Late-onset Hearing Loss Research Articles

Hearing Loss in the Newborn Infant: Early Hearing Detection and Intervention

Significant advances in health care have occurred since the 1980s and currently more than 97% of newborns in the United States undergo hearing screening, resulting in earlier identification, intervention, and improved outcomes. (1) Current technology, however, does not identify all hearing loss including mild, late onset, and progressive hearing loss. Therefore, although the rate of hearing loss at birth is approximately 1 to 2 per 1,000, it approaches 5 per 1,000 by early school age. This supports the need for continued surveillance of language milestones and hearing skills in the medical home. Types of permanent hearing loss include sensorineural, conductive, and auditory neuropathy, which occurs most commonly in NICU graduates. Multidisciplinary care is needed to ensure early access to language. Both early intervention and early amplification, no later than 6 months of age, are critical components of the formula for success.

Identification of arare COCH mutation by whole-exome sequencing : Implications for personalized therapeutic rehabilitation in an Austrian family with non-syndromic autosomal dominant late-onset hearing loss.

SummaryBackgroundNon-syndromic autosomal dominant hearing impairment is characteristically postlingual in onset. Genetic diagnostics are essential for genetic counselling, disease prognosis and understanding of the molecular mechanisms of disease. To date, 36 causative genes have been identified, many in only individual families. Gene selection for genetic screening by traditional methods and genetic diagnosis in autosomal dominant patients has therefore been fraught with difficulty. Whole-exome sequencing provides a powerful tool to analyze all protein-coding genomic regions in parallel, thus allowing the comprehensive screening of all known genes and associated alterations.MethodsIn this study, a previously undiagnosed late-onset progressive autosomal dominant hearing loss in an Austrian family was investigated by means of whole-exome sequencing. Results were confirmed by Sanger sequencing.ResultsA previously described c.151C>T missense (p.Pro51Ser) mutation in the LCCL (limulus factor C, cochlin, late gestation lung protein Lgl1) domain of the cochlin gene (COCH) was identified as causative and segregated with disease in five members of the family. Molecular diagnostics led to the decision to perform cochlear implantation in an index patient who subsequently showed excellent postoperative auditory performance. The c.151C>T mutation was not found in 18 screened Austrian families with autosomal dominant hearing loss but was represented alongside other known pathogenic mutant COCH alleles in the Genome Aggregation Database (gnomAD) in European populations. A combined allele frequency of 0.000128 implies an orphan disease frequency for COCH-induced hearing loss of 1:3900 in Europe.ConclusionsExome sequencing successfully resolved the genetic diagnosis in a family suffering from autosomal dominant hearing impairment and allowed prediction of purported auditory outcome after cochlear implantation in an index patient. Personalized treatment approaches based on the molecular mechanisms of disease may become increasingly important in the future.

Biochemical, Cellular, Physiological, and Pathological Consequences of Human Loss of N-Glycolylneuraminic Acid.

About 2-3 million years ago, Alu-mediated deletion of a critical exon in the CMAH gene became fixed in the hominin lineage ancestral to humans, possibly through a stepwise process of selection by pathogen targeting of the CMAH product (the sialic acid Neu5Gc), followed by reproductive isolation through female anti-Neu5Gc antibodies. Loss of CMAH has occurred independently in some other lineages, but is functionally intact in Old World primates, including our closest relatives, the chimpanzee. Although the biophysical and biochemical ramifications of losing tens of millions of Neu5Gc hydroxy groups at most cell surfaces remains poorly understood, we do know that there are multiscale effects functionally relevant to both sides of the host-pathogen interface. Hominin CMAH loss might also contribute to understanding human evolution, at the time when our ancestors were starting to use stone tools, increasing their consumption of meat, and possibly hunting. Comparisons with chimpanzees within ethical and practical limitations have revealed some consequences of human CMAH loss, but more has been learned by using a mouse model with a human-like Cmah inactivation. For example, such mice can develop antibodies against Neu5Gc that could affect inflammatory processes like cancer progression in the face of Neu5Gc metabolic incorporation from red meats, display a hyper-reactive immune system, a human-like tendency for delayed wound healing, late-onset hearing loss, insulin resistance, susceptibility to muscular dystrophy pathologies, and increased sensitivity to multiple human-adapted pathogens involving sialic acids. Further studies in such mice could provide a model for other human-specific processes and pathologies involving sialic acid biology that have yet to be explored.

