Mutant ADA2 in Vasculopathies

Abstract

T h e ne w e ngl a nd jou r na l o f m e dicine n engl j med 371;5 nejm.org july 31, 2014 478 CRT-D between patients with ischemic cardiomyopathy with NYHA class I or class II and patients with nonischemic cardiomyopathy. Hazard ratios were similar in these groups (0.66, 0.65, and 0.57, respectively), which denoted a similar effect size.We do, however, agree with the correspondents that because of sample-size limitations, more prospective data are necessary to corroborate the beneficial effects of CRT-D among patients with asymptomatic ischemic cardiomyopathy.To the Editor: Zhou et al. 1 and Navon Elkan et al. 2 (both in the March 6 issue) speculate that hematopoietic stem-cell transplantation (HSCT) or enzyme-replacement therapy may be beneficial in patients with adenosine deaminase 2 (ADA2) deficiency. We report the clinical course of two brothers with recently diagnosed ADA2 deficiency resulting from a homozygous mutation in CECR1 (p.R169Q). One sibling underwent HSCT in 2003. (CECR1 encodes the protein ADA2.)One brother presented in 1999, at 6 months of age, with livedo reticularis, hepatosplenomegaly, hypercoagulability, granulocytopenia, and complete red-cell aplasia. He underwent HSCT in 2003 for a presumed diagnosis of atypical Diamond-Blackfan anemia; the transplant was obtained from a matched unrelated donor after myeloablative conditioning. The patient showed rapid immune reconstitution, with resolution of cytopenias, skin lesions, hepatosplenomegaly, and hypercoagulability. He has had 100% donor chimerism in peripheral blood and has been not been taking medications for any of these conditions for 9 years. Serum ADA2 levels are now within the normal range for his age. A recent magnetic resonance image of the brain was negative for vasculopathic changes. HSCT corrected the CECR1 mutation in blood cells, but not in (somatic) buccal mucosa cells.This patient's younger brother presented in 2009, at 6 years of age, with hepatosplenomegaly, hypogammaglobulinemia, and profound lymphopenia. He also had unexplained fever, livedo reticularis, and stroke at the age of 10, which prompted us to sequence CECR1. Treatment with a tumor necrosis factor (TNF) inhibitor (etanercept) has stabilized his clinical condition, al-though he has persisting profound lymphopenia and low-grade inflammation. HSCT is being considered.The absence of vasculopathy and the resolution of hypercoagulability after HSCT in the older brother suggests that the correction of ADA2 blood levels reduces macrophage activation and endothelial disruption, both of which probably cause vasculitis and stroke in patients with ADA2 deficiency.

Monogenic polyarteritis: the lesson of ADA2 deficiency

“…Similarly a third patient with a lymphoprolipherative clinical picture, resembling Castleman’s syndrome, has been reported by the same group [5]. …”

“…Of note, despite the low immunoglobulins’ levels, only few cases displayed an increased susceptibility to infections, that was rather severe in exceptional cases [1, 3, 7, 12, 13]. …”

“…Navon et al reported ten patients treated with anti-TNF drugs (etanercept, adalimumab, infliximab) with complete response in 8, even after the failure of immunosuppressive therapies [2]; good results with anti-TNF agents were also reported in other small series [3, 11, 12]. By now, the reason why this drug is effective is still unclear.…”

The classification, genetic diagnosis and modelling of monogenic autoinflammatory disorders

“…In a subsequent study of 48 cases with polyarteritis nodosa associated with livedo reticularis and/or strokes, Gattorno et al performed Sanger sequencing of CECR1 and determined that 15 cases harboured homozygous or compound heterozygous mutations [88]. Since the time of the original description, there has been an expansion of the clinical phenotype of cases with DADA2, from cytopaenias and pure red cell aplasia [89], to lymphoproliferative disease [90–92], and combined immune deficiency, as well as common variable immune deficiency (CVID) [93]. Indeed, a cohort study of 181 cases with antibody deficiency diagnosed 11 individuals with mutation and enzyme activity confirmed DADA2 [94].…”

Adenosine deaminase type 2 deficiency masquerading as GATA2 deficiency: Successful hematopoietic stem cell transplantation

“…A 4 year-old patient with ADA2 was also successfully transplanted with an unrelated donor after myeloablative conditioning. (9) …”