Clin Exp Otorhinolaryngol.  2024 Aug;17(3):206-216. 10.21053/ceo.2024.00184.

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

• Kim BJ
• Kim Y
• Kim JA
• Han JH
• Kim MY
• Yang HK
• Rhee CS
• Kang YC
• Kim CH
• Choi BY

• KMID: 2558837
• DOI: http://doi.org/10.21053/ceo.2024.00184

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.

Keyword

FDXR; Postlingual; Post-Synaptic; Auditory Neuropathy; Optic Atrophy; Mitochondria; Cochlear Implantation; Auditory Rehabilitation

Figure

• 

  Fig. 1. Pedigree, audiologic tests, and Sanger chromatograms. (A) The pedigree demonstrated a sporadic or autosomal recessive inheritance pattern. (B) A pure-tone audiogram (PTA) showed asymmetric sensorineural hearing loss, and auditory brainstem response (ABR) testing resulted in no response at 90 dB in both ears. (C) DPOAE and TEOAE showed normal responses in both ears. (D) The Sanger chromatogram identified a homozygous variant only in the proband. R, right; L, left; DPOAE, distortion product otoacoustic emissions; TEOAE, transient evoked otoacoustic emissions.

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  Fig. 2. Intracellular mitochondrial function in the FDXR mutant-derived lymphoblastoid cell lines (LCLs). (A) Schematic diagram of the treatment of PN-101 into LCLs. Intracellular ATP, reactive oxygen species (ROS), and mitochondrial membrane potential (MtMP) were measured in LCLs derived from both the control and the FDXR mutant. Compared to the control, the LCLs derived from the FDXR mutant exhibited mitochondrial dysfunction, including decreased intracellular ATP and MtMP (B, C), and increased intracellular ROS (D). Treatment with PN-101 restored the levels of ATP, ROS, and MtMP in the FDXR mutant-derived LCLs to those of normal LCLs (B-D). The introduction of PN-101 into FDXR mutant LCLs was confirmed using fluorescence-labeled PN-101 (E). The fluorescence of control cells was set to 100%. Values are presented as mean±standard error of the mean and the Student t-test was used for comparison. NS, not significant; MT, mitochondria. a)vs. normal. b)vs. non-treatment of PN-101. *P<0.05, ***P<0.001.

• 

  Fig. 3. Expression of FDXR in the mouse cochlea. The organ of Corti was stained with phalloidin (red), FDXR antibody (green), and DAPI (blue). The upper images were captured at ×25 magnification, while the lower images are captured at ×200 magnification. The white arrow indicates the inner hair cells (IHCs), and the location of the spiral ganglion neuron (SGN) is marked on the image.

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  Fig. 4. Preoperative (Preop) imaging, intraoperative electrically evoked compound action potential (ECAP) response, and postoperative (Postop) cochlear implantation (CI) outcomes. (A) The atrophic cochlear nerve is shown (red arrow), and a poor initial ECAP response was recorded in only nine channels. (B) Increased pulse width (PW) enabled the recording of ECAP responses in all channels. (C) Both the speech recognition test and CAP score showed gradual improvement over time after. IHC, inner hair cell; SGN, spiral ganglion neuron.

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  Fig. 5. Difference in proposed auditory rehabilitation protocols between ordinary sensorineural hearing loss (SNHL) and auditory neuropathy spectrum disorder (ANSD). ANSD needs early cochlear implantation (CI), unlike ordinary SNHL, which can benefit from hearing aid use bridging to CI.

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