Mutations of human NARS2, encoding the mitochondrial asparaginyl-tRNA synthetase, cause nonsyndromic deafness and Leigh syndrome.

Here we demonstrate association of variants in the mitochondrial asparaginyl-tRNA synthetase NARS2 with human hearing loss and Leigh syndrome. A homozygous missense mutation ([c.637G>T; p.Val213Phe]) is the underlying cause of nonsyndromic hearing loss (DFNB94) and compound heterozygous mutations ([c.969T>A; p.Tyr323*] + [c.1142A>G; p.Asn381Ser]) result in mitochondrial respiratory chain deficiency and Leigh syndrome, which is a neurodegenerative disease characterized by symmetric, bilateral lesions in the basal ganglia, thalamus, and brain stem. The severity of the genetic lesions and their effects on NARS2 protein structure cosegregate with the phenotype. A hypothetical truncated NARS2 protein, secondary to the Leigh syndrome mutation p.Tyr323* is not detectable and p.Asn381Ser further decreases NARS2 protein levels in patient fibroblasts. p.Asn381Ser also disrupts dimerization of NARS2, while the hearing loss p.Val213Phe variant has no effect on NARS2 oligomerization. Additionally we demonstrate decreased steady-state levels of mt-tRNAAsn in fibroblasts from the Leigh syndrome patients. In these cells we show that a decrease in oxygen consumption rates (OCR) and electron transport chain (ETC) activity can be rescued by overexpression of wild type NARS2. However, overexpression of the hearing loss associated p.Val213Phe mutant protein in these fibroblasts cannot complement the OCR and ETC defects. Our findings establish lesions in NARS2 as a new cause for nonsyndromic hearing loss and Leigh syndrome.

Pathophysiological mechanisms and functional hearing consequences of auditory neuropathy.

The effects of inner ear abnormality on audibility have been explored since the early 20th century when sound detection measures were first used to define and quantify 'hearing loss'. The development in the 1970s of objective measures of cochlear hair cell function (cochlear microphonics, otoacoustic emissions, summating potentials) and auditory nerve/brainstem activity (auditory brainstem responses) have made it possible to distinguish both synaptic and auditory nerve disorders from sensory receptor loss. This distinction is critically important when considering aetiology and management. In this review we address the clinical and pathophysiological features of auditory neuropathy that distinguish site(s) of dysfunction. We describe the diagnostic criteria for: (i) presynaptic disorders affecting inner hair cells and ribbon synapses; (ii) postsynaptic disorders affecting unmyelinated auditory nerve dendrites; (iii) postsynaptic disorders affecting auditory ganglion cells and their myelinated axons and dendrites; and (iv) central neural pathway disorders affecting the auditory brainstem. We review data and principles to identify treatment options for affected patients and explore their benefits as a function of site of lesion.

Loudness adaptation accompanying ribbon synapse and auditory nerve disorders.

Abnormal auditory adaptation is a standard clinical tool for diagnosing auditory nerve disorders due to acoustic neuromas. In the present study we investigated auditory adaptation in auditory neuropathy owing to disordered function of inner hair cell ribbon synapses (temperature-sensitive auditory neuropathy) or auditory nerve fibres. Subjects were tested when afebrile for (i) psychophysical loudness adaptation to comfortably-loud sustained tones; and (ii) physiological adaptation of auditory brainstem responses to clicks as a function of their position in brief 20-click stimulus trains (#1, 2, 3 … 20). Results were compared with normal hearing listeners and other forms of hearing impairment. Subjects with ribbon synapse disorder had abnormally increased magnitude of loudness adaptation to both low (250 Hz) and high (8000 Hz) frequency tones. Subjects with auditory nerve disorders had normal loudness adaptation to low frequency tones; all but one had abnormal adaptation to high frequency tones. Adaptation was both more rapid and of greater magnitude in ribbon synapse than in auditory nerve disorders. Auditory brainstem response measures of adaptation in ribbon synapse disorder showed Wave V to the first click in the train to be abnormal both in latency and amplitude, and these abnormalities increased in magnitude or Wave V was absent to subsequent clicks. In contrast, auditory brainstem responses in four of the five subjects with neural disorders were absent to every click in the train. The fifth subject had normal latency and abnormally reduced amplitude of Wave V to the first click and abnormal or absent responses to subsequent clicks. Thus, dysfunction of both synaptic transmission and auditory neural function can be associated with abnormal loudness adaptation and the magnitude of the adaptation is significantly greater with ribbon synapse than neural disorders.

