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 (HL) cases. Most commonly, the m.3243A>G mtDNA variant contributes to rare monogenic Maternally Inherited Diabetes and Deafness or 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 patients with HL and diabetes in Slovakia and to evaluate the genotype-phenotype correlations and long-term cochlear implantation outcomes in a small subset.

designProbands (n = 5957) were recruited via 3 independent nationwide studies on HL (hereditary HL group, n = 1145) and diabetes (general 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 polymerase chain reaction (PCR) methods-quantitative real-time PCR and digital PCR. Audiological and other clinical data of the identified variant carriers were also collected for phenotype evaluation.

resultsWe identified 25 probands harboring the m.3243A>G variant (0.42%). The prevalence was higher in the groups where genetic etiology was suspected-0.79% in the hereditary HL group and 1.68% in the monogenic diabetes group versus 0.14% in the general diabetes group ( p < 0.001). Furthermore, we have identified the m.3243A>G variant in 38 family members. Heteroplasmy levels assessed by digital PCR 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 Maternally Inherited Diabetes and Deafness phenotype or isolated HL/diabetes, but as early as in the second decade in the probands with Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes. We observed high phenotype variability, ranging from severe multisystemic involvement through isolated symptoms to asymptomatic young "dormant" or very low heteroplasmy carriers. Only 38% of individuals with the m.3243A>G variant had both diabetes and HL. The heteroplasmy levels from buccal swabs showed a better correlation with the age of onset of both HL 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 (28% of the affected ears) and sloping (42% of the affected ears). 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 a confirmed mitochondrial disorder and otosclerosis.

conclusionsThe diagnostic yield was higher in the hereditary HL and monogenic diabetes groups than in the general diabetes group. Implementation of rigorous inclusion criteria requiring the presence of both diabetes and HL 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 predicted the age of HL and diabetes onset better.