Search Results (54)

Diffusion tensor imaging (DTI) metrics provide insights into neural pathways, which can be pivotal in differentiating congenital and acquired hearing loss to support diagnosis, especially for those diagnosed late. In this study, we analyzed DTI parameters and developed machine learning to classify these two patient groups. The study included 29 patients with congenital hearing loss and 6 with acquired hearing loss. DTI scans were performed to obtain metrics, such as fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD). Statistical analyses based on p-values highlighted the cortical auditory system’s prominence in differentiating between groups, with FA and RD emerging as pivotal metrics. Three machine learning models were trained to classify hearing loss types for each of five dataset scenarios. Random forest (RF) trained on a dataset consisting of significant features demonstrated superior performance, achieving a specificity of 87.12% and F1 score of 96.88%. This finding highlights the critical role of DTI metrics in the classification of hearing loss. The experimental results also emphasized the critical role of FA in distinguishing between the two types of hearing loss, underscoring its potential clinical utility. DTI parameters, combined with machine learning, can effectively distinguish between congenital and acquired hearing loss, offering a robust tool for clinical diagnosis and treatment planning. Further research with larger and balanced cohorts is warranted to validate these findings. Full article

Background: Syndromic inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of disorders, involving the retina and additional organs. Over 80 forms of syndromic IRD have been described. Methods: We aimed to phenotypically and genotypically characterize a cohort of 171 individuals from 140 Israeli families with syndromic IRD. Ophthalmic examination included best corrected visual acuity, fundus examination, visual field testing, retinal imaging and electrophysiological evaluation. Most participants were also evaluated by specialists in fields relevant to their extra-retinal symptoms. Genetic analyses included haplotype analysis, homozygosity mapping, Sanger sequencing and next-generation sequencing. Results: In total, 51% of the families in the cohort were consanguineous. The largest ethnic group was Muslim Arabs. The most common phenotype was Usher syndrome (USH). The most common causative gene was USH2A. In 29% of the families, genetic analysis led to a revised or modified clinical diagnosis. This included confirmation of an atypical USH diagnosis for individuals with late-onset retinitis pigmentosa (RP) and/or hearing loss (HL); diagnosis of Heimler syndrome in individuals with biallelic pathogenic variants in PEX6 and an original diagnosis of USH or nonsyndromic RP; and diagnosis of a mild form of Leber congenital amaurosis with early-onset deafness (LCAEOD) in an individual with a heterozygous pathogenic variant in TUBB4B and an original diagnosis of USH. Novel genotype–phenotype correlations included biallelic pathogenic variants in KATNIP, previously associated with Joubert syndrome (JBTS), in an individual who presented with kidney disease and IRD, but no other features of JBTS. Conclusions: Syndromic IRDs are a highly heterogeneous group of disorders. The rarity of some of these syndromes on one hand, and the co-occurrence of several syndromic and nonsyndromic conditions in some individuals, on the other hand, complicates the diagnostic process. Genetic analysis is the ultimate way to obtain an accurate clinical diagnosis in these individuals. Full article

