A dominant variant in apoptosis-related gene XKR8 is relevant to hereditary auditory neuropathy.

BACKGROUND: Auditory neuropathy is an unusual type of hearing loss. At least 40% of patients with this disease have underlying genetic causes. However, in many hereditary auditory neuropathy cases, etiology remains undetermined. METHODS: We collected data and blood samples from a four-generation Chinese family. After excluding relevant variants in known deafness-related genes, exome sequencing was conducted. Candidate genes were verified by pedigree segregation, transcript/protein expression in the mouse cochlea, and plasmid expression studies in HEK 293T cells. Moreover, a mutant mouse model was generated and underwent hearing evaluations; protein localization in the inner ear was also assessed. RESULTS: The clinical features of the family were diagnosed as auditory neuropathy. A novel variant c.710G > A (p.W237X) in apoptosis-related gene XKR8 was identified. Genotyping of 16 family members confirmed the segregation of this variant with the deafness phenotype. Both XKR8 mRNA and XKR8 protein were expressed in the mouse inner ear, predominantly in regions of spiral ganglion neurons; Moreover, this nonsense variant impaired the surface localization of XKR8 in cells. Transgenic mutant mice exhibited late-onset auditory neuropathy, and their altered XKR8 protein localization in the inner ear confirmed the damaging effects of this variant. CONCLUSIONS: We identified a variant in the XKR8 gene that is relevant to auditory neuropathy. The essential role of XKR8 in inner ear development and neural homeostasis should be explored.

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.

MiR-146a Promotes Tolerogenic Properties of Dendritic Cells and through Targeting Notch1 Signaling.

BACKGROUND: MiR-146a has been shown to negatively regulate innate immune, inflammatory response and antiviral pathway, however, its role in the tolerogenic responses remains largely unknown. This study aimed to investigate the role of miR-146a in the OVA-induced allergic inflammation of dendritic cells (DCs). METHODS: Bone marrow-derived DCs (BMDCs) were treated with OVA (100 µg/ml) for 24 h. MiR-146a expressions were assessed by quantitative RT-PCR. BMDCs were transfected with miR-146a mimics or inhibitor. Cell surface markers were analyzed by flow cytometry. Cytokine levels were determined by ELISA assay. Mixed lymphocyte culture assay was adopted to assess CD4 + T-cell differentiation. The 3' UTR luciferase reporter assay was utilized to determine the miRNA target sequence. RESULTS: OVA treatment significantly up-regulated miR-146a in BMDCs in a dose- and time-dependent manner. In the OVA-treated DCs, overexpression of miR-146a (mimics transfection) down-regulated the surface markers (CD80, CD86) and increased production of anti-inflammatory cytokines TGF-ß1 and IL-10 but decreased pro-inflammatory cytokine IL-12. MiR-146a overexpression promoted immature DC to induce regulatory T cells (Treg) differentiation. By contrast, transfection of miR-146a inhibitor into DC exhibited the opposite trends. Notch1 was a direct target of miR-146a, and Notch1 knock-down induced similar effects as miR-146a mimics transfection in BMDCs. Moreover, the effect of miR-146a inhibitor on OVA-induced DC was attenuated by Notch1 knock-down. CONCLUSION: miRNA-146a promoted tolerogenic properties of DCs, at least partially, through targeting Notch1 signaling.

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.

MicroRNA-194 Regulates the Development and Differentiation of Sensory Patches and Statoacoustic Ganglion of Inner Ear by Fgf4.

