Kim Bong Jik, Kim Yujin, Kim Ju Ang, Han Jin Hee, Kim Min Young, Yang Hee Kyung, Rhee Chae-Seo, Kang Young Cheol, Kim Chun-Hyung, Choi Byung Yoon
Department of Otorhinolaryngology, Chungnam National University Sejong Hospital, Chungnam National University College of Medicine, Sejong, Korea.
Brain Research Institute, Chungnam National University College of Medicine, Daejeon, Korea.
Clin Exp Otorhinolaryngol. 2024 Aug;17(3):206-216. doi: 10.21053/ceo.2024.00184. Epub 2024 Aug 6.
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.
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.
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.
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.
were obtained, and our.
reiterate the correlation between genotype and CI outcomes in ANSD.
FDXR编码线粒体铁氧化还原蛋白还原酶，其与听觉神经病谱系障碍（ANSD）和视神经萎缩有关。迄今为止，仅有两项研究描述了与FDXR相关的听力损失。尚未对该疾病实体的听觉康复结果进行研究，其病理生理机制仍未完全明确。在此，我们报告一名听力受损个体，其FDXR变异与突触后型ANSD共分离，该个体接受了人工耳蜗植入（CI），效果良好。我们提出了一种涉及线粒体功能障碍的成人起病型ANSD的可能病理生理机制。
一名35岁女性被确诊患有ANSD。外显子组测序确定了听力损失的遗传原因，并进行了一项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。通过免疫组织化学评估FDXR在小鼠耳蜗中的表达。术中测量电诱发复合动作电位（ECAP）反应，并相应调整标测参数。对听力结果进行了超过1年的监测。
在携带新型FDXR变异的淋巴母细胞系（LCLs）中，与对照LCLs相比，观察到ATP水平降低、线粒体膜电位降低和活性氧水平升高。通过给予从脐带间充质干细胞分离的线粒体，这些功能障碍得以恢复，证实了该变异通过线粒体功能障碍的致病潜力。CI期间的部分ECAP反应以及FDXR在小鼠耳蜗中的表达表明，与FDXR相关的ANSD是突触后型的。由于在标测过程中增加了脉冲宽度，该患者的CI结果在CI后1年显示出显著改善。
在一名韩国个体中首次鉴定出一种与线粒体功能障碍和突触后ANSD相关的新型FDXR变异。此外，文献中首次报道了CI后1年的结果。获得了出色的听力结果，我们的结果重申了ANSD中基因型与CI结果之间的相关性。
