The human OPA1delTTAG mutation induces adult onset and progressive auditory neuropathy in mice.

Dominant optic atrophy (DOA) is one of the most prevalent forms of hereditary optic neuropathies and is mainly caused by heterozygous variants in OPA1, encoding a mitochondrial dynamin-related large GTPase. The clinical spectrum of DOA has been extended to a wide variety of syndromic presentations, called DOAplus, including deafness as the main secondary symptom associated to vision impairment. To date, the pathophysiological mechanisms underlying the deafness in DOA remain unknown. To gain insights into the process leading to hearing impairment, we have analyzed the Opa1delTTAG mouse model that recapitulates the DOAplus syndrome through complementary approaches combining morpho-physiology, biochemistry, and cellular and molecular biology. We found that Opa1delTTAG mutation leads an adult-onset progressive auditory neuropathy in mice, as attested by the auditory brainstem response threshold shift over time. However, the mutant mice harbored larger otoacoustic emissions in comparison to wild-type littermates, whereas the endocochlear potential, which is a proxy for the functional state of the stria vascularis, was comparable between both genotypes. Ultrastructural examination of the mutant mice revealed a selective loss of sensory inner hair cells, together with a progressive degeneration of the axons and myelin sheaths of the afferent terminals of the spiral ganglion neurons, supporting an auditory neuropathy spectrum disorder (ANSD). Molecular assessment of cochlea demonstrated a reduction of Opa1 mRNA level by greater than 40%, supporting haploinsufficiency as the disease mechanism. In addition, we evidenced an early increase in Sirtuin 3 level and in Beclin1 activity, and subsequently an age-related mtDNA depletion, increased oxidative stress, mitophagy as well as an impaired autophagic flux. Together, these results support a novel role for OPA1 in the maintenance of inner hair cells and auditory neural structures, addressing new challenges for the exploration and treatment of OPA1-linked ANSD in patients.

Clinical and genetic architecture of a large cohort with auditory neuropathy.

Auditory neuropathy (AN) is a unique type of language developmental disorder, with no precise rate of genetic contribution that has been deciphered in a large cohort. In a retrospective cohort of 311 patients with AN, pathogenic and likely pathogenic variants of 23 genes were identified in 98 patients (31.5% in 311 patients), and 14 genes were mutated in two or more patients. Among subgroups of patients with AN, the prevalence of pathogenic and likely pathogenic variants was 54.4% and 56.2% in trios and families, while 22.9% in the cases with proband-only; 45.7% and 25.6% in the infant and non-infant group; and 33.7% and 0% in the bilateral and unilateral AN cases. Most of the OTOF gene (96.6%, 28/29) could only be identified in the infant group, while the AIFM1 gene could only be identified in the non-infant group; other genes such as ATP1A3 and OPA1 were identified in both infant and non-infant groups. In conclusion, genes distribution of AN, with the most common genes being OTOF and AIFM1, is totally different from other sensorineural hearing loss. The subgroups with different onset ages showed different genetic spectrums, so did bilateral and unilateral groups and sporadic and familial or trio groups.

Predicting the Impact of OTOF Gene Missense Variants on Auditory Neuropathy Spectrum Disorder.

Auditory neuropathy spectrum disorder (ANSD) associated with mutations of the OTOF gene is one of the common types of sensorineural hearing loss of a hereditary nature. Due to its high genetic heterogeneity, ANSD is considered one of the most difficult hearing disorders to diagnose. The dataset from 270 known annotated single amino acid substitutions (SAV) related to ANSD was created. It was used to estimate the accuracy of pathogenicity prediction using the known (from dbNSFP4.4) method and a new one. The new method (ConStruct) for the creation of the protein-centric classification model is based on the use of Random Forest for the analysis of missense variants in exons of the OTOF gene. A system of predictor variables was developed based on the modern understanding of the structure and function of the otoferlin protein and reflecting the location of changes in the tertiary structure of the protein due to mutations in the OTOF gene. The conservation values of nucleotide substitutions in genomes of 100 vertebrates and 30 primates were also used as variables. The average prediction of balanced accuracy and the AUC value calculated by the 5-fold cross-validation procedure were 0.866 and 0.903, respectively. The model shows good results for interpreting data from the targeted sequencing of the OTOF gene and can be implemented as an auxiliary tool for the diagnosis of ANSD in the early stages of ontogenesis. The created model, together with the results of the pathogenicity prediction of SAVs via other known accurate methods, were used for the evaluation of a manually created set of 1302 VUS related to ANSD. Based on the analysis of predicted results, 16 SAVs were selected as the new most probable pathogenic variants.

