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Cureus May 2024Macrothrompocytopenia (MTP) is a rare group of hereditary disorders that lead to impaired hemostasis. Macrothrompocytopenia mostly results from genetic mutations in...
Macrothrompocytopenia (MTP) is a rare group of hereditary disorders that lead to impaired hemostasis. Macrothrompocytopenia mostly results from genetic mutations in genes implicated in megakaryocyte differentiation and function. Diaphanous-related formin 1 (DIAPH1) is a protein-coding gene. Dominant gain-of-function DIAPH1 variants cause macrothrombocytopenia and sensorineural deafness (autosomal dominant non-syndromic hearing loss 1 (DFNA1)), while homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). This rare genetic disease is characterized by progressive and severe hearing loss with onset in the first decade of life, is associated with mild thrombocytopenia, and has no significant bleeding tendency. This case report presents the clinical findings of a 14-year-old Saudi pediatric girl. We investigated the potential association of DIAPH1 as a novel candidate gene linked to dominant MTP and autosomal dominant non-syndromic hearing loss (ADNSHL), which was evaluated through audiometry. Notably, a novel variant, c.3633_3636del, was identified in the DIAPH1 gene. To date, only a small number of mutations in this gene have been reported as the cause of MTP and ADNSHL.
PubMed: 38915998
DOI: 10.7759/cureus.61044 -
BioRxiv : the Preprint Server For... Jun 2024Age-related hearing impairment is the most common cause of hearing loss and is one of the most prevalent conditions affecting the elderly globally. It is influenced by a...
Age-related hearing impairment is the most common cause of hearing loss and is one of the most prevalent conditions affecting the elderly globally. It is influenced by a combination of environmental and genetic factors. The mouse and human inner ears are functionally and genetically homologous. Investigating the genetic basis of age-related hearing loss (ARHL) in an outbred mouse model may lead to a better understanding of the molecular mechanisms of this condition. We used Carworth Farms White (CFW) outbred mice, because they are genetically diverse and exhibit variation in the onset and severity of ARHL. The goal of this study was to identify genetic loci involved in regulating ARHL. Hearing at a range of frequencies was measured using Auditory Brainstem Response (ABR) thresholds in 946 male and female CFW mice at the age of 1, 6, and 10 months. We obtained genotypes at 4.18 million single nucleotide polymorphisms (SNP) using low-coverage (mean coverage 0.27x) whole-genome sequencing followed by imputation using STITCH. To determine the accuracy of the genotypes we sequenced 8 samples at >30x coverage and used calls from those samples to estimate the discordance rate, which was 0.45%. We performed genetic analysis for the ABR thresholds for each frequency at each age, and for the time of onset of deafness for each frequency. The SNP heritability ranged from 0 to 42% for different traits. Genome-wide association analysis identified several regions associated with ARHL that contained potential candidate genes, including , , , , and . We confirmed, using functional study, that Prkag2 deficiency causes age-related hearing loss at high frequency in mice; this makes a candidate gene for further studies. This work helps to identify genetic risk factors for ARHL and to define novel therapeutic targets for the treatment and prevention of ARHL.
PubMed: 38915500
DOI: 10.1101/2024.06.10.598304 -
NMC Case Report Journal 2024Superficial siderosis (SS) of the central nervous system is a rare disorder that is caused by chronic or recurrent hemorrhage in the subarachnoid space via a dural...
