Hearing health prevention has emerged as a significant public health concern worldwide. With nearly two and a half billion people experiencing some degree of hearing loss, and around seven hundred million requiring medical intervention, the impact on global health is substantial. The economic burden is equally substantial, with estimated health costs reaching 980 billion dollars in the United States alone. To shed light on this issue, we conducted a survey-based cross-sectional study involving 1150 individuals. Utilizing multiple linear regression across three models, we aimed to explore the association between demographic variables and knowledge, attitude, and behaviors related to hearing health. In Model I, we observed a correlation between knowledge and several factors, including age, smoking habits, marital status, and education. In Model II, attitudes were found to associate with non-smoking habits, education, and knowledge. Model III revealed a statistically significant correlation between behaviors and age, gender, parenthood, knowledge, and attitudes. These findings emphasize the importance of targeted public health programs aimed at improving behaviors among the general population. Such interventions can be both effective and relatively inexpensive. By addressing these determinants, we can enhance overall hearing health in the community. Our study contributes valuable information about the knowledge, attitudes, and behaviors related to hearing health in the general population. Understanding these factors is crucial in developing evidence-based strategies to promote hearing health and prevent hearing loss effectively. As we continue to work towards better hearing health, the findings from this study can serve as a cornerstone for informed decision-making and successful intervention implementation. Affecting more than half a billion people, hearing loss is the most common sensory deficit globally ,2. HeariThe World Health Organization has projected that by 2050, almost 2.5 billion individuals will experience some level of hearing loss, with at least 700 million individuals requiring some form of hearing rehabilitation . FurtherIn the European Region, roughly 190 million people have some level of hearing loss or deafness, which is equivalent to 20% of the population, meaning that one out of every five people in Europe has some form of hearing loss or deafness ,9.Hearing quality also affects health expenses, quantified at 980 billion US dollars globally . This esThere are numerous causes of hearing loss, including congenital, infectious, noise exposure through listening to music and in the workplace, age-related, traumatic, and immune-mediated causes ,12. Howe, and further decreased to 7% during the period 2017–2020 [Although the causes of hearing loss are well-established, the existing literature indicates that adopting behaviors to safeguard hearing health is challenging for individuals ,14. As r017–2020 .To the best of our knowledge, there is a paucity of evidence regarding knowledge, attitude, and behaviors regarding hearing quality. Health behavior models were used to understand hearing conservation and its determinants, including attitudes and behaviors ,18,19. ITherefore, the purpose of the present study is to address the current lack of understanding about knowledge, attitudes, and behaviors related to hearing health in a large metropolitan area population. This study will provide valuable insights into how factors such as age, gender, and occupation influence hearing health knowledge, attitudes, and behaviors in different subgroups of the population. Those findings can be used to develop targeted public health interventions, improve hearing health awareness, and promote positive behaviors related to hearing conservation.This cross-sectional study administered questionnaires  to adultThe sample size was determined using Slovin’s formula, aiming for a representative sample with a 3% margin of error and a 95% confidence interval. The calculation led to a final target of 1523 subjects. However, considering the possibility of non-response, the estimated total sample size was adjusted to 1066.During the study period, experienced interviewers submitted the questionnaire to the participants, as previously described ,24,25. The participants were thoroughly informed about the research’s typology, aims, and methodology, and the confidential handling of their collected data. Interviewers explicitly stated that they were representing the University of Naples “Federico II” while conducting the study. Importantly, the participants were assured of their right to withdraw from the study at any point without the need to provide a reason. Prior to proceeding with the interview, informed consent was obtained from all of the participants.In conclusion, it was clarified that they could end their participation at any time without disclosing a reason. Consent was obtained prior to progressing with the interview. No founding was granted for participation. The present study was carried out in conformity with the Declaration of Helsinki.The questionnaire was meticulously developed through collaborative meetings involving a diverse commission of physicians and other healthcare professionals. During this process, questions deemed irrelevant or unsuitable for the study’s objectives were carefully eliminated or replaced. To ensure the clarity and effectiveness of the questionnaire, a beta test was conducted with a separate group of 20 individuals, who were not included in the main study. This pretest allowed us to assess the participants’ comprehension of the questionnaire and make any necessary refinements.The first section of the questionnaire focused on gathering socio-demographic characteristics and other pertinent health-related information, such as gender, age, marital status, level of education, occupation, and smoking habits. In the second section, participants were probed about their knowledge, attitudes, and behaviors concerning hearing health. This section comprised a total of 32 questions. Responses for knowledge and attitudes were categorized into three options: “agree,” “uncertain,” and “disagree,” which were coded as 1, 2, and 3, respectively. On the other hand, behaviors were assessed with four response options: “yes/always”, “often”, “sometimes” and “never”, which were coded as 1, 2, 3 and 4, respectively.The data obtained from the study were analyzed using the STATA MP v14.0 statistical software program . The analysis was performed in two stages. Firstly, descriptive statistics were used to summarize the basic information of the statistical units. Secondly, a multiple linear regression analysis (MLRA) was conducted across three models: Model I and Model II were partially adjusted, while Model III was fully adjusted.To generate the knowledge, attitudes, and behaviors scores, individual scores from each section were summed up. The independent variables included in all of the models were: sex , age (in years), education level , marital status , smoking habits , and having children .p-values were less than or equal to 0.05.In Model II, the knowledge score was added to Model I, and in Model III, attitude was added to Model II. All statistical tests were two-tailed, and results were considered statistically significant if the In The findings suggest a significant association between hearing health knowledge and young age, being single, and higher education attainment.The first evidence suggests that younger people have better knowledge about hearing health. The findings are consistent with a study conducted by Khandekar  among peAnother result of this study was the association between being single and knowledge regarding hearing health. Although there is no previous research specifically examining this relationship, the previous literature indicates marital status as a proxy for attention to hearing health .In addition, there is evidence of an association between education attainment and knowledge: college graduates have more knowledge about hearing health, which is consistent with a study by Sørensen , who fouTherefore, promoting education and increasing awareness about hearing health, mainly among the elderly population, can have a positive impact on both education and health outcomes. Further research is needed to better understand the relationship between educational attainment and hearing health knowledge and develop effective interventions to promote hearing health among all individuals.The second piece of evidence of the present study highlights an association between non-smoking habits and attitudes toward hearing health. However, there is a lack of research on the specific relationship between smoking habits and attitudes towards hearing health. This outcome is novel in the existing literature.Furthermore, the study revealed a noteworthy association between knowledge and attitude, suggesting that knowledge regarding hearing health may contribute to the development of positive attitudes towards hearing health. This finding is consistent with previous research, including a study by Almutairi  that exaThe findings revealed a significant association between positive behaviors towards hearing health and older age, female gender, and good knowledge of hearing health.The results suggest that the older participants and women demonstrated slightly better behaviors. Interestingly, a population-based cohort study  conducteThe study revealed an association between a higher level of knowledge about hearing health and the adoption of healthy behaviors. Furthermore, individuals who displayed positive attitudes towards hearing health were more inclined to adopt healthy practices. For instance, in a study conducted by Crandell , it was The main limitation of this study was the reliance on self-reported behaviors through the use of questionnaires. This may have led to social desirability bias as respondents may have felt pressure to provide socially acceptable answers. However, we took steps to mitigate this bias by assuring the participants of anonymity and confidentiality. The questionnaire used in this research did not include specific sections to gather sociodemographic data, cultural information, type of families, socioeconomic levels, or studies of the parents. As a result, we were unable to provide in-depth insights into these aspects of the sample. While these factors may play a role in shaping the outcomes of the study, their absence limits the comprehensive understanding of the broader context surrounding our findings. Future studies could benefit from incorporating additional sections in the questionnaire to capture a more extensive range of participant characteristics and allow for a more comprehensive analysis. Also, being relatively new as topic in the literature, our discussions were limited to existing evidence.The present study provides compelling evidence that both knowledge and attitude play important roles in promoting hearing health and hygiene practices. Specifically, individuals with greater knowledge about hearing health tend to exhibit more positive attitudes towards hearing protection and engage in better behaviors to protect their hearing. Thus, enhancing people’s knowledge of hearing health represents a potentially effective strategy to prevent hearing loss and related problems ,37.The results suggest that educational programs can be made more efficient by focusing on specific aspects of hearing health, particularly in older populations with smoking habits and lower educational attainment. Furthermore, interventions that address attitudes towards hearing health are likely to be even more effective in promoting good hearing hygiene practices. These interventions should be targeted towards high-risk populations such as men, smokers, and individuals with low educational levels who exhibit worse attitudes towards hearing health.Improving knowledge and attitudes towards hearing health can promote better hearing hygiene practices and prevent hearing loss, especially in vulnerable populations. Therefore, public health policies that aim to promote hearing health and prevent hearing-related disabilities should prioritize the development and implementation of evidence-based educational interventions tailored to the specific needs of different population groups. By addressing knowledge gaps and promoting positive attitudes towards hearing health, these interventions could help improve hearing-related behaviors and prevent hearing loss in the long run.Raising awareness about hearing health is an urgent and critical need that demands immediate attention. The study has shed light on important factors associated with better knowledge, attitudes, and behaviors towards hearing health. Younger age, being single, and higher education attainment were found to be significantly correlated with improved knowledge about hearing health. Similarly, positive attitudes towards hearing health were associated with non-smoking habits and better knowledge on the subject. Additionally, positive behaviors towards hearing health were correlated with older age, female gender, and a good understanding of hearing health.These findings, aligning with the study’s aim, hold substantial significance for assessing hearing behaviors and carry important implications for public health policies. The data gathered can be instrumental in designing targeted interventions to enhance hearing health and address issues related to hearing loss. By implementing such policies, we can effectively improve overall hearing health and well-being for individuals and communities alike. It is evident that addressing hearing health should be prioritized in public health agendas to prevent and manage hearing-related challenges effectively.