A novel auditory ossicles membrane and the development of conductive hearing loss in Dmp1-null mice

Genetic mouse models are widely used for understanding human diseases but we know much less about the anatomical structure of the auditory ossicles in the mouse than we do about human ossicles. Furthermore, current studies have mainly focused on disease conditions such as osteomalacia and rickets in patients with hypophosphatemia rickets, although the reason that these patients develop late-onset hearing loss is unknown. In this study, we first analyzed Dmp1 lac Z knock-in auditory ossicles (in which the blue reporter is used to trace DMP1 expression in osteocytes) using X-gal staining and discovered a novel bony membrane surrounding the mouse malleus. This finding was further confirmed by 3-D micro-CT, X-ray, and alizarin red stained images. We speculate that this unique structure amplifies and facilitates sound wave transmissions in two ways: increasing the contact surface between the eardrum and malleus and accelerating the sound transmission due to its mineral content. Next, we documented a progressive deterioration in the Dmp1-null auditory ossicle structures using multiple imaging techniques. The auditory brainstem response test demonstrated a conductive hearing loss in the adult Dmp1-null mice. This finding may help to explain in part why patients with DMP1 mutations develop late-onset hearing loss, and supports the critical role of DMP1 in maintaining the integrity of the auditory ossicles and its bony membrane.

Late onset nonsyndromic hearing loss in a Dongxiang Chinese family is associated with the 593T > C variant in the mitochondrial tRNAPhe gene

We report here the clinical, genetic, molecular and biochemical characterization of a four-generation Dongxiang Chinese pedigree with suggestively maternally transmitted non-syndromic hearing loss. Five of 10 matrilineal relatives exhibited variable severity and age at onset of sensorineural hearing loss. The average ages at onset of hearing loss in matrilineal relatives of this family were 29years. Molecular analysis of their mitochondrial genomes identified the tRNAPhe 593T>C variant belonging to Asian haplogroup G2a2a. The m.593T>C variant resided at the position 17 of DHU-loop, where the position is important for the structure and function of tRNA. It was anticipated that the m.593T>C variant altered the structure and function of tRNAPhe. By using lymphoblastoid cell lines derived from the Chinese family, we showed a 46% decreases in the steady-state level of tRNAPhe in mutant cell lines. Western blotting analysis showed ∼35% reduction in the levels of mitochondrial translation in mutant cell lines carrying the m.593T>C variant. Impaired mitochondrial translation is apparently a primary contributor to the marked reduction in the rate of respiratory capacity. The respiratory deficiency lowed mitochondrial ATP production in the mutant cell lines. These data provide the evidence that mitochondrial dysfunctions caused by the m.593T>C variant lead to late-onset nonsyndromic hearing loss. Thus, our findings may provide the new insights into the understanding of pathophysiology and valuable information for management and treatment of maternally inherited hearing loss.

