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Adenosine Deaminase (ADA)-Deficient Severe Combined Immune Deficiency (SCID): Molecular Pathogenesis and Clinical Manifestations

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Abstract

Deficiency of adenosine deaminase (ADA, EC3.5.4.4), a housekeeping enzyme of purine metabolism encoded by the Ada gene, is a cause of human severe combined immune deficiency (SCID). Numerous deleterious mutations occurring in the ADA gene have been found in patients with profound lymphopenia (T− B− NK−), thus underscoring the importance of functional purine metabolism for the development of the immune defense. While untreated ADA SCID is a fatal disorder, there are multiple life-saving therapeutic modalities to restore ADA activity and reconstitute protective immunity, including enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) with autologous gene-corrected hematopoietic stem cells (HSC). We review the pathogenic mechanisms and clinical manifestations of ADA SCID.

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Abbreviations

ADA:

Adenosine deaminase

Ado:

Adenosine

AdoHCy:

S-Adenosyl-L-homocysteine

BMT:

Bone marrow transplantation

d-Ado:

2′-Deoxyadenosine

d-ATP:

Deoxyadenosine triphosphate

DFSP:

Dermatofibrosarcoma protuberans

d-Ino:

Deoxyinosine

dCydK:

Deoxycytidine kinase

ERT:

Enzyme replacement therapy

GALT:

Gut-associated lymphoid tissue

GI:

Gastrointestinal

HSCT:

Hematopoietic stem cell transplantation

Ino:

Inosine

PEG-ADA:

Polyethylene glycol conjugated adenosine deaminase

PJP:

Pneumocystis jiroveci pneumonia

SCID:

Severe combined immune deficiency

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Acknowledgements

The authors would like to acknowledge the support of Great Ormond Street Hospital Children’s Charity (HBG).

Funding

ADA SCID research in the Kohn lab has been supported by the Doris Duke Charitable Foundation (Distinguished Clinical Scientist Award), the U.S. Food and Drug Administration (Orphan Product Grant R01FD003005), the National Institutes of Health (P50-HL54850, P01-HL073104, U01-AI100801, and R01-A1074043) and the California Institute for Regenerative Medicine (UCLA-UCI Alpha Stem Cell Clinic). This study was supported by the National Institute of Health Research Biomedical Research Centre at Great Ormond Street Hospital and University College London. FM is supported by the MRC UK. KLB is a recipient of an ASH Hematology Opportunities for the Next-Generation of Research Scientists (HONORS) Award.

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  1. Denise A. Carbonaro-Sarracino

    Present address: Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, CA, USA

Authors and Affiliations

  1. Department of Pediatrics, University of California, Los Angeles (UCLA), 3163 Terasaki Life Science Bldg., 610 Charles E. Young Drive East, Los Angeles, CA, 90095, USA

    Kathryn L. Bradford & Donald B. Kohn

  2. Centre for Immunodeficiency, Molecular Immunology Unit, University College London Institute of Child Health, London, UK

    Federico A. Moretti & Hubert B. Gaspar

  3. Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, CA, USA

    Donald B. Kohn

  4. Department of Molecular & Medical Pharmacology, UCLA University of California, Los Angeles, CA, USA

    Donald B. Kohn

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  1. Kathryn L. Bradford
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  2. Federico A. Moretti
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  3. Denise A. Carbonaro-Sarracino
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  5. Donald B. Kohn
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Correspondence to Donald B. Kohn.

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Conflict of Interest

DACS is an employee of Orchard Therapeutics Limited and DBK and HBG are members of the Scientific Advisory Board and consultants to Orchard Therapeutics, who are developing a commercial lentiviral vector gene therapy product.

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Bradford, K.L., Moretti, F.A., Carbonaro-Sarracino, D.A. et al. Adenosine Deaminase (ADA)-Deficient Severe Combined Immune Deficiency (SCID): Molecular Pathogenesis and Clinical Manifestations. J Clin Immunol 37, 626–637 (2017). https://doi.org/10.1007/s10875-017-0433-3

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