Hearing loss in the elderly is a very common disease: it is estimated to affect up to a third of the population aged 65 years or more, and 50% of people over 75 years old. There is a growing amount of data concerning the association between hearing loss and cognitive decline. Various possible mechanisms at the basis of this association have been proposed, such as the “common cause hypothesis,” the “cascade hypothesis,” and the “cognitive load hypothesis.”Critically reviewing the data is essential to highlight the features of the relationship between hearing loss and cognitive decline. Most of the hearing tests available should take into account that dementia or even just mild cognitive impairment (MCI) may lead to poor performance during examination. On the other hand, clinicians should also remember that tests used to assess cognitive function require an adequate hearing capacity.In this article we propose to analyze current diagnostic tests, treatment options, auditory processing, and rehabilitation strategies for hearing loss in the elderly in order to facilitate the management of this handicap in this fragile population. Hearing loss in the elderly is a very common disease: it is estimated to affect up to a third of the population aged 65 years or more , and 50%Although the association between hearing loss and cognitive decline is solidly established, critically reviewing the data is key in highlighting the features of the relationship between the two conditions. In a recent meta-analysis , the autMoreover, many previous studies have only assessed the presence of full-blown dementia in association with hearing loss, while nowadays there is growing interest in the stages that precede dementia, that are collectively called “mild cognitive impairment” (MCI). The main reason is that in this stage of cognitive decline, interventions aiming to slow its development seem to be more effective. Clinical tools that are commonly used to screen the presence of dementia are far less capable of detecting MCI: the mini-mental-state examination (MMSE), which has been the most widely used screening tool for cognitive impairment, is currently undergoing examination due to its very low sensitivity in detecting MCI .Lastly, two important aspects must be taken into consideration. Firstly, nearly all the tests used to assess cognitive function require an adequate hearing capacity, otherwise cognitive impairment, especially in comprehension, may be overestimated; secondly, cognitive assessment tests and hearing examination require the patient’s attention and collaboration to complete the required tasks, which are often very difficult for an old patient. Therefore, in subsequent tasks, cognitive weariness may arise and be added to the overall stress of the clinical examination, consequently modifying the overall outcome of the tests.In adults and in the elderly the diagnosis of hearing loss is not particularly challenging, especially if the patient is cooperative. Common and widely used hearing assessment tools are pure tone audiometry and speech audiometry. First of all, patients are examined via otoscopy in order to exclude any visible obstacle or disease that may impair hearing.Pure tone audiometry consists in a psycho-acoustic test in which patients, in a sound-proof booth, are asked to raise a hand or press a button when they hear a sound presented in earphones or with a free speaker in the booth (free-field pure tone audiometry). Each sound presented is a pure tone of a specific frequency and can be modulated in intensity level, measured in dB hearing level (HL), a unit of measurement which takes into account the different sensitivity of the ear for different frequencies and normalizes the value. Sound can be given in a single ear at a time, and if the response threshold of the two ears shows a consistent difference, masking may be necessary. Masking consists in providing a continuous sound in the better-hearing ear in order to avoid that a high intensity sound presented in the worse ear is heard with the contralateral ear (via bone conduction). Also, sound can be provided by a bone vibrator positioned behind the ear, to assess the bone conduction threshold, as opposed to the air conduction threshold provided by the earphone and free-field audiogram. Air conduction assesses the functioning of all the parts of the ear , whereas bone conduction bypasses the external and middle ear and directly stimulates the inner ear. Differences between the two thresholds may imply an underlying condition of the external or middle ear, such as otosclerosis, otitis media, or ossicular malformations.Speech audiometry is used to assess the actual comprehension of speech: words instead of pure tones are presented to the patient, who must repeat them correctly. Different lists of words are presented at different intensity levels, and the percentage of correctly reported words is registered. Then, three intensity level thresholds are reported: the detection threshold, which represents the level at which the subject hears something, but he/she is not able to provide any correct word, the recognition threshold, which is when the patient identifies 50% of the correct answers, and the intelligibility threshold, when all the answers are correct. Since intelligibility and even recognition thresholds may sometimes not be reachable, another value considered is the word recognition score, which represents the maximum percentage of correct word identification reached by the patient. Speech audiometry is influenced far more by the cognitive status of the patient because it is a more difficult task than pure tone audiometry, and also by the patient's proficiency in the language used for the test.In addition to these two traditional tests, in the last few years the International Matrix Sentence Test (IMST) has been implemented in clinical practice in many Audiology Clinics. Since both of the previous tests are performed in a silent booth, they do not accurately represent the real-life situation of the patient, because the acoustic environment of everyday tasks is far richer in noise and other competing signals. Speech-in-noise comprehension deterioration seems to be one of the first signals of hearing loss, especially in the elderly, and patients in the Audiology Clinic frequently complain of this symptom. The IMST test tries to reproduce these conditions in the clinic: the automated system generates 5-word sentences that are grammatically correct but semantically unpredictable and presents them to the patient together with a noise at different sound-to-noise ratios (SNR). Patients must repeat all the words that they can identify, and the system automatically changes SNR and presents another sentence. At the end of the exam, the test shows the minimum SNR value that allows the patient to correctly repeat at least 50% of words. Normal values differ between languages, and language proficiency greatly influences this exam as well.Alongside this standard clinical evaluation, patients may require electrophysiological exams, such as auditory brainstem evoked potentials (ABR), or radiological imaging , according to the characteristics of each case. ABR is an objective evaluation of the auditory pathway function from the auditory nerve to the mesencephalon. Despite the ABR not being used in routine clinical practice to evaluate elderly hearing loss, it may be useful in assessing the residual neurosensorial threshold in patients who do not fully cooperate. Aging reduces amplitudes of all principal ABR peaks, reducing the numbers and/or the synchrony of contributing units in the auditory nerve and cochlear nucleus . What reIn the animal model, it seems that neural inhibition is progressively reduced with aging at the level of the midbrain. This phenomenon seems to explain the subsistence of the late waves of the ABR, while aging acts progressively on the loss of the peripheral synapsis. These electrophysiological mechanisms might be the explanation of the age-related progressive decrease in the temporal resolution and speech discrimination tasks even in the “normal hearing” elderly  and in some cases to ones that can cause severe complications (chronic otitis media). Therefore, in some cases surgery might even worsen the hearing status, due to the need to remove the external or middle ear structures that contribute to the transmission of sound to the inner ear. Hearing aids are commonly suggested or prescribed by the physician when the hearing threshold significantly impairs the speech comprehension in everyday life. Hearing aid configuration and fitting is provided by the audiologist, who adjusts the device according to the patient’s audiogram and needs. Hearing aids have become more and more sophisticated and technologically advanced in the last few years, providing a great variety of possibilities in sound amplification, compression, and probably most of all in sound pre-processing: scene analysis to reduce noise, directional microphones, and connectivity accessories have greatly improved hearing aid effectiveness, but have also raised costs. In some countries hearing aid provision is partially or completely paid for by the health care system but in some others it is not, or not completely, potentially preventing access to these devices for lower income families. It is therefore important that the choice of a hearing device is adapted not only to the patient’s hearing status/necessities but also to the actual socio-economic conditions.In case of severe to profound hearing loss, amplification by means of hearing aids may not be sufficient to guarantee a good auditory performance, making the cochlear implant the best choice for these patients. Cochlear implants were first developed in the 1960 s . Speech In some cases, patients who come to the Audiology Clinic may complain of specific hearing problems: difficulties in hearing in noisy environments, in hearing people that talk fast or even “hearing without understanding,” meaning that they can hear the sound itself, but not the information it carries. The pure tone hearing threshold in these patients often shows mild or moderate hearing loss, in contrast with a poor performance at the IMST or even at the speech audiometry. In these cases, rather than a sensory impairment, hearing difficulties are ascribable to an altered processing of the auditory information. Sound contains various types of information: where the sound comes from , how the sound changes in time , and pitch and timbre contents . All these characteristics are encoded by the hearing system and analyzed by the central nervous system in order to extract the information. Also, sound comes to the central nervous auditory regions through two ears, requiring neural integration of the two signals to avoid interaural interference.All these functions may be altered in an aging brain, especially when a certain degree of cognitive decline is also present, in particular, when working memory is involved . The evaMany tests that evaluate auditory processing have been developed over time, and each is specific for a particular auditory process.One of the most studied functions, which seems to be related to impaired speech perception when altered , is tempAnother auditory processing function is the ability to distinguish sounds of different frequencies and frequency composition. This ability is called spectral resolution. One of the tests that tries to highlight this function is the spectral ripple test, in which a sound made up of a broad band of frequencies is presented to the patients. In this stimulus the frequency is amplitude modulated. In other words, the relative intensity increases from lower to higher frequencies, reaches a peak, and then decreases, describing various crests, called “ripples.” The number of ripples can be varied in order to obtain sounds with closer or farther crest tips. This particular sound is then presented to the listener, who is asked to discriminate it from a broad band noise or from another spectrally rippled stimulus with a different number of ripples. The ability to distinguish between stimuli with a high and similar number of ripples per octave reflects