An analysis of the mutation in GJB2，GJB3，SLC26A4 and mtDNA12SrRNA in new born

Objective:To analyze deafness gene mutation in GJB2，GJB3，SLC26A4 and mtDNA12SrRNA in newborn and to explore the significance of genetic test and potential correlations between the genotype and clinical phenotype.Method:Blood samples were collected with a standard protocol and DNA templates are extracted from 501 newborn in Longgang of Shenzhen.MALDI-TOF-MS Technology was used to detect the coding region twenty mutations sites of GJB2，GJB3，SLC26A4 AND mtDNA12SrRNA，includingSLC26A4(1226G>A,1229C>T,281C>T,589G>A,IVS7-2A>T,1174A>T,IVS15+5G>A,1975G>C,2027T>A,2162C>T,2168A>G),GJB2(176-191del16,35delG,167delT,235 delC,299-300 delAT),GJB3(547G>A,538C>T),mtDNA12SrRNA(1555A>G,1494C>T).While two-step hearing screening was carried by using AABR（automatedauditory brainstem response）and DPOAE. Result:In the 501 newborns,26 cases were found have one or two allele mutations of deafness-susceptibility genes.GJB2 gene mutation(n=9,1.796%) all were 235 delC single heterozygosity mutation.GJB3 gene mutation(n=3,0.599%). SLC26A4 gene mutation(n=12,2.395%) included IVS7-2A>G heterozygosity mutation(n=5). MtDNA 12Rrna gene mutation was found in 3 child(n=3,0.599%). Finally one of 26 infants was diagnosed enlarged vestibular aqueduct syndrome. The infant was detected 2168A>G heterozygosity mutation. Conclusion:235delC is the main mutation form of GJB2 gene,while it is the hottest mutation in People. But SLC26A4 gene mutations are the main type in newborn. MtDNA 12Rrna gene mutation was found in 3 child.This genetic epidemiological study demonstrated that genetic screening is helpful for determining high risk individuals and early discovering possible late-onset hearing loss. Moreover pationts and family member can acquire more effective genetic counseling.

A Qualitative Study on Knowledge and Attitude towards Risk Factors, Early Identification and Intervention of Infant Hearing Loss among Puerperal Mothers- A Short Survey.

Maternal active participation and their support are critical for the success of early hearing loss detection program. Erroneous maternal decisions may have large life long consequences on the infant's life. The mothers' knowledge and their attitudes towards infant hearing loss is the basis for their decisions. The present study was done to determine the mothers' knowledge and their attitude towards risk factors of infant hearing loss, its early identification and intervention and also awareness of effect of consanguinity on hearing loss. In this cross-sectional questionnaire survey study, a total of 100 mothers were interviewed using the questionnaire which consisted of three sections namely risk factors, early identification and early intervention of hearing loss. Chi-square test was used to establish relationship between consanguineous and non-consanguineous mother's responses to its effect on hearing loss. A p-value < 0.05 was considered as significant. Mothers' awareness was significantly high for visible causes (ear pain/discharge, head injury and slap to ear) of hearing loss. Positive attitude was seen for importance of screening programs and follow up testing. Moderate level of awareness was found on hazards of consanguinity and benefits of early identification. However, mothers were least aware of neonatal jaundice, NICU admission (>5 days), signs of late-onset and neural hearing loss, management of hearing loss, hearing aid fitting and therapy necessity, which might interfere in early detection and intervention of hearing loss. It is crucial to educate mothers on few risk factors and management of hearing loss to reduce its consequences.

Long-term neurologic health and psychosocial function of adult survivors of childhood medulloblastoma/PNET: a report from the Childhood Cancer Survivor Study.