[Clinical protocol: audiological assessment of infants in Russian Federation. Part II]. / Protokol audiologicheskogo obsledovaniya detei pervogo goda zhizni v Rossiiskoi Federatsii. Chast' II.

This is the second part of the previously published clinical protocol of audiological assessment in infants. The goal of the protocol is unification approaches to audiological diagnosis of the infants. The following sections were included in the second part of the protocol: behavioral testing in infants, testing sequence, duration of the examination and necessity in follow-up, hearing assessment in special cases (premature children, children with congenital infections, after meningitis, with external ear abnormalities, single-sided deafness, with hydrocephalus and shunts, with auditory neuropathy spectrum disorder, with mild hearing loss and otitis media with effusion), medical report.

[Research on the variation in distortion product otoacoustic emissions in patients with auditory neuropathy during the natural course of the disease].

Objective: The purpose of this study was to investigate the characteristics of distortion product otoacoustic emissions (DPOAE) in patients with auditory neuropathy (AN). The factors affecting DPOAE elicitation rate of each frequency, elicitation rate of each ear and change rate of first and last diagnosis in the natural course were analyzed. Methods: The sample was obtained from the Multicenter Study on Clinical Diagnosis and Intervention of AN (registration number: ChiCTR2100050125), and the diagnostic criteria for AN were based on the Chinese Clinical Practice Guidelines of Auditory Neuropathy (version 2022). Patients with bilateral AN who underwent 2 or more DPOAE tests were screened and divided into infant groups (≤3 years old) and non-infant groups (>3 years old) according to the age of detection, and the trend of DPOAE elicitation rate of each frequency, elicitation rate of each ear and change rate in the natural course of disease were analyzed, in order to explore the relevant influencing factors. Results: A total of 165 patients (330 ears) with AN were included in the study. The overall DPOAE elicitation rate per ear was 77.0%±29.4% at the initial diagnosis and 65.1%±35.2% at the final diagnosis, with a reduction observed in the elicitation rate of 171 ears (51.82%). In the infant group, there were 49 cases (98 ears), including 28 males and 21 females, whose found age ranged from 0 to 3 years old, with a median age of 0.7 years. DPOAE elicitation rate per ear was 57.9%±35.5% in the initial diagnosis, and 32.4%±32.1% in the final diagnosis, with a reduction observed in the elicitation rate of 69 ears (70.41%). In the non-infant group, there were 116 cases (232 ears), including 59 males and 57 females, ranging in found age from 3.9 to 40 years old, with a median age of 14 years old. DPOAE elicitation rate per ear was 84.6%±23.4% in the initial diagnosis, and 78.3%±27.1% in the final diagnosis, with a reduction observed in the elicitation rate of 102 ears (43.97%). Age was found to be correlated with DPOAE changes by multicategorical unordered logistic regression analysis (B=-0.224, OR=0.799, P<0.001). Conclusions: The elicitation rate of DPOAE in AN patients decreases or even disappears with increasing disease duration; The rate of DPOAE extraction is found to be lower in infant patients with auditory neuropathy (AN) compared to non-infant AN patients. Additionally, it is observed that the decrease in DPOAE extraction rate is more pronounced in infant AN patients as the disease progressed, as compared to non-infant AN patients. DPOAE and cochlear microphonic potentials should be fully combined for accurate diagnosis, and regular follow-up should be conducted to understand the natural course of the disease and give personalized guidance and assistance.

[Evaluation of the outcomes of cochlear implant in children with auditory neuropathy].

