AB0221 ADA2 Deficiency: Description of a New Mutation for a Surprising Phenotype

BackgroundAutosomal recessive loss of function mutations in CECR1 encoding adenosine deaminase 2 (ADA2) were newly reported to cause early-onset stroke and inflammatory vasculoapthy with polyarteritis nodosa as pathological feature. Overexpression of interferon stimulated genes (ISGs) has been suggested as part of the physiopathology and neutrophil related genes signature has been described in some patients.ObjectivesTo describe the clinical and genetic features of two siblings; to measure ADA2 activity, secretion of inflammatory cytokines, interferon signature and expression of neutrophil related genes.MethodsDouble stranded DNA sequencing (NM_00128225.1) was performed. ADA2 activity in serum was assessed using a commercial kit. Methods for the assessment of the expression of a panel of ISGs and neutrophil stimulated genes have been previously published and validated. Cytokine secretion was assessed by ELISA.ResultsWe report the case of a 9 years old girl of non consanguineous parents presenting at the age of 3 years with fever, systemic inflammation, lesions of cutaneous vasculitis and inflammatory muscles lesions. Muscular biopsy fund focal necroziting angeitis of a minor interfascicular artery compatible with a periarteritis nodosa. The girl experienced neurological ischemic transient attack with mild lymphocytic pleocytosis in the cerebrospinal fluid and two strokes leaving here with spasticity and a diminution of her mental performances. MRI showed pedoncular and mesencephalic lesions. She was resistant to steroids, cyclosporine and azathioprine. Pulses of cyclophosphamid allowed a transient clinical remission but she presented once more an aggravation and we decided to move to antiTNF (etanercept)Her sister was followed for anemia since age of one year, with mild unexplained inflammatory syndrome. She had no cutaneous or muscular expression and no fever. At the age of 3, she presented with transient paralysis of the third cranial nerve. At the age of 5, she presented with transient vestibulitis. Both were considered as viral but cerebral MRI revealed a lacunar stroke.Double stranded DNA sequencing showed an biallelic mutation: p.Tyr453Cys, already published and known to be pathogen by prediction analysis and a deletion of exon 6 predicted to shift the reading frame. ADA2 activity showed a significant reduction compared to control. In the two cases, interferon related genes signature was significantly elevated. Neutrophil genes showed no increased ex