However, the neurological and hearing defects often persist, possibly because of the irreversible damage occurring prior to treatment ( 12, 15). Lung abnormalities also improve following HSCT ( 8). The immune defects are corrected by hematopoietic stem cells transplants (HSCT) using ADA-proficient allogeneic cells or autologous ex-vivo gene-corrected cells ( 14). Alternatively, the abnormal hearing in ADA deficiency might be directly caused by the altered Ado metabolism.ĪDA deficiency can be treated by different treatment modalities. Infections, autoimmunity, hypoxia, or increased susceptibility of the auditory structures to medications used to treat ADA-SCID patients have been proposed as a potential cause(s) for the hearing deficits. Additionally, sensory-neural auditory abnormalities have been identified in ADA-deficient patients ( 12, 13), however, the hearing defects have not been well-characterized and their pathogenesis is not clear. Diverse neurological abnormalities, such as seizures, developmental delay, and cognitive impairment have frequently been reported among ADA-deficient patients ( 9– 11). Additionally, patients often suffer from non-infectious complications including skeletal dysplasia ( 3, 4), renal mesangial sclerosis ( 5), hepatic failure ( 6), myeloid abnormalities ( 7), and pulmonary alveolar proteinosis ( 8). ADA-deficient SCID (ADA-SCID) patients typically present in the first months of life with increased susceptibility to infections ( 2). The inherited absence of ADA leads to accumulation of these metabolites that are toxic to rapidly proliferating cells such as lymphocytes ( 1), resulting in severe combined immunodeficiency (SCID). Early initiation of ERT improves the hearing and immune abnormalities.Īdenosine deaminase (ADA) is a ubiquitous enzyme important for the degradation and salvage of purine metabolites, including adenosine (Ado) and deoxyadenosine (dAdo). ERT initiated at 7 days pp significantly improved the hearing of ADA–/– mice as well as the number of thymocytes and T lymphocytes, although not all normalized.Ĭonclusions: ADA deficiency is associated with hearing deficits and damage to cochlear hair cells. Progressive immune abnormalities were detected in ADA–/– mice from 4 days pp, initially affecting the thymus followed by peripheral lymphocytes and T cells in the spleen. The hearing defects were not reversed when hypoxia in ADA–/– mice was corrected. SEM demonstrated extensive damage to the cochlear hair cells of ADA–/– mice, which were splayed, short or missing, correlating with the hearing deficits. Results: Markedly abnormal hearing thresholds responses were found in ADA–/– mice at low and medium tone frequencies. The effects of polyethylene glycol conjugated ADA (PEG-ADA) ERT or 40% oxygen initiated at 7 days pp on the hearing and immune abnormalities were assessed. The cochlea was visualized by scanning electron microscopy (SEM). Methods: Auditory brainstem evoked responses, organ weights, thymocytes numbers, and subpopulations, lymphocytes in peripheral blood as well as T lymphocytes in spleen were analyzed in ADA–/– and ADA-proficient littermate post-partum (pp). We hypothesized that ADA-deficient (–/–) mice also exhibit hearing abnormalities and that ERT from an early age will improve the hearing and immune defects in these mice. Additionally, ADA-deficient patients suffer from hearing impairment. 7Division of Immunology and Allergy, Hospital for Sick Children, Toronto, ON, Canadaīackground: Inherited defects in adenosine deaminase (ADA) cause severe immune deficiency, which can be corrected by ADA enzyme replacement therapy (ERT).6Department of Otolaryngology, University of Toronto, Toronto, ON, Canada.5Department of Laboratory Medicine & Pathology, Hospital for Sick Children, Toronto, ON, Canada.4Translational Medicine Program, Hospital for Sick Children, Toronto, ON, Canada.3Neuroscience and Mental Health Program, Hospital for Sick Children, Toronto, ON, Canada.
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