Report of rare and novel mutations in candidate genes in a cohort of hearing-impaired patients.

BACKGROUND: Many hearing-impaired patients carry mutations in rare or novel genes undetected in regular genetic hot regions/genes screening. METHODS: We collected clinical and genetic data from subjects with hearing loss who visited our department for genetic counseling. Next-generation sequencing was conducted after 154 deafness-related genes were captured using a designed genes panels in 14 unrelated families (37 participants). The results were filtered and assessed with in silico tools, in combination with pedigree mapping. RESULTS: Ten mutations in regular deafness genes (GJB2, SLC26A4) and uncommon genes (OTOF, MYO7A, MYO15A, and KARS) were detected, which constituted 57.2% of yielded rate. In particular, two patients with nonsyndromic deafness carried biallelic KARS mutations. In addition, we identified an unreported digenic mutational inheritance in GRP98/USH2A genes in a proband with isolated hearing loss. Functional analyses and molecular modeling suggested the damaging consequence of these variants on encoded proteins. According to the variant pathogenicity guidelines, the 17 identified variants in total were classified as "pathogenic" or "likely pathogenic." CONCLUSION: The candidate mutations in deafness genes were suggested to be co-segregated in at least 57.2% of the studied pedigrees. This is the new report of rare/novel mutations causing inherited hearing loss in Chinese.

Cochlear Implantation Outcomes in Children With CDH23 Mutations-Associated Hearing Loss.

OBJECTIVE: Mutations in the cadherin 23 gene (CDH23) have been reported to cause cochlear damage, but few studies have investigated the auditory and speech outcome of patients after cochlear implantation. Here, we describe the genetic, auditory, and postoperative outcomes of patients with CDH23 mutations who received cochlear implants. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. METHODS: Targeted deafness-related gene panels were sequenced in Chinese families with profound sensorineural hearing loss. The clinical features of subjects carrying potentially pathogenic CDH23 mutations were analyzed. RESULTS: Between 2017 and 2019, we identified 5 children with prelinguistically profound hearing loss at our center who harbored 6 variants of CDH23 that segregated with the disease. Of these, 4 variants were novel (c.2591G>T, c.4785G>C, c.5765A>G, and c.9280_9281insTT). All affected individuals had a loss of outer hair cell function, with an average residual hearing level of 3 to 10 dB SPL. Cochlear implantations were arranged for the patients at 11 to 36 months of age. All children made gains in their hearing, language, and speech performances 14 to 120 months after surgery. Their auditory outcomes improved during follow-up intervals. CONCLUSION: This study revealed that children with congenital cochlear defects caused by CDH23 variants can acquire an acceptable auditory and speech outcome after cochlear implantation. Early genetic detection and prenatal counseling for rare deafness genes such as CDH23 remain a priority for the future.

Labyrinthine lesions in presumed inner ear hemorrhage-related sudden deafness.

PURPOSE: Inner ear hemorrhage (IEH) is a rare cause of sudden sensorineural hearing loss (SSNHL). This study aimed to evaluate the lesional patterns in patients with presumed IEH from morphological and functional aspects. METHODS: Seventeen patients with SSNHL and presumed IEH who completed audio-vestibular tests were included. The main outcome measures included clinical characteristics, radiology, and functional test results. RESULTS: The morphological findings and functional tests revealed differences in locations and lesional spectrums. The magnetic resonance imaging (MRI) hyperintensity was likely to involve the vestibule (88.2%), the cochlea (76.5%), and the posterior and lateral semicircular canals (76.5% and 70.6%, respectively). Furthermore, 70.6% of cases showed abnormality in the entire labyrinth, and abnormalities in the vestibule/semicircular canals were observed in 17.6% of cases. Meanwhile, dysfunction was sequentially detected in the cochlea (100%), semicircular canals (94.1%), and vestibule (70.6%); 64.7% of cases showed combined deficit in the entire labyrinth, and 29.4% of cases showed combined deficit in the cochlea/semicircular canals. Although lesions in the labyrinth were frequently detected, the results of the radiological and functional tests did not always match and significantly differed in either cochlear or superior semicircular canal damage detection (p < 0.05 each). CONCLUSIONS: In this cohort, IEH preferentially caused sudden audio-vestibular impairment, which was well demonstrated by a combination of MRI and functional tests. The specific lesional configurations revealed in this study may suggest a possible pathomechanism that could be further explored as a therapeutic target.

Meta-Analysis Comparing Steroids and Diuretics in the Treatment of Acute Low-Tone Sensorineural Hearing Loss.

OBJECTIVE: Our objective was to perform a meta-analysis to compare the effectiveness of steroids and diuretics in the treatment of acute low-tone sensorineural hearing loss (ALHL). METHODS: PubMed, Google Scholar, and Sci databases were searched for randomized controlled trials (RCTs) examining the treatment of ALHL with steroids and diuretics. The Cochrane Reviewer's Handbook 5.0 evaluation criteria were used to evaluate the quality of the included RCTs. Meta-analysis was performed using Revman 5.3 software to compare the recovery rate of low-tone hearing levels between patients treated with steroids and diuretics. RESULTS: A total of 3 RCTs were included. There was no heterogeneity between the 3 studies (χ2 = 2.61, P = .27, I2 = 23%); thus, a fixed-effects model of analysis was used. Meta-analysis showed there was no significant difference in the recovery rate of patients treated with steroids and those treated with diuretics (odds ratio = 1.48, 95% confidence interval: 0.64-3.40, P = .36). CONCLUSION: Steroids and diuretics are equally effective for the treatment of ALHL.

Notched Sound Alleviates Tinnitus by Reorganization Emotional Center.

