Kozo Kumakawa

Clinical characteristics and genotype–phenotype correlation of hearing loss patients with SLC26A4 mutations

Conclusions. The present study confirmed the clinical characteristics of patients with SLC26A4 mutations: congenital, fluctuating, and progressive hearing loss usually associated with vertigo and/or goiter during long-term follow-up. This clarification should help to facilitate appropriate genetic counseling and proper medical management for patients with these mutations, but there was no particular genotype–phenotype correlation among them, suggesting that other factors may contribute to such variability. Objectives. Due to the wide range of phenotypes caused by SLC26A4 mutations, there is controversy with regard to genotype–phenotype correlation. The present study was performed: (1) to determine phenotypic range in patients with biallelic SLC26A4 mutations, and (2) to evaluate whether possible genotype–phenotype correlation exists. Subjects and methods. Phenotypes in 39 hearing loss patients with SLC26A4 mutations were summarized and genotype–phenotype correlation was analyzed. Results. Hearing level varied in the individuals from mild to profound severity. Most of the patients had fluctuating and progressive hearing loss that may have been of prelingual onset. Twenty-four (70.6%) patients had episodes of vertigo, and 10 (27.8%) patients had goiter, which had appeared at age 12 or older. In contrast to such phenotypic variabilities, no apparent correlation was found between these phenotypes and their genotypes.

Sweep-Frequency Tympanometry: Its Development and Diagnostic Value

This reports a newly developed tympanometric system using a sweep-frequency probe tone. For a sweep-frequency tone ranging from 220 to 2 000 Hz, measurements of sound pressure (P) and phase were performed at ear canal pressures of 0 and -200 mm H2O. The results were expressed as a sound pressure curve (P0-P-200 in decibels), a phase curve (formula: see text) and a polar curve (formula: see text) against probe tone frequency. Both the frequency at which the sound pressure curve crossed the 0-dB difference line and the peak frequency of the phase curve shifted lower than normal for ossicular disruption and higher than normal for ossicular fixation. Changes in the sound pressure curve and in the phase curve were exaggerated for ossicular disruption and limited for fixation. As the result of these, the polar curve showed an expanded type for disruption and a compressed type for fixation. A review of 220-Hz tympanograms and of the polar curves for 10 patients demonstrated that the latter permitted a better discrimination among ossicular disorders.

Tympanometry using a Sweep-Frequency Probe Tone and Its Clinical Evaluation

In this new tympanometric system, air pressure in the external meatus is kept constant at either -200 daPa or 0 daPa. The frequency of the probe tone is swept from 220 to 2,000 Hz (or 2,500 Hz, if necessary) in 4 s. During this frequency sweep, sound pressure in decibels and phase angle in degrees in the external meatus are sampled and the differences in sound pressure and phase angle measured at -200 and 0 daPa pressures are computed. These results are figured as a frequency-sound pressure curve and a frequency-phase angle curve. From the study on 8 fresh human cadaver temporal bones, four parameters in these curves are selected by discriminant analysis to provide diagnostic criteria: the minimum value and the 0-cross frequency of the frequency-sound pressure curve and the maximum value and its frequency of the frequency-phase angle curve. Normal parameters were determined in 50 normal ears. Evaluation of 40 patients with ossicular disorders revealed that 10 out of 12 cases of ossicular discontinuity and 5 out of 6 cases of malleus and/or incus fixation were correctly diagnosed. For stapes fixation, the diagnosis was correct in 12 out of 22 ears. This system is useful in the clinical diagnosis of ossicular disorders, producing a collection of curves and parameters that are distinctively different for the ossicular discontinuity and the ossicular fixation.

A randomized controlled clinical trial of topical insulin-like growth factor-1 therapy for sudden deafness refractory to systemic corticosteroid treatment