Cytomegalovirus (CMV) infection in pregnant women is one of the most common causes of congenital infection in children. It is often asymptomatic but can lead to serious complications, including progressive sensorineural hearing loss. Profound hearing loss is an indication for cochlear implantation (CI). Electrode impedance and neural response telemetry (NRT) thresholds can be measured to confirm correct electrode placement and speech processor programming. Background/Objectives: The aim of the study is to evaluate the hearing outcome of children with profound sensorineural hearing loss or deafness due to cCMV infection after CI compared to a control group of children born with other causes of congenital hearing loss and to identify prognostic factors predicting the outcome of patients with hearing loss due to cCMV infection after CI. Methods: A retrospective study was conducted in patients implanted between 2016 and 2023 at the Department of Otolaryngology of the Institute of the Polish Mother’s Memorial Hospital Research Institute in Łódź. Pre- and postoperative hearing levels, electrode impedance and neural response telemetry (NRT) thresholds were compared. The degree of pre-implantation hearing loss was assessed by the level of the recorded V-wave in the ABR test. Post-implantation hearing assessment was based on the last available free-field tonal audiometry measurement. Impedance measurements were included: intraoperative, 1, 6, 12 months after CI, respectively, and NRT thresholds. Results: The final analysis included 84 patients with profound sensorineural hearing loss and complete audiological follow-up data: 13 patients with congenital CMV (cCMV) infection and 71 patients with other causes of deafnes. The analysis included 175 implanted ears: 17 in the CMV group and 158 in the control group. The age at implantation ranged from 1 to 11 years in the CMV and from 1 to 13 years in the control group. Mean preoperative hearing thresholds were 94.54 dB in the CMV group and 97.04 dB in the control group. At the most recent postoperative evaluation, mean thresholds improved to 33.83 dB and 36.42 dB, respectively. No statistically significant differences were observed between the groups. Mean intraoperative NRT values were 79.74 in the CMV group and 86.90 in the non-CMV group. Final NRT values were 129.77 and 130.76, respectively. Mean impedance values measured intraoperatively and at 1, 6 and 12 months postoperatively were 11.09 kOhm, 13.40 kOhm, 8.35 kOhm and 8.25 kOhm in the CMV group; and 12.28 kOhm, 14.06 kOhm, 9.60 kOhm and 8.00 kOhm in the control group, respectively. Conclusions: CI in children with deafness caused by cCMV infection is an effective treatment option. Initial electrical impedance values of the electrodes increase after implant activation and decrease in subsequent months of follow-up, suggesting the absence of active adhesion processes in the cochlea. Full article

Background: Usher syndrome (USH), the most common cause of combined deaf-blindness, is a genetically and phenotypically heterogeneous disorder characterized by congenital hearing impairment and progressive vision loss due to rod-cone dystrophy. Although the original classification in three subtypes (USH I, USH II, and USH III) is still valid, recent findings have changed and widened perspectives in its classification, genotype–phenotype correlations, and management strategies: Objective: This study aims to provide new insights into the classification of Usher syndrome, explore the genotype-phenotype correlations, and review current and emerging management strategies. Methods: A comprehensive literature review has been conducted, incorporating data from clinical studies, genetic databases, and patient registries. Results: Recent studies have led to the identification of several novel pathogenic variants in the USH genes, leading to refined subclassifications of Usher syndrome. Interactions between different genes being part of the network of this ciliopathy have been investigated and new mechanisms unveiled. Significant correlations were found between certain genotypes and the presentation of both auditory and visual phenotypes. For instance, pathogenic variants in the MYO7A gene (USH1B) were generally associated with more severe hearing impairment and earlier onset of retinal dystrophy, if compared to other USH genes-related forms. Other genes, such as USH1G, traditionally considered as causing a specific subtype, can display phenotypic heterogeneity in some patients. Conclusions: This review provides insights into a better understanding of Usher syndrome that considers recent findings regarding its genetic causes and clinical features. Precise genotype–phenotype correlations can lead to better genetic counselling, more precise characterization of the natural history of the condition, and a personalized and effective management approach. Recent progress has been made in research into gene-specific therapies that appear promising for improving the quality of life for individuals affected by Usher syndrome. Full article

Gene therapy is a promising molecular approach for the management of familial hearing loss. This type of molecular therapy is the physical manifestation of genetic determinism—the notion that individual genes cause individual phenotypes. The current composition weaves through various branches of the biomedical sciences to uncover the molecular biologic premise for genetic determinism and the impetus behind gene therapy. Consequently, it is revealed that the underlying molecular biologic premise was scaffolded on successful observations from simple biologic assays that were devoid of the complexities of human disease biology. Furthermore, modern successful gene therapies are largely driven by commercial and academic incentives at the cost of scientific rigor. This poses several perverse challenges for patients, clinicians and the public at large. Issues concerning safety, efficacy, and ethics are far from resolved despite regulatory agency approvals, the media’s bias for gene therapy and the many lucrative investor positions. Lastly, the therapeutic claims regarding gene therapy are the most ambitious claims made within the hearing sciences. Therefore, scientists, clinicians, and patients must be equipped with the tools needed to appropriately consume and appraise such claims. These and other issues are also directly addressed, with the aim of providing a realistic sense of whether current human gene therapies are ready to be positioned within our routine clinical armamentarium against hearing loss. Full article

