A Cohort Study on Deficiency of ADA2 from China

Abstract

Purpose: Deficiency of adenosine deaminase 2 (DADA2), an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function variants in adenosine deaminase 2 (ADA2), has not been systemically investigated in Chinese population yet. We aim to further characterize DADA2 cases in China.

Methods: A retrospective analysis of patients with DADA2 identified through whole exome sequencing (WES) at seventeen rheumatology centers across China was conducted. Clinical characteristics, laboratory findings, genotype, and treatment response were analyzed.

Results: Thirty patients with DADA2 were enrolled between January 2015 and December 2021. Adenosine deaminase 2 enzymatic activity was low in all tested cases to confirm pathogenicity. Median age of disease presentation was 4.3 years and the median age at diagnosis was 7.8 years. All but one patient presented during childhood and two subjects died from complications of their disease. The patients most commonly presented with systemic inflammation (92.9%), vasculitis (86.7%), and hypogammaglobinemia (73.3%) while one patient presented with bone marrow failure (BMF) with variable cytopenia. Twenty-three (76.7%) patients were treated with TNF inhibitors (TNFi), while two (6.7%) underwent hematopoietic stem cell transplantation (HSCT). They all achieved clinical remission. A total of thirty-nine ADA2 causative variants were identified, six of which were novel.

Conclusion: To establish early diagnosis and improve clinical outcomes, genetic screening and/or testing of ADA2 enzymatic activity should be performed in patients with suspected clinical features. TNFi is considered as first line treatment for those with vascular phenotypes. HSCT may be beneficial for those with hematological disease or in those who are refractory to TNFi.

Keywords: Adenosine deaminase 2; Deficiency of adenosine deaminase 2; Hematology; Hematopoietic stem cell transplantation; TNF inhibitors; Vasculitis.

Fig. 1

ADA2 activity of novel ADA2 variants measured in patients and cell cultures. (a) ADA2 activity of DADA2 patients carrying novel ADA2 variants is lower than carriers with known ADA2 pathogenic variants (n = 2) or HC (n = 3). (b, c) ADA2 activity of whole cell lysates and supernatants of 293 T cells transfected with novel ADA2 mutants compared to WT. (d) Western blots of 293 T cells transfected with novel ADA2 mutants. As P9 has gone and P2 is lost to follow up, ADA2 activity of these patients was not been tested. HC, healthy control; WT, wild type; EV, empty vector

Fig. 2

Flow chart of diagnosis and treatment of DADA2. HSCT, hematopoietic stem cell transplantation; MMF, mycophenolate mofetil; TNFi, TNF inhibitor