Superficial siderosis (SS) of the central nervous system is a rare disorder that is caused by chronic or recurrent hemorrhage in the subarachnoid space via a dural defect at the spinal level. The most common clinical features of SS include slow-progressive sensorineural deafness, cerebellar symptoms, and pyramidal tract signs. Considering that SS can present with broad clinical manifestations, for precise diagnosis, this disease must be understood. Anti-Ro/SSA antibodies are commonly detected in patients with Sjögren's syndrome and are utilized as markers for autoimmune diseases. In this report, we present a unique pathological condition in which SS coincided with a positive anti-Ro/SSA antibody test result. During the diagnosis of gait disturbance, an elevation in anti-Ro/SSA antibody was detected, and steroid pulse therapy was initiated as the initial treatment for autoimmune diseases. Head magnetic resonance imaging (MRI) revealed extensive hypointensity as a dark band that surrounded the intracranial basal structures and cerebellar hemispheres. Spinal MRI indicated ventral longitudinal intraspinal fluid collection extending from C7 to T5 as well as a defect in the ventral T2-3 dura mater. Intraoperative visualization revealed that the intradural venous plexus was the source of bleeding that caused the SS. To our knowledge, this report is the first to discuss the presence of anti-Ro/SSA antibodies in patients with SS. The role of anti-Ro/SSA antibodies in the pathophysiology of SS remains unclear; therefore, to confirm a possible association, further research and accumulation of cases are required.
PubMed: 38911924
DOI: 10.2176/jns-nmc.2023-0214 -
Alzheimer's & Dementia (New York, N. Y.) 2024Alzheimer's disease and related dementias (ADRDs) and age-related hearing loss are the intersection of two major public health challenges. With age as the primary risk...
Alzheimer's disease and related dementias (ADRDs) and age-related hearing loss are the intersection of two major public health challenges. With age as the primary risk factor for both disease processes, the burden of ADRDs and age-related hearing loss is growing, and each field maintains significant barriers to broadscale identification and management that is affordable and accessible. With the disproportionate burden of ADRDs among racial and ethnic minority older adults and existing disparities within hearing care, both areas face challenges in achieving equitable access and outcomes across diverse populations. The publication of the Aging and Cognitive Health Evaluation in Elders (ACHIEVE) trial in July 2023 marked a significant moment in the fields of brain and hearing health. The ACHIEVE trial was the first randomized controlled trial to examine whether providing hearing intervention, specifically provision of hearing aids, compared to an education control, would reduce cognitive changes over 3 years. The participants most at risk for cognitive decline, with lower education, lower income, more likely to identify as Black, and have more cardiovascular risk factors, were the participants who benefited most from the hearing intervention and are also the least likely to be represented in research and the least likely to obtain hearing care. With growing evidence of the interconnection between cognitive and sensory health, we have an opportunity to prioritize equity, from purposeful inclusion of diverse participants in trials to influencing the emerging market of over-the-counter hearing aids to supporting expanded models of hearing care that reach those who have traditionally gone unserved. No longer can hearing go unrecognized by clinicians, researchers, and advocates for brain health. At the same time, the fields of brain and hearing health must center equity if we are going to meet the needs of diverse older adults in a world in which hearing health matters.
PubMed: 38911874
DOI: 10.1002/trc2.12484 -
BioRxiv : the Preprint Server For... May 2024Sensory hair cells of the inner ear utilize specialized ribbon synapses to transmit sensory stimuli to the central nervous system. This sensory transmission necessitates...
Sensory hair cells of the inner ear utilize specialized ribbon synapses to transmit sensory stimuli to the central nervous system. This sensory transmission necessitates rapid and sustained neurotransmitter release, which relies on a large pool of synaptic vesicles at the hair-cell presynapse. Work in neurons has shown that kinesin motor proteins traffic synaptic material along microtubules to the presynapse, but how new synaptic material reaches the presynapse in hair cells is not known. We show that the kinesin motor protein Kif1a and an intact microtubule network are necessary to enrich synaptic vesicles at the presynapse in hair cells. We use genetics and pharmacology to disrupt Kif1a function and impair microtubule networks in hair cells of the zebrafish lateral-line system. We find that these manipulations decrease synaptic-vesicle populations at the presynapse in hair cells. Using electron microscopy, along with calcium imaging and electrophysiology, we show that a diminished supply of synaptic vesicles adversely affects ribbon-synapse function. mutants exhibit dramatic reductions in spontaneous vesicle release and evoked postsynaptic calcium responses. Additionally, we find that mutants exhibit impaired rheotaxis, a behavior reliant on the ability of hair cells in the lateral line to respond to sustained flow stimuli. Overall, our results demonstrate that Kif1a-based microtubule transport is critical to enrich synaptic vesicles at the active zone in hair cells, a process that is vital for proper ribbon-synapse function.
