Clinical genetic evaluation of patients with auditory neuropathy spectrum

January 03, 2017

Hearing loss - a form of auditory neuropathy - is the most prevalent sensory disease in humans, caused by a variety of genetic and environmental factors. Auditory neuropathy is a complex set of disorders and needs to be studied and understood in a multidisciplinary context.

The non-syndromic hearing loss is about 70% of hereditary cases. Different inheritance patterns are observed, but theautosomal recessive forms are the most frequent. The heterogeneity of autosomal recessive non-syndromic hearing loss is extremely high, for which approximately 71 loci have been described and 40 genes associated with hearing loss have been identified up to this moment.

Auditory neuropathy is a type of hearing loss that constitutes a change in the conduct of the auditory stimulus by the involvement of inner hair cells or auditory nerve synapses. It is characterized by the absence or alteration of waves in the examination of brainstem auditory evoked potentials, with positives findings related to otoacoustic and/or cochlear microphonic. At present, four loci associated with nonsyndromic auditory neuropathy have been mapped: Autosomal recessive deafness?9 [DFNB9, the otoferlin (OTOF) gene] and autosomal recessive deafness?59 [DFNB59; the pejvakin (PJVK) gene], associated with autosomal recessive inheritance; the autosomal dominant auditory neuropathy gene [AUNA1, the diaphanous?3 (DIAPH3) gene] and AUNX1, linked to chromosome X.

Furthermore, mutations of connexin 26 [the gap junction β2 (GJB2) gene] have also been associated with the disease. OTOF gene mutations exert a significant role in auditory neuropathy. More than 80 pathogenic mutations have been identified in individuals with non?syndromic deafness in populations of distinct origins, with an emphasis on the p.Q829X mutation, which was found in ~3% of cases of deafness in the Spanish population. The identification of genetic alterations responsible for auditory neuropathy is one of the challenges contributing to understand the molecular bases of the different phenotypes of hearing loss.

Thus, the present study investigates molecular changes in the OTOF gene in patients with auditory neuropathy, and attempts to develop a DNA chip for the molecular diagnosis of auditory neuropathy using mass spectrometry for genotyping.

Genetic alterations were investigated in 47 patients with hearing loss and clinical diagnosis of auditory neuropathy, and the c.35delG mutation in the GJB2 gene was identified in three homozygous patients, and the heterozygous parents of one of these cases.

Additionally, OTOF gene mutations were tracked by complete sequencing of 48 exons, although these results are still preliminary. Studying the genetic basis of auditory neuropathy is of utmost importance for obtaining a differential diagnosis, developing more specific treatments and more accurate genetic counseling. The aim of this study is to investigate molecular changes in otoferlin gene (OTOF) in patients with auditory neuropathy, search for other genetic and molecular changes that may be related to auditory neuropathy, describe the clinical data of patients with clinical neuropathy diagnosis hearing followed at Unicamp Otolaryngology Department and detail the subgroup of patients undergoing treatment with cochlear implants. Mutation of GJB2 gene is present in 7.5% of patients studied in this project (p> .05) and any mutation at OTOF gene was identified. Nearly 80% of patients had symptoms in the first year of life, and 53% had severe / profound hearing loss.

The cochlear implant had excellent outcomes in these patients, with excellent speech development, gain in language acquisition and the patients and their families were satisfied with this therapeutic modality. The treatment should focus on developing methods in which the patient may be able to get more skills and could interpret the audiosignals and communicate appropriately.

Auditory training and sound stimulation are essential tools in this process. There is some positive scientific evidence related to the cochlear implants and auditory neuropathy, so this treatment should be considered when there is poor or insufficient development in the acquisition and development of speech, even with appropriate therapies.

Auditory neuropathy is still as a major diagnostic and therapeutic challenge, and its etiology (genetic and environmental) is still uncertain. We believe that the auditory neuropathy is a group of diseases where the electrophysiological hearing evaluation and genetics can be great tools to help the identification and selection of patients with this disorder.
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Reference: Carvalho, GM.; et al (2016). Relationship Between Patients with Clinical Auditory Neuropathy Spectrum Disorder and Mutations in Gjb2 Gene. The Open Neurology Journal ., DOI: 10.2174/1874205X01610010127

Bentham Science Publishers

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