Cortical Auditory Evoked Potential Testing in Children With Auditory Neuropathy Spectrum Disorder.

PURPOSE: In the present report, we reviewed the role of cortical auditory evoked potentials (CAEPs) as an objective measure during the evaluation and management process in children with auditory neuropathy spectrum disorder (ANSD). METHOD: We reviewed the results of CAEP recordings in 66 patients with ANSD aged between 2 months and 12 years and assessed the relationship between their characteristics (prevalence, morphology, latencies, and amplitudes) and various clinical features, including the mode of medical management. RESULTS: Overall, the CAEPs were present in 85.2% of the ears tested. Factors such as prematurity, medical complexity, neuronal issues, or presence of syndromes did not have an effect on the presence or absence of CAEPs. CAEP latencies were significantly shorter in ears with cochlear nerve deficiency than in ears with a normal caliber nerve. Three different patterns of CAEP responses were observed in patients with bilateral ANSD and present cochlear nerves: (a) responses with normal morphology and presence of both P1-P2complex and N2 components, (b) responses with abnormal morphology and presence of the N2 component but undefined P1-P2complex peak, and (c) entirely absent responses. None of the patients with normal, mild, or moderate degree of hearing loss had a complete absence of CAEP responses. No significant differences were uncovered when comparing the latencies across unaided and aided children and children who later received cochlear implants. CONCLUSIONS: The CAEP protocol used in our ANSD program did inform about the presence or absence of central auditory stimulation. Absent responses typically fit into an overall picture of complete auditory deprivation and all of these children were ultimately offered cochlear implants after failing to develop oral language. Present responses, on the other hand, were acknowledged as a sign of some degree of auditory stimulation but always interpreted with caution given that prognostic implications remain unclear.

A 15-year Review of 260 Children With Auditory Neuropathy Spectrum Disorder: II. Management and Outcomes.

OBJECTIVES: Following a review of the demographic and clinical characteristics of all pediatric patients diagnosed with auditory neuropathy spectrum disorder (ANSD) by a pediatric health care system from 2005 to 2020, the present report highlights the type and timing of intervention and outcomes in the same 260 patients with ANSD. DESIGN: This was a retrospective study reviewing the demographic data, medical history, imaging studies, audiological and speech language data, type of audiological intervention (hearing aids or cochlear implants), and mode of communication in 260 pediatric patients diagnosed with ANSD over a 15-year period. RESULTS: A significant decrease over time in the age at hearing aid fitting was observed. While a similar reduction in the age at implantation occurred over time, cochlear implantation is still rarely performed by 12 months of age in most ANSD patients. Among bilateral ANSD patients fitted with hearing aids, the majority (89.2%) did not benefit from conventional amplification and most received cochlear implants. Some hearing aid benefit for speech and language development was observed in 5.8%, though communication difficulties were persistent and most used a combination of oral and sign language for communication. Only six patients (5%) received significant benefit from their hearing aids for speech and language development. CONCLUSIONS: This review of ANSD management over a 15-year period reveals that hearing aids are not a viable option to develop speech and language for most infants and children with ANSD. This finding confirms previous reports and suggest that while hearing aid trials are warranted, children must be tracked closely so as to avoid delays in decision making. Cochlear implantation constitutes the major (if not only) rehabilitative intervention that allows for speech perception in patients who do not benefit from conventional amplification.

A 15-Year Review of 260 Children With Auditory Neuropathy Spectrum Disorder: I. Demographic and Diagnostic Characteristics.