BACKGROUND MicroRNA 194 is involved in the differentiation of various types of cells, such as adipose derived stem cells, human embryonic stem cells, and bone marrow mesenchymal stem cells. Previously, we found that miR-194 was highly expressed in the inner ear sensory patch and neurons in mice embryos. However, the role of miR-194 in the development of the inner ear and its underlying mechanism have not been elucidated yet. MATERIAL AND METHODS The expression level of miR-194 has been altered by using antisense morpholino oligonucleotides (MO) and synthesized miRNAs in zebrafish. RESULTS We found that miR-194 was vastly expressed in the inner ear and central nervous system (CNS) in zebrafish. Loss of function of miR-194 could strongly affected the development of zebrafish embryos, including delayed embryonic development, edema of the pericardium, small head, axial deviation, delayed development of inner ear, closer location of two otoliths, delayed fusion of the semicircular canals, and abnormal otolith number in some cases. In addition, the behavior of zebrafish was also adversely affected with impaired balance and biased swimming route. Misexpression of miR-194 could strongly affected the development and differentiation of spiral ganglion neuron (SGN) in inner ear through Fgf4 in vitro. Similar results have also been observed that the overexpression and knockdown of miR-194 strongly disturbed the development and differentiation of the sensory patches and Statoacoustic ganglion (SAG) through Fgf4 in zebrafish in vivo. Our results indicated that miR-194 may regulate the development and differentiation of sensory patches and SAG through Fgf4. CONCLUSIONS Our data revealed a vital role of miR-194 in regulating the development and differentiation of the inner ear.

GJB3/GJB6 screening in GJB2 carriers with idiopathic hearing loss: Is it necessary?

BACKGROUND: Genetic analysis detected excessive mono-allelic recessive GJB2 mutations in individuals with idiopathic deafness; the remaining alleles in trans/cis are underdetermined. The aim of this study was to assess the contributions of variants in GJB3 or GJB6 to non-syndromic sensorineural hearing impairment (NSHI) in Chinese patients with mono-allelic GJB2 mutations. METHODS: The entire coding sequences of GJB3/GJB6, as well as deletions in GJB6, in a cohort of NSHI patients (n = 100) carrying likely pathogenic heterozygous GJB2 mutations, were tested. Targeted next generation sequencing was further performed in a multiplex family GDHY with moderate to profound NSHI. RESULTS: Putatively causative GJB3 variant underlied 1% (1/100) in this cohort. In family GDHY, we identified a rare GJB3 c.250G>A mutation, as double heterozygotes with GJB2 c.109G>A and/or a novel GJB2 mutation c.638T>C predicted to be damaging in a digenic inheritance after precluding other attributable mutations from 127 deafness genes. No GJB6 mutation was found. CONCLUSIONS: GJB3/GJB6 variants account for a low proportion in autosomal recessive GJB2 mutation carriers in our cohort. Environmental causes, or other NSHI relevant genes, revealed by targeted next generation sequencing or whole exome sequencing, may play major roles in triggering deafness in these patients.

GJB2 and mitochondrial 12S rRNA susceptibility mutations in sudden deafness.

Genetic susceptibility may play an important role in the pathogenesis of sudden deafness. However, the specific genes involved are largely unknown. We sought to explore the frequency of GJB2 and mitochondrial 12S rRNA susceptibility mutations in patients with sudden deafness. Between September 2011 and May 2012, 62 consecutive patients with sudden deafness were seen. In 50 of these, no etiological factors for sudden deafness were found. We detected GJB2 and mitochondrial 12S rRNA variants by direct sequencing in these 50 patients and in 53-aged matched controls with normal hearing. In addition, we undertook functional analyses of the mitochondrial mutations which we detected, applying structural and phylogenetic analysis. GJB2 sequencing identified six mutations, including three pathogenic mutations (c.235delC, c.299-300delAT, c.109G>A) and three polymorphisms, in the study participants, giving an allele frequency of 15.0 %. A homozygous c.109G>A mutation was detected in two participants. A total of 16 variants in mitochondrial 12S rRNA gene were identified in the participants. No significant differences were found in GJB2 heterozygosity or in mitochondrial 12S rRNA variants between patients with sudden deafness and in controls. Our results suggest that the homozygous GJB2 c.109G>A mutation may be a cause of sudden deafness involving both ears. This finding should increase awareness of the likely role of genetic factors in the etiology of sudden deafness in general.

Developing regional genetic counseling for southern Chinese with nonsyndromic hearing impairment: a unique mutational spectrum.

