Clinical Characteristics and Audiological Profiles of Patients with Pathogenic Variants of WFS1.

Background: Mutations in Wolfram syndrome 1 (WFS1) cause Wolfram syndrome and autosomal dominant non-syndromic hearing loss DFNA6/14/38. To date, more than 300 pathogenic variants of WFS1 have been identified. Generally, the audiological phenotype of Wolfram syndrome or DFNA6/14/38 is characterized by low-frequency hearing loss; however, this phenotype is largely variable. Hence, there is a need to better understand the diversity in audiological and vestibular profiles associated with WFS1 variants, as this can have significant implications for diagnosis and management. This study aims to investigate the clinical characteristics, audiological phenotypes, and vestibular function in patients with DFNA6/14/38. Methods: Whole-exome or targeted deafness gene panel sequencing was performed to confirm the pathogenic variants in patients with genetic hearing loss. Results: We identified nine independent families with affected individuals who carried a heterozygous pathogenic variant of WFS1. The onset of hearing loss varied from the first to the fifth decade. On a pure-tone audiogram, hearing loss was symmetrical, and the severity ranged from mild to severe. Notably, either both low-frequency and high-frequency or all-frequency-specific hearing loss was observed. However, hearing loss was non-progressive in all types. In addition, vestibular impairment was identified in patients with DFNA6/14/38, indicating that impaired WFS1 may also affect the vestibular organs. Conclusions: Diverse audiological and vestibular profiles were observed in patients with pathogenic variants of WFS1. These findings highlight the importance of comprehensive audiological and vestibular assessments in patients with WFS1 mutations for accurate diagnosis and management.

Findings of Intravenous Gadolinium Inner Ear Magnetic Resonance Imaging in Patients With Acute Low-Tone Sensorineural Hearing Loss.

OBJECTIVES: Acute low-tone sensorineural hearing loss (ALHL) is thought to have a different etiology from that of idiopathic sudden sensorineural hearing loss. We hypothesized that endolymphatic hydrops (EH) in the inner ear organ contributes to ALHL, even in patients without vertigo. This study investigated the presence of EH in ALHL and compared the clinical characteristics of patients with or without EH. METHODS: We retrospectively reviewed 38 patients diagnosed with ALHL without vertigo from January 2017 to March 2022. EH was measured in all patients using inner ear magnetic resonance imaging (MRI). In addition, we selected patients who showed only mid- or high-frequency hearing loss and had available MRI data as a control group and compared the ALHL and control groups. RESULTS: After treatment, the pure-tone average at low frequencies significantly improved compared to the initial hearing (P<0.001). Hearing recovery was observed in 63.1% of patients; however, the recovery rate did not differ based on the treatment method. During the follow-up period, six patients (15.8%) progressed to Meniere's disease, and 18 (47.4%) experienced recurrence. In the ALHL group, the cochlear hydrops ratio on the affected side (0.34±0.09) was significantly higher than on the contralateral side (0.29±0.12) (P=0.005), and most patients showed hydrops in the apex area of the cochlea. Compared with the control group (0.25±0.15), the ALHL group showed a significantly higher cochlear hydrops ratio (P=0.043). The correlation analysis showed a tendency for hearing thresholds at low frequencies to increase as the hydrops ratio increased, albeit without statistical significance. CONCLUSION: The cochlear hydrops ratio, especially in the apex area on the affected side, was significantly higher in patients with ALHL, suggesting that EH in the cochlea contributes to the pathogenesis of ALHL.

Monogenic Causes of Low-Frequency Non-Syndromic Hearing Loss.