Background/Objectives: The OTOG gene is responsible for autosomal recessive non-syndromic sensorineural hearing loss and is assigned as DFNB18B. To date, 44 causative OTOG variants have been reported to cause non-syndromic hearing loss. However, the detailed clinical features for OTOG-associated hearing loss remain unclear. Methods: In this study, we analyzed 7065 patients with non-syndromic hearing loss (mean age 26.4 ± 22.9 years, 2988 male, 3855 female, and 222 without gender information) using massively parallel DNA sequencing for 158 target deafness genes. We identified the patients with biallelic OTOG variants and summarized the clinical characteristics. Results: Among the 7065 patients, we identified 14 possibly disease-causing OTOG variants in 26 probands, with 13 of the 14 variants regarded as novel. Patients with OTOG-associated hearing loss mostly showed congenital or childhood-onset hearing loss. They were considered to show non-progressive, mild-to-moderate hearing loss. There were no symptoms that accompanied the hearing loss in OTOG-associated hearing loss patients. Conclusions: We confirmed non-progressive, mild-to-moderate hearing loss as the clinical characteristics of OTOG-associated hearing loss. These findings will contribute to a better understanding of the clinical features of OTOG-associated HL and will be useful in clinical practice. Full article

Background and Objectives: Congenital thyroid dyshormonogenesis is caused by alterations in the synthesis of thyroid hormones in a newborn. Additionally, 10 to 20% of these cases are hereditary, caused by defects in proteins involved in hormonal synthesis. One of the most common causes is mutations in the thyroid peroxidase (TPO) enzyme gene, an autosomal recessive disease. We aimed to detect mutations of the TPO gene in 12 Chilean patients with congenital hypothyroidism due to dyshormonogenesis (CHD) and to characterize these patients clinically and molecularly. Materials and Methods: Twelve patients under 20 years of age with CHD, controlled at San Juan de Dios Hospital in Santiago, Chile, were selected according to the inclusion criteria: elevated neonatal TSH, persistent hypothyroidism, and thyroid normotopic by imaging study. Those with deafness, Down syndrome, and central or transient congenital hypothyroidism were excluded. Blood samples were taken for DNA extraction, and the 17 exons and exon–intron junctions of the TPO gene were amplified by PCR. The PCR products were sequenced by Sanger. Results: Two possibly pathogenic mutations of the TPO gene were detected: c.2242G>A (p.Val748Met) and c.1103C>T (p.Pro368Leu). These mutations were detected in 2 of 12 patients (16.6%): 1 was compound heterozygous c.1103C>T/c.2242G>A, and the other was heterozygous for c.2242G>A. In the diagnostic confirmation test, both patients presented diffuse hyper-uptake goiter on thyroid scintigraphy and high TSH in venous blood (>190 uIU/mL). Conclusions: The frequency of patients with possibly pathogenic mutations in TPO with CHD was 16.6%. Its study would allow for genetic counseling to be offered to the families of affected patients. Full article

A genetic diagnosis of primary cardiomyopathies can be a long-unmet need in patients with complex phenotypes. We investigated a three-generation family with cardiomyopathy and various extracardiac abnormalities that had long sought a precise diagnosis. The 41-year-old proband had hypertrophic cardiomyopathy (HCM), left ventricular noncompaction, myocardial fibrosis, arrhythmias, and a short stature. His sister showed HCM, myocardial hypertrabeculation and fibrosis, sensorineural deafness, and congenital genitourinary malformations. Their father had left ventricular hypertrophy (LVH). The proband’s eldest daughter demonstrated developmental delay and seizures. We performed a clinical examination and whole-exome sequencing for all available family members. All patients with HCM/LVH shared a c.4411-2A>C variant in ALPK3, a recently known HCM-causative gene. Functional studies confirmed that this variant alters ALPK3 canonical splicing. Due to extracardiac symptoms in the female patients, we continued the search and found two additional single-gene disorders. The proband’s sister had a p.Trp329Gly missense in GATA3, linked to hypoparathyroidism, sensorineural deafness, and renal dysplasia; his daughter had a p.Ser251del in WDR45, associated with beta-propeller protein-associated neurodegeneration. This unique case of three monogenic disorders in one family shows how a comprehensive approach with thorough phenotyping and extensive genetic testing of all symptomatic individuals provides precise diagnoses and appropriate follow-up, embodying the concept of personalized medicine. We also present the first example of a splicing functional study for ALPK3 and describe the genotype–phenotype correlations in cardiomyopathy. Full article