BACKGROUND: Racial and regional factors are important for the clinical diagnosis of non-syndromic hearing impairment. Comprehensive genetic analysis of deaf patients in different regions of China must be performed to provide effective genetic counseling. To evaluate the mutational spectrum of south Chinese families, we performed genetic analysis for non-syndromic hearing impairment in this population. METHODS: Complete clinical evaluations were performed on 701 unrelated patients with non-syndromic hearing impairment from six provinces in south China. Each subject was screened for common mutations, including SLC26A4 c.IVS7-2A > G, c.2168A > G; mitochondrial DNA m.1555A > G, m.1494C > T, m.7444G > A, m.7445A > G; GJB3 c.538C > T, c.547G > A; and WFS1 c.1901A > C, using pyrosequencing. GJB2 and SLC26A4 coding region mutation detection were performed using Sanger sequencing. RESULTS: Genetic analysis revealed that among the etiology of non-syndromic hearing impairment, GJB2, SLC26A4, and mitochondrial m.1555A > G mutations accounted for 18.0%, 13.1%, and 0.9%, respectively. Common mutations included GJB2 c.235delC, c.109G > A, SLC26A4 c.IVS7-2A > G, c.1229 T > C, and mitochondrial m.1555A > G. The total mutation rate was 45.1% in all patients examined in south China. Overall, the clear contribution of GJB2, SLC26A4, and mitochondrial m.1555A > G to the etiology of the non-syndromic deafness population in south China was 32.0%. CONCLUSIONS: Our study is the first genetic analysis of non-syndromic hearing impairment in south China, and revealed that a clear genetic etiology accounted for 32.0% of non-syndromic hearing cases in patients from these regions. The mutational spectrum of non-syndromic hearing impairment in the south Chinese population provides useful and targeted information to aid in genetic counseling.

Magnetic resonance imaging-detected inner ear hemorrhage as a potential cause of sudden sensorineural hearing loss.

PURPOSE: The aim of this study is to assess the value of magnetic resonance imaging in identifying the etiology of sudden sensorineural hearing loss, and to correlate the high signals in the labyrinth with clinical features to identify if inner ear hemorrhage could be implicated. MATERIALS AND METHODS: In this retrospective study, inner ear magnetic resonance imaging was given to 112 patients with sudden sensorineural hearing loss in the First Affiliated Hospital of Sun Yat-sen University from 2011 to 2012. The clinical features of patients with high signals in the labyrinth on magnetic resonance imaging were analyzed. RESULTS: Abnormal magnetic resonance images were identified in 13 (11.6%) patients. Retrocochlear pathology was found in six patients, including two cases of lacunar infarction, one case of multiple ischemias in the brainstem and bilateral centrum semiovale, two cases of acoustic neuroma, and one case of inner ear hemangioma. There were seven cases showing high signals in the labyrinth on unenhanced T1-weighted and fluid-attenuated inversion recovery images. Clinical features of these seven patients were characterized by irreversible profound hearing impairment and vestibular dysfunction. These findings were consistent with the hypothesis that their symptoms were caused by an inner ear hemorrhage. CONCLUSION: The results indicate the importance of magnetic resonance imaging in sudden sensorineural hearing loss in patients. Moreover, patients with vestibular dysfunction and sudden profound hearing loss may have an inner ear hemorrhage evident by interpreting clinical and magnetic resonance imaging results.

Deficient gap junction coupling of two common hearing loss-related variants in GJB2.

Objectives: To explore the functional consequences of two common variants, p.V37I and c.299-300delAT in hearing loss associated gene GJB2. Methods: Connexin 26 expression and gap junctional permeability were studied in HEK 293T cells transfected with plasmids expressing GJB2 wild-type, p.V37I, or c.299-300delAT CX26 proteins with fluorescent tags. Functional analyses of different GJB2 haplotypes were performed to fully assess the alteration of ionic and small-molecule coupling. Results: The p.V37I protein was localized at the plasma membrane, but failed to effectively transport intercellular propidium iodide or Ca2+ efficiently, indicating impairment of both biochemical and ionic coupling. The presence of GJB2 p.V37I appeared to increase the sensitivity of cells to H2O2 treatment. In contrast, the known variant c.299-300delAT protein was not transported to the cell membrane and could not form gap junctions, instead being confined to the cytoplasm. Ionic and biochemical coupling was defective in c.299-300delAT-transfected cells. Conclusion: The p.V37I and c.299-300delAT GJB2 mutations resulted in deficient gap junction-mediated coupling. Environmental factors may impact the functional consequences of GJB2 p.V37I. These results may inspire the development of molecular therapies targeting GJB2 mutations for hearing loss.

