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

Roberta Caorsi, Federica Penco, Alice Grossi, Antonella Insalaco, Alessia Omenetti, Maria Alessio, Giovanni Conti, Federico Marchetti, Paolo Picco, Alberto Tommasini, Silvana Martino, Clara Malattia, Romina Gallizi, Rosa Anna Podda, Annalisa Salis, Fernanda Falcini, Francesca Schena, Francesca Garbarino, Alessia Morreale, Manuela PardeoClaudia Ventrici, Chiara Passarelli, Qing Zhou, Mariasavina Severino, Carlo Gandolfo, Gianluca Damonte, Alberto Martini, Angelo Ravelli, Ivona Aksentijevich, Isabella Ceccherini, Marco Gattorno

Research output: Contribution to journalArticle

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.

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.

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.

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.

Original languageEnglish
Pages (from-to)1648-1656
Number of pages9
JournalAnnals of the Rheumatic Diseases
Volume76
Issue number10
DOIs
Publication statusPublished - Oct 2017

Keywords

  • Adenosine Deaminase
  • Adolescent
  • Age of Onset
  • Case-Control Studies
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Female
  • Heterozygote
  • Homozygote
  • Humans
  • Immunoglobulins
  • Immunosuppressive Agents
  • Infant
  • Intercellular Signaling Peptides and Proteins
  • Italy
  • Livedo Reticularis
  • Male
  • Pedigree
  • Polyarteritis Nodosa
  • Stroke
  • Thalidomide
  • Tumor Necrosis Factor-alpha
  • Young Adult
  • Journal Article
  • Multicenter Study

Fingerprint Dive into the research topics of 'ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study'. Together they form a unique fingerprint.

  • Cite this

    Caorsi, R., Penco, F., Grossi, A., Insalaco, A., Omenetti, A., Alessio, M., Conti, G., Marchetti, F., Picco, P., Tommasini, A., Martino, S., Malattia, C., Gallizi, R., Podda, R. A., Salis, A., Falcini, F., Schena, F., Garbarino, F., Morreale, A., ... Gattorno, M. (2017). ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study. Annals of the Rheumatic Diseases, 76(10), 1648-1656. https://doi.org/10.1136/annrheumdis-2016-210802