ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 894

Intermittent Fever, Immune Dysregulation, and Systemic Vasculopathy Due To Loss-Of-Function Mutations In Adenosine Deaminase2

Qing Zhou1, Dan Yang2, Andrey Zavialov3, Amanda Ombrello4, Hyesun Kuehn5, Jae Jin Chae6, Anton Zavialov3, David Chin7, Deborah Stone8, Camilo Toro9, Joshua Milner10, Chyi-chia Lee11, Edward Cowen12, Fabio Candotti13, Elaine Remmers7, Susan Moir14, Raman Sood15, Shawn Burgess16, Massimo Gadina17, Sergio Rosenzweig18, Michael Hershfield19, Daniel L. Kastner20, Manfred Boehm2 and Ivona Aksentijevich7, 1Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 2Laboratory of Cardiovascular Regenerative Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 3Turku Centre for Biotechnology, University of Turku, Turku, Finland, 4National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 5Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, 6Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 7Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 8National Human Genome Research Institute, Bethesda, MD, 9NIH Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 10Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 11National Cancer Institute, National Institutes of Health, Bethesda, MD, 12Dermatology Consultation Servce, National Cancer Institute, National Institutes of Health, Bethesda, MD, 13Disorder of Immunity Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 14Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 15Zebrafish Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 16Developmental Genomics Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 17Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, 18National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 19Department of Medicine, Duke University Medical Center, Durham, NC, 20Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: , ,

Session Information

Title: Vasculitis I

Session Type: Abstract Submissions (ACR)

Background/Purpose:

We observed a syndrome characterized by intermittent fevers and livedoreticularis, systemic inflammation, hepatosplenomegaly, cytopenias, vasculopathy, and early-onset lacunar strokes in five unrelated patients.  We suspected a genetic cause because the disorder presented in early childhood.

Methods:

We performed whole-exome and candidate gene sequencing on the patients and their unaffected parents. Patient samples were analyzed by ELISA, immunoblotting, immunohistochemistry, flow cytometry, and cytokine profiling.  Morpholino knockdowns in zebrafish embryos were used to study gene function.

Results:

Our patients were compound heterozygous for 5 missense mutations(G47A, A109D, H112Q, R169Q, Y453C) anda 28kb genomic deletion in CECR1encoding adenosine deaminase2 (ADA2).All mutations are either novel or present at low frequency (<0.001) in several large databases, consistent with the recessive inheritance. The Y453C mutation was present in an NHLBI exomedatabase in 2 siblings who suffered from late-onset ischemic stroke. This finding indicatesthat heterozygous mutations in ADA2 might be associated with susceptibility to adult stroke.Computer modeling based on the crystal structure of the human ADA2 suggests that CECR1 mutations either disrupt protein stability or impair ADA2 enzyme activity.Patients had at least a 10-fold reduction in blood ADA2, and dramatically reduced ADA2-specific adenosine deaminase activity in blood and CD14+ monocytes.  In contrast to patients with ADA1 deficiency and severe combined immunodeficiency, there was no accumulation of deoxyadenosine or its toxic metabolites in patients’ blood suggesting new functional role of ADA2 addition to its enzyme activity. cecr1bknockdown caused intracranial hemorrhages in zebrafish embryossuggesting defects in vessel development.The intracranial hemorrhage phenotype was rescued with wild type human CECR1 mRNA, but not by the R169Q mutant mRNA.Skin, liver, and brain biopsies from patients showed a diffuse vasculopathy, with evidence of impaired endothelial integrity and endothelial cellular activation.

Conclusion:

Recessive mutations in CECR1 cause ADA2 deficiency manifesting with diffuse vasculopathy, systemic inflammation, and early-onset stroke.  Ex vivo experiments with patients’ cells, in vitro cell culture studies,and animal model data suggest an important role for ADA2 in vascular and leukocyte development, consistent with its proposed role as a growth factor.ADA2 replacement with the fresh frozen plasma transfusions, enzyme therapies with recombinant ADA2, gene therapy, and hematopoietic stem cell transplantation are possible treatment options.

Disclosure:

Q. Zhou,
None;

D. Yang,
None;

A. Zavialov,
None;

A. Ombrello,
None;

H. Kuehn,
None;

J. J. Chae,
None;

A. Zavialov,
None;

D. Chin,
None;

D. Stone,
None;

C. Toro,
None;

J. Milner,
None;

C. C. Lee,
None;

E. Cowen,
None;

F. Candotti,
None;

E. Remmers,
None;

S. Moir,
None;

R. Sood,
None;

S. Burgess,
None;

M. Gadina,
None;

S. Rosenzweig,
None;

M. Hershfield,
None;

D. L. Kastner,
None;

M. Boehm,
None;

I. Aksentijevich,
None.

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