Connexin hemichannels (HCs) expressed at the plasma membrane of mammalian cells are of paramount importance for intercellular communication. In physiological conditions, HCs can form gap junction (GJ) channels, providing a direct diffusive path between neighbouring cells. In addition, unpaired HCs provide conduits for the exchange of solutes between the cytoplasm and the extracellular milieu, including messenger molecules involved in paracrine signalling. The synergistic action of membrane potential and Ca²⁺ ions controls the gating of the large and relatively unselective pore of connexin HCs. The four orders of magnitude difference in gating sensitivity to the extracellular ([Ca²⁺]_e) and the cytosolic ([Ca²⁺]_c) Ca²⁺ concentrations suggests that at least two different Ca²⁺ sensors may exist. While [Ca²⁺]_e acts as a spatial modulator of the HC opening, which is most likely dependent on the cell layer, compartment, and organ, [Ca²⁺]_c triggers HC opening and the release of extracellular bursts of messenger molecules. Such molecules include ATP, cAMP, glutamate, NAD⁺, glutathione, D-serine, and prostaglandins. Lost or abnormal HC regulation by Ca²⁺ has been associated with several diseases, including deafness, keratitis ichthyosis, palmoplantar keratoderma, Charcot–Marie–Tooth neuropathy, oculodentodigital dysplasia, and congenital cataracts. The fact that both an increased and a decreased Ca²⁺ sensitivity has been linked to pathological conditions suggests that Ca²⁺ in healthy cells finely tunes the normal HC function. Overall, further investigation is needed to clarify the structural and chemical modifications of connexin HCs during [Ca²⁺]_e and [Ca²⁺]_c variations. A molecular model that accounts for changes in both Ca²⁺ and the transmembrane voltage will undoubtedly enhance our interpretation of the experimental results and pave the way for developing therapeutic compounds targeting specific HC dysfunctions. Full article

The PTPRQ gene has been identified as one of the genes responsible for non-syndromic sensorineural hearing loss (SNHL), and assigned as DFNA73 and DFNB84. To date, about 30 causative PTPRQ variants have been reported to cause SNHL. However, the detailed clinical features of PTPRQ-associated hearing loss (HL) remain unclear. In this study, 15,684 patients with SNHL were enrolled and genetic analysis was performed using massively parallel DNA sequencing (MPS) for 63 target deafness genes. We identified 17 possibly disease-causing PTPRQ variants in 13 Japanese patients, with 15 of the 17 variants regarded as novel. The majority of variants identified in this study were loss of function. Patients with PTPRQ-associated HL mostly showed congenital or childhood onset. Their hearing levels at high frequency deteriorated earlier than that at low frequency. The severity of HL progressed from moderate to severe or profound HL. Five patients with profound or severe HL received cochlear implantation, and the postoperative sound field threshold levels and discrimination scores were favorable. These findings will contribute to a greater understanding of the clinical features of PTPRQ-associated HL and may be relevant in clinical practice. Full article

It has been demonstrated that universal hearing neonatal screening (UHNS) is efficient at providing early diagnosis and rehabilitation for deafness. The risk factors of deafness in children have been identified, but less specifically in those diagnosed after UHNS. In this study, we aim to study these factors in infants who were referred after screening and to compare our experience to recent data. We studied infants referred to our department for diagnosis after screening between January 2018 and December 2021. Their medical history and neonatal hearing risk factors were assessed. Associations between factors were also analyzed. Sixty-six infants were included. A family history of deafness (47%), syndromic deafness (41%), intrauterine growth retardation or prematurity (19.7%), and prolonged NICU admission (18%) were the most observed factors. When analyzing according to these associations, family history of deafness and syndromic cases remained the most prevalent factors (74%), while only five cases (7.8%) presented with other neonatal risk factors only. The majority of congenital hearing loss cases are observed in infants with suspected genetic deafness. Parental counseling, the diagnostic pathway, as well as the healthcare system should be adapted according to these risk factors. Full article

