Linda J. Hood

Mutations in the connexin 26 gene (GJB2) among Ashkenazi jews with nonsyndromic recessive deafness

BACKGROUND Mutations in the GJB2 gene cause one form of nonsyndromic recessive deafness. Among Mediterranean Europeans, more than 80 percent of cases of nonsyndromic recessive deafness result from inheritance of the 30delG mutant allele of GJB2. We assessed the contribution of mutations in GJB2 to the prevalence of the condition among Ashkenazi Jews. METHODS We tested for mutations in GJB2 in DNA samples from three Ashkenazi Jewish families with nonsyndromic recessive deafness, from Ashkenazi Jewish persons seeking carrier testing for other conditions, and from members of other ethnic groups. The hearing of persons who were heterozygous for mutations in GJB2 was assessed by means of pure-tone audiometry, measurement of middle-ear immittance, and recording of otoacoustic emissions. RESULTS Two frame-shift mutations in GJB2, 167delT and 30delG, were observed in the families with nonsyndromic recessive deafness. In the Ashkenazi Jewish population the prevalence of heterozygosity for 167delT, which is rare in the general population, was 4.03 percent (95 percent confidence interval, 2.5 to 6.0 percent), and for 30delG the prevalence was 0.73 percent (95 percent confidence interval, 0.2 to 1.8 percent). Genetic-linkage analysis showed conservation of the haplotype for 167delT but the existence of several haplotypes for 30delG. Audiologic examination of carriers of the mutant alleles who had normal hearing revealed subtle differences in their otoacoustic emissions, suggesting that the expression of mutations in GJB2 may be semidominant. CONCLUSIONS The high frequency of carriers of mutations in GJB2 (4.76 percent) predicts a prevalence of 1 deaf person among 1765 people, which may account for the majority of cases of nonsyndromic recessive deafness in the Ashkenazi Jewish population. Conservation of the haplotype flanking the 167delT mutation suggests that this allele has a single origin, whereas the multiple haplotypes with the 30delG mutation suggest that this site is a hot spot for recurrent mutations.

Multi-site diagnosis and management of 260 patients with Auditory Neuropathy/Dys-synchrony (Auditory Neuropathy Spectrum Disorder)

Abstract Test results and management data are summarized for 260 patients with diagnoses of Auditory Neuropathy Spectrum Disorder (ANSD). Hearing aids were tried in 85 of these patients, and 49 patients tried cochlear implants. Approximately 15% reported some benefit from hearing aids for language learning, while improvement in speech comprehension and language acquisition was reported in 85% of patients who were implanted. Approximately 5% (13/260) of the total population developed normal speech and language without intervention. Patients were diagnosed at our laboratory (n=66) or referred from other sites (n=194), and all showed absent/grossly abnormal auditory brainstem responses (ABR), often ‘ringing’ cochlear microphonics, and the presence or history of otoacoustic emissions. Etiologies and co-existing conditions included genetic (n=41), peripheral neuropathies (n=20), perinatal jaundice and/or anoxia and/or prematurity (n=74). These patients comprise 10% or more of hearing impaired patients; their language acquisition trajectories are generally unpredictable from their audiograms. Sumario Se resumen los resultados de las pruebas y los datos del tratamiento de 260 pacientes con diagnóstico de Espectro de desórdenes de la Neuropatía Auditiva (ANSD). En 85 de estos pacientes se probó el uso de auxiliares auditivos y 49 pacientes recibieron un implante coclear. Aproximadamente 15% reportaron algún beneficio con los auxiliares auditivos para la adquisición del lenguaje mientras que el 85% de los que recibieron un implante reportaron una mejoría en la comprensión y la adquisición del lenguaje. Aproximadamente 5% (13/260) de la población total desarrolló lenguaje normal sin intervención. Los paciente fueron diagnosticados en nuestro laboratorio (n=66) o referidos de algún otro lado (n=194) y todos mostraron ausencia o anormalidad importante de los potenciales evocados (ABR), frecuentemente con una microfónica coclear “timbrante” y con presencia o historia de emisiones otoacústicas. La etiología o las condiciones co-existentes incluidas fueron: genéticas (n=41), neuropatías periféricas (n=20), ictericia perinatal y/o anoxia y/o prematurez (n=74). Estos pacientes representan 10% o más de los pacientes con hipoacusia; su trayectoria en el proceso de adquisición del lenguaje es generalmente impredecible a partir de sus audiogramas.

Auditory neuropathy/dyssynchrony: Its diagnosis and management

Patients with auditory neuropathy/dyssynchrony exhibit no auditory brain stem response (ABR), no middle ear muscle response, and both normal otoacoustic emissions or normal cochlear microphonics. An absent or grossly abnormal ABR is not always associated with deafness. In contrast, a hearing loss of 30 dB or more usually predicts absent otoacoustic emissions, but normal emissions can be seen in some patients whose behavioral audiograms imply total deafness. This article reviews the underlying physiology that makes these tests both useful and potentially misleading, and recommends steps to be considered by primary care physicians and other professionals to compensate for the vulnerabilities of each of the procedures.