BACKGROUND: Low-frequency non-syndromic hearing loss (LFNSHL) is a rare form of hearing loss (HL). It is defined as HL at low frequencies (≤2,000 Hz) resulting in a characteristic ascending audiogram. LFNSHL is usually diagnosed postlingually and is progressive, leading to HL affecting other frequencies as well. Sometimes it occurs with tinnitus. Around half of the diagnosed prelingual HL cases have a genetic cause and it is usually inherited in an autosomal recessive mode. Postlingual HL caused by genetic changes generally has an autosomal dominant pattern of inheritance and its incidence remains unknown. SUMMARY: To date, only a handful of genes have been found as causing LFNSHL: well-established WFS1 and, reported in some cases, DIAPH1, MYO7A, TNC, and CCDC50 (respectively, responsible for DFNA6/14/38, DFNA1, DFNA11, DFNA56, and DFNA44). In this review, we set out audiological phenotypes, causative genetic changes, and molecular mechanisms leading to the development of LFNSHL. KEY MESSAGES: LFNSHL is most commonly caused by pathogenic variants in the WFS1 gene, but it is also important to consider changes in other HL genes, which may result in similar audiological phenotype.

Cochlear Meniere's: A Distinct Clinical Entity With Isolated Cochlear Hydrops on High-Resolution MRI?

Objective: Describe the clinical characteristics of patients with isolated cochlear endolymphatic hydrops (EH). Study design: Clinical case series. Setting: Tertiary Neurotology referral clinic. Patients: All subjects presenting to a University Neurotology clinic during a 1-year period from July 2015 until August 2016 who had isolated cochlear EH on MRI. Patients with a history of temporal bone surgery prior to the MRI were excluded. Intervention: High-resolution delayed-intravenous contrast MRI. Main outcome measures: Audiometric and vestibular testing, clinical history analysis. Results: 10 subjects demonstrated isolated, unilateral cochlear hydrops on MRI. None of these patients met the criteria for Meniere's disease. Mean age of the group was 66.4 years and most were males (70%). Unilateral aural fullness (70%), tinnitus (80%), and hearing loss (90%) were frequently observed. Only one patient presented with unsteadiness (10%) and one patient had a single isolated spell of positional vertigo 1 month prior to the MRI (10%) but no further vertigo spells in the 4 years following the MRI. The mean PTA was 37.8 dB which was significantly decreased from the non-affected ear with PTA of 17.9 (p < 0.001). One patient developed vertiginous spells and unsteadiness 4 years after initial presentation and a repeat MRI revealed progression to utricular, saccular and cochlear hydrops. Vestibular testing was obtained in five patients with one patient presenting with 50% caloric paresis and all others normal. The most common treatment tried was acetazolamide in seven patients with 86% reporting subjective clinical improvement. Two out of the 10 patients had a history of migraine (20%). Conclusions: Patients with MRI exhibiting isolated cochlear EH present with predominantly auditory symptoms: mild to moderate low-frequency hearing loss, aural fullness, tinnitus without significant vertigo. Isolated cochlear hydrops is more common in males, average age in mid-60's and there is a low comorbidity of migraine headaches. This contrasts significantly with patients with isolated saccular hydrops on MRI from our prior studies. We believe that isolated cochlear EH with hearing loss but no vertigo is distinct from Meniere's disease or its variant delayed endolymphatic hydrops. We propose that cochlear Meniere's disease represents a distinct clinical entity that could be a variant of Meniere's disease.

Visualization of Endolymphatic Hydrops in Patients With Unilateral Idiopathic Sudden Sensorineural Hearing Loss With Four Types According to Chinese Criterion.