PubMed: 38903095
DOI: 10.1101/2024.05.20.595037 -
European Journal of Medical Genetics Jun 2024This paper reports the discovery of a m.C1494T pedigree in the east of England made during a search for matrilineal relations of King Richard III. The mitochondrial DNA...
This paper reports the discovery of a m.C1494T pedigree in the east of England made during a search for matrilineal relations of King Richard III. The mitochondrial DNA variant m.C1494T has been associated with aminoglycoside-induced deafness. This variant is very uncommon. although pedigrees with this variant have previously been found in China and Spain. The members of the newly identified pedigree all belong to the mitochondrial haplogroup J1c2c3, which is also the haplogroup of King Richard III. The presence of a few people in the USA from the same haplogroup has previously been noted, and it is now known that one of the people can show his descent from a couple who lived in Nottinghamshire, England, in the late 1700's. The mitochondrial DNA sequence of this man, at present living in the USA, and of his 4th cousin, twice removed, living in Lincoln, England, has shown they belong to haplogroup J1c2c3 and both have the variant m.C1494T; thereby, allowing the production of a multi-generational pedigree originating in the east of England. Fortunately, deafness has not been found in any living member of this large pedigree. It was also noted that the link to the family of King Richard III has not been firmly defined; however the circumstantial evidence is strong as many of his family members lived in this part of England.
PubMed: 38897372
DOI: 10.1016/j.ejmg.2024.104957 -
Hearing Research Jun 2024Hearing impairment is the most prevalent sensory disease in humans and can have dramatic effects on the development, and preservation, of our cognitive abilities and... (Review)
Review
Hearing impairment is the most prevalent sensory disease in humans and can have dramatic effects on the development, and preservation, of our cognitive abilities and social interactions. Currently 20 % of the world's population suffer from a form of hearing impairment; this is predicted to rise to 25 % by 2050. Despite this staggering disease load, and the vast damage it inflicts on the social, medical and economic fabric of humankind, our ability to predict, or prevent, the loss of hearing is very poor indeed. We here make the case for a paradigm shift in our approach to studying deafness. By exploiting more forcefully the molecular-genetic conservation between human hearing and hearing in morphologically distinct models, such as the fruit fly Drosophila melanogaster, we believe, a deeper understanding of hearing and deafness can be achieved. An understanding that moves beyond the surface of the 'deafness genes' to probe the underlying bedrock of hearing, which is shared across taxa, and partly shared across modalities. When it comes to understanding the workings (and failings) of human sensory function, a simple fruit fly has a lot to offer and a fly eye might sometimes be a powerful model for a human ear. Particularly the use of fly avatars, in which specific molecular (genetic or proteomic) states of humans (e.g. specific patients) are experimentally reproduced, in order to study the corresponding molecular mechanisms (e.g. specific diseases) in a controlled yet naturalistic environment, is a tool that promises multiple unprecedented insights. The use of the fly - and fly avatars - would benefit humans and will help enhance the power of other scientific models, such as the mouse.
PubMed: 38896942
DOI: 10.1016/j.heares.2024.109047 -
Historia, Ciencias, Saude--Manguinhos 2024This text presents the partial results of ongoing research into deafness in history teaching and historiography between 2015 and 2022. The study problematizes the place...
This text presents the partial results of ongoing research into deafness in history teaching and historiography between 2015 and 2022. The study problematizes the place of disabled people in top-ranking periodicals (the top two categories in Brazil) and in pedagogical projects on degree courses in history (with and without teacher-training certification) at the University of São Paulo and the State University of Campinas. These universities were chosen because they topped the ranking in a survey conducted by Folha de S.Paulo newspaper. The study observes how the Brazilian Inclusion Law (law 13.146, of July 6, 2015) is incorporated into the initial training of these professionals.
