Beyond the cochlea: exploring the multifaceted nature of hearing loss in primary mitochondrial diseases.

Primary mitochondrial diseases, with diverse systemic manifestations, often present with auditory impairments due to mitochondrial dysfunction. This study provides an in-depth exploration of auditory deficits in primary mitochondrial diseases, highlighting the impact of various pathogenic variants on both cochlea and neural/central auditory functions. An observational study involving 72 adults with primary mitochondrial diseases was conducted. Participants underwent extensive audiological evaluations including pure-tone audiometry, tympanometry, acoustic reflex thresholds, quick speech-in-noise test, listening in spatialized noise-sentences test, auditory-evoked brainstem responses and distortion product otoacoustic emissions. Multivariate analysis of covariance and logistic regression analyses assessed the influence of various pathogenic DNA variants, accounting for age, cognitive status via the Montreal Cognitive Assessment and disease severity through the Newcastle Mitochondrial Disease Adult Scale. Participants with the pathogenic m.3243A>G/T variants (m.3243A>G = 40; m.3243A>T = 1) exhibited significant elevations in pure-tone audiometry thresholds, especially at high frequencies, suggesting cochlea involvement. Notably, the listening in spatialized noise-sentences test showed significant spatial processing deficits in the m.3243A>G/T group, possibly indicating a unique mutation-specific impact on central auditory processing. Auditory-evoked brainstem response results highlighted a higher likelihood of auditory brainstem response abnormalities in this group, further substantiating neural/central auditory pathway involvement. This study emphasizes the heterogeneous nature of hearing impairment in primary mitochondrial diseases, with a genotype-phenotype correlation, particularly in the m.3243A>G/T group. These insights advocate for personalized, genotype-specific auditory assessments and targeted management strategies. Conventional hearing aids and cochlear implants are ineffective for those with central auditory dysfunctions related to mitochondrial mutations. There is an urgent need for innovative rehabilitation strategies catering for both cochlear and neural/central auditory pathways.