Ja-Won Koo

Prevalence of p.V37I Variant of GJB2 in Mild or Moderate Hearing Loss in a Pediatric Population and the Interpretation of Its Pathogenicity

A p.V37I variant of GJB2 has been reported from subjects with moderate or slight hearing loss especially in East Asian populations. This study aimed to estimate the prevalence of the p.V37I variant among such subjects and prove, epidemiologically, its pathogenic potential to cause mild hearing loss. A total of 380 subjects from 201 families with hearing loss were enrolled. From them, 103 families were selected who had autosomal recessive inheritance or sporadic occurrence of hearing loss and who were younger than 15 years old. GJB2 sequencing was carried out for the probands of all 103 families. The prevalence of the p.V37I variant was compared between the subtle, mild or moderate hearing loss (group I) and the severe or profound hearing loss (group II) groups. Where possible, a targeted next generation sequencing of 82 deafness genes was performed from the p.V37I carrier to exclude the existence of other pathogenic genes. Five (4.8%) of 103 probands were found to carry p.V37I. The carrier frequency of p.V37I among group I (18.2%) was significantly higher than that of group II (1.2%) or the reported Korean normal hearing control group (1.0%). Detection of the p.V37I variant of GJB2 in 18.2% of Koreans with mild hearing loss strongly suggests its contribution to the pathogenesis of milder hearing loss, which might justify sequencing of GJB2 from these subjects in the Korean population.

Exploration of molecular genetic etiology for Korean cochlear implantees with severe to profound hearing loss and its implication.

BackgroundSevere to profound sensorineural hearing loss (SNHL) requires cochlear implantation (CI) for auditory rehabilitation. Etiologic diagnoses can contribute to candidacy selection and decision-making regarding the timing of successful CI. However, few studies have been performed to address the etiologic spectrum of severe SNHL in the population where there is no consanguineous marriage and the majority of SNHL cases are sporadic in small sized families. The authors sought to comprehensively understand the etiologies of Korean cochlear implantees by incorporating the targeted resequencing of 204 candidate deafness genes (TRS-204) and a phenotype-driven candidate gene approach.MethodsNinety-three that consented to molecular genetic testing and underwent at least one molecular genetic test were included. Patients with a characteristic Phenotypic marker were subject to Sanger sequencing to detect variants in corresponding candidate genes. The rest of patients without any prominent phenotype were tested on GJB2. Next, TRS-204 was applied in GJB2-negative cases without any phenotypic marker. In addition, the sibling recurrence-risk of SNHL among families with non-diagnostic genotypes after TRS-204 was performed to gain insight of etiologies in non-diagnostic cases.ResultsOverall, we could find causative variants in 51 (54.8%) of the 93 cochlear implantees. Thirty (32.3%) probands could be diagnosed by direct Sanger sequencing of candidate genes selected by their phenotypes. GJB2 sequencing added 10 subjects to the group with a diagnostic genotype. TRS-204 could detect a causative variant from additional 11 cases (11.8%). We could not detect any pathogenic deletion or duplication on 204 target genes. The sibling recurrence-risk of SNHL among 42 genetically undiagnosed families with 0.03 (1/38) was significantly lower than among genetically diagnosed recessive families with 0.19 (7/37).ConclusionDespite that the majority of severe or more degree of SNHL occurs sporadically in Koreans, at least 54.8% of such cases that were willing to join the genetic study in the Korean population are monogenic Mendelian disorders with convincing causative variants. This study also indicates that a substantial portion of unsolved cases after applying our current protocol are predicted to have non-genetic or complex etiology rather than a Mendelian genetic disorder involving new genes beyond the 204 target genes.

Bilateral duplication of the internal auditory canal

Duplication of the internal auditory canal is an extremely rare temporal bone anomaly that is believed to result from aplasia or hypoplasia of the vestibulocochlear nerve. We report bilateral duplication of the internal auditory canal in a 28-month-old boy with developmental delay and sensorineural hearing loss.