BackgroundTo date, no therapeutic option has been established for sudden deafness refractory to systemic corticosteroids. This study aimed to examine the efficacy and safety of topical insulin-like growth factor-1 (IGF-1) therapy in comparison to intratympanic corticosteroid therapy.MethodsWe randomly assigned patients with sudden deafness refractory to systemic corticosteroids to receive either gelatin hydrogels impregnated with IGF-1 in the middle ear (62 patients) or four intratympanic injections with dexamethasone (Dex; 58 patients). The primary outcome was the proportion of patients showing hearing improvement (10 decibels or greater in pure-tone average hearing thresholds) 8 weeks after treatment. The secondary outcomes included the change in pure-tone average hearing thresholds over time and the incidence of adverse events.ResultsIn the IGF-1 group, 66.7% (95% confidence interval [CI], 52.9-78.6%) of the patients showed hearing improvement compared to 53.6% (95% CI, 39.7-67.0%) of the patients in the Dex group (P = 0.109). The difference in changes in pure-tone average hearing thresholds over time between the two treatments was statistically significant (P = 0.003). No serious adverse events were observed in either treatment group. Tympanic membrane perforation did not persist in any patient in the IGF-1 group, but did persist in 15.5% (95% CI, 7.3-27.4%) of the patients in the Dex group (P = 0.001).ConclusionsThe positive effect of topical IGF-1 application on hearing levels and its favorable safety profile suggest utility for topical IGF-1 therapy in patients with sudden deafness.Trial registrationUMIN Clinical Trials Registry Number UMIN000004366, October 30th, 2010.

Massively Parallel DNA Sequencing Facilitates Diagnosis of Patients with Usher Syndrome Type 1

Usher syndrome is an autosomal recessive disorder manifesting hearing loss, retinitis pigmentosa and vestibular dysfunction, and having three clinical subtypes. Usher syndrome type 1 is the most severe subtype due to its profound hearing loss, lack of vestibular responses, and retinitis pigmentosa that appears in prepuberty. Six of the corresponding genes have been identified, making early diagnosis through DNA testing possible, with many immediate and several long-term advantages for patients and their families. However, the conventional genetic techniques, such as direct sequence analysis, are both time-consuming and expensive. Targeted exon sequencing of selected genes using the massively parallel DNA sequencing technology will potentially enable us to systematically tackle previously intractable monogenic disorders and improve molecular diagnosis. Using this technique combined with direct sequence analysis, we screened 17 unrelated Usher syndrome type 1 patients and detected probable pathogenic variants in the 16 of them (94.1%) who carried at least one mutation. Seven patients had the MYO7A mutation (41.2%), which is the most common type in Japanese. Most of the mutations were detected by only the massively parallel DNA sequencing. We report here four patients, who had probable pathogenic mutations in two different Usher syndrome type 1 genes, and one case of MYO7A/PCDH15 digenic inheritance. This is the first report of Usher syndrome mutation analysis using massively parallel DNA sequencing and the frequency of Usher syndrome type 1 genes in Japanese. Mutation screening using this technique has the power to quickly identify mutations of many causative genes while maintaining cost-benefit performance. In addition, the simultaneous mutation analysis of large numbers of genes is useful for detecting mutations in different genes that are possibly disease modifiers or of digenic inheritance.

Hearing preservation and clinical outcome of 32 consecutive electric acoustic stimulation (EAS) surgeries

Abstract Conclusions: Our results indicated that electric acoustic stimulation (EAS) is beneficial for Japanese-speaking patients, including those with less residual hearing at lower frequencies. Comparable outcomes for the patients with less residual hearing indicated that current audiological criteria for EAS could be expanded. Successful hearing preservation results, together with the progressive nature of loss of residual hearing in these patients, mean that minimally invasive full insertion of medium/long electrodes in cochlear implantation (CI) surgery is a desirable solution. The minimally invasive concepts that have been obtained through EAS surgery are, in fact, crucial for all CI patients. Objectives: This study was conducted to evaluate hearing preservation results and speech discrimination outcomes of hearing preservation surgeries using medium/long electrodes. Methods: A total of 32 consecutive minimally invasive hearing preservation CIs (using a round window approach with deep insertion of a flexible electrode) were performed in 30 Japanese patients (two were bilateral cases), including patients with less residual hearing. Hearing preservation rates as well as speech discrimination/perception scores were investigated on a multicenter basis. Results: Postoperative evaluation after full insertion of the flexible electrodes (24 mm, 31.5 mm) showed that residual hearing was well preserved in all 32 ears. In all patients, speech discrimination and perception scores were improved postoperatively.

Comprehensive genetic screening of KCNQ4 in a large autosomal dominant nonsyndromic hearing loss cohort: genotype-phenotype correlations and a founder mutation.

