Novel Variant of FDXR as a Molecular Etiology of Postlingual Post-synaptic Auditory Neuropathy Spectrum Disorder via Mitochondrial Dysfunction: Reiteration of the Correlation between Genotype and Cochlear Implantation Outcomes.

IF 2.9 3区 医学 Q1 OTORHINOLARYNGOLOGY
Bong Jik Kim, Yujin Kim, Ju Ang Kim, Jin Hee Han, Min Young Kim, Hee Kyung Yang, Chae-Seo Rhee, Young Cheol Kang, Chun-Hyung Kim, Byung Yoon Choi
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引用次数: 0

Abstract

Objectives: FDXR encodes mitochondrial ferredoxin reductase, which is associated with auditory neuropathy spectrum disorder (ANSD) and optic atrophy. To date, only two studies have described FDXR-related hearing loss. The auditory rehabilitation outcomes of this disease entity have not been investigated, and the pathophysiological mechanisms remain incompletely understood. Here we report a hearing-impaired individual with co-segregation of the FDXR variant and post-synaptic type ANSD, who underwent cochlear implantation (CI) with favorable outcomes. We suggest a possible pathophysiological mechanism of adult-onset ANSD involving mitochondrial dysfunction.

Methods: A 35-year-old woman was ascertained to have ANSD. Exome sequencing identified the genetic cause of hearing loss, and a functional study measuring mitochondrial activity was performed to provide molecular evidence of pathophysiology. Expression of FDXR in the mouse cochlea was evaluated by immunohistochemistry. Intraoperatively, electrically evoked compound action potential (ECAP) responses were measured, and the mapping parameters were adjusted accordingly. Audiological outcomes were monitored for over 1 year.

Results: In lymphoblastoid cell lines (LCLs) carrying a novel FDXR variant, decreased ATP levels, reduced mitochondrial membrane potential, and increased reactive oxygen species levels were observed compared to control LCLs. These dysfunctions were restored by administering mitochondria isolated from umbilical cord mesenchymal stem cells, confirming the pathogenic potential of this variant via mitochondrial dysfunction. Partial ECAP responses during CI and FDXR expression in the mouse cochlea indicate that FDXR-related ANSD is post-synaptic. As a result of increasing the pulse width during mapping, the patient's CI outcomes showed significant improvement over 1-year post-CI.

Conclusion: A novel FDXR variant associated with mitochondrial dysfunction and post-synaptic ANSD was first identified in a Korean individual. Additionally, 1-year post-CI outcomes were reported for the first time in the literature. Excellent audiologic.

Results: were obtained, and our.

Results: reiterate the correlation between genotype and CI outcomes in ANSD.

FDXR 的新变体是通过线粒体功能障碍导致舌后突触后听觉神经病谱系障碍的分子病因:重申基因型与人工耳蜗植入结果之间的相关性。
研究目的FDXR 编码线粒体铁氧还原酶,它与听觉神经病谱系障碍(ANSD)和视神经萎缩有关。只有两项研究描述了与 FDXR 相关的听力损失。对这种疾病的听觉康复效果尚未进行调查,其病理生理机制也未得到很好的阐明。在此,我们报告了一名同时患有 FDXR 变异和突触后型 ANSD 的听力受损患者,该患者接受了人工耳蜗植入术(CI),并取得了良好的效果。我们提出了通过线粒体功能障碍引发成人型ANSD的可能病理生理机制:方法:一名 35 岁的女性被确定患有 ANSD。外显子组测序确定了听力损失的遗传原因,并进行了测量线粒体活性的功能研究,以提供病理生理学的分子证据。小鼠耳蜗中 FDXR 的表达通过免疫组化进行了评估。术中测量了电诱发复合动作电位(ECAP)反应,并相应调整了映射参数。结果:在携带新型 FDXR 变异体的淋巴母细胞系(LCLs)中,与对照 LCLs 相比,观察到 ATP 和 MtMP 水平降低,ROS 水平升高。通过施用从脐带间充质干细胞中分离出的线粒体,这些功能障碍得以恢复,从而证实了该变体通过线粒体功能障碍致病的可能性。CI期间的部分ECAP反应和小鼠耳蜗中FDXR的表达表明,与FDXR相关的ANSD是突触后的。通过增加映射时的脉冲宽度,患者的 CI 结果在 CI 后一年内有了显著改善:结论:首次在一名韩国人身上发现了与线粒体功能障碍有关的新型 FDXR 变异导致的突触后 ANSD,并首次在文献中报告了 CI 术后 1 年的疗效。他们获得了极佳的听力效果,我们的研究结果再次证明了ANSD基因型与CI结果之间的相关性。
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来源期刊
CiteScore
4.90
自引率
6.70%
发文量
49
审稿时长
6-12 weeks
期刊介绍: Clinical and Experimental Otorhinolaryngology (Clin Exp Otorhinolaryngol, CEO) is an international peer-reviewed journal on recent developments in diagnosis and treatment of otorhinolaryngology-head and neck surgery and dedicated to the advancement of patient care in ear, nose, throat, head, and neck disorders. This journal publishes original articles relating to both clinical and basic researches, reviews, and clinical trials, encompassing the whole topics of otorhinolaryngology-head and neck surgery. CEO was first issued in 2008 and this journal is published in English four times (the last day of February, May, August, and November) per year by the Korean Society of Otorhinolaryngology-Head and Neck Surgery. The Journal aims at publishing evidence-based, scientifically written articles from different disciplines of otorhinolaryngology field. The readership contains clinical/basic research into current practice in otorhinolaryngology, audiology, speech pathology, head and neck oncology, plastic and reconstructive surgery. The readers are otolaryngologists, head and neck surgeons and oncologists, audiologists, and speech pathologists.
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