Objective: The aim of this study is to evaluate the possible value of endolymphatic hydrops (EH) in patients with unilateral idiopathic sudden sensorineural hearing loss (UISSNHL) with four types according to audiometry. Methods: Seventy-two patients (40 men and 32 women; age range, 28-78 years; mean age: 50.0 ± 12.9 years) with UISSNHL were admitted retrospectively into this study. Based on the pure tone audiometry before treatment, the hearing loss of all these patients were categorized into four types: low-frequency group (LF-G), high-frequency group (HF-G), flat group (F-G), and total deafness group (TD-G). The average time from symptom onset to the first examination was 6.9 ± 4.4 days (1-20 days). 3D-FLAIR MRI was performed 24 h after intratympanic injection of gadolinium (Gd) within 1 week after the UISSNHL onset. The incidence of EH in the affected ears based on four types of hearing loss were analyzed using the Chi-square test, and the possible relationship with vertigo and prognosis were also assessed. Results: Eleven of 21 patients (52.4%) in LF-G had the highest EH-positive rate, followed by 18.2% in HF-G, 11.8% in F-G, and 17.4% in TD-G. The significant difference was found in the four groups (P = 0.018). The EH rate of LF-G was statistically significantly higher than that of F-G and TD-G (P = 0.009, P =0.014), respectively. After being valued by the volume-referencing grading system (VR scores), the EH level was represented by the sum scores of EH. In LF-G, no statistically significant difference was found in the prognosis of ISSNHL patients between with the EH group and the no EH group (P = 0.586). The symptom "vertigo" did not correlate with EH and prognosis. Conclusions: EH was observed in UISSNHL patients by 3D-FLAIR MRI. EH may be responsible for the pathology of LF-G but not related to prognosis. It might be meaningless to assess EH in other hearing loss types, which might be more related to the blood-labyrinth dysfunction.

Deficiency of Klc2 Induces Low-Frequency Sensorineural Hearing Loss in C57BL/6 J Mice and Human.

The transport system in cochlear hair cells (HCs) is important for their function, and the kinesin family of proteins transports numerous cellular cargos via the microtubule network in the cytoplasm. Here, we found that Klc2 (kinesin light chain 2), the light chain of kinesin-1 that mediates cargo binding and regulates kinesin-1 motility, is essential for cochlear function. We generated mice lacking Klc2, and they suffered from low-frequency hearing loss as early as 1 month of age. We demonstrated that deficiency of Klc2 resulted in abnormal transport of mitochondria and the down-regulation of the GABAA receptor family. In addition, whole-genome sequencing (WGS) of patient showed that KLC2 was related to low-frequency hearing in human. Hence, to explore therapeutic approaches, we developed adeno-associated virus containing the Klc2 wide-type cDNA sequence, and Klc2-null mice delivered virus showed apparent recovery, including decreased ABR threshold and reduced out hair cell (OHC) loss. In summary, we show that the kinesin transport system plays an indispensable and special role in cochlear HC function in mice and human and that mitochondrial localization is essential for HC survival.

The Role of Anti-Endothelial Cell Autoantibodies and Immune Response in Acute Low-Tone Hearing Loss.

OBJECTIVE: Immunity is associated with acute low tone hearing loss. However, the exact pathophysiology of immunity-mediated acute low tone hearing loss remains unknown. In this study, we evaluated the presence, therapeutic effectiveness, and immunopathological mechanisms of anti-endothelial cell autoantibodies (AECEs) in patients with acute low-frequency hearing loss. MATERIAL AND METHODS: Forty-nine patients who were treated as inpatients having acute low-frequency hearing loss and additional symptoms, such as ear fullness, tinnitus, dizziness, or hyperacusis, were enrolled in this study. Serum samples from these patients were collected for laboratory serum autoimmunity detection, including AECAs, antinuclear antibodies, immunoglobulin, and circular immune complex. Therapeutic responses to combination therapy in short-term outcome and serum cytokine levels were compared between AECA-positive and AECA-negative patients. RESULTS: Anti-endothelial cell autoantibodies-positive patients tended to show significantly less response to standard therapy compared with AECAs controls (P < .05). Moreover, some serum cytokine levels elevated in both AECAs- and AECAs+ groups. Positive ratio of interleukin-8 and concentrations of macrophage inflammatory protein-1α were found higher in AECAs+ groups (P < .05). CONCLUSION: The results supported that AECAs might wield influence on the short-term outcome of acute low-tone hearing loss (ALHL) treatment. Furthermore, AECA-mediated acute low-frequency hearing loss possibly involved dysregulation of inflammation process and release of cytokines.

Is cochlear synapse loss an origin of low-frequency hearing loss associated with endolymphatic hydrops?