The present study of KCNQ4 mutations was carried out to 1) determine the prevalence by unbiased population-based genetic screening, 2) clarify the mutation spectrum and genotype/phenotype correlations, and 3) summarize clinical characteristics. In addition, a review of the reported mutations was performed for better understanding of this deafness gene. The screening using 287 probands from unbiased Japanese autosomal dominant nonsyndromic hearing loss (ADNSHL) families identified 19 families with 7 different disease causing mutations, indicating that the frequency is 6.62% (19/287). While the majority were private mutations, one particular recurrent mutation, c.211delC, was observed in 13 unrelated families. Haplotype analysis in the vicinity of c.211delC suggests existence of a common ancestor. The majority of the patients showed all frequency, but high-frequency predominant, sensorineural hearing loss. The present study adds a new typical audiogram configuration characterized by mid-frequency predominant hearing loss caused by the p.V230E mutation. A variant at the N-terminal site (c. 211delC) showed typical ski-slope type audiogram configuration. Concerning clinical features, onset age was from 3 to 40 years old, and mostly in the teens, and hearing loss was gradually progressive. Progressive nature is a common feature of patients with KCNQ4 mutations regardless of the mutation type. In conclusion, KCNQ4 mutations are frequent among ADNSHL patients, and therefore screening of the gene and molecular confirmation of these mutations have become important in the diagnosis of these conditions.

OTOF mutation screening in Japanese severe to profound recessive hearing loss patients

BackgroundAuditory neuropathy spectrum disorder (ANSD) is a unique form of hearing loss that involves absence or severe abnormality of auditory brainstem response (ABR), but also the presence of otoacoustic emissions (OAEs). However, with age, the OAEs disappear, making it difficult to distinguish this condition from other nonsyndromic hearing loss. Therefore, the frequency of ANSD may be underestimated. The aim of this study was to determine what portion of nonsyndromic hearing loss is caused by mutations of OTOF, the major responsible gene for nonsyndromic ANSD.MethodsWe screened 160 unrelated Japanese with severe to profound recessive nonsyndromic hearing loss (ARNSHL) without GJB2 or SLC26A4 mutations, and 192 controls with normal hearing.ResultsWe identified five pathogenic OTOF mutations (p.D398E, p.Y474X, p.N727S, p.R1856Q and p.R1939Q) and six novel, possibly pathogenic variants (p.D450E, p.W717X, p.S1368X, p.R1583H, p.V1778I, and p.E1803A).ConclusionsThe present study showed that OTOF mutations accounted for 3.2–7.3% of severe to profound ARNSHL patients in Japan. OTOF mutations are thus a frequent cause in the Japanese deafness population and mutation screening should be considered regardless of the presence/absence of OAEs.

High-resolution MR Imaging of the Inner Ear

The magnetic resonance (MR) images of the temporal bones have been analyzed, these MR images taken with head coils utilizing a 1.5-Tesla magnet whole-body imaging system. The MR images were acquired by means of spin-echo pulse sequences, and the thickness of the sections was 2.5 mm. By this modality, the T2-weighted images could clearly delineate the details of the liquid-containing labyrinthine structures and facial nerve. MR imaging can provide information that is unobtainable from a CT scan in the diagnosis of inner ear disorders, particularly as to whether the membranous labyrinth is filled with the lymph fluid or is fibrosed. This point is one of the greatest advantages of MR imaging over a high-resolution CT scan.

Prognostic impact of salvage treatment on hearing recovery in patients with sudden sensorineural hearing loss refractory to systemic corticosteroids: A retrospective observational study

OBJECTIVE To determine the prognostic factors for hearing recovery in patients with sudden sensorineural hearing loss (SSHL) refractory to systemic corticosteroids following salvage treatment. METHODS This is a retrospective observational study at nine tertiary referral hospitals. A total of 120 patients with sudden deafness refractory to systemic corticosteroids were enrolled. The patients were randomly assigned to receive topical application of recombinant human IGF-1 or intratympanic injection of dexamethasone as salvage treatment. Multiple regression analysis was performed to identify determinants of hearing recovery using pure tone audiometry results at 8 weeks after treatment. Clinical predictors that were evaluated included age, sex, pretreatment hearing level, presence of vertiginous symptoms, days to study entry from symptom onset and salvage treatment assignment (IGF-1 vs. dexamethasone). RESULTS The linear regression model identified age (P=0.001), pretreatment hearing level (P<0.001), days to study entry from symptom onset (P=0.011) and treatment assignment (P=0.033) at 8 weeks after treatment as significant variables influencing the recovery of pure tone audiometry average thresholds. Younger age (<60 years), early initiation of salvage treatment and treatment with topical IGF-1 therapy had significant effects on hearing recovery. CONCLUSION The results indicate that early initiation and choice of treatment modalities for salvage treatment may be important for the prognosis of patients with refractory SSHL. The positive effect of topical IGF-1 therapy on hearing recovery indicates its utility as salvage treatment.