The efficacy and safety of systemic injection of Ginkgo biloba extract, EGb761, in idiopathic sudden sensorineural hearing loss: a randomized placebo-controlled clinical trial

Steroids are currently the most frequently accepted agents for idiopathic sudden sensorineural hearing loss (ISSNHL). However, the therapeutic effect of steroids is not always satisfactory. In this pilot study, we evaluated whether systemic treatment with Ginkgo biloba extract (EGb761) has an additive therapeutic effect in patients receiving a systemic steroid due to ISSNHL. A multicenter, randomized, double-blind clinical trial was performed. Fifty-six patients with ISSNHL were allocated to either EGb761 or placebo. In both groups, methylprednisolone was administered for 14xa0days. EGb761 was infused intravenously for 5xa0days in the EGb761 group, while the same amount of normal saline was infused in the placebo group. For the efficacy evaluation, pure-tone audiometry, speech audiometry, tinnitus handicap inventory (THI) and short form-36 health (SF-36) survey outcomes were obtained before administration and on days 3, 5, 14 and 28 of administration. Twenty-four patients in each group completed the study protocol. There was no difference in hearing loss between the two groups before treatment. At day 28, air conduction threshold values in the placebo and EGb761 groups were 34.63xa0±xa028.90 and 23.84xa0±xa025.42xa0dB, respectively (pxa0=xa00.082). Speech discrimination scores in the placebo and EGb761 groups were 69.17xa0±xa040.89 and 87.48xa0±xa028.65xa0%, respectively (pxa0=xa00.050). THI and SF-36 scores in the placebo and EGb761 groups were similar. Although a combination of steroid and EGb761 for initial treatment did not show better pure tone threshold, compared with steroid alone, speech discrimination was significantly improved in combination therapy. Further studies will be needed to know if addition of EGb761 actually improves the outcome of ISSNHL treatment.

Residual Hearing in DFNB1 Deafness and Its Clinical Implication in a Korean Population.

Introduction The contribution of Gap junction beta-2 protein (GJB2) to the genetic load of deafness and its mutation spectra vary among different ethnic groups. Objective In this study, the mutation spectrum and audiologic features of patients with GJB2 mutations were evaluated with a specific focus on residual hearing. Methods An initial cohort of 588 subjects from 304 families with varying degrees of hearing loss were collected at the otolaryngology clinics of Seoul National University Hospital and Seoul National University Bundang Hospital from September 2010 through January 2014. GJB2 sequencing was carried out for 130 probands with sporadic or autosomal recessive non syndromic hearing loss. The audiograms were evaluated in the GJB2 mutants. Results Of the 130 subjects, 22 (16.9%) were found to carry at least one mutant allele of GJB2. The c.235delC mutation was shown to have the most common allele frequency (39.0%) among GJB2 mutations, followed by p.R143W (26.8%) and p.V37I (9.8%). Among those probands without the p.V37I allele in a trans configuration who showed some degree of residual hearing, the mean air conduction thresholds at 250 and 500 Hz were 57 dB HL and 77.8 dB HL, respectively. The c.235delC mutation showed a particularly wide spectrum of hearing loss, from mild to profound and significantly better hearing thresholds at 250 Hz and 2k Hz than in the non-p.V37I and non-235delC nonsyndromic hearing loss and deafness 1(DFNB1) subjects. Conclusion Despite its reputation as the cause of severe to profound deafness, c.235delC, the most frequent DFNB1 mutation in our cohort, caused a wide range of hearing loss with some residual hearing in low frequencies. This finding can be of paramount help for prediction of low frequency hearing thresholds in very young DFNB1 patients and highlights the importance of soft surgery for cochlear implantation in these patients.

