AIFM1 variants associated with auditory neuropathy spectrum disorder cause apoptosis due to impaired apoptosis-inducing factor dimerization / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Auditory neuropathy spectrum disorder (ANSD) represents a variety of sensorineural deafness conditions characterized by abnormal inner hair cells and/or auditory nerve function, but with the preservation of outer hair cell function. ANSD represents up to 15% of individuals with hearing impairments. Through mutation screening, bioinformatic analysis and expression studies, we have previously identified several apoptosis-inducing factor (AIF) mitochondria-associated 1 (AIFM1) variants in ANSD families and in some other sporadic cases. Here, to elucidate the pathogenic mechanisms underlying each AIFM1 variant, we generated AIF-null cells using the clustered regularly interspersed short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and constructed AIF-wild type (WT) and AIF-mutant (mut) (p.‍T260A, p.‍R422W, and p.‍R451Q) stable transfection cell lines. We then analyzed AIF structure, coenzyme-binding affinity, apoptosis, and other aspects. Results revealed that these variants resulted in impaired dimerization, compromising AIF function. The reduction reaction of AIF variants had proceeded slower than that of AIF-WT. The average levels of AIF dimerization in AIF variant cells were only 34.5%‍‒‍49.7% of that of AIF-WT cells, resulting in caspase-independent apoptosis. The average percentage of apoptotic cells in the variants was 12.3%‍‒‍17.9%, which was significantly higher than that (6.9%‍‒‍7.4%) in controls. However, nicotinamide adenine dinucleotide (NADH) treatment promoted the reduction of apoptosis by rescuing AIF dimerization in AIF variant cells. Our findings show that the impairment of AIF dimerization by AIFM1 variants causes apoptosis contributing to ANSD, and introduce NADH as a potential drug for ANSD treatment. Our results help elucidate the mechanisms of ANSD and may lead to the provision of novel therapies.

Effect of Quiet and Noise on P300 Response in Individuals with Auditory Neuropathy Spectrum Disorder

Abstract Introduction Auditory neuropathy spectrum disorder (ANSD) is a clinical condition in which individuals have normal cochlear responses and abnormal neural responses. There is a lack of evidence in the literature regarding the neural discrimination skill in individuals with ANSD, especially when the signal is presented in the presence of noise. Objectives The present study was performed with the aim to investigate auditory discrimination skill, in quiet and in the presence of noise, in individuals with ANSD and to compare the findings with normal-hearing individuals. Methods A total of 30 individuals with normal hearing sensitivity and 30 individuals with ANSD in the age range of 15 to 55 years old, with the mean age of 27.86 years old, were the participants. P300 response was recorded from both groups using syllable pairs /ba/-/da/ in oddball paradigm and the syllable /da/ in repetitive paradigm in quiet and at +10 dB signal-to-noise ratio (SNR). Results There was significant prolongation in latency and reaction time, and reduction in amplitude of P300 response and sensitivity in both groups with the addition of noise. The topographic pattern analysis showed activation of the central-parietal-occipital region of the brain in individuals with ANSD, whereas activation of the central-parietal region was observed in individuals with normal hearing. The activation was more diffused in individuals with ANSD compared with that of individuals with normal hearing. Conclusion The individuals with ANSD showed a significantly more adverse effect of noise on the neural discrimination skill than the normal counterpart.

Very Early (<2 h) Versus Early (12 h) Administration of Caffeine Citrate for Reducing Need for Mechanical Ventilation within 24 h of Life in Preterm Infants on Continuous Positive Airway Pressure

