Emerging Gene Therapies for Genetic Hearing Loss


              <p>Gene therapy, or the treatment of human disease using genetic material, for inner ear dysfunction is coming of age. Recent progress in developing gene therapy treatments for genetic hearing loss has demonstrated tantalizing proof-of-principle in animal models. While successful translation of this progress into treatments for humans awaits, there is growing interest from patients, scientists, clinicians, and industry. Nonetheless, it is clear that a number of hurdles remain, and expectations for total restoration of auditory function should remain tempered until these challenges have been overcome. Here, we review progress, prospects, and challenges for gene therapy in the inner ear. We focus on technical aspects, including routes of gene delivery to the inner ear, choice of vectors, promoters, inner ear targets, therapeutic strategies, preliminary success stories, and points to consider for translating of these successes to the clinic.</p><br /><br />


Incidence of Discomfort During Pure-Tone Audiometry and Measurement of Uncomfortable Loudness Levels Among People Seeking Help for Tinnitus and/or Hyperacusis


The aim of this study was to assess the proportion of patients seen in a tinnitus and hyperacusis therapy clinic for whom presentation levels based on the British Society of Audiology (BSA)–recommended procedures for pure-tone audiometry and determination of uncomfortable loudness levels (ULLs) exceed ULLs, leading to discomfort during administration of these procedures.


This was a retrospective cross-sectional study of 362 consecutive patients who attended a National Health Service audiology clinic for tinnitus and/or hyperacusis rehabilitation.


For 21% of the patients, presentation levels based on the BSA procedure for pure-tone audiometry exceeded the ULL for at least 1 of the measured frequencies (excluding the first frequency tested, 1 kHz): 0.25, 0.5, 2, 3, 4, 6, and 8 kHz. For 24% of patients, the starting presentation level of 60 dB hearing level recommended for determination of ULLs exceeded the ULL for at least 1 frequency.


The starting presentation levels used for pure-tone audiometry and measurement of ULLs should be lower than those recommended by the BSA for people with tinnitus and hyperacusis.


SLHS MA students receive awards from the American Speech-Language-Hearing Association!

MSLP logoTwo SLHS MA students, Carlos Arias and Diane Guerrero, were recently selected for ASHA’s Minority Student Leadership Program. This program is designed to enhance leadership skills for speech-language pathology and audiology students from historically under-represented racial and ethnic populations.  Applicants for this program were asked to discuss career goals and past experiences in working with people with communication disorders from culturally- and linguistically-diverse (CLD) populations.  SLHS has a strong focus in training all students to work with clients from CLD populations.  We are proud that two of our students have been selected for this highly competitive program.  

As part of this program, Carlos and Diane will attend the ASHA National Convention this November. They will have the opportunity to learn more about how ASHA works, strengthen leadership skills, and interact with leaders in the field– including researchers, university faculty from across the world, ASHA leaders, clinicians, and MSLP alumni.  

We are honored to have Carlos and Diane represent SLHS and SDSU!

Congratulations, Carlos and Diane!


Absence of KCNQ4 mutation in Bengali families with ADNSHL originated from West Bengal, India.

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Absence of KCNQ4 mutation in Bengali families with ADNSHL originated from West Bengal, India.

Int J Pediatr Otorhinolaryngol. 2017 Sep;100:35-38

Authors: Adhikary B, Bankura B, Biswas S, Paul S, Das M


OBJECTIVE: Autosomal Dominant Non-Syndromic Hearing Loss (ADNSHL) is extremely heterogeneous in nature. More than 60 loci with 30 different genes have been identified linked to ADNSHL. Mutation in KCNQ4 is considered as one of the most common causative factor responsible for ADNSHL. No study focused on the genetic alteration of KCNQ4 gene among hearing loss patients in India. The present study for the first time was carried out to determine the mutation spectrum of KCNQ4 gene in ADNSHL patients of West Bengal state, India.

METHOD: Twenty nine individuals from 10 independent ADNSHL family (with two or more generation affected) were studied both clinically and genetically. Most of the patients showed moderate progressive sensorineural hearing loss. Mutation analysis was conducted for KCNQ4 gene using polymerase chain reaction followed by direct sequencing.

RESULTS: Neither any reported nor a novel pathogenic mutation in KCNQ4was detected in our studied group, in contrast to the findings among East Asians.

