The aim of this study is to contribute to a better description of the genotypic and phenotypic spectrum of DFNA6/14/38 and aid in counseling future patients identified with this variant. Therefore, ...we describe the genotype and phenotype in a large Dutch-German family (W21-1472) with autosomal dominant non-syndromic, low-frequency sensorineural hearing loss (LFSNHL). Exome sequencing and targeted analysis of a hearing impairment gene panel were used to genetically screen the proband. Co-segregation of the identified variant with hearing loss was assessed by Sanger sequencing. The phenotypic evaluation consisted of anamnesis, clinical questionnaires, physical examination and examination of audiovestibular function. A novel likely pathogenic
variant (NM_006005.3:c.2512C>T p.(Pro838Ser)) was identified in the proband and found to co-segregate with LFSNHL, characteristic of DFNA6/14/38, in this family. The self-reported age of onset of hearing loss (HL) ranged from congenital to 50 years of age. In the young subjects, HL was demonstrated in early childhood. At all ages, an LFSNHL (0.25-2 kHz) of about 50-60 decibel hearing level (dB HL) was observed. HL in the higher frequencies showed inter-individual variability. The dizziness handicap inventory (DHI) was completed by eight affected subjects and indicated a moderate handicap in two of them (aged 77 and 70). Vestibular examinations (
= 4) showed abnormalities, particularly in otolith function. In conclusion, we identified a novel
variant that co-segregates with DFNA6/14/38 in this family. We found indications of mild vestibular dysfunction, although it is uncertain whether this is related to the identified
variant or is an incidental finding. We would like to emphasize that conventional neonatal hearing screening programs are not sensitive to HL in DFNA6/14/38 patients, because high-frequency hearing thresholds are initially preserved. Therefore, we suggest screening newborns in DFNA6/14/38 families with more frequency-specific methods.
We investigate the postoperative subjective and objective outcomes of different surgical treatments for superior semicircular canal dehiscence (SSCD): vestibular signs, auditory signs, vestibular ...evoked myogenic potential test, pure tone audiogram, speech audiogram, or video-nystagmography.
An electronic search performed in the PubMed, Cochrane Library, and EMBASE databases on 15th of September 2015. A systematic search was conducted. Articles were included if written in English, Dutch, German, or French language.
Original studies reporting on the pre and postoperative subjective and/or objective outcomes of surgical treatments for superior semicircular canal dehiscence were included.
The methodological quality of the studies was independently assessed by two reviewers using a constructed critical appraisal, to assess the directness of evidence and the risk of bias. The results of the pre and postoperative subjective and/or objective outcomes were extracted.
Comparative study was conducted.
Surgical treatment for SSCD is particularly effective for vestibular symptoms and there is no evidence for improvement of hearing loss after surgical treatment. Since plugging using transmastoid approach had a lower complication rate, lower revision rate, and a shorter hospital stay, this treatment is recommended in high disabled SSCD patients.
The tetraspanin CD151 is a cell-surface molecule known for its strong lateral interaction with the laminin-binding integrin α3β1. Patients with a nonsense mutation in CD151 display end-stage kidney ...failure associated with regional skin blistering and sensorineural deafness, and mice lacking the integrin α3 subunit die neonatally because of severe abnormalities in the lung and kidney epithelia. We report the generation of Cd151-null mice that recapitulate the renal pathology of human patients, i.e., with age they develop massive proteinuria caused by focal glomerulosclerosis, disorganization of the glomerular basement membrane, and tubular cystic dilation. However, neither skin integrity nor hearing ability are impaired in the Cd151-null mice. Furthermore, we generated podocyte-specific conditional knockout mice for the integrin α3 subunit that show renal defects similar to those in the Cd151 knockout mice. Our results support the hypothesis that CD151 plays a key role in strengthening α3β1-mediated adhesion in podocytes.
