Objective: The purpose of this review was to describe and differentiate clinical syndromes caused by lesions of the central auditory nervous system (CANS).
Design: Relevant literature was identified ...through Pubmed and Google Scholar searches using the key terms: central deafness, auditory agnosia, word deafness and cortical deafness. Given the authors' intent to review past and current perspectives on central deafness, no publication date range was imposed.
Study sample: The review is organised around complete central deafness (CCD), central deafness (CD), word deafness and nonverbal agnosia (NVA), including anatomy and pathophysiology, symptom profile and audiological findings. Four case studies are presented to demonstrate the clinical correlates of CD.
Conclusions: Central deafness is a rare condition typically resulting from bilateral compromise of the CANS. The closer to the auditory cortex bilateral lesions are located, the greater the probability of CD. A variety of symptoms present with or appear subsequent to CD, including tinnitus, hallucinations, voice changes and hypersensitivity to sounds (if heard by the patient), as well as diverse neurological symptoms depending on the non-auditory areas of the brain that may also be involved. Thorough and appropriate audiological testing is critical to accurately diagnose CD and its variants.
Individuals often have reduced ability to hear alarms in real world situations (e.g., anesthesia monitoring, flying airplanes) when attention is focused on another task, sometimes with devastating ...consequences. This phenomenon is called inattentional deafness and usually occurs under critical high workload conditions. It is difficult to simulate the critical nature of these tasks in the laboratory. In this study, dry electroencephalography is used to investigate inattentional deafness in real flight while piloting an airplane. The pilots participating in the experiment responded to audio alarms while experiencing critical high workload situations. It was found that missed relative to detected alarms were marked by reduced stimulus evoked phase synchrony in theta and alpha frequencies (6–14 Hz) from 120 to 230 ms poststimulus onset. Correlation of alarm detection performance with intertrial coherence measures of neural phase synchrony showed different frequency and time ranges for detected and missed alarms. These results are consistent with selective attentional processes actively disrupting oscillatory coherence in sensory networks not involved with the primary task (piloting in this case) under critical high load conditions. This hypothesis is corroborated by analyses of flight parameters showing greater maneuvering associated with difficult phases of flight occurring during missed alarms. Our results suggest modulation of neural oscillation is a general mechanism of attention utilizing enhancement of phase synchrony to sharpen alarm perception during successful divided attention, and disruption of phase synchrony in brain networks when attentional demands of the primary task are great, such as in the case of inattentional deafness.
Mechanoelectrical transducer (MET) currents were recorded from cochlear hair cells in mice with mutations of transmembrane channel-like protein TMC1 to study the effects on MET channel properties. We ...characterized a Tmc1 mouse with a single-amino-acid mutation (D569N), homologous to a dominant human deafness mutation. Measurements were made in both Tmc2 wild-type and Tmc2 knockout mice. By 30 d, Tmc1 pD569N heterozygote mice were profoundly deaf, and there was substantial loss of outer hair cells (OHCs). MET current in OHCs of Tmc1 pD569N mutants developed over the first neonatal week to attain a maximum amplitude one-third the size of that in Tmc1 wild-type mice, similar at apex and base, and lacking the tonotopic size gradient seen in wild type. The MET-channel Ca2+ permeability was reduced 3-fold in Tmc1 pD569N homozygotes, intermediate deficits being seen in heterozygotes. Reduced Ca2+ permeability resembled that of the Tmc1 pM412K Beethoven mutant, a previously studied semidominant mouse mutation. The MET channel unitary conductance, assayed by single-channel recordings and by measurements of current noise, was unaffected in mutant apical OHCs. We show that, in contrast to the Tmc1 M412K mutant, there was reduced expression of the TMC1 D569N channel at the transduction site assessed by immunolabeling, despite the persistence of tip links. The reduction in MET channel Ca2+ permeability seen in both mutants may be the proximate cause of hair-cell apoptosis, but changes in bundle shape and protein expression in Tmc1 D569N suggest another role for TMC1 apart from forming the channel.
Decisions about genetic testing have traditionally been based on clinical utility and cost, but personal utility is increasingly recognized when assessing the value of testing. Whole exome sequencing ...(WES) was offered to a population cohort of 106 infants diagnosed with congenital hearing loss. Parents could choose to receive results relating to hearing loss only or also learn additional information about childhood‐onset conditions (medically nonactionable and/or actionable). This study aimed to quantify the personal utility of WES for parents after a diagnosis of hearing loss in their child. Parents completed surveys pretest (63/106), after hearing loss results (52/106) and after receiving additional information (47/72). Open‐ended responses from all three surveys (N = 67) were analyzed using inductive content analysis. Answers to questions regarding the value of sequencing to parents were analyzed and collated. Parents placed high value on diagnostic WES for hearing loss but had different perspectives on the personal utility of additional information. Diagnostic results provided certainty while the choice to learn additional information about childhood‐onset disorders was associated with empowerment. WES also represented an opportunity to promote their child's best interests. Results provide insights into the utility of WES for the indication of congenital deafness and for genomic newborn screening broadly.