BACKGROUND: Tinnitus is a common disease, and sound therapy is an effective method to alleviate it. Previous studies have shown that notched sound not only changes levels of cortical blood oxygen, but affects blood oxygen in specific cerebral cortical areas, such as Brodmann area 46 (BA46), which is associated with emotion. Extensive evidence has confirmed that tinnitus is closely related to emotion. Whether notched sound plays a role in regulating the emotional center is still unclear. METHODS: This study included 29 patients with newly diagnosed chronic tinnitus who were treated with notched sound. Functional near-infrared spectroscopy (fNIRS) was conducted before and after treatment to observe bilateral changes in cortical blood oxygen in the cerebral hemispheres. We compared the changes in connectivity between the two regions of interest (the superior temporal gyrus and BA46), as wells as other cortical regions before and after treatment. RESULTS: The results showed (1) That global connectivity between the bilateral auditory cortex of the superior temporal sulcus and the ipsilateral cortex did not change significantly between baseline and the completion of treatment, and (2) That the connectivity between channel 14 and the right superior temporal sulcus decreased after treatment. The overall connectivity between the right BA46 region and the right cortex decreased after treatment, and decreases in connectivity after treatment were specifically found for channels 10 and 14 in the right parietal lobe and channels 16, 20, 21, and 22 in the frontal lobe, while there was no significant change on the left side. There were no significant changes in the questionnaire measures of tinnitus, anxiety, or depression before and after treatment. CONCLUSION: The results of the study indicate that cerebral cortex reorganization occurs in tinnitus patients after submitted to treatment with notched sound for 1 month, and that notched sound decreases the connectivity between the auditory cortex and specific brain regions. SIGNIFICANCE: Notched sound not only regulates the auditory center through lateral inhibition, but also alleviates tinnitus by reorganizing the emotional control center.

Cortical Activation Patterns of Different Masking Noises and Correlation With Their Masking Efficacy, Determined by Functional Near-Infrared Spectroscopy.

Acoustic therapy in tinnitus treatment is poorly characterized, and efficacy assessment depends on subjective descriptions. Narrow-band noise, notched sound, and white noise have positive therapeutic effects on monotonous tinnitus. Considering the tonotopic characteristics of the auditory system and the spectral characteristics of these three masking sounds, the activation pattern of the auditory cortex and the mechanism of inhibiting tinnitus may be different. This study aimed to compare the activation patterns of three spectrally different masking noises and study the correlation between the masking effects and variational amplitude of oxygenated hemoglobin (HbO) in the corresponding cortical regions. We also assessed near-infrared spectroscopy brain function imaging (NIRS) as an objective assessment tool in acoustic therapy. Patients with persistent non-pulsatile tinnitus and control volunteers without tinnitus were enrolled in this study. The subjects were seated in a sound-proof room, with two optode arrays covering the bilateral temporal lobe. Auditory stimuli were presented; stimulation sequences followed the block design: different noises appeared randomly and repeated in five cycles. Tinnitus match and residual inhibition were performed in the tinnitus group. The data analyses were conducted using the NIRS_SPM toolbox. The group analysis results showed that the narrow-band noise caused a marginally significant decrease in HbO signal in the Brodmann 21 region (BA21), while white noise caused a significant increase in HbO signal in BA21. Notched sound did not cause significant changes in the HbO signal in the temporal cortex. And none of the three masking noises caused significant changes in the HbR signal in the temporal cortex. The depth of residual inhibition induced by the narrow-band noise and white noise significantly correlated with ΔHbO in the region of interest (ROI). However, neither the depth nor duration of the residual inhibition induced by notched sound correlated with the ΔHbO. Thus, NIRS showed three cortical activation patterns induced by three different masking noises, and correlations between residual inhibition effects and change of HbO amplitude were found. NIRS could therefore be applied in objective assessment of acoustic therapy.

Audiological outcomes in sudden sensorineural hearing loss with presumed inner ear hemorrhage.

OBJECTIVE: To explore the hearing outcomes and prognostic factors in patients with sudden sensorineural hearing loss resulting from inner ear hemorrhage. METHODS: 42 patients (22 male and 20 female) were recruited from January 2016 to December 2017. Intravenous methylprednisolone and/or intratympanic corticosteroid were used as salvage therapy. The main measures included systemic risk factors and audiometric outcomes as proposed by American Academy of Otolaryngology-Head and Neck Surgery Hearing Loss Scale. All individuals were assessed at baseline, discharge (2 weeks post-treatment) and at 1, 3 and 6 months. RESULTS: The mean ages of patients were 39.3 ±â€¯14.8 yrs. Cardiovascular disorders were seen in 19.0-33.3% of cases. Restoration of hearing and speech discrimination abilities were assessed at the first month post-treatment versus initial levels (95.5 ±â€¯15.5 vs. 109.2 ±â€¯9.6 dB, p = 0.000; and 17.6 ±â€¯24.4 vs. 1.3 ±â€¯4.0%, p = 0.003, respectively). Word recognition scores continued to recover at month 6 (38.7 ±â€¯35.4%, p = 0.000), whereas puretone ceased to change (90.8 ±â€¯16.2 dB, p = 0.139). The final percentages of complete, partial and no recovery were 0%, 57.1% and 42.9% respectively. The prognosis was independent of accompanying systemic risk factors as analyzed in this study. Intratympanic intervention was associated with improved word recognition scores, although intravenous corticosteroid was not. CONCLUSIONS: Profound sudden sensorineural hearing loss caused by inner ear hemorrhage often has an unsatisfactory prognosis. However, this cohort did experience partial audiological recovery with delayed onset. Immediate and effective intratympanic corticosteroid may have therapeutic potential for this intractable disease.