Journal of Clinical Immunology | 2019
Homozygous Splice ADA2 Gene Mutation Causing ADA-2 Deficiency
Abstract
To the Editor: One recently discovered immune dysregulation syndromes is deficiency of adenosine deaminase 2 (DADA 2) caused by biallelic loss of functionmutations inADA2, previously known as CECR1 [1–3]. The clinical phenotype of DADA2 was initially described as intermittent fevers, early-onset ischemic or hemorrhagic strokes and other neurovascular manifestations, livedo reticularis, polyarteritis nodosa hepatosplenomegaly, systemic vasculopathy, and hypogammaglobulinemia [1–3]. Subsequently, case reports suggested that DADA2 patients may present with a highly variable clinical phenotype and that many symptoms are responsive to therapy with anti-tumor necrosis factor agents, including cytopenia and bone marrow failure [4–7]. Here, we present a Brazilian girl with recurrent ischemic and hemorrhagic strokes starting at age 18 months who at 6 years of age was diagnosed with a homozygous splice mutation in the CECR1 gene. The patient was born to healthy non-consanguineous parents; her older sister was asymptomatic and the family history was negative for autoimmune or autoinflammatory disorders or recurrent infections. At 9 months of age, she presented with recurrent fever episodes and at age 18 months, she was admitted to the intensive care unit (ICU) with acute onset ocular deviation, seizures, and flaccid tetraparesis, with a diagnosis of ischemic and hemorrhagic stroke by CNS imaging (Fig. 1). At that time, livedo reticularis was noticed (Fig. 2). She was hospitalized four more times with episodes of ischemic/hemorrhagic strokes, at 28months and at 4, 5, and 6 years of age. Following the last episode, she was admitted to the ICU and referred to the Immunology Division. At that time, she had mild hypogammaglobulinemia (IgG, 467 mg/dL (665–1465 mg/dL); IgA, 21 mg/dL (47–267 mg/ dL); IgM, 14mg/dL (49–218mg/dL), IgE < 25 kU/L (< 25 kU/ L)). Lymphocyte subsets: CD3 = 853 cells/μL (1280–2413 cells/μL); CD4+, 499.2 cells/μL (618–1348 cells/μL); CD8+, 353.8 cells/μL (390–1024cells/μL); CD56+, 80.9 cells/μL (217–515 cells/μL); and CD19, 113/μL (471–1031 cells/μL). Based on medical history and physical findings, we suspected DADA2 and analyzed the CECR1 gene by Sanger sequencing. A homozygous mutation located at position − 2 in the acceptor splice site of intron 6 (c.973-2A>G (genomic location Chr22: 17669339 on Assembly GRCh37) was identified, and predicted to be pathogenic (Figs. 3 and 4). To confirm the pathogenicity, we performed two additional analyses, mRNA expression and the enzyme activity of ADA2. The cDNA analysis showed lack of CECR1 mRNA expression and ADA2 enzyme activity, performed by dried plasma spot, showing 0.0 mU/g of protein, confirming a loss of function mutation. Based on these findings, she was started on the anti-TNF monoclonal antibody, etanercept, with excellent results, being symptom free for the last 2 years. ADA1 conver t s adenos ine to inos ine and 2 ′ deoxyadenosine to 2′-deoxyinosine and its deficiency causes lymphopenia and severe combined immunodeficiency disease (SCID) due to the accumulation of toxic deoxyadenosine nucleotides in the cytoplasm [1]. While human ADA1 and ADA2 show partial structural homology, they are structurally and probably functionally distinct, since the accumulation of deoxyadenosine nucleotides is absent in erythrocytes from patients with ADA2 deficiency [2, 3]. * Herberto Jose Chong-Neto