Hearing loss is the most common sensory deficit and one of the most common congenital abnormalities. The estimated prevalence of moderate and severe hearing loss in a normal newborn is 0.1–0.3%, while the prevalence is 2–4% in newborns admitted to the newborn intensive care unit. Therefore, early detection and prompt treatment are of utmost importance in preventing the unwanted sequel of hearing loss on normal language development. The problem of congenital deafness is today addressed on the one hand with hearing screening at birth, on the other with the early (at around 3 months of age) application of hearing aids or, in case of lack of benefit, by the cochlear implant. Molecular genetics, antibody tests for some viruses, and diagnostic imaging have largely contributed to an effective etiological classification. A correct diagnosis and timely fitting of hearing aids or cochlear implants is useful for deaf children. The association between congenital deafness and “mutism”, with all the consequences on/the consideration that deaf mutes have had since ancient times, not only from a social point of view but also from a legislative point of view, continued until the end of the nineteenth century, with the development on one side of new methods for the rehabilitation of language and on the other of sign language. But we need to get to the last decades of the last century to have, on the one hand, the diffusion of “universal newborn hearing screening”, the discovery of the genetic causes of over half of congenital deafness, and on the other hand the cochlear implants that have allowed thousands of children born deaf the development of normal speech. Below, we will analyze the evolution of the problem between deafness and deaf-mutism over the centuries, with particular attention to the nineteenth century. Full article

The development of language, memory and intellectual functions is linked to normal hearing and correct sounds interpretation. Hearing loss (HL), especially in its severe form, negatively affects the development of these functions. This prospective study aimed at comparing the Intelligent Quotients (IQ) of children with cochlear implants (CI) with the ones of people wearing hearing aids (HA) after one year of hearing rehabilitation. 21 subjects with severe/profound bilateral hearing loss (deafness) were included in this study. Eleven children with congenital profound HL underwent CI and ten children with moderate to severe HL (congenital and acquired) were rehabilitated by HA. Children’s IQs were assessed at enrolment (T0) and 12 months after hearing aids/CI use plus speech therapy. Statistical analyses were performed to analyze the data within and between groups. Comparison of IQs showed no statistically significant differences between CI and HA none at T0 and T1. The subtests showed lower scores in verbal comprehension and process speed index in patients treated with HA when compared to CI. This study showed that auditory rehabilitation can support the normal development of cognitive function in children between six and eight years of age. The use of the correct hearing aids based on the patient’s hearing thresholds is important to maximize the rehabilitation outcomes. Due to the small sample size, although stratified for age, our results must be considered preliminary and further analyses on larger samples are needed to confirm our data. Full article

Hearing loss stands as the most prevalent sensory deficit among humans, posing a significant global health challenge. Projections indicate that by 2050, approximately 10% of the world’s population will grapple with disabling hearing impairment. While approximately half of congenital hearing loss cases have a genetic etiology, traditional interventions such as hearing aids and cochlear implants do not completely restore normal hearing. The absence of biological treatment has prompted significant efforts in recent years, with a strong focus on gene therapy to address hereditary hearing loss. Although several studies have exhibited promising recovery from common forms of genetic deafness in mouse models, existing challenges must be overcome to make gene therapy applicable in the near future. Herein, we summarize the primary gene therapy strategies employed over past years, provide an overview of the recent achievements in preclinical studies for genetic hearing loss, and outline the current key obstacles to cochlear gene therapy. Full article

To analyze the association between stable asymptomatic white matter lesions (WMLs) and the cochlear implantation (CI) effect in congenitally deaf children, 43 CI children with stable asymptomatic WMLs determined via preoperative assessments and 86 peers with normal white matter were included. Outcome measurements included closed-set Mandarin Chinese (tone, disyllable, and sentence) recognition tests; categories of auditory performance (CAPs); and speech intelligibility rating (SIR) scales at 1, 12, and 24 months post-CI. Generalized estimating equation (GEE) models were used to analyze the association between WML and outcomes. In the WML group (control group), median CAP and SIR scores were 5 (5) and 4 (4) with mean rates of tone, disyllable, and sentence recognition of 84.8% (89.0%), 87.9% (89.7%), and 85.8% (88.0%) at 24 months post-CI, respectively. Auditory and speech performance improved significantly with implant use. Compared to their peers in the control group, for the participants with stable asymptomatic WMLs, auditory and speech abilities were not significantly different (p > 0.05). Stable asymptomatic WMLs might not be associated with poor auditory and speech intelligibility post-CI, which indicates that it is feasible to use comprehensive assessments to screen suitable candidates with WMLs who are likely to present with a good prognosis. Full article