Some pathogenic variants in mtDNA and nuclear DNA, affecting mitochondrial function, are associated with hearing loss. Behavioral and electrophysiological auditory performance are obtained from 62 ...patients, clinically diagnosed with different mitochondrial diseases (MD) using tone/speech audiometry and Auditory Brainstem Responses (ABR). Audiological variables (hearing loss type, pure tone average (PTA), interaural asymmetry, speech perception and brainstem neural conductivity) were analyzed and related to Newcastle Mitochondrial Disease Scale for Adults (NMDAS). In 35% of MDs, a mild to severe symmetrical sensorineural hearing loss (SNHL) was found. Patients with Maternally Inherited Diabetes and Deafness (MIDD) show significantly higher PTAs compared to other MDs. For all MDs, speech recognition scores were in accordance with their individual age- and gender-corrected tone audiometry, but ABR peak latencies were prolonged in patients with MIDD, Mitochondrial Encephalopathy Lactate acidosis and Stroke-like episodes (MELAS), Chronic Progressive External Ophthalmoplegia (CPEO) and Subacute necrotizing encephalopathy (Leigh). Correlations between NMDAS and audiological variables were low.
This study determined electrocochleography (ECochG) parameter settings to obtain cochlear microphonics (CM) with less invasive flexible extra-tympanic membrane electrodes. In 24 adult normal-hearing ...subjects, CMs were elicited by presenting click stimuli at 100 dBnHL, tone bursts (2 kHz) and broadband (BB) CE-chirps® LS (Interacoustics, Middelfart, Denmark), both at 80 dBnHL. Different high-pass filters (HPFs) (3.3 Hz and 100 Hz, respectively) were used to investigate response quality of the CM. CMs were successfully obtained in 92–100% with click-, 75–83% with 2 kHz tone burst- and 58–63% with CE-chirp®-LS stimuli. Click stimuli elicited significantly larger CM amplitudes compared to 2 kHz tone bursts and BB CE-chirp® LS (Interacoustics, Middelfart, Denmark). No significant differences were found between the two different high-pass filter (HPF) settings. The present study shows that it is possible to obtain clear CMs with the flexible extra-tympanic membrane electrodes using click stimuli. In contrast to 2 kHz tone bursts and CE-chirp® (Interacoustics, Middelfart, Denmark) LS, clicks show a significantly higher success rate and are the preferred stimuli to confirm the presence or absence of CMs.
Euchromatin histone methyltransferase 1 (EHMT1) is a highly conserved protein that catalyzes mono- and dimethylation of histone H3 lysine 9, thereby epigenetically regulating transcription. Kleefstra ...syndrome (KS), is caused by haploinsufficiency of the EHMT1 gene, and is an example of an emerging group of intellectual disability (ID) disorders caused by genes encoding epigenetic regulators of neuronal gene activity. Little is known about the mechanisms underlying this disorder, prompting us to study the Euchromatin histone methyltransferase 1 heterozygous knockout (Ehmt1(+/-)) mice as a model for KS. In agreement with the cognitive disturbances observed in patients with KS, we detected deficits in fear extinction learning and both novel and spatial object recognition in Ehmt1(+/-) mice. These learning and memory deficits were associated with a significant reduction in dendritic arborization and the number of mature spines in hippocampal CA1 pyramidal neurons of Ehmt1(+/-) mice. In-depth analysis of the electrophysiological properties of CA3-CA1 synapses revealed no differences in basal synaptic transmission or theta-burst induced long-term potentiation (LTP). However, paired-pulse facilitation (PPF) was significantly increased in Ehmt1(+/-) neurons, pointing to a potential deficiency in presynaptic neurotransmitter release. Accordingly, a reduction in the frequency of miniature excitatory post-synaptic currents (mEPSCs) was observed in Ehmt1(+/-) neurons. These data demonstrate that Ehmt1 haploinsufficiency in mice leads to learning deficits and synaptic dysfunction, providing a possible mechanism for the ID phenotype in patients with KS.