Contralateral suppression of transient-evoked otoacoustic emissions in humans: intensity effects

Transient evoked otoacoustic emissions (TEOAEs) were recorded to clicks presented at peak sound pressures of 50, 55, 60, 65 and 70 dB while continuous contralateral white noise was varied from 10 dB below to 10 dB above the click level. Suppression increased predictably with suppressor noise level for any given click level. However, when the suppressor noise level was held constant, suppression was greater for lower click levels. This observation is consistent with the association of suppression of otoacoustic emissions with active cochlear processes and efferent function at low intensity levels.

OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy allele

Introduction: The majority of hearing loss in children can be accounted for by genetic causes. Non-syndromic hearing loss accounts for 80% of genetic hearing loss in children, with mutations in DFNB1/GJB2 being by far the most common cause. Among the second tier genetic causes of hearing loss in children are mutations in the DFNB9/OTOF gene. Methods: In total, 65 recessive non-syndromic hearing loss families were screened by genotyping for association with the DFNB9/OTOF gene. Families with genotypes consistent with linkage or uninformative for linkage to this gene region were further screened for mutations in the 48 known coding exons of otoferlin. Results: Eight OTOF pathological variants were discovered in six families. Of these, Q829X was found in two families. We also noted 23 other coding variant, believed to have no pathology. A previously published missense allele I515T was found in the heterozygous state in an individual who was observed to be temperature sensitive for the auditory neuropathy phenotype. Conclusions: Mutations in OTOF cause both profound hearing loss and a type of hearing loss where otoacoustic emissions are spared called auditory neuropathy.

Contralateral suppression of otoacoustic emissions: An index of the function of the medial olivocochlear system

We can now distinguish, in part, between nerve deafness and hair cell deafness through the use of otoacoustic emissions. We can also assess the efferent system by carefully quantifying the effects of contralateral stimulation on these same otoacoustic emissions. The suppression of transient evoked emissions by continuous contralateral white noise is an ostensibly small effect of 2 or 3 dB when studied over a 20-msec window. However, when subjected to microstructural analysis, the effect can exceed 6 to 8 dB in the zones from 10 to 20 msec after the stimulus has subsided. Temporal and spectral analyses reveal robust effects of contralateral lateral stimulation, although in any given normal subject it may be difficult to separate middle ear effects from efferent effects. Evidence is strong that the efferent effect is mediated in part by cholinergic — primarily nicotinic — receptors in the outer hair cell. However, a unique type of patient, who shows nearly normal pure-tone audiograms and absent ABRs, shows virtually no contralateral suppression of transient evoked emissions. Some other patients, with symptoms of Charcot-Marie-Tooth disease, may paradoxically show extremely poor audiograms, but perfectly normal evoked emissions along with absent contralateral suppression. The ABR, along with middle ear muscle reflexes and masking level differences, are all absent in these patients; we therefore think they have a disorder that desynchronizes most of their primary auditory nerve fibers and thereby disconnects them from any efferent activity or masking cancellation. The existence of such an auditory disorder, characterized by severe dysfunction in speech comprehension — especially when listening in noise—suggests that what appears to be a “central auditory imperception” might stem instead from a systemic peripheral primary neuropathy.

Autosomal Recessive Nonsyndromic Neurosensory Deafness at DFNB1 Not Associated with the Compound-Heterozygous GJB2 (Connexin 26) Genotype M34T/167delT

Previous studies of the gap-junction beta-2 subunit gene GJB2 (connexin 26) have suggested that the 101T-->C (M34T) nucleotide substitution may be a mutant allele responsible for recessive deafness DFNB1. This hypothesis was consistent with observations of negligible intercellular coupling and gap-junction assembly of the M34T allele product expressed in Xenopus oocytes and HeLa cells. The results of our current study of a family cosegregating the 167delT allele of GJB2 and severe DFNB1 deafness demonstrate that this phenotype did not cosegregate with the compound-heterozygous genotype M34T/167delT. Since 167delT is a null allele of GJB2, this result indicates that the in vivo activity of a single M34T allele is not sufficiently reduced to cause the typical deafness phenotype associated with DFNB1. This observation raises the possibility that other GJB2 missense substitutions may not be recessive mutations that cause severe deafness and emphasizes the importance of observing cosegregation with deafness in large families to confirm that these missense alleles are mutant DFNB1 alleles.

A review of objective methods of evaluating auditory neural pathways.

