Jinsei Jung

Correlation between genotype and phenotype in patients with bi-allelic SLC26A4 mutations

Mutation of SLC26A4 is the most common cause of prelingual hearing loss in East Asia. Patients with SLC26A4 mutations have variable phenotypes ranging from non‐syndromic hearing loss to Pendred syndrome. Here, we analyzed the correlation between genotype and various inner ear phenotypes and found a possible underlying mechanism. This study included 111 patients with bi‐allelic SLC26A4 mutations who had bilateral enlarged vestibular aqueduct (EVA) and hearing loss. p.H723R (61%), c.919‐2A>G (24%), and p.T410M (4%) were the most common mutations in Korean patients with EVAs. Residual hearing in patients with c.919‐2A>G or p.T410M mutations was better than that of patients with p.H723R homozygous mutations. Interestingly, quantitative polymerase chain reaction showed normal pendrin transcript (6–17% of normal levels) was produced from patients with c.919‐2A>G homozygous mutations. Surface expression ratio of pendrin and residual anion exchange activity were higher in cells transfected with p.T410M in comparison to cells transfected with p.H723R. These results suggest that there is a correlation between degree of residual hearing and the SLC26A4 genotype commonly found in the East Asian population.

Clinical Presentation and Management of Jugular Foramen Paraganglioma

Objectives Jugular foramen paraganglioma is a locally invasive, benign tumor, which grow slowly and causes various symptoms such as pulsatile tinnitus and low cranial nerve palsy. Complete surgical resection is regarded as the ideal management of these tumors. The goal of this study is to identify the clinical characteristics and most effective surgical approach for jugular foramen paraganglioma. Methods Retrospective analysis of 9 jugular foramen paraganglioma patients who underwent surgical resection between 1986 and 2005 was performed. Clinical records were reviewed for analysis of initial clinical symptoms and signs, audiological examinations, neurological deficits, radiological features, surgical approaches, extent of resection, treatment outcomes and complications. Results Most common initial symptom was hoarseness, followed by pulsatile tinnitus. Seven out of 9 patients had at least one low cranial nerve palsy. Seven patients were classified as Fisch Type C tumor and remaining 2 as Fisch Type D tumor on radiologic examination. Total of 11 operations took place in 9 patients. Total resection was achieved in 6 cases, when partial resection was done in 3 cases. Two patients with partial resection received gamma knife radiosurgery (GKS), when remaining 1 case received both GKS and two times of revision operation. No mortality was encountered and there were few postoperative complications. Conclusion Neurologic examination of low cranial nerve palsy is crucial since most patients had at least one low cranial nerve palsy. All tumors were detected in advanced stage due to slow growing nature and lack of symptom. Angiography with embolization is crucial for successful tumor removal without massive bleeding. Infratemporal fossa approach can be considered as a safe, satisfactory approach for removal of jugular foramen paragangliomas. In tumors with intracranial extension, combined approach is recommended in that it provides better surgical view and can maintain the compliance of the patients.

Genetic aspects and clinical characteristics of familial meniere's disease in a South Korean population

This study was undertaken to investigate the prevalence, inheritance patterns, and clinical characteristics of familial Menieres disease (MD) in a South Korean population.

Clinical significance of subclinical varicocelectomy in male infertility: systematic review and meta-analysis

Recent meta‐analysis by the Cochrane collaboration concluded that treatment of varicocele may improve an infertile couples chance of pregnancy. However, there has been no consensus on the management of subclinical varicocele. Therefore, we determine the impact of varicocele treatment on semen parameters and pregnancy rate in men with subclinical varicocele. The randomised controlled trials that assessed the presence and/or treatment of subclinical varicocele were included for systematic review and meta‐analysis. Random effect model was used to calculate the weighted mean difference of semen parameters and odds ratio of pregnancy rates. Seven trials with 548 participants, 276 in subclinical varicocelectomy and 272 in no‐treatment or clomiphene citrate subjects, were included. Although there was also no statistically significant difference in pregnancy rate (OR 1.29, 95% CI 0.99–1.67), surgical treatment resulted in statistically significant improvements on forward progressive sperm motility (MD 3.94, 95% CI 1.24–6.65). However, the evidence is not enough to allow final conclusions because the quality of included studies is very low and further research is needed.

