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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To define the incidence of measurable vestibular disorders in patients with auditory and peripheral neuropathies.
Descriptive study of the case features of auditory neuropathy in 14 patients, 8 of ...whom had concomitant peripheral neuropathies.
University referral center.
Fourteen patients aged from 10 to 75 years and diagnosed as having auditory neuropathy, 8 of whom had concomitant peripheral neuropathies.
Incidence of abnormal vestibular caloric test results and the relationship of such incidence to clinical variables including the ages of the subjects, the presence of a concomitant peripheral neuropathy, vestibular symptoms, and audiological findings.
Abnormal vestibular caloric test results occurred in 9 of the 14 patients. These 9 patients were on average older (35.6 years) than patients with normal caloric responses (17.8 years). Seven of the 9 patients with abnormal caloric responses had concomitant peripheral neuropathies compared with only 1 of the 5 patients with normal caloric responses. None of the 14 patients experienced symptoms of vestibular disorder.
Asymptomatic vestibular disorders are common in patients with auditory neuropathy when a peripheral neuropathy is also present. The reason for the abnormal vestibular test results is likely a neuropathy of the vestibular nerves. Arch Otolaryngol Head Neck Surg. 2000;126:1453-1456
It is established that recall of an item from a list of sequentially presented items is sensitive to the item's position in the memorized list. However, little is known about the brain mechanisms ...that mediate these serial position effects. Studies of working memory retrieval using event-related potentials report amplitude reductions during retrieval (auditory cortical N100, neocortical late positive wave LPW) as memory load increases. We tested the hypothesis that N100 and LPW amplitudes to probes are also affected by serial position. Eventrelated potentials were recorded from subjects performing an auditory working memory task. A set of one or five digits was memorized, then subjects classified a probe digit as either present or absent from the memory set. A control task was also given. Amplitudes of the N100 and LPW were reduced in the 5-item versus the 1-item set. In the 5-item set N100 amplitude was significantly larger for the initial (1st) serial position, relative to Positions 2–5, while linear increases in LPW amplitude were seen across serial positions (5th > 1st position). A control task without memorization showed no N100 or LPW amplitude changes with set size or serial position. The findings reveal that the N100 and LPW are influenced differently by serial position during working memory retrieval: N100 shows a primacy effect and LPW demonstrates a recency effect. The results suggest that primacy and recency effects may be mediated by different brain regions at different times during memory retrieval.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
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.
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IJS, NUK, OILJ, UL, UM, UPUK, VSZLJ
Somatosensory evoked potentials (SEPs) were recorded from the scalp in man to magnetic stimulation of various skeletal muscles. The potentials consisted of several components, the earliest of which ...decreased in latency as the stimulated site moved rostrally, ranging from 46 msec for stimulation of the gastrocnemius, to 14 msec for stimulation of the deltoid. Experiments were performed to distinguish the mechanisms by which magnetic stimulation of the muscle was effective in evoking these cerebral potentials. For the gastrocnemius, the intensity of the magnetic stimulus needed for evoking cerebral potentials was less than that required for activating mixed or sensory nerves in proximity to the muscle belly (eg, posterior tibial nerve in the popliteal fossa, sural nerve at the ankle). Vibration of the muscle or passive lengthening of the muscle, procedures which activate muscle spindles, were accompanied by a significant attenuation of the potentials evoked by magnetic stimulation of the muscle. Anesthesia of the skin underlying the stimulating coil had no effect on the latency or amplitude of the early components of the magnetically evoked potentials, whereas electrically evoked potentials from skin electrodes were abolished. Thus, the cerebral potentials accompanying magnetic stimulation of the muscle appear to be due to activation of muscle afferents. We suggest that magnetic stimulation of muscle can provide a relatively simple method for quantifying the function of muscle afferents originating from a wide variety of skeletal musculature.
Objective: To determine if aging is associated with differences in attentional regulation using behavioral and event-related potential (ERP) measures.
Methods: Younger (
n=13;
M=20 years) and older (
...n=12;
M=76 years) subjects performed an auditory cued attention task. Verbal cues correctly (valid) or incorrectly (invalid) predicted the ear receiving a target tone 1.5 s later, or were uninformative (neutral). Targets were either ‘high’ (2000 Hz) or ‘low’ (1000 Hz) pitch monaural tones. Subjects pressed one of 4 buttons to indicate target ear and pitch. ERPs following cues and targets (P50, N100, P200, slow waves), and negative slow potentials (CNV) between cues and targets were assessed.
Results: Cue information had significant effects on reaction time for both groups (valid<neutral<invalid). Target N100 amplitude was significantly affected by cueing in younger (invalid>valid) but not older subjects. Target slow waves were also affected by cue information (invalid>valid), and the difference was larger and lasted longer in older subjects. Slow waves following cues were significantly larger in older subjects, but the subsequent CNV amplitudes were comparable among groups.
Conclusions: When performing a cued attention task, age differences are present in transient ERPs following cues and targets.
Significance: Age differences in ERPs associated with attentional regulation support the hypothesis that attentional changes contribute to cognitive aging.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract 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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Auditory neuropathy in childhood Doyle, Karen Jo; Sininger, Yvonne; Starr, Arnold
The Laryngoscope,
September 1998, Volume:
108, Issue:
9
Journal Article
Peer reviewed
Open access
Objectives: Auditory neuropathy is a recently described disorder in which patients demonstrate hearing loss for pure tones, impaired word discrimination out of proportion to pure tone loss, absent or ...abnormal auditory brainstem responses, and normal outer hair cell function as measured by otoacoustic emissions and cochlear microphonics. We have identified eight pediatric patients having hearing deficits that are most likely due to a neuropathy of the eighth nerve. In this study, the results of audiologic testing performed with these eight children are described. Study Design: Retrospective review of audiologic findings in eight children with auditory neuropathy. Methods. Each subject was tested with pure tone and speech audiologic testing, auditory brainstem response, and click‐evoked otoacoustic emissions. Results of these tests were tabulated and summarized. Results: Pure tone audiologic testing revealed five children with upsloping sensorineural hearing loss, two with high frequency loss, and one with a mild, flat configuration. Six children demonstrated poor word discrimination scores, and the other two had fair to good word discrimination. All eight subjects had normal distortion product and transient otoacoustic emissions. All eight children demonstrated absent or marked abnormalities of brainstem auditory evoked potentials. These findings suggest that while cochlear outer hair cell function is normal, the lesion is located at the eighth nerve. Conclusions: Recent advances in otoacoustic emissions testing permit differentiation of neural deafness from sensory deafness. This paper describes the clinical presentation and audiologic findings in pediatric auditory neuropathy, as well as the recommended management of these patients. Otolaryngologists should be aware of this disorder and implications for its management, which differs from treatment of sensorineural hearing loss. Key Words: Auditory neuropathy, childhood, hearing loss, auditory brainstem response, evoked otoacoustic emissions.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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