To investigate electrically evoked auditory cortical responses (eACR) elicited from the stimulation of intracochlear electrodes based on individually fitted stimulation parameters in cochlear implant ...(CI) users.
An eACR setup based on individual fitting parameters is proposed. A 50-ms alternating biphasic pulse train was used to stimulate apical, medial, and basal electrodes and to evoke auditory cortical potentials (N1-P2 complex).
The eACR setup proposed was validated with 14 adult CI users.
Individual and grand-average eACR waveforms were obtained. The eACR amplitudes were lower in the basal than in the apical and medial regions. Earlier N1 latencies were found in CI users with lower maximum comfortable loudness levels and shorter phase duration in response to apical stimulation, while medial and basal stimulation resulted in earlier N1 latencies and larger N1-P2 amplitudes in users with longer CI experience.
eACR could be elicited by direct intracochlear stimulation using individual fitting parameters with a success rate of 71%. The highest cortical peak-to-peak amplitudes were obtained in response to apical stimulation. Unlike the P2, the N1 component appeared to be a consistent cortical potential to determine eACR and gain knowledge of the auditory processing beyond the cochlea in CI users.
Highlights
eACR can be elicited through direct stimulation of intracochlear electrodes.
Stimulation of apical and medial regions yielded the highest N1-P2 amplitudes.
CI users with lower maximum comfortable loudness levels had shorter N1 latencies during apical stimulation.
The present dataset of mainly well-performing CI users suggests better cortical processing, that is, higher amplitudes and shorter latencies of N1.
The N1 potential appears a more consistent and reliable potential than the P2 to determine eACR responses in CI users.
ATP8B1 is essential for maintaining normal hearing Stapelbroek, Janneke M; Peters, Theo A; van Beurden, Denis H.A ...
Proceedings of the National Academy of Sciences - PNAS,
06/2009, Letnik:
106, Številka:
24
Journal Article
Recenzirano
Odprti dostop
ATP8B1 deficiency is caused by autosomal recessive mutations in ATP8B1, which encodes the putative phospatidylserine flippase ATP8B1 (formerly called FIC1). ATP8B1 deficiency is primarily ...characterized by cholestasis, but extrahepatic symptoms are also found. Because patients sometimes report reduced hearing capability, we investigated the role of ATP8B1 in auditory function. Here we show that ATP8B1/Atp8b1 deficiency, both in patients and in Atp8b1G³⁰⁸V/G³⁰⁸V mutant mice, causes hearing loss, associated with progressive degeneration of cochlear hair cells. Atp8b1 is specifically localized in the stereocilia of these hair cells. This indicates that the mechanosensory function and integrity of the cochlear hair cells is critically dependent on ATP8B1 activity, possibly through maintaining lipid asymmetry in the cellular membranes of stereocilia.
Pathogenic missense variants in
are associated with DFNA9, an autosomal dominantly inherited type of progressive sensorineural hearing loss with or without vestibular dysfunction. This study is a ...comprehensive overview of genotype-phenotype correlations using the PRISMA and HuGENet guidelines. Study characteristics, risk of bias, genotyping and data on the self-reported age of onset, symptoms of vestibular dysfunction, normative test results for vestibular function, and results of audiovestibular examinations were extracted for each underlying pathogenic
variant. The literature search yielded 48 studies describing the audiovestibular phenotypes of 27 DFNA9-associated variants in
. Subsequently, meta-analysis of audiometric data was performed by constructing age-related typical audiograms and by performing non-linear regression analyses on the age of onset and progression of hearing loss. Significant differences were found between the calculated ages of onset and progression of the audiovestibular phenotypes of subjects with pathogenic variants affecting either the LCCL domain of cochlin or the vWFA2 and Ivd1 domains. We conclude that the audiovestibular phenotypes associated with DFNA9 are highly variable. Variants affecting the LCCL domain of cochlin generally lead to more progression of hearing loss when compared to variants affecting the other domains. This review serves as a reference for prospective natural history studies in anticipation of mutation-specific therapeutic interventions.
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