Electrogenic transport and K+ ion channel expression by the human endolymphatic sac epithelium

The endolymphatic sac (ES) is a cystic organ that is a part of the inner ear and is connected to the cochlea and vestibule. The ES is thought to be involved in inner ear ion homeostasis and fluid volume regulation for the maintenance of hearing and balance function. Many ion channels, transporters, and exchangers have been identified in the ES luminal epithelium, mainly in animal studies, but there has been no functional study investigating ion transport using human ES tissue. We designed the first functional experiments on electrogenic transport in human ES and investigated the contribution of K+ channels in the electrogenic transport, which has been rarely identified, even in animal studies, using electrophysiological/pharmacological and molecular biological methods. As a result, we identified functional and molecular evidence for the essential participation of K+ channels in the electrogenic transport of human ES epithelium. The identified K+ channels involved in the electrogenic transport were KCNN2, KCNJ14, KCNK2, and KCNK6, and the K+ transports via those channels are thought to play an important role in the maintenance of the unique ionic milieu of the inner ear fluid.

Statistical Analysis of Pure Tone Audiometry and Caloric Test in Herpes Zoster Oticus

Objectives Pure tone audiometry and caloric test in patients with herpes zoster oticus were performed to determine the biologic features of the varicella zoster virus (VZV) and the pathogenesis of vestibulocochlear nerve disease in herpes zoster oticus. Study Design A retrospective chart review of 160 patients with herpes zoster oticus was designed in order to determine the classic characteristics of vestibulocochlear nerve disease associated with the syndrome. Speech frequency and isolated high frequency acoustic thresholds were analyzed based on severity of facial paralysis and patient age. Patients without cochlear symptoms were selected randomly, and audiological function was evaluated. Patients with symptoms of vestibular dysfunction underwent the caloric test, and canal paresis was analyzed according to the severity of facial paralysis and the age of each patient. Results Among the 160 patients, 111 exhibited pure tone audiometry; 26 (79%) of the patients with cochlear symptoms and 44 (56%) of the patients without cochlear symptoms had abnormal audiological data. Among the patients without cochlear symptoms, 15 (19%) had hearing loss at speech frequency, and 42 (54%) had hearing loss isolated to high frequency. The incidence of cochlear symptoms in herpes zoster oticus was not related to the severity of facial paralysis. The incidence of patients with isolated high frequency hearing loss statistically increased with age, however the incidence of patients with speech frequency hearing loss did not increase. Thirteen patients complained vertigo, and the incidence of vestibular disturbances and the value of canal paresis in the caloric test increased to statistical significance in parallel with increasing severity of facial paralysis. Conclusion Mild or moderate cochlear symptoms with high frequency hearing loss were related to age, and severe vestibular symptoms were related to the severity of facial paralysis after onset of herpetic symptoms. This study might suggest us a clue to the pathogenesis of vestibulocochlear nerve disease in herpes zoster oticus.

Genetic Predisposition to Sporadic Congenital Hearing Loss in a Pediatric Population

Discriminating between inherited and non-inherited sporadic hearing loss is challenging. Here, we attempted to delineate genetic inheritance in simplex cases of severe-to-profound congenital hearing loss in Korean children. Variations in SLC26A4 and GJB2 in 28 children with bilateral severe-to-profound non-syndromic hearing loss (NSHL) without familial history were analyzed using Sanger sequencing. Genetic analysis of individuals without mutations in SLC26A4 and GJB2 was performed by whole exome sequencing (WES). Bi-allelic mutations in SLC26A4 and GJB2 were identified in 12 and 3 subjects, respectively. Of the 13 individuals without mutations in SLC26A4 and GJB2, 2 and 1 carried compound heterozygous mutations in MYO15A and CDH23, respectively. Thus, 64.3% (18/28) of individuals with NSHL were determined to be genetically predisposed. Individuals with sporadic severe-to-profound NSHL were found to mostly exhibit an autosomal recessive inheritance pattern. Novel causative candidate genes for NSHL were identified by analysis of WES data of 10 families without mutations in known causative genes. Bi-allelic mutations predisposing to NSHL were identified in 64.3% of subjects with sporadic severe-to-profound NSHL. Given that several causative genes for NSHL are still unidentified, genetic inheritance of sporadic congenital hearing loss could be more common than that indicated by our results.