Background: Auditory neuropathy, auditory dys-synchrony, and auditory neuropathy spectrum disorder (ANSD) are variableterms used to describe an auditory disorder seen in patients ranging in age from infants to adults. The prevalence of ANSD indeaf schoolchildren is 2.46% within the age range of 6–12 years. In children, they are detected by the presence of otoacousticemissions (OAEs) in the absence of ABRs. In older age group, difficulty hearing in noise, fluctuating hearing, and speechperception performance not predict ed by the level of residual hearing have been reported. The multitude of etiologies forANSD results in heterogeneous group of patients – making the management strategies even more challenging. The commonetiologies put forward are – prematurity, neonatal insult, genetic abnormality, ototoxic drugs, and head injury.Aim of the Study: This study aims to study the audiological profile in ANSD in a tertiary care hospital and to study the etiologyof ANSD cases.Materials and Methods: A total of 42 patients attending the ENT Outpatient Department of Government Medical College,Kozhikode, with ANSD were included in the study. An ethical committee clearance was obtained before the commencement ofthe study. An ethical committee cleared consent form was used for the study. All ANSD patients were evaluated with a detailedhistory including perinatal and development history, ototoxic drug exposure, head trauma, neurodegenerative conditions, andfamily history. Following clinical evaluation which included general examinations, ENT examination, and central nervous systemexamination, an audiological evaluation, which included pure tone audiometry, speech audiometry, immittance evaluation, OAE,and auditory brainstem response, was done. Radiological investigation (magnetic resonance imaging brain with inner ear – focusingon any structural anomalies; cochlea, vestibulocochlear nerve, and internal auditory canal) was done. Patients were counseledregarding the rehabilitation options based on their audiological and radiological results and the need for follow-up was explained.Observation and Results: A total of 42 patients attending the ENT Outpatient Department (OPD) of Government MedicalCollege, Kozhikode, with ANSD were included in the study. Among the 42 patients, 21 (50%) were in the age group of 11–20 yearsfollowed by 13 patients who were between 0 and 10 years (30.95%). The remaining 8 were aged above 20 years (19.04%).The youngest patient was 10 months old and the oldest was aged 38 years with a mean age of 10.35 ± 2.10 years. Therewere 29 (69.04%) females and 13 (30.95%) males. 3/42 (7.14%) patients gave a history of exposure to ototoxic drugs suchas streptomycin, gentamicin, and kanamycin, but never had a history of loss of hearing before that. History of premature birthwas noted in 10 (23.80%) patients and the remaining patients did not show premature birth history. Among the 42 patients ofthis study group, 23 (54.76%) had low birth weight, of which 2/42 (4.76%) were <1.5 kg. 21/42 (50%) patients had birth weightabove 1.5 kg. 10/42 patients (23.80%) gave a history of neonatal intensive care unit (NICU) admissions at the time of their birth.Conclusions: The major risk factor identified in this study for ANSD was low birth weight with prematurity, NICU admissions,and viral infections having significant contributions. On audiological evaluation, hearing loss was of mild-to-moderate rangewith a low-frequency loss. There was no statistical correlation between pure audiometry values and speech audiometry whichwas a characteristic observation. OAEs were present in the majority of patients with absent cochlear microphonics (reversepolarity) and acoustic reflexes.

Audiological Profile of Adult Persons with Auditory Neuropathy Spectrum Disorders

BACKGROUND AND OBJECTIVES: The auditory profile of a large number of persons with late onset auditory neuropathy spectrum disorder (ANSD) is recently described in the Indian context. The purpose of study was 1) to profile data on routine audiological parameters, cortical evoked potentials, and temporal processing, 2) to analyze the benefit from hearing aids for persons with ANSD, and 3) to understand the association between benefit from hearing aids and auditory profile. SUBJECTS AND METHODS: Thirty-eight adults with late onset ANSD and a matched group of 40 normally hearing adults participated in the study. Basic audiological tests, recording of cortical evoked potentials, and temporal processing tests were carried out on both groups of participant while only persons with ANSD were fitted with hearing aid. RESULTS: Subjects in the two groups were significantly different on all the audiological parameters. ANSD group seemed to benefit from hearing aids variably. The mean amplitude of N2 was significantly different between normally-hearing participants and patients with ANSD. CONCLUSIONS: Residual temporal processing, particularly amplitude modulation detection seems to be associated with benefit from hearing aids in patients with ANSD.

Auditory Brainstem Response Improvements in Hyperbillirubinemic Infants

BACKGROUND AND OBJECTIVES: Hyperbillirubinemia in infants have been associated with neuronal damage including in the auditory system. Some researchers have suggested that the bilirubin-induced auditory neuronal damages may be temporary and reversible. This study was aimed at investigating the auditory neuropathy and reversibility of auditory abnormalities in hyperbillirubinemic infants. SUBJECTS AND METHODS: The study participants included 41 full term hyperbilirubinemic infants (mean age 39.24 days) with normal birth weight (3,200-3,700 grams) that admitted in hospital for hyperbillirubinemia and 39 normal infants (mean age 35.54 days) without any hyperbillirubinemia or other hearing loss risk factors for ruling out maturational changes. All infants in hyperbilirubinemic group had serum bilirubin level more than 20 milligram per deciliter and undergone one blood exchange transfusion. Hearing evaluation for each infant was conducted twice: the first one after hyperbilirubinemia treatment and before leaving hospital and the second one three months after the first hearing evaluation. Hearing evaluations included transient evoked otoacoustic emission (TEOAE) screening and auditory brainstem response (ABR) threshold tracing. RESULTS: The TEOAE and ABR results of control group and TEOAE results of the hyperbilirubinemic group did not change significantly from the first to the second evaluation. However, the ABR results of the hyperbilirubinemic group improved significantly from the first to the second assessment (p=0.025). CONCLUSIONS: The results suggest that the bilirubin induced auditory neuronal damage can be reversible over time so we suggest that infants with hyperbilirubinemia who fail the first hearing tests should be reevaluated after 3 months of treatment.

