Three case studies of children with late onset or progressive hearing loss

Objectives: To evaluate the clinical features of Japanese DFNA9 families with mutations of the COCH gene. Methods: Mutation screening was performed using targeted next-generation sequencing (NGS) for 63 previously reported deafness genes. The progression of hearing loss and vestibular dysfunction were evaluated by pure-tone audiometry, caloric testing, cVEMP, and computed dynamic posturography. Results: We detected 1 reported mutation of p.G88E and 2 novel mutations of p.I372T and p.C542R. The patients with the novel mutations of p.I372T and p.C542R within the vWFA2 domain showed early onset progressive hearing loss, and the patients with the p.G88E mutation showed late onset hearing loss and acute hearing deterioration over a short period. Vestibular symptoms were reported in the patients with p.G88E and p.C542R. Vestibular testing was performed for the family with the p.G88E mutation. Severe vestibular dysfunction was observed in the proband, and the proband’s son showed unilateral semicircular canal dysfunction with mild hearing loss. Conclusions: Targeted exon resequencing of selected genes using NGS successfully identified mutations in the relatively rare deafness gene, COCH, in the Japanese population. The phenotype is compatible with that described in previous reports. Additional supporting evidence concerning progressive hearing loss and deterioration of vestibular function was obtained from our study.

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Late-onset, acquired and progressive hearing loss: surveillance and the role of the pediatrician

Italian Journal of Pediatrics ◽

10.1186/1824-7288-40-s1-a56 ◽

2014 ◽

Vol 40 (S1) ◽

Author(s):

Giovanni Lenzi ◽

Stefano Berrettini ◽

Jodi M Cutler

Keyword(s):

Hearing Loss ◽

Late Onset ◽

Progressive Hearing Loss

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Clinical Characteristics and In Vitro Analysis of MYO6 Variants Causing Late-onset Progressive Hearing Loss

Genes ◽

10.3390/genes11030273 ◽

2020 ◽

Vol 11 (3) ◽

pp. 273

Author(s):

Shin-ichiro Oka ◽

Timothy F. Day ◽

Shin-ya Nishio ◽

Hideaki Moteki ◽

Maiko Miyagawa ◽

...

Keyword(s):

Hearing Loss ◽

Clinical Characteristics ◽

Large Scale ◽

Autosomal Dominant ◽

Late Onset ◽

Site Directed Mutagenesis ◽

Molecular Characteristics ◽

Progressive Hearing Loss ◽

Cochlear Hair Cells

MYO6 is known as a genetic cause of autosomal dominant and autosomal recessive inherited hearing loss. In this study, to clarify the frequency and clinical characteristics of hearing loss caused by MYO6 gene mutations, a large-scale genetic analysis of Japanese patients with hearing loss was performed. By means of massively parallel DNA sequencing (MPS) using next-generation sequencing for 8074 Japanese families, we found 27 MYO6 variants in 33 families, 22 of which are novel. In total, 2.40% of autosomal dominant sensorineural hearing loss (ADSNHL) in families in this study (32 out of 1336) was found to be caused by MYO6 mutations. The present study clarified that most cases showed juvenile-onset progressive hearing loss and their hearing deteriorated markedly after 40 years of age. The estimated hearing deterioration was found to be 0.57 dB per year; when restricted to change after 40 years of age, the deterioration speed was accelerated to 1.07 dB per year. To obtain supportive evidence for pathogenicity, variants identified in the patients were introduced to MYO6 cDNA by site-directed mutagenesis and overexpressed in epithelial cells. They were then assessed for their effects on espin1-induced microvilli formation. Cells with wildtype myosin 6 and espin1 co-expressed created long microvilli, while co-expression with mutant constructs resulted in severely shortened microvilli. In conclusion, the present data clearly showed that MYO6 is one of the genes to keep in mind with regard to ADSNHL, and the molecular characteristics of the identified gene variants suggest that a possible pathology seems to result from malformed stereocilia of the cochlear hair cells.

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THOC1 deficiency leads to late-onset nonsyndromic hearing loss through p53-mediated hair cell apoptosis

10.1101/719823 ◽

2019 ◽

Author(s):

Luping Zhang ◽

Yu Gao ◽

Ru Zhang ◽

Feifei Sun ◽

Cheng Cheng ◽

...

Keyword(s):

Hearing Loss ◽

Hair Cell ◽

Hair Cells ◽

Cell Apoptosis ◽

Late Onset ◽

Nonsyndromic Hearing Loss ◽

Progressive Hearing Loss ◽

Age Related ◽

Age Related Hearing Loss ◽

Shed Light

AbstractApoptosis of cochlear hair cells is a key step towards age-related hearing loss. Although numerous genes have been implicated in the genetic causes of late-onset, progressive hearing loss, few show direct links to the proapoptotic process. By genome-wide linkage analysis and whole exome sequencing, we identified a heterozygous p.L183V variant in THOC1 as the probable cause of the late-onset, progressive, non-syndromic hearing loss in a large dominant family. Thoc1, a member of the conserved multisubunit THO/TREX ribonucleoprotein complex, is highly expressed in mouse and zebrafish hair cells. The Thoc1 mutant zebrafish generated by gRNA-Cas9 system lacks the C-startle response, indicative of the hearing dysfunction. Both Thoc1 mutant and knockdown zebrafish have greatly reduced hair cell numbers, while the latter can be rescued by embryonic microinjection of human wild-type THOC1 mRNA but to significantly lesser degree by the p.L183V mutant mRNA. The Thoc1 deficiency resulted in marked apoptosis in zebrafish hair cells. Consistently, transcriptome sequencing of the mutants showed significantly increased gene expression in the p53-associated signaling pathway. Depletion of p53 or applying the p53 inhibitor Pifithrin-α significantly rescued the hair cell loss in the Thoc1 knockdown zebrafish. Our results suggested that THOC1 deficiency lead to late-onset, progressive hearing loss through p53-mediated hair cell apoptosis. This is to our knowledge the first human disease associated with THOC1 mutations and may shed light on the molecular mechanism underlying the age-related hearing loss.Significance StatementFor the first time, we found that THOC1 deficiency leads to late-onset nonsyndromic hearing loss. Furthermore, we revealed the hypomorphic THOC1 induced p53-mediated hair cell apoptosis. This is to our knowledge the first human disease associated with THOC1 mutations and may shed light on the molecular mechanism underlying the age-related hearing loss.

