Mutations in LOXHD1 gene can cause auditory neuropathy spectrum disorder.

Objectives: The aim of this paper was to study the auditory phenotype of three related children with sensorineural hearing loss (2 sisters and their cousin) following genetic analysis revealing mutations in LOXHD1. Methods: Genetic testing was conducted on three related children. They were assessed with a standard clinical test battery including distortion otoacoustic emissions, auditory brainstem responses and audiometry. Results: We identified heterozygous variants in LOXHD1 in a family of Irish/German and Italian/Irish ancestry with autosomal recessive auditory neuropathy spectrum disorder (ANSD). Mutations in LOXHD1 (MIM #613072) have been linked to an autosomal recessive nonsyndromic hearing loss (DFNB77), mapped to the locus 18q12-q21. All three subjects had evidence of some, albeit few, functioning cochlear hair cells as revealed by the presence of a cochlear microphonic and/or partial otoacoustic emissions early in life. Conclusion: To our knowledge, this is the first association between LOXHD1 mutations and ANSD in two patients who have been successfully managed with cochlear implants.

Balance in healthy individuals assessed with Equitest: maturation and normative data for children and young adults.

OBJECTIVE: The purpose of the present prospective study was to obtain normative data for Equitest computerized dynamic posturography (CDP) in children and young adults and to observe the balance maturation process. METHODS: Equilibrium pattern and SOT of 195 healthy children aged from 6 to 14 years were compared to those of 64 young adults aged 20 years, using Equitest. RESULTS: The mean stability scores for children progressively improve with age and are significantly lower than those of young adults. Furthermore, sensory organization scores were lower in children compared to young adults, whereas visual preference scores were similar for the whole studied groups. CONCLUSIONS: According to previous literature, it may be stressed that due to a presumed incomplete development of vestibular system and central nervous system integration, children unlike young adults have lower equilibrium scores, especially when visual information was not available or was incorrect. Our results confirm previous ones obtained in children and young adults with Equitest CDP. This study also provides Equitest data for these age groups, which complete those that have been previously reported.

Vestibular assessment with Balance Quest Normative data for children and young adults.

OBJECTIVE: The purpose of the present study was to compare equilibrium pattern in 12-year-old children with 20-year-old young adults and to obtain normative data for the BQ in both groups. METHODS: Mean stability percentages and synthesis ratios of 29 healthy children aged 12 years were compared to those of 68 young adults aged 20 years, using BQ. RESULTS: The mean stability percentages for children were significantly lower than for young adults. Vestibular ratios were lower in children compared to young adults, whereas somesthesic ratios were similar for the two groups. Visual dependence was significant higher in children. CONCLUSIONS: Children unlike young adults had lower stability percentages when visual information was not available or was incorrect. Ratio synthesis pattern was different in the two groups. Our results on BQ partially confirms previous results obtained in children assessed with Equitest CDP. This study also provides BQ normative data for these two age groups.

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.

Assessment of medial olivocochlear system function in pre-term and full-term newborns using a rapid test of transient otoacoustic emissions.

This study was conducted to investigate maturation of the medial olivocochlear efferent system (MOCS) in pre- and full-term neonates using Quickscreen (Otodynamics Ltd) and to confirm previous findings on transient otoacoustic emission (TEOAE) suppression in neonates. MOCS maturation was investigated in 46 neonates born at the Chaim Sheba Medical Center, Tel Hashomer, Israel, using Quickscreen. All neonates were normal with no family history of general or auditory disease and no risk factors for hearing impairment. MOCS function appears gradually in human pre-term neonates and is considered to reach maturity shortly after term birth. The clinical value of MOCS testing in specific populations of newborns at risk for hearing and/or brainstem function can be legitimately raised as activation of the MOCS clearly alters cochlear output. The present results can be interpreted to support the testing of infants at risk of developing abnormal MOCS function using a commercially available rapid TEOAE measurement system.

TEOAE recording protocols revised: data from adult subjects.