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.

Early Functional and Cognitive Declines Measured by Auditory-Evoked Cortical Potentials in Mice With Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by a progressive loss of memory and cognitive decline. However, the assessment of AD-associated functional and cognitive changes is still a big challenge. Auditory-evoked cortical potential (AECP) is an event-related potential reflecting not only neural activation in the auditory cortex (AC) but also cognitive activity in the brain. In this study, we used the subdermal needle electrodes with the same electrode setting as the auditory brainstem response (ABR) recording and recorded AECP in normal aging CBA/CaJ mice and APP/PS1 AD mice. AECP in mice usually appeared as three positive peaks, i.e., P1, P2, and P3, and three corresponding negative peaks, i.e., N1, N2, and N3. In normal aging CBA mice, the early sensory peaks P1, N1, and P2 were reduced as age increased, whereas the later cognitive peaks N2, P3, and N3 were increased or had no changes with aging. Moreover, the latency of the P1 peak was increased as age increased, although the latencies of later peaks had a significant reduction with aging. In AD mice, peak P1 was significantly reduced in comparison with wild-type (WT) littermates at young ages, proceeding AD phenotype presentation. In particular, the later cognitive peak P3 was diminished after 3 months old, different from the normal aging effect. However, the latencies of AECP peaks in AD mice generally had no significant delay or changes with aging. Finally, consistent with AECP changes, the accumulation of amyloid precursor protein (APP) at the AC was visible in AD mice as early as 2 months old. These data suggest that AECP could serve as an early, non-invasive, and objective biomarker for detecting AD and AD-related dementia (ADRD).

Hearing loss is an early biomarker in APP/PS1 Alzheimer's disease mice.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive loss of memory and cognitive decline. Over the last decade, it has been found that defects in sensory systems could be highly associated with AD. Hearing is an important neural sense. However, little is known about hearing functional changes in AD. In this study, APP/PS1 AD mice (Jackson Lab: Stack No. 004462) were used. Hearing function was assessed by auditory brainstem response (ABR), distortion product otoacoustic emission (DPOAE), and cochlear microphonics (CM) recordings. Wild-type (WT) littermates served as control. We found that APP/PS1 AD mice measured as ABR threshold had hearing loss. The hearing loss appeared at high frequency as early as 2 months old, prior to the reported occurrence of spatial learning deficit at 6-7 months of age in this AD mouse model. The hearing loss was progressive and extended from high frequency to low frequency. At 3-4 months old, the hearing loss appeared in the whole-frequency range. Moreover, the wave IV and V in the super-threshold ABR were eliminated, indicating substantial impairment in inferior colliculus, nuclei of lateral lemniscus, and medial geniculate body in the upper brainstem. DPOAE in APP/PS1 AD mice was also reduced. However, there was no reduction in CM in APP/PS1 mice. These data demonstrate that unlike age-related hearing loss APP/PS1 AD mice have early onset of hearing loss. These data also suggest that hearing function testing could provide a simple, sensitive, non-invasive screen-tool for early detecting AD and localizing lesion.

Different prognoses in patients with profound sudden sensorineural hearing loss.