Objective: To investigate the auditory and speech abilities of children with congenital auditory neuropathy (AN) after cochlear implant (CI), and to analyze the role of genetic testing in predicting the postoperative outcomes of CI in AN patients. Methods: Fourteen children diagnosed with AN by audiological battery test and underwent CI surgery in Xijing Hospital of the Air Force Medical University from 2002 to 2021 were included in this study (9 males and 5 females), with an implantation age of (3.1±1.7) years (mean±standard deviation, the same as follows). The preoperative audiological results and deafness gene results were analyzed. Another 52 children with ordinary sensorineural hearing loss (SNHL) were selected as the control group (30 males and 22 females), with an implantation age of (2.2±0.9) years. The demographic factors such as age and gender were matched with those of the AN group. The modified Category Auditory Performance (CAP-Ⅱ) and Speech Intelligence Rate (SIR) were used to evaluate the development of postoperative auditory and speech abilities in two groups. The Mandarin Speech Test System was used to test the speech recognition rate of monosyllabic and disyllabic words and sentences. Matlab 2022 software was used to analyze the data. Results: The results of gene in 14 children with AN showed that 6 cases had OTOF gene mutations, 2 cases (siblings) were confirmed to have TNN gene mutations through whole exome sequencing, and the remaining 6 cases were not find any clear pathogenic gene mutations. All subjects underwent CI surgery with electrodes implanted into the cochlea smoothly, and there were no postoperative complications. After surgery, all AN children had improved auditory and speech abilities, but only 64% (9/14) of AN children with CI had auditory ability scores comparable to the control group of SNHL children (including 2 children with TNN gene mutations), and 36% (5/14) of AN children had lower scores than the control group of SNHL children.The average speech recognition rate of two children with TNN gene mutations was 86.5%, and of two children with OTOF gene mutations was 83.2%. Conclusions: AN children achieved varying degrees of auditory and speech abilities after CI, but the postoperative effects varied greatly. Some children achieved similar results as ordinary SNHL children, but there were still some children whose effects were worse than those of ordinary SNHL children. The postoperative efficacy of CI in two children with AN caused by TNN pathogenic genes were comparable to that of ordinary SNHL in children. Genetic testing had certain reference value for predicting the postoperative effect of CI in AN children.

[Study on the clinical characteristics of auditory neuropathy patients with normal pure tone average or mild hearing loss].

Objective: The purpose of this study was to analyze the clinical characteristics of auditory neuropathy (AN) patients with normal hearing or mild hearing loss. Methods: Data from Multicenter Study on Clinical Diagnosis and Intervention of Acoustic Neuropathy (registration number: ChiCTR2100050125). According to the Chinese clinical practice guideline of auditory neuropathy (version 2022), these patients divided into two groups: the normal hearing group (PTA Normal, PTAN group, the average hearing threshold<20 dB HL) and the mild hearing loss group (PTA Mild hearing loss, PTAM group, the average hearing threshold between 20-35 dBHL). The audiology characteristics, clinical features, and follow-up were analyzed. Data analysis was conducted using GraphPad Prism 8 and SPSS 20.0 software. Results: A total of 75 AN with normal hearing or mild hearing loss were included in this study. The PTAN group consisted of 19 patients (38 ears), including 12 males and 7 females. The average onset age was (16.9±4.5) years old, while the test age was (22.1±5.8) years old for PTAN group. The PTAM group consisted of 56 patients (112 ears), including 29 males and 27 females. The average onset age was (16.2±7.9) years old, while the test age was (23.9±9.0) yeas old for PTAM group. The average hearing threshold of low frequency (0.125-0.5 kHz) was significantly decreased. ABR disappeared in 86.00% (126/150) of the patients. The speech recognition rate was 71.80±22.44% in the PTAN group and 58.08±29.28% in the PTAM group.-SP/AP was 0.98±0.47 in the PTAN and 1.07±0.63 in PTAM group; 40 (53.33%) patients had tinnitus. 29 patients (58 ears) were followed up, including 10 patients (20 ears) in the PTAN group and 19 patients (38 ears) in the PTAM group. There was no significant change in hearing threshold in short-term follow-up (<3 years). With the extension of the disease duration (>3 years), the PTAN group tended to decrease at low frequency, and the PTAM group decreased at high frequency first. The hearing threshold at 0.25 kHz in the PTAN group and 4 kHz in the PTAM group decreased significantly. Conclusions: AN patients with normal hearing or mild hearing loss exhibit abnormal results in audiological examination results, including ABR, electrocochleography and speech discrimination score. A combination of audiological tests should be used to make the diagnosis of AN. With the progression of the disease, AN with normal hearing or mild hearing loss tends to decrease.