The objective of this study was the experimental re-evaluation of the current clinical transiently evoked otoacoustic emission (TEOAE) protocols, based on linear and non-linear protocol paradigms from a population of 42 adult subjects serving as a normative database. The linear and non-linear TEOAE responses were elicited by clicks with average intensities of 72 and 84 dB p.e. SPL respectively. An initial comparison between non-processed non-linear and linear recordings, at early recording segments from 3.2 to 5.2 ms, showed that the responses had highly similar contours and no statistically significant mean differences. The stimulus-induced artefact in the linear TEOAE responses was suppressed by post-processing the data with a window function (3.8-13.8 ms) and by a high-pass filter at 830 Hz. A repeated-measures model was used to evaluate the differences between post-processed linear and non-linear responses across clinical variables of interest (such as TEOAE response, noise, correlation, and signal-to-noise ratios (SNRs) at 1.0-5.0 kHz). The data indicated that the linear recordings demonstrate significantly lower levels of noise (and thus superior SNRs) and higher values of reproducibility. Normative adult scoring criteria were calculated from free distribution tolerance intervals for the TEOAE correlation and the SNRs at 2.0 and 3.0 kHz.

[Hearing disorders screening in neonates at risk]. / Dépistage des troubles auditifs chez des nouveau-nés à risque.

The present report concerns a three year, eight month hearing screening in 1 531 high-risk neonates by means of two successive transient evoked otoacoustic emissions (TEOAE) recordings followed, cin cases of suspected hearing loss, by brainstem auditory evoked potential (BAEP) recording and otolaryngology (ORL) consultation. After TEOAE1 and 2 and BAEP testing, 1 361 infants (88.9%) were declared normal, and 170 (11%) suspected of hearing loss. Of these 170, 58 showed bilateral and 26 unilateral impairment. Definite hearing loss on ORL consultation was diagnosed in 14 infants (0.9% of the screened population as a whole); 22 are still followed, while 86 (5.6%) failed to consult for diagnosis. The mean age on diagnosis of definite hearing loss on ORL consultation was 9.9 +/- 4.9 (range 4-20) months. Several auditory function risk factors have been proved to be more frequent in deaf than in normal children. Our results show that early hearing loss screening in at-risk neonates needs to be pursued.

Effect of sleep stages on synchronized spontaneous otoacoustic emissions in pre-term neonates.

OBJECTIVES: In infants, auditory tests are mainly performed during sleep, since they spend most of their time asleep, and because quiet is required for the duration of the recording session to obtain a precise and reliable response. The aim of this study was to investigate the effect of sleep stages on synchronized spontaneous otoacoustic emissions (sSOAEs) in pre-term neonates at the age where the sleep states begin to be well established and auditory screening can be performed in a neonatology unit before discharge. METHODS: Synchronized SOAEs were repeatedly recorded during a polygraphic sleep recording using the Otodynamic ILO88 system in 10 pre-term neonates at 36 weeks post-conception. RESULTS: Variations of sSOAE peak numbers occurred in each subject during the recording session. There was no clear relation between sSOAE peak number fluctuations and the different sleep stages. CONCLUSIONS: The sSOAE variations appeared to be closely related to experimental conditions, i.e. the mean background noise level. sSOAEs with the highest amplitude were always recorded; however, those with the smallest amplitude were the first to disappear from the recordings with higher background noise.

Optimization of TEOAE recording protocols: a linear protocol derived from parameters of a time-frequency analysis: a pilot study on neonatal subjects.

Linear and non-linear TEOAE protocols were compared in terms of nine parameters in order to define the protocol producing recordings with the highest signal quality (lowest noise and highest signal-to-noise ratio). The pilot project acquired data using ILO-92 apparatus from 220 neonates (397 ears) at the second/third day after birth in three European laboratories. A Gabor spectrogram time-frequency representation of the recordings showed considerable frequency dispersion in TEOAE latencies >4.0 ms. The data, analysed with a Wilcoxon test, indicated that a linear TEOAE protocol: (i) generates recordings of a lower noise and a higher signal-to-noise (S/N) ratio in the 2.0, 3.0, 4.0 kHz TEOAE bands; (ii) the increase in the S/N ratio can result in a decrement of the required number of TEOAE sweeps; (iii) the higher values of S/N can be used in the estimation of more robust pass-fail criteria, minimizing the percentage of false positives and negatives.

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.

[Precocious maturation of auditory evoked potentials in prematures: influence of gestational age and sex]. / Maturation des potentiels évoqués auditifs précoces chez le prématuré: influence de l'âge gestationnel et du sexe.