CONCLUSION: The result of the present study suggests that mutations in KCNQ4 gene are unlikely to be a major causative factor of ADNSHL in our studied patients from West Bengal, India, pointing to other genes might be responsible for ADNSHL in our studied patients.

PMID: 28802383 [PubMed – in process]


The first sporadic case of DFNA11 identified by next-generation sequencing.

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The first sporadic case of DFNA11 identified by next-generation sequencing.

Int J Pediatr Otorhinolaryngol. 2017 Sep;100:183-186

Authors: Kaneko Y, Nakano A, Arimoto Y, Nara K, Mutai H, Matsunaga T


We report the first sporadic case of nonsyndromic autosomal dominant hearing loss (DFNA11). The patient was a 5-year-old boy with moderate bilateral hearing loss. Targeted next-generation sequencing analysis of patient DNA identified a known heterozygous DFNA11 mutation, c.689C > T, in MYO7A, encoding p.Ala230Val. The mutation was not detected in the parents of the patient and is considered to be de novo. This mutation is identical to the one reported previously in an Italian family. Accumulation of mutation data increases the feasibility of identifying autosomal dominant mutations in sporadic sensorineural hearing loss.

PMID: 28802369 [PubMed – in process]


Exploring reasons for late identification of children with early-onset hearing loss.

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Exploring reasons for late identification of children with early-onset hearing loss.

Int J Pediatr Otorhinolaryngol. 2017 Sep;100:160-167

Authors: Fitzpatrick EM, Dos Santos JC, Grandpierre V, Whittingham J


INTRODUCTION: Several studies have shown that early identification of childhood hearing loss leads to better language outcomes. However, delays in the confirmation of hearing loss persist even in the presence of well-established universal newborn hearing screening programs (UNHS). The objective of this population-based study was to document the proportion of children who experienced delayed confirmation of congenital and early onset hearing loss in a UNHS program in one region of Canada. The study also sought to determine the reasons for delayed confirmation of hearing loss in children.

METHODS: Population level data related to age of first assessment, age of identification and clinical characteristics were collected prospectively for all children identified through the UNHS program. We documented the number of children who experienced delay (defined as more than 3 months) from initial audiologic assessment to confirmation of hearing loss. A detailed chart review was subsequently performed to examine the reasons for delay to confirmation.

RESULTS: Of 418 children identified from 2003 to 2013, 182 (43.5%) presented with congenital or early onset hearing loss, of whom 30 (16.5%) experienced more than 3 months delay from initial audiologic assessment to confirmation of their hearing disorder. The median age of first assessment and confirmation of hearing loss for these 30 children was 3.7 months (IQR: 2.0, 7.6) and 13.8 months (IQR: 9.7, 26.1) respectively. Close examination of the factors related to delay to confirmation revealed that for the overwhelming majority of children, a constellation of factors contributed to late diagnosis. Several children (n = 22; 73.3%) presented with developmental/medical issues, 15 of whom also had middle ear dysfunction at assessment, and 9 of whom had documented family follow-up concerns. For the remaining eight children, additional reasons included ongoing middle ear dysfunction for five children, complicated by family follow-up concerns (n = 3) and mild hearing loss (n = 1) and the remaining three children had isolated reasons related to family follow-up (n = 1) or mild hearing loss (n = 2).

CONCLUSION: Despite the progress made in the early detection of pediatric hearing loss since UNHS, a substantial number of children referred for early assessment can experience late confirmation and intervention. In particular, infants with developmental and/or medical issues including middle ear disorders are at particular risk for longer time to confirmation of hearing loss.

PMID: 28802365 [PubMed – in process]


Exome sequencing identifies a novel missense mutation of WFS1 as the cause of non-syndromic low-frequency hearing loss in a Chinese family.

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Exome sequencing identifies a novel missense mutation of WFS1 as the cause of non-syndromic low-frequency hearing loss in a Chinese family.

Int J Pediatr Otorhinolaryngol. 2017 Sep;100:1-7

Authors: Niu Z, Feng Y, Hu Z, Li J, Sun J, Chen H, He C, Wang X, Jiang L, Liu Y, Cai X, Wang L, Cai Y, Liu X, Mei L


OBJECTIVE: Autosomal dominant non-syndromic low-frequency sensorineural hearing loss (LFSNHL) DFNA6/14/38 is an uncommon type of hearing loss that classically affects low frequencies of 2000 Hz and below, demonstrating an ascending configuration. The current study aimed to investigate the cause of LFSNHL in a five-generation Chinese family.