Spatiotemporal distribution of cortical processing of first and second languages in bilinguals. II. Effects of phonologic and semantic priming.

This study determined the effects of phonology and semantics on the distribution of cortical activity to the second of a pair of words in first and second language (mixed pairs). The effects of relative proficiency in the two languages and linguistic setting (monolinguistic or mixed) are reported in a companion paper. Ten early bilinguals and 14 late bilinguals listened to mixed pairs of words in Arabic (L1) and Hebrew (L2) and indicated whether both words in the pair had the same or different meanings. The spatio-temporal distribution of current densities of event-related potentials were estimated for each language and according to semantic and phonologic relationship (same or different) compared with the first word in the pair. During early processing (<300 ms), brain activity in temporal and temporoparietal auditory areas was enhanced by phonologic incongruence between words in the pair and in Wernicke's area by both phonologic and semantic priming. In contrast, brain activities during late processing (>300 ms) were enhanced by semantic incongruence between the two words, particularly in temporal areas and in left hemisphere Broca's and Wernicke's areas. The latter differences were greater when words were in L2. Surprisingly, no significant effects of relative proficiency on processing the second word in the pair were found. These results indicate that the distribution of brain activity to the second of two words presented bilingually is affected differently during early and late processing by both semantic and phonologic priming by- and incongruence with the immediately preceding word.

Spatiotemporal distribution of cortical processing of first and second languages in bilinguals. I. Effects of proficiency and linguistic setting.

The study determined how spatiotemporal distribution of cortical activity to words in first and second language is affected by language, proficiency, and linguistic setting. Ten early bilinguals and 14 late adult bilinguals listened to pairs of words presented in Arabic (L1), Hebrew (L2), or in mixed pairs and indicated whether both words had the same meaning or not. Source current densities of event-related potentials were estimated. Activity to first words in the pair lateralized to right hemisphere, higher to L1 than L2 during early processing (<300 ms) among both groups but only among late bilinguals during late processing (>300 ms). During early and late processing, activities were larger in mixed than monolinguistic settings among early bilinguals but lower in mixed than in monolinguistic settings among late bilinguals. Late processing in auditory regions was of larger magnitude in left than right hemispheres among both groups. Activity to second words in the pair was larger in mixed than in monolinguistic settings during both early and late processing among both groups. Early processing of second words in auditory regions lateralized to the right among early bilinguals and to the left among late bilinguals, whereas late processing did not differ between groups. Wernicke's area activity during late processing of L2 was larger on the right, while on the left no significant differences between languages were found. The results show that cortical language processing in bilinguals differs between early and late processing and these differences are modulated by linguistic proficiency and setting.

Auditory processing deficits in individuals with primary open-angle glaucoma.

OBJECTIVE: The high energy demand of the auditory and visual pathways render these sensory systems prone to diseases that impair mitochondrial function. Primary open-angle glaucoma, a neurodegenerative disease of the optic nerve, has recently been associated with a spectrum of mitochondrial abnormalities. This study sought to investigate auditory processing in individuals with open-angle glaucoma. DESIGN/STUDY SAMPLE: Twenty-seven subjects with open-angle glaucoma underwent electrophysiologic (auditory brainstem response), auditory temporal processing (amplitude modulation detection), and speech perception (monosyllabic words in quiet and background noise) assessment in each ear. A cohort of age, gender and hearing level matched control subjects was also tested. RESULTS: While the majority of glaucoma subjects in this study demonstrated normal auditory function, there were a significant number (6/27 subjects, 22%) who showed abnormal auditory brainstem responses and impaired auditory perception in one or both ears. CONCLUSIONS: The finding that a significant proportion of subjects with open-angle glaucoma presented with auditory dysfunction provides evidence of systemic neuronal susceptibility. Affected individuals may suffer significant communication difficulties in everyday listening situations.