There is a strong association between endolymphatic hydrops and low-frequency hearing loss, but the origin of the hearing loss remains unknown. A reduction in the number of cochlear afferent synapses between inner hair cells and auditory nerve fibres may be the origin of the low-frequency hearing loss, but this hypothesis has not been directly tested in humans or animals. In humans, measurements of hearing loss and postmortem temporal-bone based measurements of endolymphatic hydrops are generally separated by large amounts of time. In animals, there has not been a good objective, physiologic, and minimally invasive measurement of low-frequency hearing. We overcame this obstacle with the combined use of a reliable surgical approach to ablate the endolymphatic sac in guinea pigs and create endolymphatic hydrops, the Auditory Nerve Overlapped Waveform to measure low-frequency hearing loss (≤ 1 kHz), and immunohistofluorescence-based confocal microscopy to count cochlear synapses. Results showed low- and mid-(1-4 kHz) frequency hearing loss at all postoperative days, 1, 4, and 30. There was no statistically significant loss of cochlear synapses, and there was no correlation between synapse loss and hearing function. We conclude that cochlear afferent synaptic loss is not the origin of the low-frequency hearing loss in the early days following endolymphatic sac ablation. Understanding what is, and is not, the origin of a hearing loss can help guide preventative and therapeutic development.

Comorbid Symptoms Occurring During Acute Low-Tone Hearing Loss (AHLH) as Potential Predictors of Menière's Disease.

Acute low-tone sensorineural hearing loss (ALHL) is a type of idiopathic sudden sensorineural hearing loss. ALHL is rarely a solitary condition but rather co-occurs with vertigo and tinnitus, being an element of contemporary diagnostic criteria for Menière's disease (MD). The goal of our present study was to determine the value of ALHL for the early diagnosis of MD in patients presenting in the emergency room with ALHL as a main complaint. The files of 106 patients with ALHL who were admitted to the emergency room over the period of 7 years and 104 patients with acute high- tone sensorineural hearing loss (AHHL) from the same period were included in this retrospective study. Forty ALHL patients presented with recurrent episode of hearing loss and 66 remaining patients presented with ALHL for the first time. Of the latter group, 25 patients gave consent for the follow-up. First, we analyzed the difference in the occurrence of tinnitus and vertigo between the ALHL and AHHL groups. In patients with ALHL, the incidence of vertigo with tinnitus and the number of recurrent episodes were statistically higher than in patients with AHHL. Next, we focused on the ALHL follow-up group (25 patients). In that group, two patients had all MD symptoms at presentation, 18 had ALHL and tinnitus and five ALHL only. Of 18 patients with ALHL and tinnitus at admission, five developed vertigo and thus the triad of Menière's disease. None of the five patients with AHLH as a sole symptom developed MD during the follow-up time but four of them have developed tinnitus. Patients with recurrent ALHL had significantly higher incidence of MD than the patients with first episode. We conclude that some patients who present with ALHL and concomitant tinnitus or have recurrent episodes of ALHL are more likely to develop Menière's disease than these patients, who present with ALHL as a sole symptom. Nonetheless, we recommend otological follow-up for all patients presenting with ALHL.

Clinical Characteristics and Short-term Outcomes of Acute Low Frequency Sensorineural Hearing Loss With Vertigo.

OBJECTIVES: This study analyzed short-term prognosis in patients with acute low frequency hearing loss (ALHL), and also investigate hearing recovery rates in patients with ALHL accompanied vertigo. METHODS: Retrospective medical record review of the patients who received treatment for ALHL between June 2005 and June 2015 were analyzed. Of the 84 patients, 53 were without vertigo, and 31 were with vertigo. Of the 31 patients, eight were treated with steroids, seven with diuretics alone, and 16 with both. Clinical and auditory characteristics before and after treatment were compared in these three groups. RESULTS: Pure tone audiometry after 8 weeks of treatment showed that patients with vertigo had significantly higher than patients without vertigo (P=0.020). Patients with vertigo who recovered from ALHL had a greater tendency to receive early treatment than patients who did not recover. Patients who received the two steroid therapy groups (steroids alone and steroids plus diuretics) had a higher recovery rate than patients who received diuretics alone (P=0.043 and P=0.037, respectively). CONCLUSION: The prognosis of patients with ALHL is worse in those with vertigo compared to without vertigo. The hearing recovery rate in patients with vertigo tends to be higher in those treated with steroids than with diuretics alone.