Background: Inner ear hemorrhage is increasingly recognized as a cochlear lesion that can cause profound sudden sensorineural hearing loss (SSNHL). Objectives: To investigate changes of cochlear and vestibular function and to compare therapeutic recovery from profound SSNHL induced by different etiologies. Material and methods: Eighty patients with profound SSNHL (≥90 dB) were divided into an inner ear hemorrhage group and a non-inner ear hemorrhage group by MRI. Statistical analysis was performed to compare the therapeutic effects from vertigo and hearing loss and the outcomes of follow-up in the two groups. Results: There were significant differences between the two groups in terms of the overall 14-day therapeutic response rate (20 vs. 48%), the incidence of imbalance (26.7 vs. 6%), the incidence of semicircular canal dysfunction on the affected side (60 vs. 20%), the incidence of abnormal C-VEMP and O-VEMP on the affected side (63.3 vs. 38%; and 60 vs. 30%, respectively), the average hearing threshold (74.2 ± 10.7 vs. 53.6 ± 11.4 dB), and the word recognition score (65.5 ± 21.7 vs. 83.5 ± 24.5%) at a 12-month follow-up. Conclusions and significance: A higher percentage of patients with profound SSNHL induced by inner ear hemorrhage were associated with vertigo and had a poor prognosis.

Side-related differences in sudden sensorineural hearing loss in children.

OBJECTIVE: Most studies on sudden sensorineural hearing loss (SSNHL) do not differentiate the outcomes within varied affected ears in children. The present study was designed to determine the clinical differences between unilateral and bilateral SSNHL in children. METHODS: The clinical data, from a total of 101 pediatric patients with SSNHL, was retrospectively analyzed from January 2003 to December 2016. The main outcome measures included basic characteristics, etiology, clinical symptoms and treatment courses. RESULTS: When the bilateral group (n = 28) was compared to the unilateral group (n = 73), neither gender nor onset of SSNHL was significantly different (p > 0.05 each); However, bilateral SSNHL tended to occur in younger ages (8.1 ±â€¯4.0 yrs), with higher percentages of suspected etiologies (50%) and proportion of profound deafness (55.4%, p < 0.05 each). The short-term recovery rate was superior in the unilateral cases over the bilateral cases (37.0% vs. 12.5%, p < 0.05). Milder initial hearing threshold, early onset of treatment (5.6 ±â€¯4.8 days) with unilateral involvement and an older age (11.3 ±â€¯3.0 yrs) in bilaterally affected cases were associated with a better prognosis in this cohort. In addition, the unilateral group showed comparable outcomes, when sub-analyzed by comparison to that in either left- (n = 42) or right-sided (n = 31) SSNHL. CONCLUSION: Although bilateral and unilateral pediatric SSNHL could cause partial to complete cochlear lesion, they may be relevant to distinct backgrounds. Our data also provides valuable information about demographics and outcomes of SSNHL in children.

Targeted next generation sequencing reveals OTOF mutations in auditory neuropathy spectrum disorder.

OBJECTIVE: To study the genetic etiology of auditory neuropathy spectrum disorder (ANSD) in a Chinese family and perform a literature review of OTOF mutations and cochlear implantation (CI). METHODS: Sequential targeted next generation sequencing (NGS) and CI was performed for the proband. Further, 50 DNA samples from unrelated families with nonsyndromic deafness were examined for frequency determination. The impact of OTOF mutations on hearing recovery after CI was assessed through the literature survey. RESULTS: In the proband, the targeted NGS panel revealed five suspected variants in four genes (OTOF, EYA4, PCDH15, and GIPC3), of which two mutations-c.5098G > C (p.Glu1700Gln) and c.1702C > T (p.Arg568Trp)-in the OTOF gene were found to be correlated with ANSD. The c.5098G > C allele was identified in only one child from the 50 unrelated participants. The proband's hearing and speech abilities were restored 2 years after the surgery. Most ANSD patients (90.9%; 30/33) with OTOF mutations have acceptable surgical outcomes, as indicated by existing reports. CONCLUSIONS: Our results support the feasibility of CI for patients with ANSD and OTOF mutations, and this hypothesis was supported by the review of existing data. A larger number of cases studies is required to determine possible modifies on the prognosis of surgery.

Germinal mosaicism of PAX3 mutation caused Waardenburg syndrome type I.

