.

The variant spectrum in DADA2 includes missense and loss-of-function changes; a recurrent founder allele is c.139G>C (p.Gly47Arg) (PMID:24737293). This variant has been observed in pediatric vasculopathy and demonstrates reduced ADA2 dimer stability. Other missense changes cluster in the catalytic and dimerization domains, correlating with clinical heterogeneity across neurologic and hematologic phenotypes.

Functional studies reveal that plasma ADA2 activity is undetectable in DADA2 patients and distinguishes them from primary SnS with 100% sensitivity and specificity (PMID:30645994). Serum immunoglobulin M levels are also significantly lower in DADA2, providing an adjunct triage marker. Enzymatic assays thus offer moderate experimental evidence of pathogenicity through direct measurement of ADA2 loss.

Mechanistically, ADA2 deficiency disrupts purinergic signaling and endothelial homeostasis, leading to neutrophil-driven vascular damage. An interferon-driven neutrophil signature has been documented in ADA2-deficient patients, implicating dysregulated innate immunity in cerebrovascular lesions (PMID:25278816). These data support a loss-of-function mechanism underpinning SnS phenotypes in DADA2.

Integration of genetic and functional evidence yields a Strong gene–disease association. ADA2 testing, combining sequencing and enzymatic assays, enables precise diagnosis of DADA2 within the SnS spectrum. Early identification informs targeted therapies, including anti-TNF agents, and guides familial screening. Key Take-home: ADA2 deficiency should be considered in adult Sneddon's syndrome, as genetic and enzymatic confirmation directly impacts management and prognosis.

References

• Cerebrovascular diseases (Basel, Switzerland) • 2018 • Adenosine Deaminase Two and Immunoglobulin M Accurately Differentiate Adult Sneddon's Syndrome of Unknown Cause PMID:30645994
• European Journal of Pediatrics • 2014 • Novel adenosine deaminase 2 mutations in a child with a fatal vasculopathy PMID:24737293
• Pediatric rheumatology online journal • 2014 • Mutations in CECR1 associated with a neutrophil signature in peripheral blood PMID:25278816

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