Screening for Maternally Inherited Diabetes and Deafness in Large Cohorts of Hearing Impaired and Diabetic Patients

ObjectivesMitochondrial DNA (mtDNA) mutations account for up to 5% of hereditary hearing loss cases. Most commonly, the m.3243A>G mtDNA variant contributes to rare monogenic MIDD (Maternally Inherited Diabetes and Deafness) or MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes) syndromes. Different proportions of the mutated mtDNA (heteroplasmy) among the affected tissues result in variability in the clinical manifestation and severity of the phenotype. The aim of the presented study was to establish the prevalence of the m.3243A>G variant in large cohorts of hearing-impaired and diabetic patients in Slovakia and to evaluate the genotype-phenotype correlations and long-term cochlear implantation outcomes. DesignProbands (n=5957) were recruited via three independent nationwide studies on hereditary hearing loss (n=1145) and diabetes (unselected diabetes group, n=4158 and Monogenic diabetes group, n=654; total n=4812). DNA from peripheral blood and/or buccal mucosa was tested for the presence of the m.3243A>G variant using two PCR methods - qPCR and dPCR. Audiological and other clinical data of the identified variant carriers were also collected for phenotype evaluation. ResultsWe identified 25 probands/families harboring the m.3243A>G variant (0.42%). The prevalence was higher in the groups where monogenic disorder was suspected - 0.79% in the Hearing loss group and 1.68% in the Monogenic diabetes group versus 0.14% in the general diabetes group (p < 0.001). Heteroplasmy levels assessed by dPCR ranged between 0.04% and 76% in peripheral blood and 0.01% and 92% in buccal samples. In most individuals, the symptoms manifested in the fourth decade of life in affected subjects with the MIDD phenotype or isolated hearing loss/diabetes, but as early as in the second decade in the probands with MELAS. We observed high phenotype variability, ranging from severe multisystemic involvement through isolated symptoms to asymptomatic young "dormant" or very low heteroplasmy carriers. Only 54% of individuals with the m.3243A>G variant had both diabetes and hearing loss. The heteroplasmy levels from buccal swabs showed a better correlation with the age of onset of both hearing loss and diabetes than the age-adjusted blood heteroplasmy. On the other hand, the age-adjusted blood heteroplasmy was associated with overall severity of the disease (i.e., with a higher number of clinical symptoms). We show that the most typical audiogram configurations are flat and sloping. Three individuals identified as cochlear implant recipients showed excellent and long-term stable functional outcomes. In addition, the authors report the first case of successful stapes surgery in a patient with confirmed mitochondrial disorder. ConclusionsThe diagnostic yield was higher in the deafness and monogenic diabetes groups than in the unselected diabetes group. Implementation of rigorous inclusion criteria requiring the presence of both diabetes and hearing loss may lead to a lower detection rate due to different or incomplete phenotype manifestation. Age-adjusted blood heteroplasmy levels seem to be a good predictor of overall severity of m.3243A>G-associated diseases, but buccal mucosa heteroplasmy better predicted the age of hearing loss and diabetes onset. We further confirm that cochlear implantation and stapedectomy are safe and efficient options for hearing restoration and rehabilitation in m.3243A>G carriers.