-
Diabetic Medicine : a Journal of the... Feb 2024Maternally inherited diabetes and deafness (MIDD) is a rare form of adult-onset diabetes that can be difficult to diagnose due to its variable clinical phenotype....
AIMS
Maternally inherited diabetes and deafness (MIDD) is a rare form of adult-onset diabetes that can be difficult to diagnose due to its variable clinical phenotype. Transfer RNA-derived small fragments are a novel, emerging class of small non-coding RNAs (sncRNAs) that have significant potential as serum biomarkers due to their stress-induced generation, abundance, stability and ease of detection.
METHODS
We investigated the levels of tiRNA 5'ValCAC (alone and in combination with miR-23b-3p) identified from small RNA sequencing studies in serum samples from healthy controls, type 1 diabetes, type 2 diabetes and MIDD subjects.
RESULTS
Serum levels of 5'ValCAC were reduced in MIDD and type 2 diabetes subjects compared to controls. Type 2 diabetes subjects had higher serum levels of miR-23b-3p compared to all other subjects. Receiver Operating Characteristic analysis showed the potential of 5'ValCAC and miR-23b-3p as MIDD biomarkers, with the combination showing excellent separation from type 2 diabetes subjects.
CONCLUSIONS
This is the first report showing altered serum levels of tiRNAs in diabetes subjects. The combined use of 5'ValCAC and miR-23b-3p as serum biomarkers could potentially differentiate between MIDD subjects and type 2 diabetes subjects.
Topics: Adult; Humans; Diabetes Mellitus, Type 2; Biomarkers; RNA, Transfer; MicroRNAs; Deafness; Mitochondrial Diseases
PubMed: 37935454
DOI: 10.1111/dme.15258 -
Laryngo- Rhino- Otologie Jan 2024
Topics: Humans; Cochlear Implantation; Biomarkers; Deafness
PubMed: 38181770
DOI: 10.1055/a-2177-5330 -
Gene Therapy Mar 2024The adeno-associated virus (AAV) gene therapy has been widely applied to mouse models for deafness. But, AAVs could transduce non-targeted organs after inner ear...
The adeno-associated virus (AAV) gene therapy has been widely applied to mouse models for deafness. But, AAVs could transduce non-targeted organs after inner ear delivery due to their low cell-type specificity. This study compares transgene expression and biodistribution of AAV1, AAV2, Anc80L65, AAV9, AAV-PHP.B, and AAV-PHP.eB after round window membrane (RWM) injection in neonatal mice. The highest virus concentration was detected in the injected cochlea. AAV2, Anc80L65, AAV9, AAV-PHP.B, and AAV-PHP.eB transduced both inner hair cells (IHCs) and outer hair cells (OHCs) with high efficiency, while AAV1 transduced IHCs with high efficiency but OHCs with low efficiency. All AAV subtypes finitely transduced contralateral inner ear, brain, heart, and liver compared with the injected cochlea. In most brain regions, the enhanced green fluorescent protein (eGFP) expression of AAV1 and AAV2 was lower than that of other four subtypes. We suggested the cochlear aqueduct might be one of routes for vectors instantaneously infiltrating into the brain from the cochlea through a dye tracking test. In summary, our results provide available data for further investigating the biodistribution of vectors through local inner ear injection and afford a reference for selecting AAV serotypes for gene therapy toward deafness.
Topics: Animals; Mice; Tissue Distribution; Genetic Vectors; Cochlea; Genetic Therapy; Deafness; Dependovirus; Transduction, Genetic
PubMed: 38097651
DOI: 10.1038/s41434-023-00431-z -
Ear and HearingIn this Point of View, we review a number of recent discoveries from the emerging, interdisciplinary field of Network Science , which uses graph theoretic techniques to... (Review)
Review
In this Point of View, we review a number of recent discoveries from the emerging, interdisciplinary field of Network Science , which uses graph theoretic techniques to understand complex systems. In the network science approach, nodes represent entities in a system, and connections are placed between nodes that are related to each other to form a web-like network . We discuss several studies that demonstrate how the micro-, meso-, and macro-level structure of a network of phonological word-forms influence spoken word recognition in listeners with normal hearing and in listeners with hearing loss. Given the discoveries made possible by this new approach and the influence of several complex network measures on spoken word recognition performance we argue that speech recognition measures-originally developed in the late 1940s and routinely used in clinical audiometry-should be revised to reflect our current understanding of spoken word recognition. We also discuss other ways in which the tools of network science can be used in Speech and Hearing Sciences and Audiology more broadly.