OBJECTIVES: The aim of the study was to review the demographic and clinical characteristics of all pediatric patients diagnosed with auditory neuropathy spectrum disorder (ANSD) by a pediatric health care system from 2005 to 2020 and examine whether or not our diagnostic capabilities in an ANSD population have evolved as our institutional experience has grown and knowledge in the field has expanded. DESIGN: This was a retrospective study reviewing the demographic data, medical history, imaging studies, audiological and speech-language data, type of audiological intervention and mode of communication in 260 pediatric patients diagnosed with ANSD over a 15-year period. RESULTS: The study revealed that male and female children were equally affected with all levels of hearing detection being represented and that about 40% of affected children were premature and most were admitted to the neonatal intensive care unit. More than a third of our patients presented with a complex medical history and/or neural involvement while about 30% were full-term newborns with normal pregnancy, no prenatal complications or infections, normal birth weight, no neonatal intensive care unit need, no hyperbilirubinemia, no respiratory distress requiring ventilation, and no known syndrome. Review of audiological findings confirms that otoacoustic emissions are not always present in ANSD cases, and that the presence of an abnormal wave V on the auditory brainstem response tracings (only present at high intensities and with an absent intensity/latency function) is not a rare finding and should not immediately be dismissed as not being a case of ANSD. CONCLUSIONS: This review of ANSD diagnosis over a 15-year period clearly reveals the drastic improvements made in the identification of ANSD, with a drastic decrease in the age at diagnosis and a reduction in the percentage of misdiagnosed patients. The study also stresses the need for continued improvement in different areas such as genetic studies and physiological measures to help clinicians distinguish between pre- and postsynaptic ANSD.

Hearing outcomes in children with Congenital Cytomegalovirus: A multi-center, single-enterprise experience.

BACKGROUND: Cytomegalovirus (CMV) is the most common cause of non-genetic sensorineural hearing loss (SNHL) in the United States; yet screening for congenital CMV (cCMV) remains controversial. CMV related SNHL can be present at birth, or develop in a delayed manner, and it is a consistent feature in children with either symptomatic or asymptomatic disease. A retrospective chart review was performed to determine the characteristics of patients diagnosed with cCMV and SNHL. METHODS: The electronic database warehouse of the Nemours Children's Health System (NCHS) was queried from 01/01/2004 to 10/05/2019. ICD 9 (771.1) and ICD 10 (B25.9, P35.1) diagnostic codes were used to identify patients throughout the system with a diagnosis of cCMV infection. Patient demographics including gender, race/ethnicity, age of diagnosis, results of newborn hearing screening (NBHS), detection and progression of hearing loss, presence of antiviral therapy, and frequency of monitoring were collected, and descriptive statistics performed. RESULTS: Of the 170 patients confirmed to have cCMV, 153 (90%) were symptomatic and 17 (10%) were asymptomatic. CNS involvement (63.5%), radiographic evidence of disease present (69.4%), and SNHL (50.6%) were the most common manifestations of the disease. Of these 170 patients, 83 (48.8%) were determined to have SNHL eligible for evaluation. For these patients with SNHL, the average time of hearing monitoring was 50.6 months. At the time of initial reported detection 63 of 83 (76%) had bilateral hearing loss and 20 (24%) had unilateral loss. Over the study period 3 (15%) progressed from unilateral to bilateral involvement, and 32 (47%) had a deterioration in hearing, with severe to profound SNHL in at least one ear identified at the last visit in 53 (64%) patients. Newborn hearing testing results were available for 69 (83%) of those with hearing loss and 26 patients passed initial testing. However, of the 26 patients who passed, 22 (85%) eventually developed SNHL by their last visit. Within our cohort, females with cCMV were significantly more likely to have SNHL than males with cCMV (62.3% versus 37.6%; p < 0.01). CONCLUSION: In the absence of targeted or universal cCMV screening, the majority of children identified with this condition present symptomatically. Approximately one half of children with symptomatic cCMV failed NBHS at birth while at least 25% develop SNHL later in life. Children with cCMV are at high risk of delayed onset loss and such children, particularly females, should be monitored closely.

Cochlear implantation in a patient with mucopolysaccharidosis IVA.

Mucopolysaccharidosis IVA (OMIM 253000; also known as Morquio A syndrome) is associated with skeletal, airway, and hearing abnormalities. Cochlear implantation is an effective intervention for patients with severe-to-profound hearing loss. Patients can gain substantial improvement in auditory performance, speech perception, and their quality of life from cochlear implantation. Although severe progressive sensorineural hearing loss is a common feature of mucopolysaccharidosis IVA, no detailed description of cochlear implantation for mucopolysaccharidosis IVA has been reported. To review the effectiveness and special considerations associated with cochlear implantation in patients with mucopolysaccharidosis IVA, we here report the case of cochlear implantation in mucopolysaccharidosis IVA by a multidisciplinary team. A retrospective chart review was conducted on a 34-year-old female with mucopolysaccharidosis IVA, who received a cochlear implant. Audiometric thresholds, speech perception scores, and cochlear implant processor mapping information were reviewed during the first 12 months following cochlear implantation. The results of audiological tests indicate improved hearing thresholds as well as remarkable enhancement of speech perception skills over 12 months of cochlear implant use. Cochlear implantation improved auditory performance in a mucopolysaccharidosis IVA patient with postlingually severe-to-profound sensorineural hearing loss. The benefits of cochlear implantation could be meaningful for other Morquio patients with progressive hearing loss, although the risks of surgery and anesthesia should be carefully considered by a multidisciplinary team of experts during the cochlear implant candidacy process.