In humans, the onset of the auditory function occurs at the beginning of the third trimester of pregnancy. Brainstem auditory evoked potentials (BAEPs) can be recorded in preterm neonates as early as 25-26 weeks of gestational age. The latency of BAEP waves show a significant decrease according to increasing age to achieve adult values at the end of the first month after birth for wave I and near 3 to 5 years old for waves III and V. Auditory evoked responses are influenced by gender, notably with significantly higher wave latencies in males than in females. These gender differences in auditory function appear early in humans, some being observed as soon as 34 weeks of gestational age.

Auditory screening in high-risk pre-term and full-term neonates using transient evoked otoacoustic emissions and brainstem auditory evoked potentials.

The present report concerns a 3 year, 8 month hearing screening in 1531 high-risk neonates by means of two successive transient evoked otoacoustic emission (TEOAE) recordings followed, in cases of suspected hearing loss, by brainstem auditory evoked potential (BAEP) recording and otolaryngology (ORL) consultation. After TEOAE 1 and 2 and BAEP testing, 1361 infants (88.9%) were declared normal, and 170 (11.1%) suspected of hearing loss. Of these 170, 58 showed bilateral and 26 unilateral impairment. Definite hearing loss on ORL consultation was diagnosed in 14 infants (0.9% of the screened population as a whole); 22 are still being followed, while 86 (5.6%) failed to consult for diagnosis. The mean age on diagnosis of definite hearing loss was 9.9 +/- 4.9 (range 4-20) months. Several auditory function risk factors proved more frequent in deaf than in normal children. Our results show that early hearing loss screening in at-risk neonates needs to be pursued.

[Peripheral auditory lateralization]. / Existence d'une latéralisation de l'appareil auditif périphérique.

Neuropsychological studies have demonstrated that language perception is lateralized at the hemispheric level. There is also much evidence for a peripheral lateralization of the auditory system in humans. Spontaneous otoacoustic emissions are more frequent in the right than in the left ear. The medial olivo-cochlear system is also more functional in the right than in the left ear in normal subjects. The study of specific samples shows that this asymmetry is found in professional musicians which have more functional efferent system in both ears. A link is hypothesized between peripheral and central laterality because of a dysfunctional peripheral asymmetry in pathological cases which show hemispheric lateralization disorders. Consequences of those pathological data will be discussed.

Evidence of peripheral hearing asymmetry in humans: clinical implications.

Auditory system hemispheric asymmetry in language processing is well-established, and there are many indications of lateralization as of the peripheral auditory system i.e., as of the cochlea. The left ear is more susceptible to noise damage; tinnitus is more predominant there, while spontaneous otoacoustic emissions (SOAEs) are more often found in the right ear. The present study addressed the following two questions: Does this right-ear SOAE prevalence exist as early as preterm birth? Is there any functional asymmetry in the medial olivo-cochlear (MOC) efferent system, known to modulate outer hair cell contractions? The study involved 483 preterm neonates (gestional age: 24-37 weeks) and 70 right-handed adults (age: 18-31 years). In each ear, SOAEs and evoked otoacoustic emissions (EOAEs) were recorded and analysed, and, for the adults, functional MOC system assessment was made. Results showed SOAEs and EOAE amplitude to be right-predominant and in adults a right MOC functional predominance. These results indicate peripheral auditory system lateralisation, and an early origin thereof. The MOC system being thought to play a protective role, its physiological lateralisation may be relevant to the left prevalence of tinnitus and of auditory fatigue.

Development of cochlear active mechanisms in humans differs between gender.

Despite onset of function early during the third term of gestation, the human auditory system demonstrates continued maturation, thought previously to occur primarily at the neural level. The electromotile properties of outer hair cells appear to contribute substantially to hearing sensitivity and frequency selectivity and lead to the generation of otoacoustic emissions (OAEs). This report demonstrates continued development of cochlear active mechanisms (i.e. end-organ level) after onset of cochlear function, as reflected by OAEs. Significant gender differences also are reported, corresponding to recently observed intersex differences in cochlear length and precursory to gender differences observed in the adult.

Type of initial brainstem auditory evoked potentials (BAEP) impairment and risk factors in premature infants.