a good spectral discrimination capability. An association has been reported between spectral ripple test performance and hearing in noisy environments, especially in cochlear implant users . More reLastly, another important aspect of auditory processing is binaural integration. In the presence of inadequate central auditory functioning, the signals coming from both ears may interfere with each other, resulting in a deterioration in auditory perception. To evaluate this aspect, dichotic listening tests are usually implemented. In these tests, the patient is synchronously presented with two different stimuli, one in each ear, and is asked to repeat them. The stimuli used may be phonemes, words, and sentences. A similar test to evaluate binaural integration is the staggered spondaic word test, in which two different two-syllable words are presented one in the right ear and one in the left ear not entirely synchronous: the second syllable of the first word and the first syllable of the second word overlap, thus allowing central cognitive integration in understanding the two words, using the syllables that are not overlapped as semantic cues. When these tests are altered, typically patients show right-ear dominance: the stimulus that is correctly identified is more frequently the one presented in the right ear, which occurs because the pathway to the auditory cortex is more direct for the right ear than for the left. Like the previous test, an altered binaural integration may imply different rehabilitation strategies.Considering the complexity of sound and the high technological development in hearing aids and cochlear implants, highlighting specific auditory central functioning of patients may lead to more tailored and efficient methods of aural rehabilitation, and consequent improvement in hearing and daily life.A patient showing binaural integration impairment, for example, may not benefit from a bilateral hearing aid. Conversely, the patient may get a better advantage from using only a single hearing aid (preferably in the right ear), if the hearing threshold is similar between the two ears. Reduction in spectral resolution may direct the audiologist to specific compression strategies for sounds, even if compression may not work with a perfect spectral resolution, to the point in which traditional analog hearing aids may result similar in hearing outcome than more modern digital ones. Lastly, temporal processing ability decay is probably the most challenging central auditory condition to treat. To properly balance this impairment, a combined cognitive and audiological rehabilitation program could be useful, to implement and train different cognitive strategies capable of reestablishing a hearing that is good enough to sustain social activities in daily life.In general, reduced compliance to hearing aids use is frequently considered a sign of poor cognitive performance or psychological disturbances, but we should consider that hearing difficulties or inadequate hearing aids’ fitting may lead to frustration for the patient. In certain cases, the discomfort can be reduced by a tailored fitting based on an in-depth audiological evaluation, thus facilitating the overall management of fragile patients. In general, a good auditory outcome is not impaired by the age of the patient  or by ho


Multiple bone disorders due to mutations in the human noggin (NOG) causes a variety of phenotypes. Hearing impairment due to stapes ankylosis secondary to bony degeneration is also a feature of these syndromes. We describe the case of an individual in a Japanese family with conductive hearing loss due to stapes ankylosis and hyperopia and dactylosymphysis. We revealed a novel NOG mutation, NM_005450.6:c.222 C > A / p.Tyr74*, and confirmed genetic significance. Additionally, some families reportedly have an autosomal-dominant form of congenital stapes ankylosis3. They describe clinical manifestations and corresponding bone abnormalities, including multiple synostosis, proximal symphalangism, and facial abnormalities. They also list several corresponding NOG gene mutations identified for these genealogy changes. Noggin is a secreted protein encoded by NOG that is essential for normal bone and joint formation in both humans and mice4, and appears to play a regulatory role as a bone morphogenetic protein (BMP) antagonist during joint formation. Mutations in NOG are in multiple autosomal-dominant syndromes that often share symptoms, such as conductive hearing loss, hyperopia, and digital anomalies6. These include stapes ankylosis syndromes such as proximal symphalangism , multiple-synostoses syndrome , stapes ankylosis with broad thumbs and toes , tarsal-carpal coalition syndrome , and brachydactyly type B2 . Currently, similarities and variations in overlapping features have led to the categorization of all these syndromes as NOG-related symphalangism spectrum disorder (NOG-SSD). Here, we describe the pedigree of a Japanese family with inherited stapes ankylosis, hyperopia, and digital anomalies, and show that a novel heterozygous NOG mutation results in NOG-SSD.Stapes ankylosis is characterized by hearing loss due to congenital or acquired stapes fixation. While otosclerosis is the most common progressive conductive hearing loss caused by stapes ankylosis in adults, congenital stapes ankylosis is often difficult to differentiate from otosclerosis if diagnosed later in life. Congenital stapes ankylosis seems to be associated with osteodysplasty, such as osteogenesis imperfecta type I. It may occur as an isolated temporal bone anomaly, such as X-linked stapes fixation with perilymphatic gusher (DFN3)The proband (Case B: III-3) was a 27-year-old woman referred to our hospital due to bilateral hearing loss. She was not administered a newborn hearing screening test but seemed to have been aware of her hearing disability since early childhood and continued to suffer in her job due to hearing difficulties. Pure tone audiometry showed a bilateral conductive hearing loss, especially in the low pitch area. Although tympanometry yielded a type A curve, a stapedial reflex test indicated no response in either ear. A High-resolution computed tomography scan showed no ossicular malformation or inner ear abnormalities.Her medical history and pedigree, including hearing loss, symphalangism, dactylosymphysis, brachydactyly, and hyperopia, were evaluated before surgery. Fig. NOG, we analyzed the NOG-coding region in each case by sequencing genomic DNA. Primer pairs were designed to include the entire protein-coding region consisting of 698 nucleotides, and the NOG-coding region was amplified by polymerase chain reaction using the following primers pairs: NOG (forward), 5'-CTCGGCGTGCTCTCCTC-3'; NOG (reverse), 5' - ATCGATCAAGTGTCCGGGTG-3'. DNA sequencing was performed using the standard protocol of the Applied Biosystems 3130 l gene sequence analyzer . Study participants provided written informed consent. The Ethical Review Committee of the Hiroshima University, Japan, approved the research protocol.Blood samples were obtained from the proband (caseB: III-3) and her mother (caseA:II-2), and DNA was extracted from peripheral lymphocytes using the PAXgene Blood DNA kit . As pedigree and clinical features were suggestive of mutations in Due to significant conductive hearing loss, we performed surgery on her left ear using an endoscope, which revealed ankylosis of the stapes footplate; hence, we performed a stapedotomy. The patient’s hearing threshold improved significantly, and her hearing level has remained stable for >1.5 years after surgery.NOG in the proband (Case B) and in her mother (Case A)  Fig. , which hNOG gene is present on chromosome 17q22, has one exon, and codes a secreted protein, Noggin, that seems to be involved in BMP signaling as an antagonist essential for bone formation in both humans and mice8. BMP promotes mesenchymal cell proliferation and differentiation into chondroblasts and osteoblasts and induces apoptosis during joint formation9.The human 10, e.g., the typical features of SYM1 are narrow proximal interphalangeal joint space and symphalangism of the 4th and/or 5th fingers12. SYM1 is characterized by an autosomal-dominant heritability with minimal genetic heterogeneity, and mutations in NOG are thought to be predominantly responsible for SYM1; nevertheless, other genes such as GDF5 have also been implicated13. Thus, even though our patient presented with conductive hearing loss, a proximal phalangeal fusion of the fingers, and limited range of motion in the shoulder, we considered it reasonable to clinically diagnose her with SYM1 despite the absence of other systemic skeletal abnormalities or ocular symptoms. Additionally, a variety of syndromes, such as SYNS1, TCC, BDB2, SABTT, have been attributed to heterozygous NOG, and are described as subtypes of SSD.NOG mutations have been previously described in the context of multiple bone diseases15. Gong et al. reported that the key features differentiating SYM1 from SYNS1 are characteristic physiognomy, hyperopia, and the absence of cervical vertebral fusion and symphalangism17. Similarly, it is hard to accurately categorize such patients as having a particular disease because, to date, >50 mutations in NOG are reportedly involved in a wide variety of bone development anomalies, as listed by Yuan et al7. Congruently, previous case reports confirm that mutations in the same NOG-coding sequence can lead to various phenotypes within one family21,indicating that disease expression may correlate to either location or type of NOG mutation.Notably, the same variant of NOG can result in dissimilar phenotypes among different families or various affected members of the same familyNOG c.222 C > A/p.Tyr74*. This mutation site is present between c.163 G > T/p.Asp55Tyr and c.328 C > T/p.Gln110*, which, according to Yuan et al.7, are pathognomic for SYM1 and FOP, respectively. Further, as these two mutations reportedly result in a termination codon and consequent degeneration of the noggin protein, a codon in this specific region is expected to be crucial for BMP7 binding; hence, its loss can affect joint morphogenesis. Congruently, evaluation of the pathogenicity of this mutation in “MutationTaster” and “Provean” confirmed its significance, as the results were “Prediction disease causing” and “Deteleous,” respectively. Thus, and under ACMG guidelines, we posit that the c.222 C > A mutation causes a meaningful change in NOG that is pathogenic .We describe the pedigree of a Japanese family with SSD, and analysis of the genetic changes in the proband and her mother revealed a novel NOG. Unlike the NOG mutation reported in SYM 1 and SYNS1, family lineages with stapes ankylosis but no other fusions presumably have a protein with a dysfunctional terminal domain otherwise abundant in cysteine (C). Some pathogenic differences due to cysteine may exist among patients without osseous abnormality.The occurrence of bilateral congenital stapes ankylosis without other anomalies is rare, and it is sometimes not found in mild hearing loss. Further, congenital stapes ankylosis syndrome is difficult to distinguish from otosclerosis when first identified in adults. Thus, as some patients diagnosed with sporadic or non-syndromic familial otosclerosis may indeed have SSD, those with conductive hearing loss should be evaluated for other osseous lesions. The degree of hearing impairment in SSD is different from those described previously, i.e., mild to profound, possibly due to disease progression. Thus, attention must be paid to patients with suspected bilateral conductive hearing loss due to mutations in NOG mutation in a Japanese family, which helped clarify the relationship between phalangeal fusion disease and conductive hearing loss. Apart from genetic counseling, we could also provide beneficial information about progressive hearing loss, which would help affected siblings as they could recover hearing after surgery. Thus, managing patients presenting with bilateral conductive hearing loss requires careful physical evaluation of osteodystrophy based on both past and family medical histories.We identified a novel


