Abstract
Background: Inherited defects in adenosine deaminase (ADA) cause severe immune deficiency, which can be corrected by ADA enzyme replacement therapy (ERT). Additionally, ADA-deficient patients suffer from hearing impairment. 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.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). The cochlea was visualized by scanning electron microscopy (SEM). 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.Results: Markedly abnormal hearing thresholds responses were found in ADA–/– mice at low and medium tone frequencies. SEM demonstrated extensive damage to the cochlear hair cells of ADA–/– mice, which were splayed, short or missing, correlating with the hearing deficits. The hearing defects were not reversed when hypoxia in ADA–/– mice was corrected. 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. 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.Conclusions: ADA deficiency is associated with hearing deficits and damage to cochlear hair cells. Early initiation of ERT improves the hearing and immune abnormalities.
Highlights
Adenosine deaminase (ADA) is a ubiquitous enzyme important for the degradation and salvage of purine metabolites, including adenosine (Ado) and deoxyadenosine
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
Hearing onset in mice occurs at 11–13 days pp [30] and ADA–/– mice suffer respiratory failure and death by 19–21 days pp, auditory brainstem evoked response (ABR) testing was performed at 17 days pp
Summary
Adenosine deaminase (ADA) is a ubiquitous enzyme important for the degradation and salvage of purine metabolites, including adenosine (Ado) and deoxyadenosine (dAdo). 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]. Diverse neurological abnormalities, such as seizures, developmental delay, and cognitive impairment have frequently been reported among ADA-deficient patients [9,10,11]. Inherited defects in adenosine deaminase (ADA) cause severe immune deficiency, which can be corrected by ADA enzyme replacement therapy (ERT). We hypothesized that ADA-deficient (–/–) mice exhibit hearing abnormalities and that ERT from an early age will improve the hearing and immune defects in these mice
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