[Recognition of unilateral auditory neuropathy in children].

Objective: This study aimed to compare the audiological characteristics between children with unilateral auditory neuropathy (UAN) and single-sided deafness (SSD) to establish a valid basis for the differential diagnosis of children with UAN. Methods: A retrospective analysis was conducted on audiological and imaging evaluations of children with UAN and SSD who were treated at Beijing Children's Hospital of Capital Medical University between May 2015 and June 2023. There were 17 children with UAN, comprising 10 males and 7 females, with an average age of 4.7 years. Additionally, there were 43 children with SSD, consisting of 27 males and 16 females, with an average age of 6.5 years. Audiological assessments included Auditory brainstem response (ABR), Steady-state auditory evoked potential (ASSR), Behavioural audiometry, Cochlear microphonic potential (CM), Distortino-product otoacoustic emission (DPOAE), and acoustic immittance test. The results of the audiological assessment and imaging phenotypic between the two groups of children were compared and analyzed by applying SPSS 27.0 statistical software. Results: (1) The UAN group (77.8%) had a significantly higher rate of ABR wave IIIL than the SSD group (20.9%) (P<0.01). The PA thresholds at 500 Hz and 1 000 Hz of children with SSD were higher than those of children with UAN, while the ASSR thresholds at 500 Hz, 1000 Hz, 2 000 Hz, and 4 000 Hz of children with SSD were significantly higher than those of children with UAN (P<0.05). (2) The degree of hearing loss in both UAN and SSD children was predominantly complete hearing loss. The percentage of complete hearing loss was significantly higher (χ²=4.353, P=0.037) in the SSD group (93.0%, 40/43) than in the UAN group (63.6%, 7/11). However, the percentage of profound hearing loss was significantly higher in the UAN group (27.3%, 3/11) than in the SSD group (2.3%, 1/43) (Fisher's exact test, P=0.023). In terms of hearing curve configuration, the percentage of flat type was significantly higher in the SSD group (76.7%, 33/43) than in the UAN group (36.4%, 4/11). The proportion of the UAN group (27.3%, 3/11) was significantly higher than that in the SSD group (2.3%, 1/43) in ascending type (P<0.05). There were no statistically significant differences in the hearing curves of the declining type and other types between the two groups (P>0.05). (3) The proportion of imaging assessment without abnormality was significantly more common in the UAN group (81.8%) than in the SSD group (37.1%) (χ²=6.695, P=0.015). Conclusions: Compared to children with SSD, the occurrence of wave IIIL on the ABR test was significantly more common in children with UAN. The percentage of ascending hearing curves was significantly higher in children with UAN than in children with SSD. ASSR thresholds were significantly lower in children with UAN. The normal imaging phenotype was significantly more common in children with UAN than in children with SSD.

Preparing for Otoferlin gene therapy trials: A survey of NHS Paediatric Audiology and Cochlear Implant services on diagnosis and management of Auditory Neuropathy Spectrum Disorder.

OBJECTIVES: Gene therapy for monogenic hearing loss is on the horizon. The first trials in patients with Auditory Neuropathy Spectrum Disorder (ANSD) due to pathogenic variants in the Otoferlin (OTOF) gene will open this year. In the UK, the new NHS Genomic Medicine Service (GMS) offers genetic testing in each child diagnosed with congenital or early onset sensorineural hearing loss. This survey study aims to map preexisting clinical pathways for the diagnosis and management of children with ANSD and identify opportunities for improvement in early identification of OTOF- related ANSD. METHODS: A Google form with 24 questions in English covering the ANSD clinical pathway was developed with clinicians involved in the diagnosis and management ANSD. The survey was disseminated via email to all Lead clinicians of NHS Tertiary Paediatric Audiology and Cochlear Implant Services within the UK. RESULTS: Data was received from 27 (34 %) NHS Tertiary Paediatric Audiology Services and 8 (n = 57 %) Paediatric Cochlear Implant Services. Services follow existing national guidance and provide multidisciplinary care with structured patient pathways for referral, diagnosis, and management of children with ANSD and multidisciplinary input throughout. Clinicians are aware of the genetic causes of ANSD and new processes for genetic testing, but do not uniformly refer children with ANSD for testing for OTOF pathogenic variants. As such, they had difficulty estimating numbers of children with OTOF pathogenic variants under their care. CONCLUSION: Those results highlight the urgency of implementing hearing gene panel sequencing for all children with ANSD to provide opportunities for early diagnosis and candidacy for OTOF gene therapy trials.