Virus infection is one of the most common etiologies of hearing loss. Hearing loss associated with viral infection can be unilateral or bilateral, mild or severe, sudden or progressive, and permanent or recoverable. Many viruses cause hearing loss in adults and children; however, the pathogenesis of hearing loss caused by viral infection is not fully understood. This review describes cytomegalovirus, the most common virus causing hearing loss, and other reported hearing loss-related viruses. We hope to provide a detailed description of pathogenic characteristics and research progress on pathology, hearing phenotypes, possible associated mechanisms, treatment, and prevention measures. This review aims to provide diagnostic and treatment assistance to clinical workers. Hearing loss (HL) is one of the most common sensory disorders in humans. According to the World Hearing Report released by the World Health Organization (WHO), 1.5 billion people worldwide suffer from varying degrees of hearing loss , and eveMany viruses are responsible for congenital or acquired hearing loss; additionally, viruses may cause otosclerosis, and conductive hearing loss has also been reported . HearingIn this review, we describe reported viruses related with hearing loss, along with their pathology, hearing phenotypes, possible associated mechanisms, treatment, and prevention measures, which may be helpful for researchers and clinical doctors to increase understanding about pathophysiological of virus-associated hearing loss.Herpesviridae. The modes of transmission of CMV include vertical transmission ) has been evaluated as a potential therapy to prevent vertical transmission in women with primary CMV infection during pregnancy. However, the therapeutic efficacy of HIG is still controversial. Recent studies have shown that HIG is ineffective in reducing the risk of CMV in women with primary infection during pregnancy . A prospp-value = 0.002; OR 10.26 ) ) . In the  81.92]) . A retro 81.92]) . CompareHerpesviridae. The incubation period of HSV is two to twelve days. HSV has two serotypes, HSV-1 and HSV-2. HSV-1 transmits mainly through close contact [Herpes simplex virus (HSV) belongs to the family  contact , and HSV contact . HSV-1 i contact . The rea contact . In 2016 contact . In-utero infection and HSV culture-positive postpartum infection remain risk indicators for permanent congenital, delayed, or progressive hearing loss in childhood, and such children should have a routine early hearing test at the age of 24–30 months . The repHSV antigen and virus capsid could be detected in the cochlea of virus-infected animal models, while tympanum, vestibular fibrosis, outer hair cell loss, and vascular atrophy were observed in the HSV-infected cochlea . MorpholAll pregnant women with primary HSV infection should be offered antiviral therapy regardless of timing of occurrence during pregnancy . SuppresVaricella-zoster virus (VZV) is a pathogen that causes chickenpox and herpes zoster. VZV, HSV-1, and HSV-2 belong to the alpha subfamily of herpesviruses, thus VZV is also known as human herpesvirus type 3. The host range of VZV is highly limited to humans. In a systematic review of research conducted from 2002 to 2018, researchers estimated its cumulative incidence to be about 2.9–19.5 cases per 1000 people, most of whom were women .VZV can spread via droplets or directly through contact with fluid in vesicles, enter the body through the respiratory tract, spread rapidly from the pharyngeal lymphatic tissue to circulating T lymphocytes, and cause viremia . After 1Reactivation of VZV has been reported as a cause of SSNHL ,73,74. LHistopathological studies have shown inflammatory cell infiltration in the vestibular and cochlear ganglia and degeneration of the inner ear end organs in patients with RHS ,80. AlthThe diagnosis of RHS and HZO usually depends on history, physical examination, and a serological test or PCR for VZV in the blood or cerebrospinal fluid. The standard therapy for VZV is acyclovir or valganciclovir . In some®  , based on the VZV attenuated Oka strain, and the other is a recombinant, adjuvanted VZV glycoprotein E subunit vaccine called Shingrix® . Shingrix® is not approved for the prevention of chickenpox in children. A VZV immunoglobulin preparation, VariZIG® , can be used for prophylaxis in groups at high risk of severe disease that lack immunity to VZV and are not suited to receive the VZV vaccine.For the prevention of herpes zoster, two vaccines are currently available. One is a live-attenuated VZV vaccine called VarivaxEpstein-Barr virus (EBV) belongs to the herpesvirus family of viruses. EBV contains double-stranded linear DNA of 170–175 kb, which is transmitted mainly via the salivary transfer of EBV-infected B cells and by aerosol . EBV is EBV is usually spread through contact with respiratory secretions . The symEBV detection in SSNHL cases has been reported sporadically over the years. Williams et al. reported that evidence of altered cell-mediated responses to Epstein-Barr virus antigens have been found in three young patients with sudden permanent hearing loss one to four months before the onset of hearing loss . Erzurum4 IU/mL (reference range: undetectable) [Buza et al. reported a case of a young man diagnosed with EBV-associated hearing loss for four years . Wong etectable) . The patectable) . In 2019ectable) . Williamectable) . Anotherectable) . In addiectable) .Coronaviridae and is an enveloped virus containing a single-stranded, positive-sense RNA genome (+ssRNA) [Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to the family of (+ssRNA) . SARS-Co(+ssRNA) . The maiThe common initial symptoms of SARS-CoV-2 infection include fever, cough, sore throat, headache, muscle pain, diarrhea, and difficulty breathing. It mainly affects the human respiratory system, but it can also harm the central nervous, cardiovascular, gastrointestinal, hepatobiliary, and renal systems . In rareMuch of the literature has reported the relationship between SARS-CoV-2 and sudden sensorineural hearing loss (SSNHL); it spans the period from 2020 to 2022, is not limited to a particular country or region, and suggests that many SARS-CoV-2 variants can cause otological symptoms. Ong et al. reported that 68% of patients presenting with otological symptoms began to experience hearing loss within one month of the onset of the typical symptoms or diagnosis of SARS-CoV-2 infection, and 23.1% presented with SSNHL . Of thosThe mechanism of hearing loss caused by SARS-CoV-2 is still not clear. It has been reported that SARS-CoV-2 may cause hearing loss by damaging the auditory center of the brain and cochlea. The spike protein of SARS-CoV-2 binds to its host cell receptor angiotensin-converting enzyme 2 (ACE2) and is hydrolyzed and cleaved by the transmembrane protease serine 2 (TMPRSS2) protein, which pulls the virus and host membrane together to initiate the fusion of the virus and cell membrane and facilitate viral entry . The ampKandimalla et al. have summarized various vaccines’ epidemiology, effectiveness, and status, which we will not repeat here . SARS-CoStudies have shown a risk of vertical transmission of SARS-CoV-2 . The ACESARS-CoV-2 is still prevalent worldwide, and there is no specific treatment for SARS-CoV-2 -related hearing loss. Systemic supportive therapy and oral, intravenous, and intra-drum steroid injections play a role to some extent, but some patients still fail to experience significant efficacy .Hepadnaviridae and genus Orthohepadnavirus, is a global public health concern. The number of HBV carriers in the world is estimated to be as high as 370 million. China is a country with a high endemicity of hepatitis B, and the overall population HBV carrier rate is about 7.18% [Infection with hepatitis B virus (HBV), which belongs to the family ut 7.18% ,150. Theut 7.18% . The number of SNHL in HBV-infected patients is approximately 0.92 per 10,000 people per year . Nasab eSimilarly, Tsai et al. selected 279 patients from an HBV cohort and 845 patients from a control cohort without HBV infection in Taiwan to investigate the risk of developing SSNHL in patients with HBV. The study showed that the incidence of SSNHL was 1.33 times higher in the HBV group than in the control group . Islam ePolyarteritis nodosa caused by HBV infection may be the cause of hearing loss in HBV patients . HoweverOrthoretrovirinae of the family Retroviridae. 650,000 people died of acquired immune deficiency syndrome (AIDS) in 2021, with about 1.5 million new HIV infections [Human immunodeficiency virus (HIV) is a lentivirus belonging to the subfamily fections . The maiThere is a significant difference in the prevalence of hearing loss between HIV-infected and HIV-negative people. About 13.1–38.8% of HIV-positive children have some kind of hearing loss ,163,164,Hearing loss related to HIV infection may result from direct damage by the virus or auditory pathway damage caused by inflammation; ototoxic drugs may also be related to hearing loss . Jr et aHIV infection-induced conductive hearing loss can be corrected with hearing aids, but infectious complications and low immunity may limit their application. For patients with HIV infection related SNHL, after evaluating their surgical tolerance, hearing can be improved with cochlear implantation . AlthougRubivirus, family Togaviridae, transmitted via respiratory droplets and direct contact. Children’s rubella mainly manifests as fever and a mild measles-like rash, with retroauricular and suboccipital lymph node swelling, while infection symptoms are more severe in adults. In addition to the rash, arthritis and joint pain, thrombocytopenia, and encephalitis occur after the rash. Rubella virus infection causes the most harm through vertical transmission. In the first 12 weeks of pregnancy, the risk of congenital infection and congenital disabilities is the highest [Rubella virus is a member of genus  highest , causing highest . Before  highest ; such chThe literature shows that 21% of hearing loss among children in Brazil is from the vertical transmission of rubella virus, and the incidence of deafness in children whose mothers have rubella during pregnancy is close to 30%, manifested as bilateral profound hearing loss in most cases . In addiThere is currently no specific antiviral therapy for rubella, but it can be prevented by vaccination, which is vital given the high incidence of deafness among the children of rubella-infected mothers during pregnancy. By the end of 2020, the rubella vaccine had been introduced in 173 WHO member states, with an estimated global coverage of 70% .It is recommended that infant hearing screening be performed, preferably in the first month of life, if mothers acquire a primary infection during pregnancy. Treatment of hearing impairment includes the use of hearing aids or cochlear implants .Flaviviridae family. ZIKV is mainly transmitted through the bite of infected mosquitoes, with Aedes aegypti and Aedes albopictus being the main vectors [Zika virus (ZIKV) is an arthropod-borne arbovirus belonging to the  vectors ,186. The vectors . ZIKV is vectors , and is  vectors . Much evidence of the link between ZIKV and hearing loss emerged during the ZIKV outbreak in Brazil that began in May 2015. Leal et al. assessed hearing in 70 children with microcephaly following ZIKV infection, 5.8% of whom developed SNHL (excluding one child using the ototoxic drug kanamycin), ranging from mild to severe and being unilateral or bilateral. SNHL occurs predominantly in infants whose mothers developed a rash in the first trimester of pregnancy, with all infants with profound hearing loss having severe microcephaly . Lage etThe gold-standard method for diagnosing ZIKV infection is the real-time polymerase chain reaction (RT-PCR) test of serum, saliva, or urine during the first few days of acute infection . After tFlavivirus. WNV is rarely transmitted from person to person. It spreads mainly through the bite of infected mosquitoes, and a minimal number of people are infected through organ transplants, blood transfusions, and breast milk [West Nile virus (WNV) is a member of the genus ast milk . It has ast milk . About 2ast milk .Hearing