Resistance to hypertension and high Cl(-) excretion in humans with SLC26A4 mutations.

Pendrin is a membrane transporter encoded by solute carrier family26A4 (SLC26A4). Mutations in this gene are known to cause hearing loss, and recent data from animal studies indicate a link between pendrin expression and hypertension; although, this association in humans is unclear. To clarify this issue, we investigated the influence of pendrin on blood pressure by analyzing demographic and biochemical data – including blood pressure and urinary electrolyte excretion – in patients with bi‐allelic SLC26A4 mutations. Systolic and diastolic blood pressure and the left ventricular hypertrophy index were lower in subjects with pendrin mutations than in controls. In addition, fractional excretion of Na+ and Cl− was increased and serum renin, angiotensin I and II levels were higher in subjects with pendrin mutations as compared to controls. Thus, patients with impaired pendrin function are likely to be resistant to high blood pressure due to enhanced urinary Na+/Cl− excretion. These results suggest that pendrin may regulate blood pressure through increased urinary salt excretion.

Evaluation of quality of life after intratympanic streptomycin injection in patients with Ménière's disease.

Objectives: Quality of life (QOL) and satisfaction level of patients with Ménières disease who underwent intratympanic streptomycin injection were evaluated across physical, psychological, and social domains of function. Study Design: Preoperative and postoperative QOL of patients were evaluated based on the chart records of patients and questionnaire surveys. From January 2000 to August 2005, 81 patients underwent intratympanic streptomycin injection at Yonsei University Severance Hospital, and their medical records were retrospectively reviewed. In addition, a mailed questionnaire survey was conducted. Ménières Disease Outcome Questionnaire-Retrospective Version, proposed by Kato et al., was used as the QOL measure and was completed by 51 patients. Results: The average QOL score was 35.6 ± 9.6 before surgery and 52.8 ± 10.3 after surgery, indicating improvement of QOL by 17.2 after surgery. The improvement of QOL score did not correlate to age and sex of patients; nonetheless, higher improvement of score was found in patients with professional career (p < 0.001). The improvement of QOL in the preoperative Stage 3 and 4 patient groups was greater than that in the preoperative Stage 1 and 2 patient groups (p = 0.032). The mean change in hearing of the patients after surgery was 1.5 + 7.2 dB hearing loss based on a 4-frequency pure-tone average (500, 1,000, 2,000, 3,000 Hz). Furthermore, 4 (7.8%) of 51 patients demonstrated greater than 10-dB change in 4-frequency pure-tone average. The status of hearing loss after surgery did not influence the QOL score (p = 0.530). As the frequency of vertigo decreased, the improvement of QOL score increased (p = 0.042). Conclusion: The level of satisfaction with intratympanic streptomycin injection was strongly correlated to the QOL score in Ménières Disease Outcome Questionnaire-Retrospective Version. As for the factors that improved the QOL after surgery, the status of hearing was not closely associated; however, the frequency of vertiginous symptom was the most important factor.

β 1 - and β 2 -adrenergic stimulation-induced electrogenic transport by human endolymphatic sac epithelium and its clinical implications

The endolymphatic sac (ES) is a cystic structure of the inner ear connected to the cochlea and vestibule, which plays a role in regulating ion homeostasis in inner ear fluid. Disruption of ion homeostasis can cause inner ear disorders with hearing loss and dizziness, such as Meniere’s disease. Herein, we found, for the first time, functional evidence for the involvement of β1- and β2-adrenergic receptors in apical electrogenic ion transport by human ES epithelium by using electrophysiological/pharmacological and molecular biological methods, which were dependent on K+ and Cl− ion transport. The apical electrogenic transport was absent or very weak in ES epithelia of patients with Meniere’s disease. These results suggested that adrenergic stimulation via β1- and β2-adrenergic receptors in the human ES was involved in regulation of inner ear fluid ion homeostasis and impairment of this response could be a pathological mechanism of Meniere’s disease.