Clinical Characteristics and Short-term Outcomes of Acute Low Frequency Sensorineural Hearing Loss With Vertigo

OBJECTIVES: This study analyzed short-term prognosis in patients with acute low frequency hearing loss (ALHL), and also investigate hearing recovery rates in patients with ALHL accompanied vertigo. METHODS: Retrospective medical record review of the patients who received treatment for ALHL between June 2005 and June 2015 were analyzed. Of the 84 patients, 53 were without vertigo, and 31 were with vertigo. Of the 31 patients, eight were treated with steroids, seven with diuretics alone, and 16 with both. Clinical and auditory characteristics before and after treatment were compared in these three groups. RESULTS: Pure tone audiometry after 8 weeks of treatment showed that patients with vertigo had significantly higher than patients without vertigo (P=0.020). Patients with vertigo who recovered from ALHL had a greater tendency to receive early treatment than patients who did not recover. Patients who received the two steroid therapy groups (steroids alone and steroids plus diuretics) had a higher recovery rate than patients who received diuretics alone (P=0.043 and P=0.037, respectively). CONCLUSION: The prognosis of patients with ALHL is worse in those with vertigo compared to without vertigo. The hearing recovery rate in patients with vertigo tends to be higher in those treated with steroids than with diuretics alone.

Whole-exome sequencing identified a missense mutation in WFS1 causing low-frequency hearing loss: a case report.

BACKGROUND: Low-frequency nonsyndromic hearing loss (LF-NSHL) is a rare, inherited disorder. Here, we report a family with LF-NSHL in whom a missense mutation was found in the Wolfram syndrome 1 (WFS1) gene. CASE PRESENTATION: Family members underwent audiological and imaging evaluations, including pure tone audiometry and temporal bone computed tomography. Blood samples were collected from two affected and two unaffected subjects. To determine the genetic background of hearing loss in this family, genetic analysis was performed using whole-exome sequencing. Among 553 missense variants, c.2419A → C (p.Ser807Arg) in WFS1 remained after filtering and inspection of whole-exome sequencing data. This missense mutation segregated with affected status and demonstrated an alteration to an evolutionarily conserved amino acid residue. Audiological evaluation of the affected subjects revealed nonprogressive LF-NSHL, with early onset at 10 years of age, but not to a profound level. CONCLUSION: This is the second report to describe a pathological mutation in WFS1 among Korean patients and the second to describe the mutation in a different ethnic background. Given that the mutation was found in independent families, p.S807R possibly appears to be a "hot spot" in WFS1, which is associated with LF-NSHL.

Exome sequencing identifies a novel missense mutation of WFS1 as the cause of non-syndromic low-frequency hearing loss in a Chinese family.

OBJECTIVE: Autosomal dominant non-syndromic low-frequency sensorineural hearing loss (LFSNHL) DFNA6/14/38 is an uncommon type of hearing loss that classically affects low frequencies of 2000 Hz and below, demonstrating an ascending configuration. The current study aimed to investigate the cause of LFSNHL in a five-generation Chinese family. METHODS: The phenotype of the Chinese family was characterized using audiologic testing and pedigree analysis. The combined approach of array screening and whole-exome sequencing was used to identify the disease-causing gene in this family. RESULTS: This pedigree, in which the affected subjects presented isolated low-frequency sensorineural hearing impairment with childhood onset, was associated with autosomal dominant inheritance of the c.2591A > G mutation in exon 8 of the Wolframin syndrome 1 (WFS1) gene which was not present in 286 unrelated controls with matched ancestry and is highly conserved across species. In addition, several mutations affecting the Glu864 residue have been previously identified in different populations, suggesting that this site is likely to be a mutational hot spot. CONCLUSIONS: We identified a novel substitution, Glu864Gly, of WFS1 as the causative variant for this pedigree. Our data extend the mutation spectrum of the WFS1 gene in Chinese individuals and may contribute to establishing a better genotype-phenotype correlation for LFSNHL.