loss is very rare in patients infected with West Nile virus. The first case of WNV infection with deafness was reported in 2006 by McBride et al. A 57-year-old white woman with WNV infection was diagnosed with SNHL of moderate severity. During hospitalization, the patient received medications, such as piperacillin/tazobactam, vancomycin, prednisone, azathioprine, and acetaminophen, as well as supportive treatments, such as intravenous fluids, nutritional support, and incentive spirometry, which resulted in hearing improvement . CasettaWNV can be tested in different ways, such as with ELISA for antibody testing, RT-PCR for virus detection, or cell culture for virus isolation. For symptomatic patients, the primary treatment is symptomatic supportive treatment .Enterovirus belongs to the picornavirus family and is divided into 12 types: enterovirus A to H, enterovirus J, and rhinovirus A to C. There are many serotypes of EVs due to the mutation of viral structural proteins. The serotypes that cause human diseases are formally divided into five categories: poliovirus, coxsackievirus, rhinovirus, enterovirus, and echovirus [Human enteroviruses (EVs) were originally classified according to their pathogenicity. chovirus . EVs maychovirus . Schattner et al. reported on a 27-year-old male patient with sudden severe bilateral hearing loss and tinnitus. PTA showed that the right ear’s hearing threshold was 60 dB, that of the left ear 65 dB, and the discrimination score was 76%. All measuring frequencies from 250 to 8000 Hz were affected. Brain imaging (CT contrast and MRI gadolinium), cerebrospinal fluid biochemistry, and cytology were normal. The patient received methylprednisolone pulse therapy (1 g/day intravenous injection lasting for three days) and then used prednisone . After five days, the patient’s hearing improved, with speech reception thresholds of 15 dB (right ear) and 25 dB (left ear) at all measured frequencies and 100% discrimination. EV (echovirus type 4) was subsequently cultivated from the stool of the patient . Thus, sSome studies have shown the ability of various gut viruses to invade the cochlea and their correlation with hearing loss. A complete absence of the cochlear nerves and substantially reduced peripheral and central axes with loss of some inner hair cells was observed in a study carried out on temporal bone specimens of 26-month-old white female with a paralytic syndrome clinically and pathologically identical to poliomyelitis . The coxMastomys natalensis rodent [Lassa virus (LASV) is the causative agent of Lassa fever, a common disease in West Africa . The nats rodent . Its traThe incubation period for Lassa fever is 2 to 21 days. About 80% of people infected with LASV are asymptomatic, and mild symptoms can be relieved within a week . In termIn a study by Mateer et al., an average of 33.2% of Lassa fever survivors developed unilateral or bilateral SNHL, and these SNHL cases were identified at 10 to 15 days after the onset of Lassa fever symptoms or at the convalescent stage of the disease . In a caRibavirin has been considered the standard treatment for many years . RibavirOrthomyxoviridae and has a segmented negative-sense, single-stranded RNA genome. The main symptoms of infection are fever, cough, sore throat, and diarrhea and other gastrointestinal symptoms [Influenza A virus belongs to family symptoms . Blum et al. reported, for the first time, that a 73-year-old male patient developed hearing loss after being infected with the H1N1 variant of influenza A. The patient was treated with high-dose prednisolone (60 mg per day). After 24 h, hearing improved, the sensation of fullness was reduced, and the patient felt well and did not complain of discomfort . AlsanosH1N1 is sensitive to neuraminidase inhibitors, and mainly oseltamivir or zanamivir are used for antiviral therapy, in addition to supportive therapy . AccordiParamyxoviridae. Humans are the only reservoir for the mumps virus. The virus is mainly transmitted through droplets. The virus first proliferates in the epithelial cells of the nose or upper respiratory tract and then enters the blood to cause viremia, which spreads to the salivary glands and other organs [Mumps virus is an enveloped single-stranded virus belonging to the family r organs . This car organs . The incr organs . The disSNHL is a common complication of mumps , and theRelevant studies have shown that, when the mumps virus is inoculated into mouse cerebrospinal fluid or immature cochlea, viral antigens can be observed in stria vascularis, vestibular membrane, and supporting cells . Tanaka The clinical diagnosis of Mumps virus is based on the acute attack of the unilateral or bilateral parotid gland or other salivary gland swellings, which lasts for two days or more, and no other apparent cause is found . SwellinThere is currently no specific antiviral therapy for mumps, and interventions are mainly based on relieving clinical symptoms and treating complications. For the treatment of hearing loss, steroid hormones, vitamin B, and hyperbaric oxygen therapy may be ineffective in most patients. In the study of Morita et al., only one patient showed complete hearing recovery. While patients with total bilateral deafness received cochlear implants and achieved good results in speech perception, and a patient with unilateral deafness improved directional hearing by using audiphones . Noda etParamyxoviridae, a family of measles viruses and mumps. Measles is a highly contagious, acute infectious disease to which the population is universally susceptible, most commonly in infants, adults over 20 years of age, pregnant women, and immunocompromised or malnourished individuals, especially children who are vitamin A-deficient [Measles virus is a member of the genus eficient . The Meaeficient .Measles is an acute febrile disease associated with characteristic erythematous papules. The disease begins with fever and is usually accompanied by at least one of the symptoms of cough, rhinitis, and conjunctivitis. The virus can proliferate in the dermis and form a characteristic Koplik spot. Koplik spots usually appear as bluish-white spots, slightly raised with a diameter of approximately 2 to 3 mm on an erythematous base on the buccal mucosa opposite the first molar. The Koplik spot can serve as a characteristic sign and provide a clinical diagnosis of measles one to two days prior to the appearance of the rash. After three to four days of fever, the patient develops a characteristic rice bran-like rash that spreads throughout the body and lasts about one week . Most chIt is estimated that measles infection accounted for 5–10% of all cases of severe bilateral SHNL before the introduction of the live measles vaccine . MeaslesThe most common laboratory method to confirm measles virus infection is the detection of measles virus-specific IgM in serum or plasma. However, measles virus-specific IgM may only be detected four or more days after the onset of the rash, leading to false-negative results if samples are collected too early . ConfirmLive attenuated measles virus vaccine has the potential to cause HL. There is one case suffer from HL per 6–8 million doses based on the annual use of MMR vaccine . The heaAfter measles infection, adults or children with normal immunity should be given supportive therapy to correct or prevent dehydration and nutritional deficiencies. At the same time, secondary bacterial infections should be promptly detected and treated, and patients should be provided with vitamin A. Antibiotics are applicable when there is clinical evidence of infection, but preventive use of antibiotics is not recommended . PatientLymphocytic choriomeningitis mammarenavirus (LCMV) belong to the Arenaviridea family Mammavirus. Human infection occurs through mucosal exposure to aerosols contaminated with rodent excreta, direct contact with rodents, or through rodent bites [nt bites ; organ tnt bites  and vertnt bites  are alsont bites . In rarent bites .Fetal LCMV infection may occur during symptomatic maternal viremia, mainly in the first and second trimesters of pregnancy, and LCMV has embryonic teratogenicity. Ninety percent of the infants surveyed by Barton et al. developed chorioretinitis, 91.7% of infants who had undergone imaging had hydrocephalus or periventricular calcification, and 86% had long-term neurological abnormalities during follow-up, including microcephaly, moderate to severe mental retardation, seizures, and visual impairment. Although the incidence of hearing impairment is low, such cases are still reported . Currently, the primary detection method of LCMV is the antibody titer of acute and convalescent serum samples, while detecting specific IgM in blood and cerebrospinal fluid is of diagnostic value . Both enAntiviral therapy is limited. Ribavirin has been proven effective against LCMV in vitro, but there is still a lack of solid evidence treating of human LCMV infection . FarraviPhlebovirus, family Phenuiviridae, order Bunyavirales, is a kind of arbovirus closely related to the distribution of insect vectors [Toscana virus (TOSV), belonging to the genus  vectors . TOSV is vectors . An 82-y vectors .Although the distribution of TOSV is concentrated, there are still imported cases in other areas. The key to diagnosis is to consider the patient’s symptoms and sojourn history. TOSV infection can be diagnosed directly through identification of the virus by molecular detection and/or serologically through the detection of specific antibodies. There are already several commercial test kits available to detect TOSV. Viruses can be isolated from blood or cerebrospinal fluid during the acute phase of the disease, but detection of the TOSV genome using real-time RT-PCR is currently the reference test for diagnostic purposes .Researchers believe that the three mechanisms of hearing loss caused by viral infection are: neuritis caused by viral involvement of cochlear nerves, cochlear inflammation caused by viruses, and stress response caused by cross-reaction of inner ear antigens to viral infection . Prevention is essential to reduce the incidence of viral infections and complications. Safe, effective, and inexpensive vaccines are an essential means of controlling the spread of the virus. However, in many less developed countries, the vaccination rate is still low, large-scale herd immunity cannot be formed, and small-scale or large-scale outbreaks remain. Even in developed countries, there are often imported cases. In addition, vaccine prevention and control are difficult to achieve for sudden outbreaks, large-scale epidemics, and rapidly mutating viruses, such as SARS-CoV-2. Therefore, there is a need to develop drug treatment regimens for virus-induced hearing loss.Unfortunately, the effect of antiviral therapy on virus-associated congenital hearing loss is still controversial. After cessation of antiviral therapy, viral replication may rebound with hearing loss. In the actual diagnosis and treatment of SSNHL patients, virus screening or antiviral treatment is usually not considered. For congenital deafness, it is difficult to determine whether the infant’s hearing loss is caused by congenital CMV infection, as CMV screening is not included in the newborn hearing screening. Delayed testing can only speculate whether the newborn has been infected with CMV, but cannot prove that CMV infection caused hearing loss, which makes it difficult for doctors to choose whether to use antiviral therapy or not and may miss the best treatment opportunity. In addition, it is difficult to judge whether the virus content in the blood can represent the virus content in the cochlea and predict the severity of the hearing loss, as the virus content in each system tissue of an infected person is different. More efficient tests are needed to assess the relationship between viral infection and hearing loss severity. This review summarizes the viruses reported to cause hearing loss, including their epidemiological characteristics, hearing phenotypes, and possible pathogenesis. Further research is needed to elucidate the precise etiopathogenesis of virus-induced hearing loss to better understand of the disease.