Brainstem auditory evoked potentials (BAEPs) were recorded in 89 premature infants aged between 34 and 52 weeks. 47.2% had normal and 52.8% abnormal BAEPs in at least one ear. Seven risk factors were taken into account: birth weight lower than 1500 g, hypoxia, neurological damage, fetal pathology, associated malformation, the use of ototoxic drugs, and exchange transfusion. The type of BAEP impairment was defined as either endocochlear, transmission or retrocochlear damage. Percentage BAEP impairment was higher in case of hypoxia (63.3%) but remained similar whether the other risk factors were present or absent. Transmission impairment was more frequent in case of birth weight lower than 1500 g, hypoxia or ototoxic drug administration; Endocochlear damage occurred more frequently when ototoxic drugs had been used or exchange transfusion performed. When birth weight was lower than 1500 g, transmission damage was more frequent than when birth weight was higher than 1500 g. In contrast, endocochlear damage was more frequent when birth weight was higher than compared with lower than 1500 g. In male infants, BAEP impairment was more frequent and more often of retrocochlear type than in female infants. BAEP impairment was more frequently of endocochlear type in female compared to male infants. Among the 89 premature infants recorded, 11.2% has endocochlear damage corresponding to potentially handicapping hearing loss. These results are discussed with reference to the literature.

Spontaneous and evoked otoacoustic emissions in pre-term and full-term neonates: is there a clinical application?

In neonates and infants, hearing impairment leads to impaired language and cognitive development. For that reason, early detection of this sensory deficit is of outstanding importance, particularly in pre-term neonates, who constitute a high risk population in regard to very early acquired hearing loss. Evoked (EOAE) and spontaneous otoacoustic emission (SOAE) recording in 93 pre-term and full-term neonates revealed that this technique is potentially useful for auditory screening in neonatology units. EOAEs and SOAEs can be recorded successfully from 30 weeks of conceptional age. SOAEs were found to be prevalent in females and presented higher peak numbers in right than in left ears. Furthermore, SOAE incidence in pre-term and full-term neonates was found to be high in EOAE positive ears, associated with strong and robust EOAEs.

Spontaneous otoacoustic emissions in preterm neonates: prevalence and gender effects.

A number of lines of evidence indicate that the human cochlea is fully functional as a mature sound transducer by 6 months of age. However, information about the development of the active cochlear mechanisms and notably the development of outer hair cell (OHC) activity is yet incomplete. Recording and analysis of otoacoustic emissions (OAEs), probably generated by the OHCs of the organ of Corti, have led to a better understanding, in humans, of how sounds are analysed in the cochlea by means of active mechanisms. Evoked OAEs (EOAEs) and spontaneous OAEs (SOAEs), when they can be recorded in full-term and preterm neonates, show different characteristics from those in adults, suggesting that maturation of the peripheral auditory system is incomplete at birth. To learn more about this maturation, using the best-established facts concerning SOAEs in adults, such as their greater prevalence in females and also in right ears, SOAEs were studied in more detail in 81 preterm neonates, from 30 to 40 weeks of conceptional age, all presenting bilateral EOAEs according to objective criteria. The first finding of this study was that SOAEs existed and could be recorded as of 30 weeks of conceptional age in humans. Some SOAE characteristics in preterm neonates, such as prevalence, peak number and acoustic frequencies, showed similarity with full-term neonates. Comparison of other criteria between the two populations, such as greater SOAE prevalence in right ears and higher SOAE peak number in females, suggested that these developmental factors emerge around term in humans. Comparison of SOAE characteristics between male and female preterms suggested that male preterms were less advanced in peripheral auditory development than were female preterms.

Contralateral suppression of evoked otoacoustic emissions and detection of a multi-tone complex in noise.

Although some findings suggest that auditory efferent fibers are involved in perception in noise, their function remains controversial. The contralateral suppression of evoked otoacoustic emissions (EOAEs) has recently provided a means of exploring the medial olivocochlear system (MOCS) in humans. In an experiment based on this paradigm, the present study examined the relationships between variations of both EOAEs and detection-in-noise thresholds, induced in the same subjects by a contralateral 50-dB-SPL broad-band noise masker. EOAEs were recorded in response to a burst of a multitone complex composed of 1, 1.5 and 2-kHz components. The detection thresholds of this 3-component complex were measured at 2 ipsilateral noise levels: 50 and 70 dB SPL. The main finding was a significant correlation between EOAE suppression and threshold variations under contralateral masking. A relationship was also found between the contralateral suppression of EOAEs and threshold variation induced by the increase in ipsilateral noise level. These findings support the notion that the MOCS is involved in the detection of multicomponent stimuli in noise.