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 - TY - JOUR T1 - Clinical Characteristics of Patients Carrying the Q703K Variant of the NLRP3 Gene: A 10-year Multicentric National Study. JF - J Rheumatol Y1 - 2016 A1 - Naselli, Aldo A1 - Penco, Federica A1 - Cantarini, Luca A1 - Insalaco, Antonella A1 - Alessio, Mariolina A1 - Tommasini, Alberto A1 - Maggio, Cristina A1 - Obici, Laura A1 - Gallizi, Romina A1 - Cimmino, Marco A1 - Signa, Sara A1 - Lucherini, Orso Maria A1 - Carta, Sonia A1 - Caroli, Francesco A1 - Martini, Alberto A1 - Rubartelli, Anna A1 - Ceccherini, Isabella A1 - Gattorno, Marco AB -

OBJECTIVE: The aim of our study was to analyze the clinical and functional effect of the p.Q703K (p. Q705K, c. 2107C>A) variant of the NLRP3 gene in a population of patients screened for suspected cryopyrin-associated periodic syndrome (CAPS).

METHODS: Since 2002, 580 patients underwent molecular analysis for NLRP3. Data on clinical presentation, response to treatment, and longterm followup were collected using a uniform questionnaire. The pattern of cytokine secretion after lipopolysaccharide stimulation from isolated monocytes was analyzed in 3 patients carrying the p.Q703K variant and 1 patient with a chronic infantile neurologic, cutaneous, articular syndrome phenotype carrying both the p.M406I and p.Q703K, and compared with 7 patients with CAPS with sure pathogenic variants and 6 healthy controls.

RESULTS: The p.Q703K variant was found in 57 screened patients with an overall allelic frequency of 5%. The frequency in normal controls was 5.5%. Clinical data at the moment of molecular analysis and at followup were available in 36 patients. Two patients displayed additional mutations of NLRP3. The mean followup was 2.5 years. Thirteen patients (39%) had a final diagnosis different from the original suspicion of CAPS. The remaining 21 patients displayed a mild phenotype mainly characterized by recurrent episodes of urticarial rash and arthralgia. Only 8 patients were treated with anti-interleukin (IL)-1 treatment, with a complete response in 5 patients. The pattern of secretion of IL-1β and other cytokines (IL-6 and IL-1 receptor antagonist) in patients did not display the aberrancies observed in patients with CAPS and was similar to that observed in healthy controls.

CONCLUSION: The present study confirms the weak clinical and functional effect of the p.Q703K variant.

VL - 43 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27036377?dopt=Abstract ER -