Adult-onset progressive hearing loss is a common, complex disease with a strong genetic component. Although to date over 150 genes have been identified as contributing to human hearing loss, many more remain to be discovered, as does most of the underlying genetic diversity. Many different variants have been found to underlie adult-onset hearing loss, but they tend to be rare variants with a high impact upon the gene product. It is likely that combinations of more common, lower impact variants also play a role in the prevalence of the disease.Here we present our exome study of hearing loss in a cohort of 532 older adult volunteers with extensive phenotypic data, including 99 older adults with normal hearing, an important control set. Firstly, we carried out an outlier analysis to identify genes with a high variant load in older adults with hearing loss compared to those with normal hearing. Secondly, we used audiometric threshold data to identify individual variants which appear to contribute to different threshold values. We followed up these analyses in a second cohort. Using these approaches, we identified genes and variants linked to better hearing as well as those linked to worse hearing.These analyses identified some known deafness genes, demonstrating proof of principle of our approach. However, most of the candidate genes are novel associations with hearing loss. While the results support the suggestion that genes responsible for severe deafness may also be involved in milder hearing loss, they also suggest that there are many more genes involved in hearing which remain to be identified. Our candidate gene lists may provide useful starting points for improved diagnosis and drug development. Hearing loss is a common, complex condition with a strong genetic component. More than 700 genes have been found to underlie Mendelian hearing loss in humans and/or mice (reviewed in ), but laMIR96 , but th6  Institutional Review Board (for the MUSC cohort) and Guys & St Thomas’ Trust (GSTT) Ethics Committee (for the TwinsUK cohort).The primary cohort consisted of 532 volunteers enrolled in an ongoing longitudinal study of age-related hearing loss at MUSC, dating from 1987, described in detail in For the follow-up cohort, we selected 159 participants from the TwinsUK study based on age (55 years and older), self-reported ethnicity (“White”), and availability of both exome and pure-tone audiometry data. The pure-tone audiometry data collection has previously been described ; brieflyPhenotype cohorts were formed based on selection criteria to define individuals with representative metabolic or sensory hearing losses, as well as normal hearing, to enable comparisons between specific phenotypes. Audiograms were classified into one of three main categories  based on the estimated metabolic and sensory components of the observed hearing loss . The typTo classify these cohorts, first, metabolic and sensory estimates and line-fit error were calculated for each of the right/left pairs of audiograms. Second, poorly fit audiograms were excluded from classification using the criterion of line-fit error ≥15 dB, which identifies audiograms with configurations inconsistent with age-related hearing loss . These rejected audiograms are referred to as “Unselected” below. Third, a set of simple rules (below) using the metabolic and sensory estimates were applied to classify cases into the four remaining categories.Using this approach, the Older-Normal category was defined by cases with summed metabolic + sensory estimates that were <20 dB HL, with <10 dB difference in the estimates between ears. The Metabolic category was selected from the remaining cases  with metabolic estimates ≥20 dB, ear asymmetries in the metabolic estimate ≤15 dB, sensory estimates <20 dB, and metabolic > sensory estimates. The Sensory category was selected from the remaining cases  with sensory estimates ≥15 dB, ear asymmetries in the sensory estimate ≤20 dB, metabolic estimates <25 dB, and sensory > metabolic estimates. Finally, the remaining cases  were less clearly representative of metabolic or sensory hearing loss, and were labelled Unclassified. After completing the rule-based selection, all audiograms in each category were reviewed by eye; a few anomalous cases were removed and a few cases were added based on consistency with a category. There were a total of 1-10 manual additions or removals for each category ,2.Libraries for exome sequencing of the MUSC cohort were prepared using the Agilent SureSelect X2 Target Enrichment System (version 5) and the Agilent SureSelect Human All Exon V5 kit, which included 5’ and 3’ UTRs. DNA was sheared using the Covaris S220 focused ultrasonicator. Libraries were sequenced on the Illumina HiSeq 2500.The exome sequencing of the Twins UK cohort has been previously described . BrieflyFor both cohorts, fastq files were aligned to GRCh38 using Hisat2.0 , followihttps://gatk.broadinstitute.org/hc/en-us/sections/360007226651-Best-Practices-Workflows). BCFtools calls were filtered using vcfutils  and 281,261 (TwinsUK) variants passed these quality filters, and were then tested for excess heterozygosity using the R HardyWeinberg package  to identMitochondrial variants were called using GATK Mutect2  and filtGenomic and mitochondrial variants were annotated using the Ensembl Variant Effect Predictor (VEP) v100 . AnnotatChosen variants from the MUSC cohort were resequenced using Sanger sequencing . Primers for Sanger sequencing were designed using primer3 , and seqFour comparisons were carried out: Older-Normal hearing to all hearing loss (including Unselected and Unclassified participants); Older-Normal hearing to Metabolic hearing loss; Older-Normal hearing to Sensory hearing loss; and Metabolic hearing loss to Sensory hearing loss. 12176 genes  had at least one variant called in one sample, and were assessed in each analysis. For each comparison, a linear regression was carried out on the total number of variants per gene per group. In the first three comparisons, the number of variants in the Older-Normal hearing group was used to predict the expected number of variants in the hearing loss group, and in the fourth comparison, the number of variants in the Metabolic hearing loss group was used to predict the expected number of variants in the Sensory hearing loss group. The residuals (the difference between the observed and predicted variant load for each gene) were used to determine the outlier genes. Briefly, the first (Q1) and third (Q3) quartile and the interquartile distance D (Q3-Q1) were calculated for each regression’s residuals, and outlier genes were defined as those with residuals > Q3 + 6D and those with residuals < Q1 – 6D . Hypergehereditaryhearingloss.org/) and genes which, when mutated, result in altered hearing thresholds in mutant mice, as reported by the International Mouse Phenotyping Consortium (www.mousephenotype.org) . This list is an update of that reported in our previous study , expression levels were averaged. The expression of each gene was plotted in 12 different cell types, as defined by the original experiments. Eleven marker genes were plotted for comparison . These are known marker genes for their cell types, with the exception of Gm525, which was chosen based on its fibrocyte-specific expression at P30 . Datasegear.org , P15 , and exn at P30 .github.com/moraglewis/ThreADD.To assess each individual variant, audiograms were plotted with participants separated into groups by genotype and sex. Variants with fewer than 5 people/group in all alternate allele groups were excluded. Each stimulus frequency was tested for a difference of 20 dB or more in average thresholds, and a maximum limit was imposed on standard deviation in the alternate allele group which differed by stimulus frequency  to prioritise variants associated with consistent threshold patterns. All variants where at least two stimulus frequencies in each ear passed this filter were put through to permutation testing. Permutations  were then carried out, with individuals from the cohort assigned randomly to groups of the same number and sex, to assess the likelihood that those stimulus frequencies passing the filter were observed by chance. If more than 1000 random shufflings produced a similar result, the variant was rejected. This was carried out automatically, and the scripts can be found at Our primary cohort consisted of 532 participants; 292 female and 240 male participants, with an overall average age of 72.25 years . 62 women and 182 men reported a positive noise history . 99 partThere were 159 female participants from the TwinsUK cohort meeting our requirements, including ten dizygotic twin pairs. There were no monozygotic twin pairs, and no other relatedness was reported. The overall mean age was 64.82 years. There were few positive responses to questions about noise exposure in work or leisure activities, so no participants were classified as having a positive noise history. We carried out the same ancestry analysis on these 159 participants, and found they also had a non-Finnish European ancestry, and like the MUSC cohort, they were most similar to the “British in England and Scotland” and “Utah residents with Northern and Western European ancestry” sub-populations from the 1000 Genomes .One twin of each pair was removed from the cohort; where twins were classified into the same category, the removed twin was chosen at random (6 pairs). For 3 pairs, one twin was classified as Older-Normal or Metabolic, with the other either Unclassified or Unselected; in those cases, the Unclassified or Unselected twin was removed. The last pair consisted of one twin classified as Older-Normal and one classified as Metabolic; both were removed for the outlier analysis but for the threshold analysis, one  was chosen at random for removal. After twin removal, there were 49 in the Older-Normal category (average age 61.37 years), 62 in the Metabolic category (average age 66.26 years) and 7 in the Sensory category (average age 68.14 years) .To investigate variant load in hearing loss, and in and between the specific phenotypes, the number of variants per gene in participants belonging to one group  were compared to the number of variants in the same gene in participants belonging to another group (eg Metabolic). The participants were also compared segregated by sex, because the genetic contribution to adult-onset hearing