Neural and receptor cochlear potentials obtained by transtympanic electrocochleography in auditory neuropathy.

OBJECTIVE: Transtympanic electrocochleography (ECochG) was recorded bilaterally in children and adults with auditory neuropathy (AN) to evaluate receptor and neural generators. METHODS: Test stimuli were clicks from 60 to 120dB p.e. SPL. Measures obtained from eight AN subjects were compared to 16 normally hearing children. RESULTS: Receptor cochlear microphonics (CMs) in AN were of normal or enhanced amplitude. Neural compound action potentials (CAPs) and receptor summating potentials (SPs) were identified in five AN ears. ECochG potentials in those ears without CAPs were of negative polarity and of normal or prolonged duration. We used adaptation to rapid stimulus rates to distinguish whether the generators of the negative potentials were of neural or receptor origin. Adaptation in controls resulted in amplitude reduction of CAP twice that of SP without affecting the duration of ECochG potentials. In seven AN ears without CAP and with prolonged negative potential, adaptation was accompanied by reduction of both amplitude and duration of the negative potential to control values consistent with neural generation. In four ears without CAP and with normal duration potentials, adaptation was without effect consistent with receptor generation. In five AN ears with CAP, there was reduction in amplitude of CAP and SP as controls but with a significant decrease in response duration. CONCLUSIONS: Three patterns of cochlear potentials were identified in AN: (1) presence of receptor SP without CAP consistent with pre-synaptic disorder of inner hair cells; (2) presence of both SP and CAP consistent with post-synaptic disorder of proximal auditory nerve; (3) presence of prolonged neural potentials without a CAP consistent with post-synaptic disorder of nerve terminals. SIGNIFICANCE: Cochlear potential measures may identify pre- and post-synaptic disorders of inner hair cells and auditory nerves in AN.

Auditory nerve is affected in one of two different point mutations of the neurofilament light gene.

OBJECTIVE: To define auditory nerve and cochlear functions in two families with autosomal dominant axonal Charcot-Marie-Tooth (CMT). METHODS: Affected members in two families with different point mutations of NF-L gene were screened with auditory brainstem responses (ABRs). Those with abnormal ABRs were further investigated with clinical, neurophysiological and audiological procedures. The point mutations of NF-L gene involved were Glu397Lys in 8 affected members of the family with AN, and Pro22Ser in 9 affected members of the family without AN. RESULTS: ABRs and stapedial muscle reflexes were absent or abnormal in affected members of only one family consistent with auditory neuropathy (AN). In them, audiograms, otoacoustic emissions, and speech comprehension were normal. Absent or abnormal ABRs were consistent with slowing of conduction along auditory nerve and/or brainstem auditory pathway. Wave I when present was of normal latency. CONCLUSIONS: Auditory nerve involvement in the presence of normal cochlear outer hair cell activity is asymptomatic in one of two families with CMT disorder with different point mutations of the NF-L gene. The nerve disorder is consistent with altered synchrony and slowed conduction. SIGNIFICANCE: The absence of "deafness" may reflect the ability of central mechanisms to compensate for the slowly developing auditory nerve abnormalities.

Frequency changes in a continuous tone: auditory cortical potentials.