METHODS: The phenotype of the Chinese family was characterized using audiologic testing and pedigree analysis. The combined approach of array screening and whole-exome sequencing was used to identify the disease-causing gene in this family.

RESULTS: This pedigree, in which the affected subjects presented isolated low-frequency sensorineural hearing impairment with childhood onset, was associated with autosomal dominant inheritance of the c.2591A > G mutation in exon 8 of the Wolframin syndrome 1 (WFS1) gene which was not present in 286 unrelated controls with matched ancestry and is highly conserved across species. In addition, several mutations affecting the Glu864 residue have been previously identified in different populations, suggesting that this site is likely to be a mutational hot spot.

CONCLUSIONS: We identified a novel substitution, Glu864Gly, of WFS1 as the causative variant for this pedigree. Our data extend the mutation spectrum of the WFS1 gene in Chinese individuals and may contribute to establishing a better genotype-phenotype correlation for LFSNHL.

PMID: 28802351 [PubMed – in process]


A recessive mutation in beta-IV-spectrin (SPTBN4) associates with congenital myopathy, neuropathy, and central deafness.

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A recessive mutation in beta-IV-spectrin (SPTBN4) associates with congenital myopathy, neuropathy, and central deafness.

Hum Genet. 2017 Jul;136(7):903-910

Authors: Knierim E, Gill E, Seifert F, Morales-Gonzalez S, Unudurthi SD, Hund TJ, Stenzel W, Schuelke M


Congenital myopathies are a heterogeneous group of muscle disorders that are often genetically determined. Here, we investigated a boy with congenital myopathy, deafness, and neuropathy from a consanguineous Kurdish family by autozygosity mapping and whole exome sequencing. We found a homozygous nonsense mutation in SPTBN4 [c.1597C>T, NM_020971.2; p.(Q533*), NP_066022.2; ClinVar SUB2292235] encoding βIV-spectrin, a non-erythrocytic member of the β-spectrin family. Western blot confirmed the absence of the full-length 288 kDa isoform in muscle and of a specific 72 kDa isoform in fibroblasts. Clinical symptoms of the patient largely corresponded to those described for the quivering mouse, a loss-of-function animal model. Since the human phenotype of βIV-spectrin deficiency included a myopathy with incomplete congenital fiber-type disproportion, we investigated muscle of the quivering (qv4J) mouse and found complete absence of type 1 fibers (fiber-type 2 uniformity). Immunohistology confirmed expression of βIV-spectrin in normal human and mouse muscle at the sarcolemma and its absence in patient and quivering (qv4J) mouse. SPTBN4 mRNA-expression levels in healthy skeletal muscle were found in the range of other regulatory proteins. More patients have to be described to confirm the triad of congenital myopathy, neuropathy and deafness as the defining symptom complex for βIV-spectrin deficiency.

PMID: 28540413 [PubMed – indexed for MEDLINE]


Exome sequencing reveals a de novo POLD1 mutation causing phenotypic variability in mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL).

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Exome sequencing reveals a de novo POLD1 mutation causing phenotypic variability in mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL).

Metabolism. 2017 Jun;71:213-225

Authors: Elouej S, Beleza-Meireles A, Caswell R, Colclough K, Ellard S, Desvignes JP, Béroud C, Lévy N, Mohammed S, De Sandre-Giovannoli A


BACKGROUND: Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL) is an autosomal dominant systemic disorder characterized by prominent loss of subcutaneous fat, a characteristic facial appearance and metabolic abnormalities. This syndrome is caused by heterozygous de novo mutations in the POLD1 gene. To date, 19 patients with MDPL have been reported in the literature and among them 14 patients have been characterized at the molecular level. Twelve unrelated patients carried a recurrent in-frame deletion of a single codon (p.Ser605del) and two other patients carried a novel heterozygous mutation in exon 13 (p.Arg507Cys). Additionally and interestingly, germline mutations of the same gene have been involved in familial polyposis and colorectal cancer (CRC) predisposition.