loss differs by sex ; howeverELMO3, CDH23, UBE3B, ADGRV1, COL9A3, NAV2, DMD, AFAP1L2, MPDZ, LOXHD1, and CELSR1).To investigate these gene lists, findings were compared to a list of 734 genes which are known to underlie hearing loss in humans and/or mice ). These To prioritise the list of candidate genes, a third list of outlier genes was obtained from the TwinsUK cohort. In this case there were not sufficient participants classified as having Sensory hearing loss, and so only two comparisons were carried out , resultiPKHD1L1) . The remaining 10 genes were strongly expressed in at least one cell type and age  . Of thesPKHD1L1) . Eleven  and age . Based oer Myo7a , 6.DMD, DUOX2, CELSR1 and ELMO3) and 54 genes linked only to Sensory hearing loss   , 5. Afte ADGRV1) . The foull types . The Senral wall .KIRREL1 and CCDC171), both the non-segregated alternate allele group and one of the sex-segregated groups exhibited a significant difference in thresholds. In the remaining 38 cases, only one group exhibited a significant threshold difference. One mitochondrial variant  also was found to pass the filter and permutation tests, and was associated with better thresholds in male participants , and ZDHHC6 (n=3) also had a similar average threshold shape to that seen in the MUSC cohort carriers  but didHADH, also identified in the MUSC cohort. The other three genes were AKR7A3, SCN7A and ME1  had, on average, slightly worse thresholds than homozygous carriers of the reference allele, resembling the thresholds of carriers in the TwinsUK cohort, but the difference was not significant . One gene, GORASP1, was identified from both analyses, since MUSC carriers of the rs575892658 missense variant had improved thresholds  and Arhgap21 heterozygous mutants exhibit variably raised thresholds across most frequencies tested (https://www.mousephenotype.org/data/genes/MGI:1918685). Mice with a disrupted Ube3b gene display mild hearing impairment at all frequencies at 3 months old, and this impairment was more severe when tested at 6 months old (Pkhd1l1 mutants show early-onset progressive hearing loss (Lmo7 expression in mice results in late-onset progressive hearing impairment (Duox2 have severely raised thresholds (Celsr1 exhibit vestibular defects and misoriented outer hair cells (type.org ); Elmo3 nths old . Pkhd1l1ing loss , while apairment . All theresholds , and micir cells .SYNE2, FKBP2, and ABCB8 from the main analysis, and MADD and CHMP4C from the phenotype-specific analysis. SYNE2 forms part of the LINC (Linker of Nucleoskeleton and Cytoskeleton) Complex, which is part of the nuclear envelope and is essential for maintenance of normal hearing  protein which is upregulated in response to cellular stress such as heat shock, or the accumulation of unfolded protein precursors in the ER  compared to women  . The proThe only regression analysis which could be performed using male participants alone from the MUSC cohort was the comparison of variant counts in men classified with Sensory hearing loss versus those classified with Metabolic hearing loss . Some ofB4GALT1 which is protective against cardiovascular disease (GPR75 which reduce the risk of obesity (Gjb6, which protects against hearing loss in mice (Intriguingly, a subset of candidates from both outlier and threshold analyses are associated with better hearing, suggesting that some variants may lead to protection against age-related hearing loss and/or protection against damage from noise exposure. This is not the first report of protective mutations. Examples of other protective variants include the N352S variant in  disease  and prot obesity , as well in mice . IdentifSupplement 1Supplement 2


Retinitis Pigmentosa (RP) is an inherited retinal dystrophy (IRD) that causes progressive visual loss. Patients suffering from RP have a substantial influence on their everyday activities, social contacts, and jobs, lowering their quality of life. Frequent referral delays, as well as the lack of a standard therapy for the majority of patients, contribute to the significant unmet demand for RP. Any retinal injury has the potential to result in total blindness and visual impairment. Despite the fact that there is no cure for RP, people can manage it using rehabilitation programs and low-vision gadgets. The purpose of this research is to characterize the expanding treatment landscape for RP, as well as the justification for advanced therapy medicinal products (ATMPs).Vitamin A supplements can help prevent the sluggish visual loss caused by a prevalent kind of RP. The presence of visual purple in the rods and the underlying vascular choroid causes the retina to look purplish red. The major portion of the retina damaged is the rod photoreceptor electric cell; the development of diverse diseases is progressive. Because of the retina's accessibility, immunological privilege, and compartmentalization, hereditary retinal diseases are amenable to cell and gene therapy. Therapeutic techniques that attempt to rescue photoreceptors (gene therapies) require the existence of non-functional target cells, but other therapies (cell therapies) do not require the presence of live photoreceptors. To provide successful therapy choices for RP patients at all disease phases, the development pipeline must be continually diversified and advanced, as well as ongoing efforts to encourage early patient identification and quick diagnosis. Future research will focus on avoiding vision loss in genetic eye illnesses and assisting patients in regaining their eyesight. Retinal implants, cell therapies, supplementary medications, and gene therapies may become common treatments for reducing vision loss in the future. Retinitis Pigmentosa (RP) is a hereditary retinal dystrophy that causes progressive visual loss. The most prevalent inherited retinal dystrophy (IRD) is RP, which affects over 1.5 million people globally. RP is classified into two types: syndromic and non-syndromic. Non-syndromic RP begins as night blindness, develops into vision loss, and eventually falls into the peripheral vision range. Retinal dystrophies are defined depending on the location of the retina, the kind of cells damaged , the retinal pigment epithelium (RPE), the inner retina, and whether the progression is stagnant or progressive. RP is a degenerative condition that causes individuals to lose their night vision first, followed by decreased visual acuity and a gradual narrowing of the visual field. By the age of 40, the majority of patients are legally blind. Increased difficulty completing everyday tasks and decreased autonomy are connected with worsening symptoms. Anxiety and depression levels are higher, social isolation is greater, and overall quality of life is lower. As a result, RP has a severe impact on all aspects of the patient's life, imposing a huge cost on patients, families and caregivers, and society.Progressive dystrophy only related to cones is called cone dystrophy. Only one copy of a disease allele is required for a person to be susceptible to expressing the phenotype in autosomal dominant (AD) inheritance. Two copies of a disease allele are necessary for an individual to be at risk of manifesting the phenotype in autosomal recessive (AR) inheritance. For an X-linked dominant disease (XD) in the AD inheritance, just one copy of a disease allele on the X chromosome is necessary. For a person with two X chromosomes  to have an X-linked recessive disease (XR), two copies of a disease allele on the X chromosome are necessary. This is similar to AR inheritance. The electric response of the light is delayed or received in less amount in RP, as the result is given by electroretinogram (ERG) with the characteristic resemblance of 'bone spicules' in the retina . Usher sThe study delves into the genetic heterogeneity of the disease, diagnostic methods such as electroretinography (ERG) and optical coherence tomography (OCT), and potential treatments, including gene therapy, stem cell therapy, and vitamin supplements.MethodologyThis is a comprehensive review article that focuses on a rare eye disease of the retina known as RP and describes the pathogenesis, symptoms, diagnosis, and treatment. Numerous peer-reviewed journals and research articles, in addition to articles from Google Scholar and PubMed were used in this comprehensive review. Keywords used for the study are RP, visual impairment, retinal dystrophy, treatment, gene therapy, cell therapy, and therapeutic landscape. Studies from the previous 15 years were comprised and 32 references were included in this review article, which comprises accessing websites, articles from peer-reviewed journals, and medical books. The preferred report items for systematic reviews and meta-analyses (PRISMA) method used for the study is depicted in Figure The overall results of generic reporting aspects of reviews applicable to this systematic review are presented in Table PathogenesisThe majority of patients have symptoms of diminished peripheral vision on both an upper and lower visual field, as well as night vision loss. The dark pigmented spots are the pigments of melanin. Deoxyribonucleic acid (DNA) testing, visual field testing (VFT), ocular coherence tomography (OCT), and electroretinography (ERG) are some supportive testing methods used to determine the gene accountable for a particular type of RP called an inherited retinal dystrophy. Night blindness and peripheral vision are caused by rod cell degeneration. The eye is a non-digital camera with many elements, such as the lens, retina, and cornea. Any injury to these structures might lead to visual loss ,8. CycliRP is mostly caused by mutations in numerous rod-specific genes, which then cause cone degeneration and alterations in the retinal pigment epithelium and ganglion cells. The fundus examination reveals the loss in retinal blood vessels in addition to the peripheral bone-spicule deposits. ERG is the prosperous diagnostic standard, showing the reduction in the rod and the cone response that are united with a delay in their timing. The visual field (VF) loss is a crucial indicator since it shows the disease's course and the effectiveness of treatment, ranging from patchy loss of the peripheral visual region to tunnel vision, ring scotoma, and eventually leading to total blindness. With the patterned advance of retinal degeneration in disease and the development of effective medical care of retinal and choroidal