Topics: Humans; Hearing; Deafness; Hearing Loss; Speech; Speech Perception; Audiometry, Pure-Tone
PubMed: 37316992
DOI: 10.1097/AUD.0000000000001395 -
EMBO Molecular Medicine Nov 2023Cingulin (CGN) is a cytoskeleton-associated protein localized at the apical junctions of epithelial cells. CGN interacts with major cytoskeletal filaments and regulates...
Cingulin (CGN) is a cytoskeleton-associated protein localized at the apical junctions of epithelial cells. CGN interacts with major cytoskeletal filaments and regulates RhoA activity. However, physiological roles of CGN in development and human diseases are currently unknown. Here, we report a multi-generation family presenting with autosomal dominant non-syndromic hearing loss (ADNSHL) that co-segregates with a CGN heterozygous truncating variant, c.3330delG (p.Leu1110Leufs*17). CGN is normally expressed at the apical cell junctions of the organ of Corti, with enriched localization at hair cell cuticular plates and circumferential belts. In mice, the putative disease-causing mutation results in reduced expression and abnormal subcellular localization of the CGN protein, abolishes its actin polymerization activity, and impairs the normal morphology of hair cell cuticular plates and hair bundles. Hair cell-specific Cgn knockout leads to high-frequency hearing loss. Importantly, Cgn mutation knockin mice display noise-sensitive, progressive hearing loss and outer hair cell degeneration. In summary, we identify CGN c.3330delG as a pathogenic variant for ADNSHL and reveal essential roles of CGN in the maintenance of cochlear hair cell structures and auditory function.
Topics: Animals; Humans; Mice; Cytoskeletal Proteins; Deafness; Hair Cells, Auditory; Hearing; Hearing Loss
PubMed: 37691516
DOI: 10.15252/emmm.202317611 -
Human Molecular Genetics Oct 2023DNA methyltransferase type 1 (DNMT1) is a major enzyme involved in maintaining the methylation pattern after DNA replication. Mutations in DNMT1 have been associated...
DNA methyltransferase type 1 (DNMT1) is a major enzyme involved in maintaining the methylation pattern after DNA replication. Mutations in DNMT1 have been associated with autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). We used fibroblasts, induced pluripotent stem cells (iPSCs) and induced neurons (iNs) generated from patients with ADCA-DN and controls, to explore the epigenomic and transcriptomic effects of mutations in DNMT1. We show cell type-specific changes in gene expression and DNA methylation patterns. DNA methylation and gene expression changes were negatively correlated in iPSCs and iNs. In addition, we identified a group of genes associated with clinical phenotypes of ADCA-DN, including PDGFB and PRDM8 for cerebellar ataxia, psychosis and dementia and NR2F1 for deafness and optic atrophy. Furthermore, ZFP57, which is required to maintain gene imprinting through DNA methylation during early development, was hypomethylated in promoters and exhibited upregulated expression in patients with ADCA-DN in both iPSC and iNs. Our results provide insight into the functions of DNMT1 and the molecular changes associated with ADCA-DN, with potential implications for genes associated with related phenotypes.
Topics: Humans; Cerebellar Ataxia; DNA (Cytosine-5-)-Methyltransferases; Transcriptome; Epigenomics; DNA (Cytosine-5-)-Methyltransferase 1; DNA Methylation; Deafness; Mutation; DNA
PubMed: 37584462
DOI: 10.1093/hmg/ddad123 -
Clinical Drug Investigation Dec 2023Spinal muscular atrophy (SMA) is a genetic disorder with limited treatment options. It is crucial to have a comprehensive understanding of drug safety in order to make...