OBJECTIVE: We examined auditory cortical potentials in normal hearing subjects to spectral changes in continuous low and high frequency pure tones. METHODS: Cortical potentials were recorded to increments of frequency from continuous 250 or 4000Hz tones. The magnitude of change was random and varied from 0% to 50% above the base frequency. RESULTS: Potentials consisted of N100, P200 and a slow negative wave (SN). N100 amplitude, latency and dipole magnitude with frequency increments were significantly greater for low compared to high frequencies. Dipole amplitudes were greater in the right than left hemisphere for both base frequencies. The SN amplitude to frequency changes between 4% and 50% was not significantly related to the magnitude of spectral change. CONCLUSIONS: Modulation of N100 amplitude and latency elicited by spectral change is more pronounced with low compared to high frequencies. SIGNIFICANCE: These data provide electrophysiological evidence that central processing of spectral changes in the cortex differs for low and high frequencies. Some of these differences may be related to both temporal- and spectral-based coding at the auditory periphery. Central representation of frequency change may be related to the different temporal windows of integration across frequencies.

The auditory P50 component to onset and offset of sound.

OBJECTIVE: The auditory Event-Related Potentials (ERP) of component P50 to sound onset and offset have been reported to be similar, but their magnetic homologue has been reported absent to sound offset. We compared the spatio-temporal distribution of cortical activity during P50 to sound onset and offset, without confounds of spectral change. METHODS: ERPs were recorded in response to onsets and offsets of silent intervals of 0.5 s (gaps) appearing randomly in otherwise continuous white noise and compared to ERPs to randomly distributed click pairs with half second separation presented in silence. Subjects were awake and distracted from the stimuli by reading a complicated text. Measures of P50 included peak latency and amplitude, as well as source current density estimates to the clicks and sound onsets and offsets. RESULTS: P50 occurred in response to noise onsets and to clicks, while to noise offset it was absent. Latency of P50 was similar to noise onset (56 ms) and to clicks (53 ms). Sources of P50 to noise onsets and clicks included bilateral superior parietal areas. In contrast, noise offsets activated left inferior temporal and occipital areas at the time of P50. Source current density was significantly higher to noise onset than offset in the vicinity of the temporo-parietal junction. CONCLUSIONS: P50 to sound offset is absent compared to the distinct P50 to sound onset and to clicks, at different intracranial sources. P50 to stimulus onset and to clicks appears to reflect preattentive arousal by a new sound in the scene. Sound offset does not involve a new sound and hence the absent P50. SIGNIFICANCE: Stimulus onset activates distinct early cortical processes that are absent to offset.

Auditory cortical activity in amnestic mild cognitive impairment: relationship to subtype and conversion to dementia.

Mild cognitive impairment (MCI) patients have a high risk of converting to Alzheimer's disease. The most common diagnostic subtypes of MCI have an episodic memory disorder (amnestic MCI) occurring either alone [single domain (SD)] or with other cognitive impairments [multiple domain (MD)]. Previous studies report increased amplitudes of auditory cortical potentials in MCI, but their relationships to MCI subtypes and clinical outcomes were not defined. We studied subjects with amnestic MCI (n = 41: 28 SD, 13 MD), Alzheimer's disease (n = 14), and both younger (n = 22) and age-matched older controls (n = 44). Baseline auditory sensory (P50, N100) and cognitive potentials (P300) were recorded during an auditory discrimination task. MCI patients were followed for up to 5 years, and outcomes were classified as (i) continued diagnosis of MCI (MCI-stable, n = 16), (ii) probable Alzheimer's disease (MCI-convert, n = 18), or other outcomes (n = 7). Auditory potentials were analysed as a function of MCI diagnosis and outcomes, and compared with young, older controls, and mild Alzheimer's disease subjects. P50 amplitude increased with normal ageing, and had additional increases in MCI as a function of both initial diagnosis (MD > than SD) and outcome (MCI-convert > MCI-stable). P300 latency increased with normal ageing, and had additional increases in MCI but did not differ among outcomes. We conclude that auditory cortical sensory potentials differ among amnestic MCI subtypes and outcomes occurring up to 5 years later.

Cholinesterase inhibitors affect brain potentials in amnestic mild cognitive impairment.