[Distribution characteristics and correlation analysis of GJB2 variation in patients with auditory neuropathy].

Objective:To elucidate the correlation between the GJB2 gene and auditory neuropathy, aiming to provide valuable insights for genetic counseling of affected individuals and their families. Methods:The general information, audiological data（including pure tone audiometry, distorted otoacoustic emission, auditory brainstem response, electrocochlography）, imaging data and genetic test data of 117 auditory neuropathy patients, and the patients with GJB2 gene mutation were screened out for the correlation analysis of auditory neuropathy. Results:Total of 16 patients were found to have GJB2 gene mutations, all of which were pathogenic or likely pathogenic.was Among them, one patient had compound heterozygous variants GJB2[c. 427C>T][c. 358_360del], exhibiting total deafness. One was GJB2[c. 299_300delAT][c. 35_36insG]compound heterozygous variants, the audiological findings were severe hearing loss.The remaining 14 patients with GJB2 gene variants exhibited typical auditory neuropathy. Conclusion:In this study, the relationship between GJB2 gene and auditory neuropathy was preliminarily analyzed,and explained the possible pathogenic mechanism of GJB2 gene variants that may be related to auditory neuropathy.

Cochlear Implant Outcomes in Patients With TMTC2 -Associated Sensorineural Hearing Loss and Auditory Neuropathy/Auditory Dys-Synchrony.

OBJECTIVE: To investigate the outcomes of cochlear implantation in patients with TMTC2 -associated sensorineural hearing loss and auditory neuropathy/auditory dys-synchrony. PATIENTS: Adult and pediatric cochlear implant (CI) patients followed in an academic center who tested positive for TMTC2 genetic variant rs35725509. INTERVENTION: Cochlear implantation. MAIN OUTCOME MEASURES: Speech perception scores in quiet. RESULTS: Ten CI patients were identified with TMTC2 variant rs35725509 out of 157 patients who underwent genetic testing (i.e., 6.3% of patients tested). All demonstrated progressive, bilateral hearing loss with severe-to-profound audiometric thresholds preoperatively. Pre-CI and 1-year post-CI speech recognition percent correct scores were compared. Post-CI speech perception (mean 61.0%, standard deviation 31.4%) was significantly higher than pre-CI speech perception (mean 21.0%, standard deviation 27.0%) ( p = 0.002). Individually, 9 of the 10 subjects experienced significant improvements in speech perception pre- to post-CI ( p < 0.05). Electrically evoked compound action potential measures were available for five patients, and all showed normal electrically evoked compound action potential thresholds. CONCLUSION: Patients with TMTC2 -associated sensorineural hearing loss and auditory neuropathy/auditory dys-synchrony have significantly improved speech perception outcomes with cochlear implantation and should be considered candidates for this intervention if there are no other contraindications.

Predictors of cochlear implant outcomes in pediatric auditory neuropathy: A matched case-control study.

OBJECTIVES: Current evidence supports the benefits of cochlear implants (CIs) in children with hearing loss, including those with auditory neuropathy spectrum disorder (ANSD). However, there is limited evidence regarding factors that hold predictive value for intervention outcomes. DESIGN: This retrospective case-control study consisted of 66 children with CIs, including 22 with ANSD and 44 with sensorineural hearing loss (SNHL) matched on sex, age, age at CI activation, and the length of follow-up with CIs (1:2 ratio). The case and control groups were compared in the results of five open-set speech perception tests, and a Forward Linear Regression Model was used to identify factors that can predict the post-CI outcomes. RESULTS: There was no significant difference in average scores between the two groups across five outcome measures, ranging from 88.40% to 95.65%. The correlation matrix revealed that younger ages at hearing aid fitting and CI activation positively influenced improvements in speech perception test scores. Furthermore, among the variables incorporated in the regression model, the duration of follow-up with CIs, age at CI activation, and the utilization of two CIs demonstrated prognostic significance for improved post-CI speech perception outcomes. CONCLUSIONS: Children with ANSD can achieve similar open-set speech perception outcomes as children with SNHL. A longer CI follow-up, a lower age at CI activation, and the use of two CIs are predictive for optimal CI outcome.