BACKGROUND AND OBJECTIVE
Spinal muscular atrophy (SMA) is a genetic disorder with limited treatment options. It is crucial to have a comprehensive understanding of drug safety in order to make informed clinical drug selections for patients with SMA. Assessing the safety profiles of therapeutic drugs for SMA has been challenging due to the limited number of patients included in clinical trials. This study aims to investigate and compare the potential safety concerns associated with three leading SMA therapeutic drugs: nusinersen, risdiplam, and onasemnogene abeparvovec.
METHODS
The FDA Adverse Event Reporting System database was used to analyze drug safety, and a case (SMA drug)/noncase (all other drugs in the database) approach was employed to estimate safety signals through disproportionality analysis and reporting odds ratio (ROR). Veen analysis was conducted to compare and select the idiosyncratic adverse events (AEs) associated with each drug.
RESULTS
The study included 5324 cases of nusinersen, 1184 cases of risdiplam, and 1277 cases of onasemnogene abeparvovec. Venn analysis revealed 27 common AEs among the three drugs, including cardiac, gastrointestinal, metabolism, musculoskeletal, renal, respiratory disorders, and infections. Additionally, 196 AEs exclusively found in nusinersen included post lumbar puncture syndrome [ROR (95% CI) = 6120.91 (5057.01-7408.64), n = 372], procedural pain [ROR (95% CI) = 54.86 (48.13-62.54), n = 234], idiopathic intracranial hypertension [ROR (95% CI) = 6.12 (2.29-16.33), n = 4], and hypokalemia [ROR (95% CI) = 2.02 (1.24-3.31), n = 16]. Additionally, transient deafness was identified as an unexpected and rare, yet severe, AE for nusinersen [ROR (95% CI) = 23.32 (8.71-62.44), n = 4]. Risdiplam exhibited 50 AEs exclusively, with notable idiosyncratic AEs including diarrhea [ROR (95% CI) = 4.55 (3.79-5.46), n = 121], fatigue [ROR (95% CI) = 2.03 (1.6-2.57), n = 70], photosensitivity reaction [ROR (95% CI) = 9.50 (4.25-21.13), n = 6], rash [ROR (95% CI) = 1.90 (1.36-2.67), n = 34], and [ROR (95% CI) = 4.3 (1.93-9.58), n = 6] in comparison with the other two drugs. Moreover, ileus [ROR (95% CI) = 11.11 (4.14-29.51), n = 4], gastrointestinal hemorrhage [ROR (95% CI) = 2.55 (1.15-5.69), n = 6], and hypoglycemic unconsciousness [ROR (95% CI) = 153.58 (62.98-374.54), n = 5] were rare but severe AEs associated with risdiplam. Onasemnogene abeparvovec had 143 exclusively identified AEs, with significant high signals for troponin I increase [ROR (95% CI) = 627.1 (492.2-798.99), n = 78], troponin T increase [ROR (95% CI) = 233.98 (153.29-357.15), n = 23], blood lactate dehydrogenase increase [ROR (95% CI) = 39.81 (28.88-54.87), n = 38], and transaminases increase [ROR (95% CI) = 36.88 (29.24-46.52), n = 73].
CONCLUSIONS
This study highlights the importance of monitoring injection-related injuries and transient deafness events in patients treated with nusinersen. For onasemnogene abeparvovec, careful monitoring for renal impairment, liver injury, and myocardial damage is necessary. Risdiplam requires attention to the potential risk of rare but severe gastrointestinal damage events and hypoglycemia. Importantly, risdiplam exhibited lower liver and renal toxicity, making it a potential consideration for patients with liver or renal insufficiency or for combined use with other drugs that possess high liver or renal toxicity. These findings can be a reference for drug selection and further prospective studies.
Topics: Humans; Pharmacovigilance; Prospective Studies; Deafness
PubMed: 37995087
DOI: 10.1007/s40261-023-01320-4 -
EMBO Molecular Medicine Apr 2024Approximately half a billion people—5% of the world’s population—suffer from disabling hearing impairment (HI) according to the WHO...