Amnestic mild cognitive impairment (MCI) is an isolated episodic memory disorder that has a high likelihood of progressing to Alzheimer's disease. Auditory sensory cortical responses (P50, N100) have been shown to be increased in amplitude in MCI compared to older controls. We tested whether (1) cortical potentials to other sensory modalities (somatosensory and visual) were also affected in MCI and (2) cholinesterase inhibitors (ChEIs), one of the therapies used in this disorder, modulated sensory cortical potentials in MCI. Somatosensory cortical potentials to median nerve stimulation and visual cortical potentials to reversing checkerboard stimulation were recorded from 15 older controls and 15 amnestic MCI subjects (single domain). Results were analyzed as a function of diagnosis (Control, MCI) and ChEIs treatment (Treated MCI, Untreated MCI). Somatosensory and visual potentials did not differ significantly in amplitude in MCI subjects compared to controls. When ChEIs use was considered, somatosensory potentials (N20, P50) but not visual potentials (N70, P100, N150) were of larger amplitude in untreated MCI subjects compared to treated MCI subjects. Three individual MCI subjects showed increased N20 amplitude while off ChEIs compared to while on ChEIs. An enhancement of N20 somatosensory cortical activity occurs in amnestic single-domain MCI and is sensitive to modulation by ChEIs.

The N1 complex to gaps in noise: effects of preceding noise duration and intensity.

OBJECTIVE: To study the effects of duration and intensity of noise that precedes gaps in noise on the N-Complex (N(1a) and N(1b)) of Event-Related Potentials (ERPs) to the gaps. METHODS: ERPs were recorded from 13 normal subjects in response to 20 ms gaps in 2-4.5 s segments of binaural white noise. Within each segment, the gaps appeared after 500, 1500, 2500 or 4000 ms of noise. Noise intensity was either 75, 60 or 45 dBnHL. Analysis included waveform peak measurements and intracranial source current density estimations, as well as statistical assessment of the effects of pre-gap noise duration and intensity on N(1a) and N(1b) and their estimated intracranial source activity. RESULTS: The N-Complex was detected at about 100 ms under all stimulus conditions. Latencies of N(1a) (at approximately 90 ms) and N(1b) (at approximately 150 ms) were significantly affected by duration of the preceding noise. Both their amplitudes and the latency of N(1b) were affected by the preceding noise intensity. Source current density was most prominent, under all stimulus conditions, in the vicinity of the temporo-parietal junction, with the first peak (N(1a)) lateralized to the left hemisphere and the second peak (N(1b)) - to the right. Additional sources with lower current density were more anterior, with a single peak spanning the duration of the N-Complex. CONCLUSIONS: The N(1a) and N(1b) of the N-Complex of the ERPs to gaps in noise are affected by both duration and intensity of the pre-gap noise. The minimum noise duration required for the appearance of a double-peaked N-Complex is just under 500 ms, depending on noise intensity. N(1a) and N(1b) of the N-Complex are generated predominantly in opposite temporo-parietal brain areas: N(1a) on the left and N(1b) on the right. SIGNIFICANCE: Duration and intensity interact to define the dual peaked N-Complex, signaling the cessation of an ongoing sound.

Auditory neuropathy--neural and synaptic mechanisms.

Sensorineural hearing impairment is the most common form of hearing loss, and encompasses pathologies of the cochlea and the auditory nerve. Hearing impairment caused by abnormal neural encoding of sound stimuli despite preservation of sensory transduction and amplification by outer hair cells is known as 'auditory neuropathy'. This term was originally coined for a specific type of hearing impairment affecting speech comprehension beyond changes in audibility: patients with this condition report that they "can hear but cannot understand". This type of hearing impairment can be caused by damage to the sensory inner hair cells (IHCs), IHC ribbon synapses or spiral ganglion neurons. Human genetic and physiological studies, as well as research on animal models, have recently shown that disrupted IHC ribbon synapse function--resulting from genetic alterations that affect presynaptic glutamate loading of synaptic vesicles, Ca(2+) influx, or synaptic vesicle exocytosis--leads to hearing impairment termed 'auditory synaptopathy'. Moreover, animal studies have demonstrated that sound overexposure causes excitotoxic loss of IHC ribbon synapses. This mechanism probably contributes to hearing disorders caused by noise exposure or age-related hearing loss. This Review provides an update on recently elucidated sensory, synaptic and neural mechanisms of hearing impairment, their corresponding clinical findings, and discusses current rehabilitation strategies as well as future therapies.