PATIENTS AND METHODS: We describe a male and a female patient with MDPL respectively affected with mild and severe phenotypes. Both of them showed mandibular hypoplasia, a beaked nose with bird-like facies, prominent eyes, a small mouth, growth retardation, muscle and skin atrophy, but the female patient showed such a severe and early phenotype that a first working diagnosis of Hutchinson-Gilford Progeria was made. The exploration was performed by direct sequencing of POLD1 gene exon 15 in the male patient with a classical MDPL phenotype and by whole exome sequencing in the female patient and her unaffected parents.

RESULTS: Exome sequencing identified in the latter patient a de novo heterozygous undescribed mutation in the POLD1 gene (NM_002691.3: c.3209T>A), predicted to cause the missense change p.Ile1070Asn in the ZnF2 (Zinc Finger 2) domain of the protein. This mutation was not reported in the 1000 Genome Project, dbSNP and Exome sequencing databases. Furthermore, the Isoleucine1070 residue of POLD1 is highly conserved among various species, suggesting that this substitution may cause a major impairment of POLD1 activity. For the second patient, affected with a typical MDPL phenotype, direct sequencing of POLD1 exon 15 revealed the recurrent in-frame deletion (c.1812_1814del, p.S605del).

CONCLUSION: Our work highlights that mutations in different POLD1 domains can lead to phenotypic variability, ranging from dominantly inherited cancer predisposition syndromes, to mild MDPL phenotypes without lifespan reduction, to very severe MDPL syndromes with major premature aging features. These results also suggest that POLD1 gene testing should be considered in patients presenting with severe progeroid features.

PMID: 28521875 [PubMed – indexed for MEDLINE]


Speech Perception in Noise and Listening Effort of Older Adults With Nonlinear Frequency Compression Hearing Aids.

Objectives: The purpose of this laboratory-based study was to compare the efficacy of two hearing aid fittings with and without nonlinear frequency compression, implemented within commercially available hearing aids. Previous research regarding the utility of nonlinear frequency compression has revealed conflicting results for speech recognition, marked by high individual variability. Individual differences in auditory function and cognitive abilities, specifically hearing loss slope and working memory, may contribute to aided performance. The first aim of the study was to determine the effect of nonlinear frequency compression on aided speech recognition in noise and listening effort using a dual-task test paradigm. The hypothesis, based on the Ease of Language Understanding model, was that nonlinear frequency compression would improve speech recognition in noise and decrease listening effort. The second aim of the study was to determine if listener variables of hearing loss slope, working memory capacity, and age would predict performance with nonlinear frequency compression.

Design: A total of 17 adults (age, 57-85 years) with symmetrical sensorineural hearing loss were tested in the sound field using hearing aids fit to target (NAL-NL2). Participants were recruited with a range of hearing loss severities and slopes. A within-subjects, single-blinded design was used to compare performance with and without nonlinear frequency compression. Speech recognition in noise and listening effort were measured by adapting the Revised Speech in Noise Test into a dual-task paradigm. Participants were required trial-by-trial to repeat the last word of each sentence presented in speech babble and then recall the sentence-ending words after every block of six sentences. Half of the sentences were rich in context for the recognition of the final word of each sentence, and half were neutral in context. Extrinsic factors of sentence context and nonlinear frequency compression were manipulated, and intrinsic factors of hearing loss slope, working memory capacity, and age were measured to determine which participant factors were associated with benefit from nonlinear frequency compression.

Results: On average, speech recognition in noise performance significantly improved with the use of nonlinear frequency compression. Individuals with steeply sloping hearing loss received more recognition benefit. Recall performance also significantly improved at the group level, with nonlinear frequency compression revealing reduced listening effort. The older participants within the study cohort received less recall benefit than the younger participants. The benefits of nonlinear frequency compression for speech recognition and listening effort did not correlate with each other, suggesting separable sources of benefit for these outcome measures.

Conclusions: Improvements of speech recognition in noise and reduced listening effort indicate that adult hearing aid users can receive benefit from nonlinear frequency compression in a noisy environment, with the amount of benefit varying across individuals and across outcome measures. Evidence supports individualized selection of nonlinear frequency compression, with results suggesting benefits in speech recognition for individuals with steeply sloping hearing losses and in listening effort for younger individuals. Future research is indicated with a larger data set on the dual-task paradigm as a potential cognitive outcome measure.

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