[The updates of the ACMG variant interpretation guidelines affect the pathogenicity determination of OTOF gene variations in patients with auditory neuropathy].

Objective: To compare the differences between the variation interpretation standards and guidelines issued by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) in 2015 (The 2015ACMG/AMP guideline) and the Deafness Specialist Group of the Clinical Genome Resource (ClinGen) in 2018 for hereditary hearing loss (Healing loss, HL) issued the expert specification of the variation interpretation guide (The 2018 HL-EP guideline) in evaluating the pathogenicity of OTOF gene variation in patients with auditory neuropathy. Methods: Thirty-eight auditory neuropathy patients with OTOF gene variant were selected as the study subjects (23 males and 15 females, aged 0.3-25.9 years). Using whole-genome sequencing, whole exome sequencing or target region sequencing (Panel) combined with Sanger sequencing, 38 cases were found to carry more than two OTOF mutation sites. A total of 59 candidate variants were independently interpreted based on the 2015 ACMG/AMP guideline and 2018 HL-EP guideline. Compared with the judgment results in 2015 ACMG/AMP guideline, the variants interpreted as lower pathogenic classifications in the 2018 HL-EP guideline were defined as downgraded variants, and the variants regarded as higher pathogenic classifications were defined as upgraded variants. Statistical analysis was conducted using SPSS 20.0. Results: The concordance rate of variant classification between the guidelines was 72.9%(43/59). The 13.6%(8/59) of variants were upgraded and 13.6% (8/59) of variants downgraded in the classifications of the 2018 HL-EP guideline. A couple of rules saw significant differences between the guidelines (PVS1, PM3, PP2, PP3 and PP5). The distribution of pathogenicity of splicing mutation was statistically different (P=0.013). Conclusions: The 2018 HL-EP guideline is inconsistent with the 2015 ACMG/AMP guideline, when judging the pathogenicity of OTOF gene variants in patients with auditory neuropathy. Through the deletion and refinement of evidence and the breaking of solidification thinking, the 2018 HL-EP guideline makes the pathogenicity grading more traceable and improves the credibility.

Epidemiology, aetiology and diagnosis of congenital hearing loss via hearing screening of 153 913 newborns.

BACKGROUND: Congenital hearing loss (HL), one of the most common paediatric chronic conditions, significantly affects speech and language development. Its early diagnosis and medical intervention can be achieved via newborn hearing screening. However, data on the prevalence and aetiology of congenital HL in infants who fail newborn hearing screening are limited. METHODS: The sample population included 153 913 infants who underwent newborn hearing screening, and the prevalence of congenital HL, defined as moderate to profound bilateral HL (BHL) or unilateral HL (UHL) (≥40 dB HL), in one prefecture of Japan was measured to minimize the loss-to-follow-up rate, a common factor affecting the screening procedure. Comprehensive aetiological investigation, including physiology, imaging, genetic tests, and congenital cytomegalovirus screening, was performed on children diagnosed with congenital HL. RESULTS: The calculated prevalence of congenital HL was 1.62 per 1000 newborns (bilateral, 0.84; unilateral, 0.77). More than half of the cases with congenital bilateral or severe to profound UHL showed genetic aetiology or cochlear nerve deficiency (CND), respectively. Approximately 4% and 6% of the cases of congenital BHL and UHL were associated with congenital cytomegalovirus infection and auditory neuropathy spectrum disorder, respectively. CONCLUSIONS: This is an epidemiological and comprehensive aetiological study of congenital HL, as determined via newborn hearing screening according to its severity and laterality, in a large-scale general population of a developed country. Our findings can serve as a reference for optimizing care and intervention options for children with HL and their families.

Neurophysiological and brain structural insights into cyclin-dependent kinase-like 5 deficiency disorder: Visual and auditory evoked potentials and MRI analysis.