Clinical efficacy of the Romberg test using a foam pad to identify balance problems: a comparative study with the sensory organization test

The modified Romberg test using a foam pad (“MRuFP”) as a bedside examination has been used to assess the function of the complex sensory input needed for upright stance. The objective of this study was to assess its clinical valuexa0detecting vestibular falls in comparison with the sensory organization test (SOT), the gold standard. In total, 80 patients who had undergone the MRuFP, SOT, and bithermal caloric tests were included in this study. The MRuFPs were performed on two (height 12xa0cm, MRu2FP) or three (18xa0cm, MRu3FP) layers of foam pads. The odds ratios of falling on SOT were calculated. Iterative algorithms were used for linear curve fitting between the balance time on the MRuFP and SOT equilibrium score (ES). The diagnostic performance of MRuFP under different conditions was poor, with low sensitivity (0.07–0.63), when the results of SOT were used as the gold standard. However, the odds ratios of failing SOT conditionxa05 were 6.78 (95xa0% CIxa0=xa01.26–36.50) for patients with abnormal findings on eyes closed (EC)–MRu2FP and 10.91 (95xa0% CIxa0=xa02.58–46.11) for those on the EC–MRu3FP in patients without caloric weakness. In patients with caloric weakness, the odds ratio of failing SOT conditionxa05 for patients with abnormal findings on EC–MRu2FP was 7.0 (95xa0% CIxa0=xa00.69–70.74, pxa0>xa00.05), and 32.0 for those on EC-MRu3FP (95xa0% CIxa0=xa02.81–364.7). A linear equation was presented as the model fit (adjusted R2xa0=xa00.355) predicting the SOT conditionxa05xa0ES according to the balance time on EC–MRu3FP. In conclusion, the EC–MRu3FP, as a bedside examination, correlated well with SOT conditionxa05 as an objective measure.

Electrocochleographic findings in superior canal dehiscence syndrome.

This study evaluated the electrocochleographic findings of patients with superior canal dehiscence (SCD) syndrome and determined their diagnostic values and relationships with audiometric parameters. Thirteen symptomatic SCD patients (1 bilateral) confirmed by temporal bone computed tomography (TBCT) and cervical vestibular evoked myogenic potentials (cVEMP) were recruited. SCD sizes were measured on reformatted images in the plane of the superior canal (SC). Results of audiologic tests (audiometry, cVEMP, electrocochleography (ECoG)) for 14 affected and 12 contralateral unaffected ears were evaluated. Relationships between summating potential (SP) to action potential (AP) ratios, as measured by ECoG, and other audiometric parameters were evaluated. Sensitivity analysis of SP/AP ratios was performed by plotting receiver operating characteristic (ROC) curves for SCD syndrome patients and 19 age-matched healthy controls. Mean SP/AP ratio of SCD ears was significantly higher than that of unaffected ears (0.52 versus 0.25, pxa0<xa00.001) and SPs were significantly elevated in affected ears (pxa0=xa00.011), whereas APs were similar for affected and unaffected ears. SP/AP ratio showed a sensitivity of 92.3% and a specificity of 94.0% for distinguishing SCD syndrome patients given the inclusion criteria applied (symptoms, TBCT, cVEMP threshold) at a cutoff value of 0.34 (pxa0<xa00.001). SP/AP ratio was not correlated with SCD size or cVEMP threshold in affected ears. Negative absolute values of bone conduction at low frequency tended to increase with SP/AP ratio. Five out of 13 patients underwent surgical repair experienced symptomatic improvement with normalization of SP/AP ratios. ECoG appears to be a valuable diagnostic adjunct for functional demonstration of the third window in the otic capsule with high sensitivity and specificity, and thus, can support a clinical diagnosis of SCD when used in conjunction with clinical and radiological findings.

