Current Advances in Gene Therapies of Genetic Auditory Neuropathy Spectrum Disorder

Saidia, Anissa Rym; Ruel, Jérôme; Bahloul, Amel; Chaix, Benjamin; Venail, F.; Wang, Jing

doi:10.3390/jcm12030738

Cited by 14 publications

(8 citation statements)

References 138 publications

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“…However, the real prevalence of hearing impairments associated with DOA might be higher than reported due to the high variability in disease manifestation and progression [ 58 ] as well as the heterogeneity of the clinical profiles of auditory neuropathy [ 59 ]. In this respect, it was reported that 25% of patients harboring mitochondrial DNA mutations responsible for Leber’s hereditary optic neuropathy, previously considered as having normal hearing, had electrophysiological evidence of auditory neuropathy [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

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The human OPA1delTTAG mutation induces adult onset and progressive auditory neuropathy in mice

Affortit,

Coyat,

Saidia

et al. 2024

Cell. Mol. Life Sci.

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Dominant optic atrophy (DOA) is one of the most prevalent forms of hereditary optic neuropathies and is mainly caused by heterozygous variants in OPA1, encoding a mitochondrial dynamin-related large GTPase. The clinical spectrum of DOA has been extended to a wide variety of syndromic presentations, called DOAplus, including deafness as the main secondary symptom associated to vision impairment. To date, the pathophysiological mechanisms underlying the deafness in DOA remain unknown. To gain insights into the process leading to hearing impairment, we have analyzed the Opa1delTTAG mouse model that recapitulates the DOAplus syndrome through complementary approaches combining morpho-physiology, biochemistry, and cellular and molecular biology. We found that Opa1delTTAG mutation leads an adult-onset progressive auditory neuropathy in mice, as attested by the auditory brainstem response threshold shift over time. However, the mutant mice harbored larger otoacoustic emissions in comparison to wild-type littermates, whereas the endocochlear potential, which is a proxy for the functional state of the stria vascularis, was comparable between both genotypes. Ultrastructural examination of the mutant mice revealed a selective loss of sensory inner hair cells, together with a progressive degeneration of the axons and myelin sheaths of the afferent terminals of the spiral ganglion neurons, supporting an auditory neuropathy spectrum disorder (ANSD). Molecular assessment of cochlea demonstrated a reduction of Opa1 mRNA level by greater than 40%, supporting haploinsufficiency as the disease mechanism. In addition, we evidenced an early increase in Sirtuin 3 level and in Beclin1 activity, and subsequently an age-related mtDNA depletion, increased oxidative stress, mitophagy as well as an impaired autophagic flux. Together, these results support a novel role for OPA1 in the maintenance of inner hair cells and auditory neural structures, addressing new challenges for the exploration and treatment of OPA1-linked ANSD in patients.

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Section: Discussionmentioning

confidence: 99%

“…These hidden auditory neuropathies are undiagnosed by classic, current clinical audiological tests such as audiogram. In animal models, hidden auditory neuropathy can be caused by moderate noise exposure-, aging-, or genetic factors-inducing a loss of IHC synapses, auditory nerve terminals, and cochlear Schwann cells [ 59 , 61 , 62 ].…”

Section: Discussionmentioning

confidence: 99%

The human OPA1delTTAG mutation induces adult onset and progressive auditory neuropathy in mice

Affortit,

Coyat,

Saidia

et al. 2024

Cell. Mol. Life Sci.

Self Cite

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“…MRI testing reviled that the electrophysiological picture of congenital ANSD might be also due to the hypoplastic cochlear nerve (cochlear nerve deficiency). ANSD might be also acquired letter in life as a result of late-onset genetic-based mechanisms or due to an autoimmune reaction [3][4][5][6].…”

Section: Etiology Of Auditory Neuropathy Spectrum Disordermentioning

confidence: 99%

Auditory Neuropathy Spectrum Disorder: Genetic and Electrophysiological Testing for Predicting Rehabilitation Outcomes after Cochlear Implantation

Lalayants¹

2023

Latest Advances in Cochlear Implant Technologies and Related Clinical Applications

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Reviling the etiology or at least pathophysiology of auditory neuropathy spectrum disorder is crucial for choosing rehabilitation pathway and predicting rehabilitation outcomes. Some patients with auditory neuropathy spectrum disorder undergo cochlear implantation, but it is not always possible to foresee the results of rehabilitation. Genetic testing, especially in cases without obviously perinatal hearing loss risk factors, might help to understand etiology and pathophysiology, whether it is synaptopathy or neuropathy; therefore, it becomes possible to predict rehabilitation outcomes. More than 20 genes related to auditory neuropathy spectrum disorder phenotype are known already. Modern genetic approaches, such as whole genome and whole exome sequencing, reveal etiology of auditory neuropathy spectrum disorder in many cases. But there are still auditory neuropathy spectrum disorder cases with unknown etiology and site of the lesion. Electrophysiological methods (electrocochleography, electrically evoked brainstem potentials) might help to localize the site of lesion in hearing system and therefore help to predict rehabilitation outcomes. Electrically evoked brainstem potential testing after cochlear implantation seems to be applicable and useable tool to predict potential CI outcomes and to choose optimal rehabilitation trace.

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“…It is a very promising procedure for the future. Specially for the field of neurodegeneration of auditory pathways [84].…”

Section: Author Detailsmentioning

confidence: 99%

Auditory neuropathy

Kravos

2023

Updates on Hearing Loss and Its Rehabilitation

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Some patients visit the doctor because of hearing problems in noise. The hearing examination, however, does not show any specifics. Only an extended and targeted investigation leads to the suspicion of auditory neuropathy, which means altered temporal coding of the acoustic signal and explains the problems. Additional investigations show pathology of the synapse between the inner auditory sense and the auditory nerve or the process of conduction along the nerve. The combination of otoacoustic emissions and the auditory brainstem evoked potentials investigations raises the suspicion of auditory neuropathy. Auditory neuropathy occurs in both children and adults. In children, the diagnostic procedure is quite difficult.

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Current Advances in Gene Therapies of Genetic Auditory Neuropathy Spectrum Disorder

Cited by 14 publications

References 138 publications

The human OPA1delTTAG mutation induces adult onset and progressive auditory neuropathy in mice

The human OPA1delTTAG mutation induces adult onset and progressive auditory neuropathy in mice

Auditory Neuropathy Spectrum Disorder: Genetic and Electrophysiological Testing for Predicting Rehabilitation Outcomes after Cochlear Implantation

Auditory neuropathy

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