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Acquired, late onset and progressive hearing loss - data from one newborn hearing screening site

Archives of Disease in Childhood ◽

10.1136/adc.2011.212563.71 ◽

2011 ◽

Vol 96 (Supplement 1) ◽

pp. A33-A33 ◽

Cited By ~ 1

Author(s):

S. E. Rose

Keyword(s):

Hearing Loss ◽

Late Onset ◽

Hearing Screening ◽

Newborn Hearing Screening ◽

Progressive Hearing Loss ◽

Loss Data ◽

Newborn Hearing ◽

Screening Site

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Novel connexin 30 and connexin 26 mutational spectrum in patients with progressive sensorineural hearing loss

The Journal of Laryngology & Otology ◽

10.1017/s0022215112001119 ◽

2012 ◽

Vol 126 (8) ◽

pp. 763-769 ◽

Cited By ~ 6

Author(s):

S Battelino ◽

B Repič Lampret ◽

M Žargi ◽

K Trebušak Podkrajšek

Keyword(s):

Hearing Loss ◽

Sensorineural Hearing Loss ◽

Gap Junction ◽

Late Onset ◽

Gene Mutations ◽

Sensorineural Hearing ◽

Progressive Hearing Loss ◽

Junction Protein ◽

Gap Junction Protein ◽

Beta 2

AbstractObjective:Mutations in the gap junction protein beta-2 gene (‘GJB2’) are known to be responsible for mild to profound congenital and late-onset hearing loss. This study aimed to investigate the molecular basis of progressive hearing loss compared with non-progressive hearing loss.Methods:Following clinical otorhinolaryngological evaluation, a genetic analysis was performed in a cohort of 72 patients with progressive sensorineural hearing loss.Results:Pathological genotypes were established in 16 patients (22.2 per cent). Six different gap junction protein beta-2 gene mutations were detected in 15 patients, with the c.35delG mutation responsible for 56 per cent of the mutated alleles. A novel gap junction protein beta-6 gene (‘GJB6’) mutation (p.Met203Val) was observed in one patient with mild progressive hearing loss.Conclusion:Analyses of gap junction protein beta-2 and -6 genes revealed that similar pathological genotypes, occurring with similar frequencies, were responsible for progressive hearing loss, compared with reported genotypes for non-progressive hearing loss patients. Thus, genotype cannot be used to differentiate non-progressive from progressive hearing loss cases; in this study, patients both with and without an established pathological genotype had a similar clinical course.

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Hearing Outcome of Stapes Surgery in NIENT, Bangladesh

Bangladesh Journal of Otorhinolaryngology ◽

10.3329/bjo.v26i1.47950 ◽

2020 ◽

Vol 26 (1) ◽

pp. 31-36

Author(s):

Md Zakaria Sarkar ◽

AHM Ferdows Nur ◽

Utpal Kumar Dutta ◽

Muhammad Rafiqul Islam ◽

Debabrota Roy ◽

...

Keyword(s):

Hearing Loss ◽

Cross Sectional Study ◽

Surgical Trauma ◽

Group 14 ◽

Progressive Hearing Loss ◽

Cross Sectional ◽

Hearing Gain ◽

Hearing Outcome

Objective: The aim of this study was to evaluate hearing outcome after stapedotomy in patients with Otosclerosis. Methods: This cross sectional study was carried out from July 2017 to January 2019 in National Institute of ENT, Unit V. About 22 patients with Otosclerosis were included in this study. Diagnosis of Otosclerosis was based on the history, medical status with Otoscopy, Tuning fork tests and Audiometric tests. We compiled data on the pre and post operative air-bone gap (ABG) at 0.5, 1, 2 KHZ. The ABG was Calculated using AC and BC thresholds on the same audiogram. Post operative hearing gain was then Calculated from the ABG before the operation minus the ABG of the last follow up examination Results: In this study most of the cases were age group 14-30 years (72.7%), female (54.5%). Most common symptoms was progressive hearing loss, tinnitus (77.8%).The average preoperative hearing loss in this study was (AC) was 48.31±7.68. The average post opt. hearing (AC) at follow up was 28.95±10.30 with an average hearing gain of 15.40±8.53 dB which was significant. The average pre-operative ABG was 28.99 dB ± 8.10. The average post opt. ABG was analyzed at 1 follow up showed ABG 13.18±8.09 dB which was found to be significant. Conclusion: Stapedotomy is an effective surgical procedure for the treatment of otosclerosis which leads to improvement in patient’s quality of life. A favorable hearing outcome can be obtained by the combination of experienced hands with minimal surgical trauma and appropriate surgical technique. Bangladesh J Otorhinolaryngol; April 2020; 26(1): 31-36

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