Event-related potentials accompanying motor preparation and stimulus expectancy in the young, young-old and oldest-old.

Although aging is accompanied by neurobiological changes and increased susceptibility to many neurological disorders, little is known about neurophysiological changes that start in old age. Here, neurophysiological changes during old age were assessed by recording brain potentials associated with motor preparation and stimulus expectancy (contingent negative variation, CNV) in young-old (60-69), oldest-old (85-98), and young (17-23) subjects. Individual trials began by a button press, followed 2.5 s later by either a low or high pitch tone. In the "motor" condition subjects responded following high pitch tones (P=0.20); in the "non-motor" condition subjects did not respond. Motor condition CNV amplitudes in the oldest old were more positive than the young and young-old groups, which were similar. In the non-motor condition, the young-old and oldest-old had similar CNV amplitudes that were positive in polarity, and were significantly different from young subjects. Motor potentials before button presses that started the trials were comparable among groups. Results show that neural activity associated with motor preparation and stimulus expectancy changes during advanced age, and that group differences can be modulated by task requirements.

Auditory temporal processes in normal-hearing individuals and in patients with auditory neuropathy.

OBJECTIVE: To study objectively auditory temporal processing in a group of normal hearing subjects and in a group of hearing-impaired individuals with auditory neuropathy (AN) using electrophysiological and psychoacoustic methods. METHODS: Scalp recorded evoked potentials were measured to brief silent intervals (gaps) varying between 2 and 50ms embedded in continuous noise. Latencies and amplitudes of N100 and P200 were measured and analyzed in two conditions: (1) active, when using a button in response to gaps; (2) passive, listening, but not responding. RESULTS: In normal subjects evoked potentials (N100/P200 components) were recorded in response to gaps as short as 5ms in both active and passive conditions. Gap evoked potentials in AN subjects appeared only with prolonged gap durations (10-50ms). There was a close association between gap detection thresholds measured psychoacoustically and electrophysiologically in both normals and in AN subjects. CONCLUSIONS: Auditory cortical potentials can provide objective measures of auditory temporal processes. SIGNIFICANCE: The combination of electrophysiological and psychoacoustic methods converged to provide useful objective measures for studying auditory cortical temporal processing in normals and hearing-impaired individuals. The procedure used may also provide objective measures of temporal processing for evaluating special populations such as children who may not be able to provide subjective responses.

Auditory neuropathy.

Neural disorders of the auditory nerve are associated with particular disorders of auditory perceptions dependent on processing of acoustic temporal cues. These include: (1) speech perception; (2) localizing a sound's origin in space; and (3) identifying sounds in background noise. Auditory neuropathy (AN) is a consequence of: (1) presynaptic disorders affecting inner hair cell ribbon synapses; (2) postsynaptic disorders of auditory nerve dendrites; and (3) postsynaptic disorders of auditory nerve axons. The etiologies of these disorders are diverse, similar to other cranial or peripheral neuropathies. The pathologies cause attenuated and dyssynchronous auditory nerve discharges. Therapies and management of patients with AN are reviewed.

Audibility, speech perception and processing of temporal cues in ribbon synaptic disorders due to OTOF mutations.