Medulloblastoma is the most common malignant childhood brain tumor, although long-term risks for chronic neurologic health and psychosocial functioning in aging adult survivors are incompletely characterized. The Childhood Cancer Survivor Study (CCSS) includes 380 five-year survivors of medulloblastoma/primitive neuroectodermal tumor (PNET; median age at follow-up: 30 y, interquartile range 24-36) and sibling comparison (n = 4031). Cumulative incidence of neurologic health conditions was reported. Cox regression models provided hazard ratios (HRs) and 95% CIs. Cross-sectional outcomes were assessed using generalized linear models. Compared with siblings, survivors were at increased risk of late-onset hearing loss (HR: 36.0, 95% CI: 23.6-54.9), stroke (HR: 33.9, 95% CI: 17.8-64.7), seizure (HR: 12.8, 95% CI: 9.0-18.1), poor balance (HR: 10.4, 95% CI: 6.7-15.9), tinnitus (HR: 4.8, 95% CI: 3.5-6.8), and cataracts (HR: 31.8, 95% CI: 16.7-60.5). Temporal/frontal lobe radiotherapy of 50 Gy or more increased risk for hearing loss (HR: 1.9, 95% CI: 1.1-1.3), seizure (HR: 2.1, 95% CI: 1.1-3.9), stroke (HR: 3.5, 95% CI: 1.3-9.1), and tinnitus (HR: 2.0, 95% CI: 1.0-3.9). Survivors were less likely than siblings to earn a college degree (relative risk [RR]: 0.49, 95% CI: 0.39-0.60), marry (RR: 0.35, 95% CI: 0.29-0.42), and live independently (RR: 0.58, 95% CI: 0.52-0.66). Adult survivors of childhood medulloblastoma/PNET demonstrate pronounced risk for hearing impairment, stroke, lower educational attainment, and social independence. Interventions to support survivors should be a high priority.

A case report on ATP6V0A4 gene mutation: Forecast of familial deafness by genetic investigation in a patient with autosomal recessive distal renal tubular acidosis

The autosomal recessive form of distal renal tubular acidosis (dRTA), a condition associated with the systemic accumulation of acid owing to its reduced elimination through kidneys, is caused by ATP6V0A4 mutation, which is typically related to either late-onset sensorineural hearing loss (SNHL) or normal hearing. This article reports dRTA in seven year old boy, born to a Chinese couple who have family history of deafness. The patient does not have hearing impairment. ATP6V0A4 gene sequencing demonstrated that there were 2 heterozygous mutations, c.1376C&gt;T and c.1029+5G&gt;A, in gene ATP6V0A4. c.1376C &gt; T (p.Ser459Phe) is a kind of missense mutation in gene ATP6V0A4. c.1029+5G&gt;A is a kind of intragenic mutation near the cutting area of gene ATP6V0A4. ATP6V0A4 gene mutation study substantiated the autosomal recessive dRTA without hearing impairment in the patient. This case report emphasizes the significance of early diagnosis and genetic screening of recessive forms of dRTA independent of hearing status and offer suitable intervention to treat dRTA as well as diminish the influence of SNHL on the child’s learning and communication in daily life.Keywords: Renal tubular acidosis, Homeostasis, Electrolytes, Hearing impairment, ATP6V0A4 gene, Mutation

遅発性難聴を認めた先天性風疹症候群（CRS）の１例

遅発性難聴を認めた先天性風疹症候群（CRS）の１例

Prevalence of 2.2 per mille of significant hearing loss at school age suggests rescreening after NHS

ObjectivesThe study aims to determine the prevalence of different degrees of significant hearing loss in a complete sample of Austrian school-age children born between 1997 and 2001 living in the federal state of Carinthia and to evaluate the role of Newborn Hearing Screening (NHS) in the identification of later hearing loss. MethodsIn Carinthia, all school-age children with significant hearing loss (mean pure tone average in the better ear above 40 dB) are registered by the Department of Education. From five complete birth cohorts from 1997 to 2001 (n = 28.171) all the children with sensorineural hearing loss (n = 61, mean age 10.5, age range 7.5–13.6 years) were assessed for their hearing threshold and level of cognitive functioning. Socio-demographic data, including information about NHS and amplification with hearing devices, were collected from parents and teachers using structured interviews. Results2.2 children per thousand (49.2% male) were found to be affected by significant bilateral hearing loss at school age, with 36.1% of them having a moderate hearing loss, 34.4% severe, and 29.5% profound. Fourteen children (23.0%) used cochlear implants. Their mean nonverbal IQ was 93.4 (SD 23.1), including 13.1% of children with intellectual disabilities (IQ < 70). Of those who had undergone NHS (85.2%), 50.0% had passed the screening according to parents' reports. ConclusionsA rate of significant hearing loss in school-age children was observed which was twice the rate found in newborns. Ongoing awareness of late-onset hearing loss to improve identification and hearing screening at school entry are recommended.