The Ability of Temporal Gap Detection in Listeners with Auditory Neuropathy Spectrum Disorder / 听力学及言语疾病杂志

Objective This study was aimed at investigating the ability of temporal gap detection (TGD) in listeners with auditory neuropathy spectrum disorder (ANSD ) .Methods The temporal gap detection thresholds were measured for subjects using a TGD program developed by University of California ,Irvine .Three groups of subjects were recruited in this study ,including 12 subjects with normal hearing ,12 subjects with sensorineural hearing loss (SNHL) ,and 15 subjects with ANSD .The differences of TGD thresholds among the three groups of subjects were analyzed using a one - sample ANOVA method .Results No significant difference of the TGD thresh‐old was observed between two ears for all the subjects .The mean and standard deviation of the gap - detection threshold for both ears was about 3 .9 ± 1 .1 ms ,3 .6 ± 1 .1 ms ,and 13 .7 ± 9 .9 ms for normal - hearing subjects , subjects with SNHL ,and subjects with ANSD ,respectively .The TGD threshold in subjects with ANSD was sig‐nificantly higher than those of in normal hearing group (P< 0 .01) and SNHL group (P< 0 .01) ,while no signifi‐cant difference was found in TGD thresholds between normal - hearing subjects and subjects with SNHL .Conclusion For listeners with auditory neuropathy spectrum disorder ,their ability to resolve temporal information was de‐graded with a large individual variability .

Estudio electrofisiológico y electroacústico de un desorden del espectro de neuropatía auditiva: reporte de un caso en recién nacido de alto riesgo / Electrophysiology and electroacoustic study of spectrum disorder of auditory neuropathy: report of a case in high-risk newborn

El desorden del espectro de neuropatía auditiva (DENA) describe una condición en la cual se observa o se ha observado emisiones otoacústicas (EOA) junto con potenciales evocados auditivos de tronco (PEAT) anormales o ausentes. Su identificación se basa en la presencia de potencial microfónico coclear (PMIC) junto con un PEAT anormal o ausente y EOA presentes o antecedentes de su presencia. Los umbrales tonales pueden encontrarse entre los rangos de normalidad hasta pérdidas auditivas profundas. El reconocimiento del habla generalmente se encuentra afectado particularmente en presencia de ruido de fondo, sin embargo en algunos individuos se mantiene conservado (sin ruido). Se presenta caso clínico de un recién nacido de sexo femenino de pretérmino de 29 semanas y 810 grs (GIII), apgar 7/8, presenta displasia broncopulmonar, sospecha de infección connatal tratada, hiperbilirrubinemia (max 11 mg/dl) tratada con fototerapia. Es derivada al Servicio de Otorrinolaringología para su evaluación auditiva. La evaluación auditiva realizada corresponde a potenciales evocados auditivos de tronco (PEAT), impedanciometria, audiometría de campo de respuesta reflejas y emisiones oto-acústicas. Los resultados obtenidos concuerdan con lo descrito en la literatura para un DENA.

Auditory neuropathy spectrum disorder (ANSD) describes a condition in which it is possible to find otoacoustic emissions (OAE) in presence of abnormal or absent auditory brainstem evoked potentials (ABR). The pure tone thresholds may show a spectrum from normal to profound hearing loss. Speech recognition is often affected in presence of background noise, but in some individuals remains intact. We report a case of a pre term newborn (female) of 29 weeks and 810 grams, Apgar 7/8, bronchopulmonary dysplasia, suspected connatal infection, and hyperbilirubinemia (max 11 mg / dl). She was referred to Hospital Padre Hurtado for hearing assessment. The hearing test performed were an ABR, tympanometry & acoustic reflex, visual reinforcement audiometry and otoacoustic emissions. The results are consistent with those described in the literature for ANSD.