TY - JOUR T1 - ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study. JF - Ann Rheum Dis Y1 - 2017 A1 - Caorsi, Roberta A1 - Penco, Federica A1 - Grossi, Alice A1 - Insalaco, Antonella A1 - Omenetti, Alessia A1 - Alessio, Maria A1 - Conti, Giovanni A1 - Marchetti, Federico A1 - Picco, Paolo A1 - Tommasini, Alberto A1 - Martino, Silvana A1 - Malattia, Clara A1 - Gallizi, Romina A1 - Podda, Rosa Anna A1 - Salis, Annalisa A1 - Falcini, Fernanda A1 - Schena, Francesca A1 - Garbarino, Francesca A1 - Morreale, Alessia A1 - Pardeo, Manuela A1 - Ventrici, Claudia A1 - Passarelli, Chiara A1 - Zhou, Qing A1 - Severino, Mariasavina A1 - Gandolfo, Carlo A1 - Damonte, Gianluca A1 - Martini, Alberto A1 - Ravelli, Angelo A1 - Aksentijevich, Ivona A1 - Ceccherini, Isabella A1 - Gattorno, Marco KW - Adenosine Deaminase KW - Adolescent KW - Age of Onset KW - Case-Control Studies KW - Child KW - Child, Preschool KW - DNA Mutational Analysis KW - Female KW - Heterozygote KW - Homozygote KW - Humans KW - Immunoglobulins KW - Immunosuppressive Agents KW - Infant KW - Intercellular Signaling Peptides and Proteins KW - Italy KW - Livedo Reticularis KW - Male KW - Pedigree KW - Polyarteritis Nodosa KW - Stroke KW - Thalidomide KW - Tumor Necrosis Factor-alpha KW - Young Adult AB -

OBJECTIVES: To analyse the prevalence of mutations in patients diagnosed with early onset livedo reticularis and/or haemorrhagic/ischaemic strokes in the context of inflammation or polyarteritis nodosa (PAN). Forty-eight patients from 43 families were included in the study.

METHODS: Direct sequencing of was performed by Sanger analysis. Adenosine deaminase 2 (ADA2) enzymatic activity was analysed in monocyte isolated from patients and healthy controls incubated with adenosine and with or without an ADA1 inhibitor.

RESULTS: Biallelic homozygous or compound heterozygous mutations were detected in 15/48 patients. A heterozygous disease-associated mutation (p.G47V) was observed in two affected brothers. The mean age of onset of the genetically positive patients was 24 months (6 months to 7 years). Ten patients displayed one or more cerebral strokes during their disease course. Low immunoglobulin levels were detected in six patients. Thalidomide and anti-TNF (tumour necrosis factor) blockers were the most effective drugs. Patients without mutations had a later age at disease onset, a lower prevalence of neurological and skin manifestations; one of these patients displayed all the clinical features of adenosine deaminase 2deficiency (DADA2) and a defective enzymatic activity suggesting the presence of a missed mutation or a synthesis defect.

CONCLUSIONS: DADA2 accounts for paediatric patients diagnosed with PAN-like disease and strokes and might explain an unrecognised condition in patients followed by adult rheumatologist. Timely diagnosis and treatment with anti-TNF agents are crucial for the prevention of severe complications of the disease. Functional assay to measure ADA2 activity should complement genetic testing in patients with non-confirming genotypes.

VL - 76 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28522451?dopt=Abstract ER -