Objectives: Review physiological methods of evaluating function of the auditory neural pathways in infants, children, and adults. Present two case studies to demonstrate the usefulness of physiological measures in assessing abnormalities of the auditory neural pathways.

Development of human cochlear active mechanism asymmetry: involvement of the medial olivocochlear system?

To study the functional development of the medial olivocochlear system, transient-evoked otoacoustic emission suppression experiments were conducted in 73 ears of 38 pre-term and 11 full-term neonates. The continuous contralateral stimulation was a broad band white noise, presented at 70 dB SPL. Efferent suppression was determined by subtracting the without-contralateral stimulation condition from the with-contralateral stimulation condition. Across this population, a mean suppression effect of contralateral stimulation on transient-evoked otoacoustic emissions was found, with most of the suppression effect observed after 8 ms. The amount of suppression is linearly, positively correlated with the conceptional age. In the subgroup of bilaterally tested neonates, the suppression of transient-evoked otoacoustic emissions is similar in the right ear and the left ear in subjects whose conceptional age is less than 36 weeks and significantly higher in the right ear than in the left ear in older neonates. This last observation was seen at frequencies where transient-evoked otoacoustic emission amplitudes became higher in the right ear than in the left ear as the conceptional age increased, a finding already reported in adults. This study shows that the functional adult pattern of the medial efferent system, probably involved in the detection of signals in noise such as speech sounds, seems to appear gradually in neonates and represents one of the several arguments in favor of functional auditory lateralization in humans, with a right ear advantage.

Normal characteristics of the ocular vestibular evoked myogenic potential.

BACKGROUND Stimulus-evoked electromyographic changes can be recorded from the extraocular muscles. These short-latency negative-polarity evoked myogenic potentials are called ocular vestibular evoked myogenic potentials (oVEMPs). To date there has not yet been a large-scale study examining the effects of age on the amplitude, latency, threshold, and interaural differences of the oVEMP to air-conducted stimuli. Further, before the oVEMP can become a useful clinical tool, the test-retest reliability of the response must be established. The oVEMP response, once more completely understood, may provide diagnostic information that is complementary to the cervical vestibular evoked myogenic potential (cVEMP; i.e., sternocleidomastoid muscle). PURPOSE To describe the normal characteristics of oVEMP in a cohort of age-stratified subjects, to assess the test-retest reliability of the oVEMP, and to determine if reference contamination occurs using a common recommended infraorbital reference electrode derivation. RESEARCH DESIGN A prospective, descriptive study design was used for an investigation with a threefold purpose in which oVEMP recordings were made from the extraocular muscles (e.g., inferior oblique muscle). STUDY SAMPLE Fifty otologically and neurologically normal adults and children served as subjects. Subjects ranged in age from 8 to 88 yr. DATA COLLECTION AND ANALYSIS In Investigation 1, oVEMPs were recorded from the ipsilateral and contralateral inferior oblique muscles for all subjects. The stimulus was a 95 dB nHL 500 Hz tone burst. Next, oVEMP thresholds were obtained. Amplitude, latency, and thresholds were tabulated, and descriptive statistics were used to calculate normative values. Age-related differences in oVEMP component latencies, amplitudes, interaural amplitude asymmetries (IAAs), and thresholds were determined using an analysis of variance. In Investigation 2, oVEMPs were recorded twice in 10 subjects, once (test) and once approximately 10 weeks later (retest). Test-retest reliability for the oVEMP peak-to-peak amplitude, n1 latency, p1 latency, n1 threshold, and IAA were assessed with intraclass correlation coefficients (ICCs) calculated using a two-way random-effects, absolute-agreement model. In Investigation 3, a four-channel oVEMP recording was conducted in 10 subjects. Both observational methods and paired-sample t-tests were used to evaluate the effect that reference electrode location had on the oVEMP. RESULTS oVEMP responses were present bilaterally in 90% of our subjects. The upper limit of oVEMP amplitude asymmetry, defined as the mean plus two standard deviations, was 34% (mean = 14%, SD 10), and the mean n1 latency was 12.5 (SD 1.0) msec. The amplitude of the response significantly decreased and the threshold significantly increased with increasing age, with the greatest age effects occurring in subjects 50 yr and older. Test-retest reliability was acceptable (ICCs for the measurement variables ranged from .53 to .87). Using conventional recommended recording techniques, evidence of reference contamination occurred for all subjects, resulting in a mean amplitude reduction of 30% (range = 18%-43%). CONCLUSIONS Age results in systematic changes in oVEMP measurement parameters. The test-retest reliability is acceptable, and reference contamination averaging 30% is guaranteed using a second infraorbital electrode as the inverting input (i.e., reference electrode) for bipolar recordings. The oVEMP can be used as a complementary diagnostic tool to the cVEMP in evaluating subjects with suspected peripheral vestibular disorders.