vasculature the imaging information from the high-resolution, optical coherence tomography angiography (OCTA), a valuable imaging technique, has become necessary. The lyonization is termed as turned off or inactivated development of one of the X chromosomes during development; the genes present on that chromosome are usually inactivated. To date, around 260 hereditary causal genes of genetically heterogeneous blinding diseases have been identified. The photoreceptor genetic modifications lead to the secondary degeneration of cones and the primary degeneration of rods. Rod photoreceptors begin to deteriorate in blinding disorderliness, progressing to cone photoreceptor death ,13.The causes of vision loss are affected retinal ganglion cells (RGC) and retinal pigment epithelium (RPE), changed inner retinal vascular supply, and damage to the outer retina as a result of these alterations. The microglias accumulated in the retina's plexiform layers are principally responsible for the continual monitoring of microenvironmental homeostasis. The movement of various photoreceptor triggers quickly degenerates microglia, which finally destroys the layers and transforms into phagocytes. In addition to phagocytosis, a considerable number of pro-inflammatory neurotoxic substances are secreted when interacting with invading blood cells. Other variables, such as hemodynamics and retinal vasculature, are linked to RP. The parasympathetic and sympathetic nervous systems control the choroidal tissue, whereas the retinal blood vessels can be regulated. The trigger for blood vessel autoregulation might be hypoxic or hyperoxic, which helps maintain retinal homeostasis. Vascular malfunction, rather than the presence of photoreceptors in the retina, may be related to mortality in RP . AccordiWhen RP is advanced, there are no distinguishing features of rod and cone degeneration. The boundary that separates RP from congenital retinal sightlessness is also blurry. Congenital retinal vision impairment is difficult to identify since the ophthalmologist does not know how early and severe the visual loss must have happened in childhood. The loss of photoreceptors is measured by the ERG amplitudes and quantitative measures. The optic nerve atrophy followed by arteriolar attenuation and the changes in the pigment are the characteristics of RP. The particular genetic defect determines if rod cells are involved or the cone cells. The most common being the rod cell photoreceptor defect, cone cell dystrophy is rarely present. More than 80 genetic abnormalities and various other inheritance patterns have been identified. In the Usher syndrome, visual decline advances more rapidly than sensorineural deafness does. External ophthalmoplegia and heart block are also symptoms of Kearns-Sayre syndrome. Mental impairment is linked to the Bardet-Biedl and Laurence-Moon disorders. There is loss and breakdown of the photoreceptor cell. Arteriolar attenuation, retinal pigmentary alterations (either hypopigmentation or hyperpigmentation in the form of bone spicules and pigment clumping), and waxy disc pallor are the typical clinical trials of RP. The atrophy of the optic disc and the optical field failure are also characteristics of open-angle glaucoma. In the pathogenesis of the open-angle glaucoma (OAG), there are specific genetic variants and elevated intraocular pressure. There is the same cone vulnerability in the pathways of RP and OAG, which includes S and M cone loss. There is a similarity between the vascular dysfunction in OAG and the reduction in the blood flow in RP ,17.The retina's thin covering on the back of the eye is the primary source of vision and acceptance of a light beam. The retinal cells are neuroectoderm, the early embryonic ectoderm component that gives rise to the central and peripheral nervous systems. They are divided into seven layers and contain six different kinds of neuronal cells. The layers are the retinal pigment epithelium, photoreceptor cell layer, inner plexiform, nuclear region, and ganglion cell region. The role of the ganglion cell layer cells is to send visual signals to the optic nerve. The photoreceptor cell layer comprises the retina's light-excitable neurons. Cone and rod cell nuclei with synaptic connections are found in the outer nuclear and outer plexiform regions . The retSymptoms and diagnosisThe longer to adjust to the darkness is the first symptom because rod cells are affected first also known as night blindness. There is also a loss of peripheral vision at night, as well as a reduction in eyesight and tunnel vision. When you can't see items to the side without rotating your head, you have tunnel vision. Cones are frequently impacted later in the disease's progression. There is photophobia, which is an excessive sensitivity to light, and it may be difficult to see in strong lighting since the cone cells die first. A thorough history, as well as a neurologic and neuro-ophthalmic examination that takes into account visual fields, are required for the treatment of photophobia; it is a condition that causes bursts of light to shimmer or flicker . The majThe initial indication of the condition is trouble seeing in bright or low light, as well as poor night vision. People suffering from RP also lose their visual acuity and side vision. Tunnel vision occurs when the outer vision is dark and the center of vision is contracting. An ophthalmoscope is required to check the illness since it allows the physician to view into the eye via the pupils. The orange or orange-red fundus is observed by the physician in normal eyes. The appearance of black or dark-brown spots in the fundus indicates that the person has RP. The ERG is used to confirm the diagnosis of RP; in this test, lights of various colors and intensity levels are scarcely flashed into the patient's eyes through an enormous reflecting globe. Ensure the proper functioning of the photoreceptors in the retina since there is less electric activity in that area . Ocular Retinal rods are damaged, resulting in poor night vision that generally begins in maturity but can occur as early as childhood. The development of the ailment is early in the severe types, whereas it may occur in the fifth or sixth decades of life in the lesser variants. The narrowing peripheral vision loss is followed by tunnel vision. The condition causes a ring pattern of vision loss apparent by visual field tests, in which the peripheral ring scotoma gradually spreads, and central vision may be compromised as well. Furthermore, macular dystrophy becomes more active and can lead to blindness; patients suffer from RP report of little shimmering of flickering lights and flashes of light. Hearing loss is one of the symptoms of Usher syndrome and is related to RP in certain people. Funduscopy, in conjunction with electroretinography, is used to diagnose suspected patients with poor night vision .TreatmentIn terms of treatment for RP, the ERG, which shows how the retina responds to vision and optical coherence tomography are used. Light mobility is used in tomography to provide detailed pictures of the retina. The technique is known as fundus autofluorescence imaging, and it involves the physician photographing the retina using blue light. The heterogeneity of RP determines the vast range of onset of symptoms. The importance of the Luxturna® results may be seen in the increased number of gene-based clinical research focusing on specific retinal degenerative diseases. The formal treatment is given to the patient; symptoms frequently intensify as they develop to the advanced stage. Luxturna is now the sole approved treatment for RP. It is an approved medication for people with mutations to overcome RPE65 deficiency. Vitamin supplements, protection from visible radiation, and visual assistance can provide the greatest supportive care. Night blindness caused by RP symptoms can be treated with vitamin A supplementation. RPE65 is required for the production of 11-cis-vitamin A during the retinal visual cycle. There is presently no cure or effective medication available to delay or stop the progression of the condition .In more severe instances, the therapy is primarily focused on preventing cone photoreceptor degeneration, which prevents blindness, as well as vision improvement, photophobia reduction, and peripheral vision improvement. Inhibiting the visual cycle is a currently under-investigation strategy for treating retinal degenerative diseases. Furthermore, the night blindness associated with this medication may significantly impair patients' ability to drive at night, among other serious problems . ClinicaThe correct method of capturing history can provide information on the type of rapid representation. Genetic counseling and testing can determine a child's risk for the condition. The advancements made to reduce the risk of this condition have been based on a better knowledge of the pathophysiological pathways and scientific developments in these disorders . Gene thThis comprehensive review investigates the complexities of retinitis pigmentosa (RP), an inherited retinal disorder. The article explores the pathogenesis, symptoms, diagnosis, and treatment options associated with RP. It discusses the genetic heterogeneity of the disease, the diagnostic methods like clinical symptoms, the functional test used to identify it, and the current treatment approaches, including gene therapy. While RP remains a challenging condition with no known cure, advancements in research, such as Luxturna® and ongoing clinical trials, offer hope for potential treatments. The preliminary findings are favorable, and we anticipate great growth in the coming years. Understanding the multifaceted nature of RP, from its genetic origins to clinical manifestations, is critical for both medical professionals and patients. For therapy, researchers examined the condition and developed visual aids, sunglasses to reduce contact with UV radiation, and dorzolamide or acetazolamide eye drops, as well as vitamin A and E supplements.As further studies and innovations unfold, the quest to mitigate the impact of this condition continues, and individuals affected by RP can find some solace in the ongoing pursuit of effective treatments. This article serves as a foundation for grasping the intricate landscape of RP and highlights the importance of ongoing research to improve the lives of those living with this condition.