OBJECTIVE: CDKL5 deficiency disorder (CDD), an epileptic encephalopathy for which novel therapeutics are under development, lacks valid and reliable measures of therapeutic efficacy. We aimed to elucidate the neurophysiological and brain structural features of CDD patients and identify objective indicators reflecting the clinical severity. METHODS: Twelve CDD patients and 12 healthy controls (HCs) participated. The clinical severity of CDD was scored using the CDD severity assessment (CDD-SA). The participants underwent visual evoked potential (VEP), auditory brainstem response (ABR), structural MRI, and diffusion tensor imaging (DTI) analyses. Measurements from each modality were compared with normal values of age-matched cohorts (VEP and ABR) or statistically compared between CDD patients and HCs (MRI). RESULTS: VEP showed a significant correlation between P100 latency and CDD-SA in CDD patients. ABR showed abnormalities in six patients (50%), including prolonged V-wave latency (n = 2), prolonged inter-peak latency between waves I and V (n = 3), and mild hearing loss (n = 4). Structural MRI showed a significant reduction in cortical volume in the left pars triangularis and right cerebellum compared with HCs. DTI showed a widespread decrease in fractional anisotropy and an increase in mean and radial diffusivity compared with HCs. CONCLUSION: CDD patients had reduced cortical volume in the left pars triangularis, a brain region crucial for speech, and one-third of patients had mild hearing loss. These changes may be involved in language impairments in CDD patients. Additionally, P100 latency significantly correlated with the clinical severity. These features can be used to assess the clinical severity of CDD.

Ensino por múltiplos exemplares e integração de comportamentos de ouvinte e falante com unidades sintáticas substantivo-adjetivo em crianças com DENA e IC / Multiple exemplar instruction and integration of listening and speaking behaviors with substantive-adjective syntactic units in children with ANSD and CI

RESUMO Objetivo Verificar o efeito do ensino por múltiplos exemplares na aquisição e integração dos comportamentos de ouvinte e falante, com substantivos e combinações substantivo-adjetivo, em crianças com Desordem do Espectro da Neuropatia Auditiva (DENA) e implante coclear (IC). Método Participaram duas crianças com DENA que usavam IC. Foram adotados estímulos ditados e figuras que correspondiam a palavras (substantivo) e unidades sintáticas substantivo+adjetivo. O estudo foi organizado em passos de ensino que foram intercalados por avaliações dos comportamentos de ouvinte e falante, com todos os estímulos. O ensino por múltiplos exemplares apresentou tarefas de imitação oral (ecoico), reconhecimento auditivo (ouvinte) e nomeação de figuras (tato) de maneira rotativa; os substantivos foram ensinados primeiro e, em seguida, as combinações substantivo-adjetivo. Resultados No pré-teste, os participantes mostraram variabilidade e discrepância nas porcentagens de acertos de ouvinte e de falante. Todos alcançaram primeiro 100% de acertos nas tarefas de ouvinte e os desempenhos de falante ficaram próximos aos de ouvinte após o ensino. Todos estenderam a aprendizagem dos substantivos para as unidades sintáticas substantivo-adjetivo. Conclusão Crianças com DENA e IC podem aprender e integrar comportamentos de ouvinte e de falante por meio do ensino por múltiplos exemplares, de palavras a unidades sintáticas.

ABSTRACT Purpose To verify the effect of the multiple exemplar instruction at the acquisition and integration of listening and speaking behaviors, with substantives and substantive-adjective combinations, in children with Auditory Neuropathy Spectrum Disorder (ANSD) and cochlear implant (CI). Methods Participants were two children with ANSD that were users of CI. We adopted dictated stimulus and pictures that corresponded to words (substantive) and substantive-adjective syntactic units. The study was arranged in teaching steps that were intercalated with listening and speaking behaviors probes, with all stimuli. The multiple exemplar instruction presented oral imitation (echoic), auditory recognition (listening) and pictures naming (touch) tasks, on a rotating way; the substantives were taught first and, after that, the substantive-adjective combinations. Results In the pre-test, the participants showed variability and discrepancy in the correct responses percentages of listening and speaking. All achieved firstly 100% correct responses in the listening task and the speaking performances were close to listening after the teaching. All extended substantive learning to substantive-adjective syntactic units. Conclusion Children with ANSD and CI can learn and integrate listening and speaking behaviors by multiple exemplar instruction, from words to syntactic units.