This study aimed to explore the molecular epidemiology characteristics of deafness susceptibility genes in neonates in northern Guangdong and provide a scientific basis for deafness prevention and ...control. A total of 10,183 neonates were recruited between January 2018 and December 2022 at Yuebei People's Hospital. Among these, a PCR hybridization screening group of 8276 neonates was tested for four deafness genes: GJB2, SLC26A4, mtDNA, and GJB3 by PCR hybridization. Another group used next-generation sequencing (NGS) to detect genetic susceptibility genes in 1907 neonates. In PCR hybridization screening group, 346 (4.18%) of 8276 neonates were found to be carriers of the deafness gene. Among these, 182 (2.2%) had GJB2 variants, 114 (1.38%) had SLC26A4 variants, 35 (0.42%) had mtDNA variants, and 15 (0.18%) had GJB3 variants. In NGS Screening Group, 195 out of 1907 neonates were found to be carriers of the deafness gene, with a positive rate of 10.22%. Among these, 137 (7.18%) had GJB2 variants, 41 (2.15%) had SLC26A4 variants, 11 (0.58%) had mtDNA variants, and 6 (0.31%) had GJB3 variants. The prevalence of deafness gene variants was high in Northern Guangdong Province. The most common gene for deafness was GJB2, followed by SLC26A4 and mtDNA. GJB3 variants are rare. Compared with PCR hybridization method, NGS technology can expand the screening scope and greatly improve the detection rate of deafness genes. The c.109G>A of GJB2 was found to occur at a high frequency, which should be considered. Therefore, it is important to conduct neonatal deafness gene screening to prevent and control hereditary deafness.
Leukoencephalopathies are a broad class of common neurologic deterioration for which the etiology remains unsolved in many cases. In a Chinese Han family segregated with sensorineural hearing loss ...and leukoencephalopathy, candidate pathogenic variants were identified by targeted next‐generation sequencing of 144 genes associated with deafness and 108 genes with leukoencephalopathy. Novel compound heterozygous mutations p.R477H and p.P505S were identified in KARS, which encodes lysyl‐tRNA synthetase (LysRS), as the only candidate causative variants. These two mutations were functionally characterized by enzymatic assays, immunofluorescence, circular dichroism analysis, and gel filtration chromatography. Despite no alteration in the dimer‐tetramer oligomerization and cellular distribution by either mutation, the protein structure was notably influenced by the R477H mutation, which subsequently released the protein from the multiple‐synthetase complex (MSC). Mutant LysRSs with the R477H and P505S mutations had decreased tRNALys aminoacylation and displayed a cumulative effect when introduced simultaneously. Our studies showed that mutations in KARS lead to a newly defined subtype of leukoencephalopathy associated with sensorineural hearing impairment. The combined effect of reduced aminoacylation and release of LysRS from the MSC likely underlies the pathogenesis of the KARS mutations identified in this study.
In this study, we showed that two novel compound heterozygous mutations p.R477H and p.P505S in the lysyl‐tRNA synthetase (LysRS)‐encoding gene KARS lead to a newly defined subtype of leukoencephalopathy associated with sensorineural hearing impairment. The R477H mutation released LysRS from the multiple‐synthetase complex (MSC) and both R477H and P505S mutant LysRS had decreased tRNALys aminoacylation. The combined effect of reduced aminoacylation and release of LysRS from the MSC likely underlies the pathogenesis of the KARS mutations identified in this study.
Since the 1990s, the study of inherited hearing disorders, mostly those detected at birth, in the prelingual period or in young adults, has led to the identification of their causal genes. The genes ...responsible for more than 140 isolated (non-syndromic) and about 400 syndromic forms of deafness have already been discovered. Studies of mouse models of these monogenic forms of deafness have provided considerable insight into the molecular mechanisms of hearing, particularly those involved in the development and/or physiology of the auditory sensory organ, the cochlea. In parallel, studies of these models have also made it possible to decipher the pathophysiological mechanisms underlying hearing impairment. This has led a number of laboratories to investigate the potential of gene therapy for curing these forms of deafness. Proof-of-concept has now been obtained for the treatment of several forms of deafness in mouse models, paving the way for clinical trials of cochlear gene therapy in patients in the near future. Nevertheless, peripheral deafness may also be associated with central auditory dysfunctions and may extend well beyond the auditory system itself, as a consequence of alterations to the encoded sensory inputs or involvement of the causal deafness genes in the development and/or functioning of central auditory circuits. Investigating the diversity, causes and underlying mechanisms of these central dysfunctions, the ways in which they could impede the expected benefits of hearing restoration by peripheral gene therapy, and determining how these problems could be remedied is becoming a research field in its own right. Here, we provide an overview of the current knowledge about the central deficits associated with genetic forms of deafness.
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