Myeloid dysplasia and bone marrow hypocellularity in adenosine deaminase-deficient severe combined immune deficiency

Abstract

Genetic deficiency of adenosine deaminase (ADA) can cause profound lymphopenia and result in the clinical presentation of severe combined immune deficiency (SCID). However, because of the ubiquitous expression of ADA, ADA-deficient patients often present also with nonimmunologic clinical problems, affecting the skeletal, central nervous, endocrine, and gastrointestinal systems. We now report that myeloid dysplasia features and bone marrow hypocellularity are often found in patients with ADA-SCID. As a clinical correlate to this finding, we have observed vulnerability to antibiotic-induced myelotoxicity and prolonged neutropenia after nonmyeloablative chemotherapy. We have also noted that, in the absence of enzyme replacement therapy, absolute neutrophil counts of patients with ADA deficiency vary inversely with the accumulation of deoxynucleotides. These data have significant implications for the application of standard and investigational therapies to patients with ADA-SCID and support further studies to investigate the possibility that ADA deficiency is associated with a stem cell defect. These trials were registered at www.clinicaltrials.gov as #NCT00018018 and #NCT00006319. (Blood. 2011;118(10):2688-2694)

Gene therapy for adenosine deaminase–deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans

“…The persistence of low ANC (200-500/mm 3 ) at 70-100 days after transplantation in the 3 subjects who eventually recovered neutrophil counts in response to G-CSF may be explained as a consequence of the myeloid dysplasia features that have been recognized recently to accompany ADA deficiency. 33 We also observed transitory elevation of transaminases that reached values over 5 times normal in 2 subjects (304C and 306N), who had previous histories of mild hepatosteatosis or hepatomegaly of undetermined nature. Although these complications were self-limited and without clinical sequelae, they are significant in that they did not correlate with AUC of busulfan and may reflect the specific hepatic sensitivity of some ADA-deficient patients.…”

Atypical hemolytic-uremic syndrome in a patient with adenosine deaminase deficiency

“…(Bollinger et al 1996;Grunebaum et al 2012). ADA deficiency can also affect patients' bone marrow (Sokolic et al 2011) and kidneys (Ratech et al 1985).…”

Gene Therapy with Hematopoietic Stem Cells: The Diseased Bone Marrow's Point of View

“…Among the various therapeutic options proposed to ADA patients, gene therapy appeared largely superior to haplo-identical HSCT in terms of survival and immune recovery [18]. When studying the bone marrow of patients with ADA deficiency, Sokolic et al found clear morphologic evidence of myeloid lineage dysplasia, including marrow hypocellularity, megaloblastic erythropoiesis, and abnormal megakaryocytes [19]. The dysplastic features seen in all hematopoietic lineages reflect adenosine metabolite toxicity at the stem cell level, and thus explain the relative degree of hypocellularity seen in the bone marrow of all patients for whom a core biopsy was performed.…”