Novel Pathogenic Variants in PJVK, the Gene Encoding Pejvakin, in Subjects with Autosomal Recessive Non-Syndromic Hearing Impairment and Auditory Neuropathy Spectrum Disorder

Pathogenic variants in the PJVK gene cause the DFNB59 type of autosomal recessive non-syndromic hearing impairment (AR-NSHI). Phenotypes are not homogeneous, as a few subjects show auditory neuropathy spectrum disorder (ANSD), while others show cochlear hearing loss. The numbers of reported cases and pathogenic variants are still small to establish accurate genotype-phenotype correlations. We investigated a cohort of 77 Spanish familial cases of AR-NSHI, in whom DFNB1 had been excluded, and a cohort of 84 simplex cases with isolated ANSD in whom OTOF variants had been excluded. All seven exons and exon-intron boundaries of the PJVK gene were sequenced. We report three novel DFNB59 cases, one from the AR-NSHI cohort and two from the ANSD cohort, with stable, severe to profound NSHI. Two of the subjects received unilateral cochlear implantation, with apparent good outcomes. Our study expands the spectrum of PJVK mutations, as we report four novel pathogenic variants: p.Leu224Arg, p.His294Ilefs*43, p.His294Asp and p.Phe317Serfs*20. We review the reported cases of DFNB59, summarize the clinical features of this rare subtype of AR-NSHI and discuss the involvement of PJVK in ANSD.

A Rare Case of Perrault Syndrome with Auditory Neuropathy Spectrum Disorder: Cochlear Implantation Treatment and Literature Review

Perrault syndrome (PRLTS) is a rare autosomal recessive disorder characterised by ovarian failure in females and sensorineural hearing loss (SNHL) in both genders. In the present paper we describe a child affected by PRLTS3, due to CLPP homozygous mutations, presenting auditory neuropathy spectrum disorder (ANSD) with bilateral progressive SNHL. This is the first case reported in the literature of an ANSD in PRLTS3. CLPP is a nuclear encoded mitochondrial protease directed at the mitochondrial matrix. It is encoded on chromosome 19. This protease participates in mitochondrial protein quality control by degrading misfolded or damaged proteins, thus maintaining the normal metabolic function of the cell. In PRLTS3, the peptidase activity of CLPP is suppressed. Neurological impairments involved in PRLTS3 suggest that the pathogenic mutations in CLPP might trigger a mitochondrial dysfunction. A comprehensive description of the clinical and audiological presentation, as well as the issues related to cochlear implant (CI) procedure and the results, are addressed and discussed. A brief review of the literature on this topic is also provided.

Effectiveness of Channel-Free Hearing Aid and Noise Desensitisation Training in Auditory Neuropathy Spectrum Disorder - Single Case Study

Auditory Neuropathy Spectrum Disorder is a rare condition wherein neural transmission through the VIIIth nerve and auditory brainstem is disrupted with intact peripheral hearing. Most frequently reported symptoms by individuals suffering from such conditions include impaired speech discrimination especially in presence of background noise. The aim of this single case study is to emphasize the effectiveness of channel-free technology as a rehabilitative option and to demonstrate the improvement in speech perception in noise with noise desensitisation training. A 24-year-old male patient reported to the National Institute of Speech and Hearing with the complaint of poor speech comprehension. The audiological profile revealed, bilateral moderate sensorineural hearing loss in pure tone audiometry with poor speech discrimination scores, bilateral ‘A’ type tympanogram with absent acoustic reflexes, good signal to noise ratio in otoacoustic emissions, and absent Auditory Brainstem Response at 95 dBnHL bilaterally suggestive of auditory neuropathy spectrum disorder in both the ears. As a part of rehabilitation, hearing aids with multiple channels and channel-free technology were tried and better speech discrimination scores were obtained with channel-free technology. In order to address poor speech discrimination in presence of noise, noise desensitisation training was given at different Signal to Noise Ratio with channel-free hearing aids and was found to be effective in improving the speech discrimination scores especially in adverse listening conditions. Key words: Auditory neuropathy spectrum disorder, Channel free hearing aid, Noise desensitisation.

The audiovestibular profile of Brown-Vialetto-Van Laere syndrome

BackgroundBrown-Vialetto-Van Laere syndrome, a rare disorder associated with motor, sensory and cranial nerve neuropathy, is caused by mutations in riboflavin transporter genes SLC52A2 and SLC52A3. Hearing loss is a characteristic feature of Brown-Vialetto-Van Laere syndrome and has been shown in recent studies to be characterised by auditory neuropathy spectrum disorder.MethodThis study reports the detailed audiovestibular profiles of four cases of Brown-Vialetto-Van Laere syndrome with SLC52A2 and SLC52A3 mutations. All of these patients had auditory neuropathy spectrum disorder.ResultsThere was significant heterogeneity in vestibular function and in the benefit gained from cochlear implantation. The audiological response to riboflavin therapy was also variable, in contrast to generalised improvement in motor function.ConclusionWe suggest that comprehensive testing of vestibular function should be conducted in Brown-Vialetto-Van Laere syndrome, in addition to serial behavioural audiometry as part of the systematic examination of the effects of riboflavin.

Cochlear Implant Behavioral Outcomes for Children With Auditory Neuropathy Spectrum Disorder: A Mini-Systematic Review

Objective The aim of this mini-systematic review was to evaluate the evidence reporting speech, language, and auditory behavioral outcome measures for children with a diagnosis of auditory neuropathy spectrum disorder (ANSD) who received cochlear implants (CIs) prior to 3 years of age. Method A mini-systematic review of the literature supporting evidence-based practices was performed. Two databases were searched utilizing a search strategy derived from the PICO (patient, intervention, comparison, outcome) framework. Peer-reviewed articles published between 2009 and 2019 evaluating children with a diagnosis of ANSD who were implanted prior to 3 years of age with a range of speech, language, and auditory behavioral outcomes were included. Four articles meeting inclusion criteria were critically appraised for reputable research design and risks of bias. Each of the four studies was assigned a level of evidence for effectiveness and quality assessment rating. Results Evidence supports cochlear implantation as an appropriate intervention for children with ANSD. Improvements in outcome performance were observed in all the included studies. Children with ANSD fit with CIs can achieve outcomes similar to children with sensorineural hearing loss and CIs, despite the heterogeneity of ANSD. Conclusion These findings have implications for clinical practice and for future research with current CI technology for facilitating parent education, counseling, and realistic expectations for children with ANSD and CIs.