Expanding the genotypic spectrum of Perrault syndrome.

Perrault syndrome is a rare autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) in both sexes and primary ovarian insufficiency in 46, XX karyotype females. Biallelic variants in five genes are reported to be causative: HSD17B4, HARS2, LARS2, CLPP and C10orf2. Here we present eight families affected by Perrault syndrome. In five families we identified novel or previously reported variants in HSD17B4, LARS2, CLPP and C10orf2. The proband from each family was whole exome sequenced and variants confirmed by Sanger sequencing. A female was compound heterozygous for a known, p.(Gly16Ser) and novel, p.(Val82Phe) variant in D-bifunctional protein (HSD17B4). A family was homozygous for mitochondrial leucyl aminocyl tRNA synthetase (mtLeuRS) (LARS2) p.(Thr522Asn), previously associated with Perrault syndrome. A further family was compound heterozygous for mtLeuRS, p.(Thr522Asn) and a novel variant, p.(Met117Ile). Affected individuals with LARS2 variants had low frequency SNHL, a feature previously described in Perrault syndrome. A female with significant neurological disability was compound heterozygous for p.(Arg323Gln) and p.(Asn399Ser) variants in Twinkle (C10orf2). A male was homozygous for a novel variant in CLPP, p.(Cys144Arg). In three families there were no putative pathogenic variants in these genes confirming additional disease-causing genes remain unidentified. We have expanded the spectrum of disease-causing variants associated with Perrault syndrome.

Apical hair cell degeneration causes the increase in the amplitude of summating potential.

CONCLUSION: This study indicates that the lesion of hair cells in the apical turn of the cochlea can cause the change in the summating potential (SP)/Compound potential (CAP) ratio. OBJECTIVES: Electrocochleography is a valuable clinic test for diagnosis of cochlear pathologies and the ratio of SP to CAP has been used to identify Meniere's disease. However, it remains controversial whether the increase of the SP/CAP ratio represents exclusively the endolymphatic hydrops. METHOD: This study measured the SP and CAP in mice that displayed outer hair cell (OHC) degeneration in the apical section of the cochlea as their age increased. RESULTS: As compared with the mice aged 8-10 months, the 24-month old mice displayed a significant increase in the amplitude of SP at 12-16 kHz. This result suggests that the degeneration of OHCs in the apical turn leads to the increase of the + SP at the middle frequencies. In contrast, the aging mice did not have a significant change in the CAP amplitude at super-threshold levels.

Episodic Dizziness with Unilateral Hearing Loss: Clinical Characteristics According to Hearing Loss Pattern / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: ZLow frequency hearing loss is known to be the most common hearing loss form in Meniere's disease (MD) and episodic dizziness with low frequency sensorineural hearing loss is considered a very crucial symptom for the diagnosis of MD. However, flat or high frequency hearing loss is also commonly encountered in the Ear, Nose and Throat clinic. The aim of this study is to investigate the differences in clinical manifestation between episodic dizzy patients with low frequency hearing loss (LFHL) group and non-low frequency hearing loss (non-LFHL) group. SUBJECTS AND METHOD: We reviewed medical records of 78 patients (36 of LFHL group and 42 of non-LFHL group) who had episodic dizziness with unilateral hearing loss and analyzed clinical characteristics according to hearing loss pattern. RESULTS: The clinical features of LFHL include a predominance of female sufferers, high incidence of tinnitus and short duration of dizziness. There was no significant difference in frequency, nature of dizziness, and results of vestibular function test. Although the proportion of patients diagnosed with definite MD was higher in LFHL group at initial and final diagnosis, there were no statistically significant differences between two groups. CONCLUSION: Therefore, when episodic dizziness is accompanied with unilateral hearing loss, not only low frequency but flat or high frequency hearing loss could be considered as a critical sign for possible progression to Meniere's disease and careful observation should be taken.