Detection of CMV DNA in the Perilymph of a 6-Year-Old Boy with Congenital Cytomegalovirus Infection

We present the case of a 6-year-old boy who received a cochlear implant for profound sensorineural hearing loss after being born with cytomegalovirus (CMV) infection. Even after 6 years, CMV DNA was still found in the perilymph of the cochlea. Our case shows that CMV DNA can be present in the cochlea years after congenital CMV infection, and it can explain why progressive and/or late-onset hearing loss occurs in these children.

Follow-up of infants with congenital cytomegalovirus and normal fetal imaging

ObjectiveTo evaluate the outcome of infants with congenital cytomegalovirus (CMV) infection and normal fetal imaging.DesignRetrospective cohort study.SettingTertiary paediatric medical centre.Patients98 infants born to mothers with primary CMV infection in the...

The Role of the Transcription Factor Foxo3 in Hearing Maintenance: Informed Speculation on a New Player in the Cochlea

Molecular genetics has proven to be a powerful approach for understanding early-onset hearing loss. Recent work in late-onset hearing loss uses mouse genetics to identify molecular mechanisms that promote the maintenance of hearing. One such gene, Foxo3, is ontologically involved in preserving mitochondrial function. Significant evidence exists to support the idea that mitochondrial dysfunction is correlated with and can be causal for hearing loss. Foxo3 is also ontologically implicated in driving the circadian cycle, which has recently been shown to influence the molecular response to noise damage. In this review, the molecular framework connecting these cellular processes is discussed in relation to the cellular pathologies observed in human specimens of late-onset hearing loss. In bringing these observations together, the possibility arises that distinct molecular mechanisms work in multiple cell types to preserve hearing. This diversity offers great opportunities to understand and manipulate genetic processes for therapeutic gain.

A Novel Nonsense Mutation of POU4F3 Gene Causes Autosomal Dominant Hearing Loss.

POU4F3 gene encodes a transcription factor which plays an essential role in the maturation and maintenance of hair cells in cochlea and vestibular system. Several mutations of POU4F3 have been reported to cause autosomal dominant nonsyndromic hearing loss in recent years. In this study, we describe a pathogenic nonsense mutation located in POU4F3 in a four-generation Chinese family. Target region capture sequencing was performed to search for the candidate mutations from 81 genes related to nonsyndromic hearing loss in this family. A novel nonsense mutation of POU4F3, c.337C>T (p. Gln113⁎), was identified in a Chinese family characterized by late-onset progressive nonsyndromic hearing loss. The novel mutation cosegregated with hearing loss in this family and was absent in 200 ethnicity-matched controls. The mutation led to a stop codon and thus a truncated protein with no functional domains remained. Transient transfection and immunofluorescence assay revealed that the subcellular localization of the truncated protein differed markedly from normal protein, which could be the underlying reason for complete loss of its normal function. Here, we report the first nonsense mutation of POU4F3 associated with progressive hearing loss and explored the possible underlying mechanism. Routine examination of POU4F3 is necessary for the genetic diagnosis of hereditary hearing loss in the future.

IVS8+1 DelG, a Novel Splice Site Mutation Causing DFNA5 Deafness in a Chinese Family