Topics: Humans; Brazil; Historiography; Deafness; Universities; History, 21st Century; Disabled Persons
PubMed: 38896751
DOI: 10.1590/S0104-59702024000100028 -
Ear, Nose, & Throat Journal Jun 2024To analyze the etiology, diagnosis, and treatment of unexplained conductive hearing loss (UCHL) with intact tympanic membrane. A systematic review was conducted based... (Review)
Review
To analyze the etiology, diagnosis, and treatment of unexplained conductive hearing loss (UCHL) with intact tympanic membrane. A systematic review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 642 articles were retrieved from databases such as PubMed, Embase, Web of Science, and Cochrane. Fifty-four research articles and 21 case reports were screened out according to the inclusion and exclusion criteria for analysis of the etiology of UCHL. Seven research articles with UCHL who underwent exploratory tympanotomy were selected for data extraction and analysis of clinical characteristics. UCHL is a common manifestation of various diseases, including congenital ossicular anomalies (COA), otosclerosis (OTS), congenital middle ear cholesteatoma (CMEC), oval window atresia, superior semicircular-canal dehiscence, congenital stapedial footplate fixation, middle ear osteoma or adenoma, congenital ossification of stapedial tendon, and so on. A total of 522 patients were included in the 7 articles; among whom OTS showed a tendency to increase with age. The main symptoms were hearing loss, followed by tinnitus, dizziness, ear fullness, ear pain, facial paralysis. A total of 87.5% to 93.0% patients with COA manifested as nonprogressive deafness that occurred since childhood, with tinnitus incidence of 15.6% to 30.2%, and 86.4% to 96.4% patients with OTS presented with progressive hearing loss, with tinnitus incidence of 60.1% to 90.9%. The diagnosis positive rate of high-resolution computed tomography (HRCT) was 33.8% to 87.1%, and CMEC was higher than that of COA (83.3%-100% vs 28.6%-64%). All the articles reported good hearing recovery. The most common surgical complications included taste abnormalities, tinnitus, and dizziness. UCHL presents with similar clinical manifestations and poses challenges in preoperative diagnosis. Exploratory tympanotomy is the primary method for diagnosis and treatment, with good prognosis after removing the lesion and reconstructing hearing during the operation. Children can also safely undergo the surgery.
PubMed: 38895947
DOI: 10.1177/01455613241262129 -
BioRxiv : the Preprint Server For... Jun 2024Noise can induce hearing loss. In particularly, noise can induce cochlear synapse degeneration leading to hidden hearing loss, which is the most common type of hearing...
UNLABELLED
Noise can induce hearing loss. In particularly, noise can induce cochlear synapse degeneration leading to hidden hearing loss, which is the most common type of hearing disorders in the clinic. Currently, there is no pharmacological treatment, particularly, no post-exposure (i.e., therapeutic) treatment available in the clinic. Here, we report that systematic administration of K channel blockers before or after noise exposure could significantly attenuate NIHL and synapse degeneration. After systematic administration of a general K-channel blocker tetraethylammonium (TEA), the elevation of auditory brainstem response (ABR) thresholds after noise-exposure significantly reduced, and the active cochlear mechanics significantly improved. The therapeutic effect was further improved as the post-exposure administration time extending to 3 days. BK channel is a predominant K channel in the inner hair cells. Systematic administration of a BK channel blocker GAL-021 after noise exposure also ameliorated hearing loss and improved hearing behavioral responses tested by acoustic startle response (ASR). Finally, both TEA and GAL-021 significantly attenuated noise-induced ribbon synapse degeneration. These data demonstrate that K -channel blockers can prevent and treat NIHL and cochlear synapse degeneration. Our finding may aid in developing therapeutic strategies for post-exposure treatment of NIHL and synapse degeneration.
SIGNIFICANCE STATEMENT
Noise is a common deafness factor affecting more 100 million people in the United States. So far, there is no pharmacological treatment available. We show here that administration of K channel blockers after noise exposure could attenuate noise-induced hearing loss and synapse degeneration, and improved behavioral responses. This is the first time to real the K channel blockers that could treat noise-induced hearing loss and cochlear synaptopathy after noise exposure.
PubMed: 38895254
DOI: 10.1101/2024.06.04.597382