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ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study.

Authors :
Caorsi R
Penco F
Grossi A
Insalaco A
Omenetti A
Alessio M
Conti G
Marchetti F
Picco P
Tommasini A
Martino S
Malattia C
Gallizzi R
Podda RA
Salis A
Falcini F
Schena F
Garbarino F
Morreale A
Pardeo M
Ventrici C
Passarelli C
Zhou Q
Severino M
Gandolfo C
Damonte G
Martini A
Ravelli A
Aksentijevich I
Ceccherini I
Gattorno M
Source :
Annals of the rheumatic diseases [Ann Rheum Dis] 2017 Oct; Vol. 76 (10), pp. 1648-1656. Date of Electronic Publication: 2017 May 18.
Publication Year :
2017

Abstract

Objectives: To analyse the prevalence of CECR1 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.<br />Methods: Direct sequencing of CECR1 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.<br />Results: Biallelic homozygous or compound heterozygous CECR1 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 CECR1 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.<br />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.<br />Competing Interests: Competing interests: None declared.<br /> (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Details

Language :
English
ISSN :
1468-2060
Volume :
76
Issue :
10
Database :
MEDLINE
Journal :
Annals of the rheumatic diseases
Publication Type :
Academic Journal
Accession number :
28522451
Full Text :
https://doi.org/10.1136/annrheumdis-2016-210802