Mutations in the OTOF gene encoding otoferlin result in a disrupted function of the ribbon synapses with impairment of the multivesicular glutamate release. Most affected subjects present with congenital hearing loss and abnormal auditory brainstem potentials associated with preserved cochlear hair cell activities (otoacoustic emissions, cochlear microphonics [CMs]). Transtympanic electrocochleography (ECochG) has recently been proposed for defining the details of potentials arising in both the cochlea and auditory nerve in this disorder, and with a view to shedding light on the pathophysiological mechanisms underlying auditory dysfunction. We review the audiological and electrophysiological findings in children with congenital profound deafness carrying two mutant alleles of the OTOF gene. We show that cochlear microphonic (CM) amplitude and summating potential (SP) amplitude and latency are normal, consistently with a preserved outer and inner hair cell function. In the majority of OTOF children, the SP component is followed by a markedly prolonged low-amplitude negative potential replacing the compound action potential (CAP) recorded in normally-hearing children. This potential is identified at intensities as low as 90 dB below the behavioral threshold. In some ears, a synchronized CAP is superimposed on the prolonged responses at high intensity. Stimulation at high rates reduces the amplitude and duration of the prolonged potentials, consistently with their neural generation. In some children, however, the ECochG response only consists of the SP, with no prolonged potential. Cochlear implants restore hearing sensitivity, speech perception and neural CAP by electrically stimulating the auditory nerve fibers. These findings indicate that an impaired multivesicular glutamate release in OTOF-related disorders leads to abnormal auditory nerve fiber activation and a consequent impairment of spike generation. The magnitude of these effects seems to vary, ranging from no auditory nerve fiber activation to an abnormal generation of EPSPs that occasionally trigger a synchronized electrical activity, resulting in high-threshold CAPs.

Brainstem auditory evoked potentials and cochlear microphonics in the HMSN family with auditory neuropathy.

The aim of this work was to assess the he ' g impairment in patients with hereditary motor and sensory neuropathy (HMSN). Elevation of pure tone thresholds in the presence of preserved inner ear function as suggested by cochlear microphonics (CM), absent or markedly abnormal brainstem auditory evoked potentials (BAEP), and elevation of speech perception out of proportion to the pure tone loss were found in the patients. From 28 members of a Gypsy family, we examined two siblings aged 31 and 30 years and their nephew aged 20 years, all suffering from HMSN that was associated with auditory neuropathy. All three affected members with difficulty of understanding speech had following investigations: pure tone and speech audiograms, BAEP, cochlear microphonics, and nerve conduction studies (NCV). RESULTS: the older two siblings had a flat 80 dB audiogram, whereas the younger one has flat 20 dB audiogram on the Lt. ear and 30 dB audiogram on the Rt. ear. All had no speech comprehension and no BAEP. Two patients had preserved cochlear microphonics on one ear. Peripheral nerves were electrically not elicitable, however, at the beginning of the disease nerve conduction was slow. CONCLUSION: in all three affected members with distinct clinical picture of HMSN their hearing impairment was proved to be due to severe auditory neuropathy in the presence of preserved inner ear function.

A dominantly inherited progressive deafness affecting distal auditory nerve and hair cells.

We have studied 72 members belonging to a large kindred with a hearing disorder inherited in an autosomal dominant pattern. We used audiological, physiological, and psychoacoustic measures to characterize the hearing disorders. The initial phenotypic features of the hearing loss are of an auditory neuropathy (AN) with abnormal auditory nerve and brainstem responses (ABRs) and normal outer hair cell functions [otoacoustic emissions (OAEs) and cochlear microphonics (CMs)]. Psychoacoustic studies revealed profound abnormalities of auditory temporal processes (gap detection, amplitude modulation detection, speech discrimination) and frequency processes (difference limens) beyond that seen in hearing impairment accompanying cochlear sensory disorders. The hearing loss progresses over 10-20 years to also involve outer hair cells, producing a profound sensorineural hearing loss with absent ABRs and OAEs. Affected family members do not have evidence of other cranial or peripheral neuropathies. There was a marked improvement of auditory functions in three affected family members studied after cochlear implantation with return of electrically evoked auditory brainstem responses (EABRs), auditory temporal processes, and speech recognition. These findings are compatible with a distal auditory nerve disorder affecting one or all of the components in the auditory periphery including terminal auditory nerve dendrites, inner hair cells, and the synapses between inner hair cells and auditory nerve. There is relative sparing of auditory ganglion cells and their axons.