OBJECTIVES: Waardenburg syndrome mutations are most often recurrent or de novo. The rate of familial recurrence is low and families with several affected children are extremely rare. In this study, we aimed to clarify the underlying hereditary cause of Waardenburg syndrome type I in two siblings in a Chinese family, with a mother affected by prelingual mild hearing loss and a father who was negative for clinical symptoms of Waardenburg syndrome and had a normal hearing threshold. METHODS: Complete characteristic features of the family members were recorded and genetic sequencing and parent-child relationship analyses were performed. RESULTS: The two probands were found to share double mutations in the PAX3/GJB2 genes that caused concurrent hearing loss in Waardenburg syndrome type I. Their mother carried the GJB2 c.109G > A homozygous mutation; however, neither the novel PAX3 c.592delG mutation, nor the Waardenburg syndrome phenotype, was observed in either parent. CONCLUSION: These previously unreported digenic mutations in PAX3/GJB2 resulted in deafness associated with Waardenburg syndrome type I in this family. To our knowledge, this is the first report describing germinal mosaicism in Waardenburg syndrome. This concept is important because it complicates genetic counseling of this family regarding the risk of recurrence of the mutations in subsequent pregnancies.

Delayed Recovery in Pediatric Sudden Sensorineural Hearing Loss Predicted via Magnetic Resonance Imaging.

OBJECTIVES: To evaluate the potential origins via magnetic resonance imaging and the relevant hearing recovery course of pediatric sudden sensorineural hearing loss. METHODS: We retrospectively analyzed data of 25 pediatric patients from our center with sudden sensorineural hearing loss from January 2011 to December 2016. All individuals were closely followed up at baseline and 1 and 6 months. RESULTS: Magnetic resonance imaging identified presumed causes in 9 cases, 5 of which showed intralabyrinthine hyperintensity, suggesting presumptive intralabyrinthine hemorrhage. The remaining 20 patients showed no hyperintensity. Restoration of hearing and speech discrimination abilities were noted in these 25 children at 6 months versus the initial levels (74.2 ± 22.6 vs 93.5 ± 20.5 dB, p = .000, and 45.8 ± 36.0 vs. 18.3 ± 22.1%, p = .004, respectively). The prognosis of the individuals with intralabyrinthine hemorrhage were superior in terms of frequency and hearing threshold at 6 months compared with that of the no-hemorrhage participants. Word recognition scores improved in either studied group. CONCLUSION: The potential recovery of hearing in children raises concerns about very early surgical intervention within the first 6 months. Rational imaging and sequential audiometric evaluation to monitor the progression of recovery may be beneficial.

microRNA­183 is involved in the differentiation and regeneration of Notch signaling­prohibited hair cells from mouse cochlea.

Auditory hair cell regeneration following injury is critical to hearing restoration. The Notch signaling pathway participates in the regulation of inner ear development and cell differentiation. Recent evidence suggests that microRNA (miR)­183 has a similar role in the inner ear. However, it is unclear how Notch signaling functions in hair cell regeneration in mammals and if there is cross­talk between Notch signaling and miR­183. The present study used a gentamicin­induced cochlear injury mouse model. Gentamicin­induced damage of the hair cells activated the Notch signaling pathway and downregulated miR­183 expression. Notch signaling inhibition by the γ­secretase inhibitor, 24­diamino­5­phenylthiazole (DAPT), attenuated gentamicin­induced hair cell loss and reversed the downregulation of miR­183 expression. Further investigation revealed that the novel hair cells produced, induced by DAPT, were derived from transdifferentiated supporting cells. Additionally, myosin VI­positive hair cell numbers were increased by Notch signaling inhibition in in vitro experiments with cultured neonatal mouse inner ear precursor cells. This effect was reversed by miR­183 inhibition. These findings indicate that the Notch signaling pathway served a repressing role during the regeneration of hair cells. Inhibiting this signal improved hair cell regeneration in the gentamicin­damaged cochlear model. miR­183 was demonstrated to be involved in hair cell differentiation and regeneration, and was required for the differentiation of the Notch­inhibited hair cells.