Clinical implication of ocular torsion in peripheral vestibulopathy

Acute unilateral vestibular loss presents as ocular torsion (OT) and caloric unilateral weakness (UW). However, the amount of OT is frequently dissociated from UW depending on when the examination was performed and the extent and cause of the vestibular lesion. This study evaluated the relationship between OT and UW in peripheral vestibular diseases, including Ménière’s disease (MD) and vestibular neuritis (VN), and determined whether it contributed to OT as a means of differentiating between the two diseases. A retrospective chart review was performed in 64 patients with VN and 67 patients with MD. We divided the patients into three groups according to the interval from symptom onset to when the tests were performed: within 7 (group A), from 8 to 30 (group B) and over 30 (group C) days. UW, OT and the chronological correlation/dissociation between the two parameters were analyzed. For the 64 patients with VN, the degree of OT and severity of UW were positively correlated in group A (rxa0=xa00.749, Pxa0<xa00.001). OT and UW were significantly dissociated with time (Pxa0<xa00.001). For the 67 patients with MD, no correlation between the degree of OT and severity of UW was seen in MD group A. No significant dissociation change was revealed among the groups (Pxa0=xa00.114). The OT abnormality is remarkable during the acute phase of VN, whereas it might not be remarkable immediately after a vertigo attack in MD. This finding can be used to differentiate MD and VN, especially when no definite hearing loss is seen or VN recurs.

Contralateral suppression of distortion-product otoacoustic emissions: A potential diagnostic tool to evaluate the vestibular nerve

The amplitude of distortion-product otoacoustic emission (DPOAE) is suppressed in one ear when the contralateral ear is subjected to sound stimulation. Contralateral suppression of DPOAE is the phenomenon resulted by the efferent cochlear innervation on the outer hair cells via medial olivocochlear bundle (MOCB) and inferior vestibular nerve. We assumed that DPOAE would not be suppressed by contralateral sound stimulation in patients with vestibular nerve lesion as long as the specific pathway conveying that efferent innervation is affected. To test this hypothesis, we compared the amount of DPOAE contralateral suppression in patients with vestibular neuritis and healthy controls. Twenty healthy volunteers without hearing loss and vestibulopathy, and 13 patients with vestibular neuritis were recruited. DP audiogram was measured without contralateral sound stimulation and then with contralateral sound stimulation (70 dB HL of 2 kHz narrow band noise, NBN). The suppression value of DPOAE was evaluated according to the f2 frequency and was defined as the amount of DPOAE suppression: An-Ao, where An represents the DPOAE amplitude in the presence of contralateral NBN, and Ao represents the DPOAE amplitude in the absence of NBN. Cervical vestibular evoked myogenic potential (cVEMP) was performed in some patients with vestibular neuritis. The suppression values of DPOAE were compared between groups and were analyzed according to the results of cVEMP. The amount of suppression of DPOAE during contralateral sound stimulation was significantly reduced in the patient group compared to control at the f2 frequencies of 1257, 1587, and 2002 Hz (P=0.045, P<0.001, P=0.009, respectively). However, the results of contralateral suppression of DPOAE were not consistent with the results of cVEMP in this study. Efferent cochlear innervation was affected in vestibular neuritis. Evaluation of contralateral suppression of DPOAE can be a potential diagnostic tool to evaluate the functional integrity of the vestibular nerve. Further studies are necessary to clarify this mechanism.

Head Position Dependency of Induced Nystagmus to Ice-Water Irrigation in Peripheral Vestibulopathy

OBJECTIVE: Evaluation of head-position dependency during the ice-water test is essential when the test is indicated. Because ice-water irrigation (IWI) in the prone position is frequently skipped in many laboratories, we investigated the importance of evaluating position dependency in an ice-water test. DESIGN AND SETTING: Twenty-five unilateral peripheral vestibulopathy patients showing no nystagmus during warm irrigation were included. IWI was performed in supine and prone positions, and maximum slow-phase velocity and direction of nystagmus were assessed by using video nystagmography. RESULTS: Eleven cases showed head-position dependency and were interpreted as hypofunctional. Fourteen cases showed no dependency, suggesting the absence of end organ function. In the latter group, 6 patients showing definite nystagmus in supine position could have been misinterpreted as hypofunctional, had it not been for prone-position results. CONCLUSIONS: Evaluation of head position dependency by using IWI is important in the determination of lateral semicircular canal function.