Background:Nonsyndromic hearing loss (NSHL) is highly heterogeneous, in which more than 90 causative genes have currently been identified. DFNA5 is one of the deafness genes that known to cause autosomal dominant NSHL. Until date, only five DFNA5 mutations have been described in eight families worldwide. In this study, we reported the identification of a novel pathogenic mutation causing DFNA5 deafness in a five-generation Chinese family.Methods:After detailed clinical evaluations of this family, the genomic DNA of three affected individuals was selected for targeted exome sequencing of 101 known deafness genes, as well as mitochondrial DNA and microRNA regions. Co-segregation analysis between the hearing loss and the candidate variant was confirmed in available family members by direct polymerase chain reaction (PCR)-Sanger sequencing. Real-time PCR (RT-PCR) was performed to investigate the potential effect of the pathogenic mutation on messenger RNA splicing.Results:Clinical evaluations revealed a similar deafness phenotype in this family to that of previously reported DFNA5 families with autosomal dominant, late-onset hearing loss. Molecular analysis identified a novel splice site mutation in DFNA5 intron 8 (IVS8+1 delG). The mutation segregated with the hearing loss of the family and was absent in 120 unrelated control DNA samples of Chinese origin. RT-PCR showed skipping of exon 8 in the mutant transcript.Conclusions:We identified a novel DFNA5 mutation IVS8+1 delG in a Chinese family which led to skipping of exon 8. This is the sixth DFNA5 mutation relates to hearing loss and the second one in DFNA5 intron 8. Our findings provide further support to the hypothesis that the DFNA5-associated hearing loss represents a mechanism of gain-of-function.

Cellular and Deafness Mechanisms Underlying Connexin Mutation-Induced Hearing Loss - A Common Hereditary Deafness.

Hearing loss due to mutations in the connexin gene family, which encodes gap junctional proteins, is a common form of hereditary deafness. In particular, connexin 26 (Cx26, GJB2) mutations are responsible for ~50% of non-syndromic hearing loss, which is the highest incidence of genetic disease. In the clinic, Cx26 mutations cause various auditory phenotypes ranging from profound congenital deafness at birth to mild, progressive hearing loss in late childhood. Recent experiments demonstrate that congenital deafness mainly results from cochlear developmental disorders rather than hair cell degeneration and endocochlear potential reduction, while late-onset hearing loss results from reduction of active cochlear amplification, even though cochlear hair cells have no connexin expression. However, there is no apparent, demonstrable relationship between specific changes in connexin (channel) functions and the phenotypes of mutation-induced hearing loss. Moreover, new experiments further demonstrate that the hypothesized K+-recycling disruption is not a principal deafness mechanism for connexin deficiency induced hearing loss. Cx30 (GJB6), Cx29 (GJC3), Cx31 (GJB3), and Cx43 (GJA1) mutations can also cause hearing loss with distinct pathological changes in the cochlea. These new studies provide invaluable information about deafness mechanisms underlying connexin mutation-induced hearing loss and also provide important information for developing new protective and therapeutic strategies for this common deafness. However, the detailed cellular mechanisms underlying these pathological changes remain unclear. Also, little is known about specific mutation-induced pathological changes in vivo and little information is available for humans. Such further studies are urgently required.

Insight into Ocular Genetic Research: Trends in Oman.

Insight into Ocular Genetic Research: Trends in Oman.

Cross-modal and multisensory training may distinctively shape restored senses.

Cross-modal and multisensory training may distinctively shape restored senses.

The impact of hearing loss in the life of adults: A comparison between congenital versus late onset hearing loss

Aim of the Study: The aim of our study was to compare the impact of hearing loss in the life of adults who had congenital hearing loss with that of adults with acquired adult onset hearing loss (auditory neuropathy). Methodology: The quality of life scale questionnaire was administered on two groups. One group consisted of 10 adults with prelingual bilateral severe to profound hearing loss identified before the age of 3 years and who were using hearing aids and had received regular intervention for speech and language development by a qualified speech language pathologist. Second group consisted of 10 adults with auditory neuropathy. Results and Discussion: Wilcoxon rank sum test was used to compare the domains across the groups and the gender distributions between two groups were analyzed using Fisher's exact test. The results revealed that differences between the adults with early-onset hearing loss and late onset hearing loss was statistically significant for most of the domains. The results indicated the fact that accepting a hearing loss during adulthood leads to more psychological trauma than adjusting and living with the hearing loss from the early years of life. Loss of hearing is quite traumatic to adults. Psychological trauma that they undergo is as important as their physiological problem and psychological referral to a clinical psychologist may be beneficial to many of them.