Approximately half a billion people—5% of the world’s population—suffer from disabling hearing impairment (HI) according to the WHO (http://www.who.int/features/factfiles/deafness/en/). HI commonly hampers speech acquisition, leads to social isolation and increases risk for depression and cognitive decline. One to two per thousand children are born with disabling HI and over 50% of sensorineural HI is caused by defects in individual genes (deafness genes) of which roughly 150 have been identified so far (http://hereditaryhearingloss.org/). In case of profound hearing impairment or deafness, cochlear implants that bypass the dysfunctional or lost sensory hair cells and electrically stimulate the auditory nerve partially restore hearing. However, hearing with cochlear implants has shortcomings such as limited understanding of speech in background noise. So, there remains a major unmet medical need for improved hearing restoration (Wolf et al, 2022). Yet, despite major research efforts, a causal treatment based on pharmacology, gene therapy, or stem cells had, so far, not been clinically available. Now, this is finally changing at least for some patients: first in human trials prove the concept for inner ear gene therapy of otoferlin-related synaptic deafness.
Topics: Humans; Deafness; Genetic Therapy
PubMed: 38528140
DOI: 10.1038/s44321-024-00058-6 -
Matrix Biology : Journal of the... Jan 2024The extracellular matrix (ECM) consists in a complex meshwork of collagens, glycoproteins, and proteoglycans, which serves a scaffolding function and provides... (Review)
Review
The extracellular matrix (ECM) consists in a complex meshwork of collagens, glycoproteins, and proteoglycans, which serves a scaffolding function and provides viscoelastic properties to the tissues. ECM acts as a biomechanical support, and actively participates in cell signaling to induce tissular changes in response to environmental forces and soluble cues. Given the remarkable complexity of the inner ear architecture, its exquisite structure-function relationship, and the importance of vibration-induced stimulation of its sensory cells, ECM is instrumental to hearing. Many factors of the matrisome are involved in cochlea development, function and maintenance, as evidenced by the variety of ECM proteins associated with hereditary deafness. This review describes the structural and functional ECM components in the auditory organ and how they are modulated over time and following injury.
Topics: Humans; Hearing; Cochlea; Deafness; Extracellular Matrix; Extracellular Matrix Proteins
PubMed: 38070832
DOI: 10.1016/j.matbio.2023.12.002 -
International Journal of Audiology Nov 2023To date, auditory rehabilitation mainly focuses on the person with hearing impairment (PHI). This study aimed to analyse the burden of hearing loss on significant others...
OBJECTIVE
To date, auditory rehabilitation mainly focuses on the person with hearing impairment (PHI). This study aimed to analyse the burden of hearing loss on significant others (SOs), and to explore the impact of contextual and mediating psychosocial co-factors and auditory rehabilitation by cochlear implantation (CI).
DESIGN AND STUDY SAMPLE
Third-party disability (SOS-HEAR) and quality of life (Nijmegen Cochlear Implant Questionnaire) were evaluated in 41 PHI scheduled for CI surgery and their close partners pre- and 6-month post-implantation. Further, age, hearing status, educational level, depressive symptoms (GDS-15), coping strategies (Brief-COPE), resilience (RS-13), stress (PSQ) of SOs and PHI were studied.
RESULTS
Hearing loss imposes a burden on SOs, particularly in relation to changes in communication and socialisation. Third-party disability was higher in SOs of PHI with lower educational background ( = 0.04) and of advanced age ( = 0.008). Hearing status of SOs negatively correlated with SOS-HEAR ( = 0.04). After CI, quality of life of PHI and third-party disability of SOs improved ( < 0.001), except in relationship changes. SOs with higher pre-operative burden also experienced more third-party disability afterwards ( ≤ 0.003).
CONCLUSION
Audiological rehabilitation should expand to include SOs in the rehabilitation process, as the burden experienced by SOs might persist even after CI.
Topics: Humans; Cochlear Implants; Cochlear Implantation; Quality of Life; Hearing Loss; Deafness; Speech Perception
PubMed: 36411948
DOI: 10.1080/14992027.2022.2125913