Recessive GM3 synthase deficiency: Natural history, biochemistry, and therapeutic frontier.

GM3 synthase, encoded by ST3GAL5, initiates synthesis of all downstream cerebral gangliosides. Here, we present biochemical, functional, and natural history data from 50 individuals homozygous for a pathogenic ST3GAL5 c.862C>T founder allele (median age 8.1, range 0.7-30.5 years). GM3 and its derivatives were undetectable in plasma. Weight and head circumference were normal at birth and mean Apgar scores were 7.7 ±â€¯2.0 (1 min) and 8.9 ±â€¯0.5 (5 min). Somatic growth failure, progressive microcephaly, global developmental delay, visual inattentiveness, and dyskinetic movements developed within a few months of life. Infantile-onset epileptic encephalopathy was characterized by a slow, disorganized, high-voltage background, poor state transitions, absent posterior rhythm, and spike trains from multiple independent cortical foci; >90% of electrographic seizures were clinically silent. Hearing loss affected cochlea and central auditory pathways and 76% of children tested failed the newborn hearing screen. Development stagnated early in life; only 13 (26%) patients sat independently (median age 30 months), three (6%) learned to crawl, and none achieved reciprocal communication. Incessant irritability, often accompanied by insomnia, began during infancy and contributed to high parental stress. Despite catastrophic neurological dysfunction, neuroimaging showed only subtle or no destructive changes into late childhood and hospitalizations were surprisingly rare (0.2 per patient per year). Median survival was 23.5 years. Our observations corroborate findings from transgenic mice which indicate that gangliosides might have a limited role in embryonic neurodevelopment but become vital for postnatal brain growth and function. These results have critical implications for the design and implementation of ganglioside restitution therapies.

Auditory event-related potentials and function of the medial olivocochlear efferent system in children with auditory processing disorders.

OBJECTIVE: The objectives were to investigate the function of central auditory pathways and of the medial efferent olivocochlear system (MOCS). DESIGN: Event-related potentials (ERP) were recorded following the delivery of the stimulus /da/ in quiet and in ipsilateral, contralateral, and binaural noise conditions and correlated to the results of the auditory processing disorders (APD) diagnostic test battery. MOCS function was investigated by adding ipsilateral, contralateral, and binaural noise to transient evoked otoacoustic emission recordings. Auditory brainstem responses and pure tone audiogram were also evaluated. STUDY SAMPLE: Nineteen children (7 to 12 years old) with APD were compared with 24 age-matched controls. RESULTS: Otoacoustic emissions and ABR characteristics did not differ between groups, whereas ERP latencies were significantly longer and of higher amplitudes in APD children than in controls, in both quiet and noise conditions. The MOCS suppression was higher in APD children. CONCLUSIONS: Findings indicate that children with APD present with neural deficiencies in both challenging and nonchallenging environments with an increase in the timing of several central auditory processes correlated to their behavioural performances. Meanwhile, their modulation of the auditory periphery under noisy conditions differs from control children with higher suppression.

Cofactors of Pediatric Tinnitus: A Look at the Whole Picture.

Retrospective chart review of 248 children (1-19 years old) with tinnitus who presented to a tertiary pediatric hospital between 2006 and 2011, looking at which cofactors are predictors of pediatric tinnitus. In our review, we extracted demographics, symptoms, historical data, imaging, and laboratory results; we compared with the general population. Eighty-seven percent had normal hearing. Age distribution, noise exposure, and frequency of psychiatric diagnoses in our cohort were consistent with previous reports. We found a lower incidence of otitis media and the same prevalence of dizziness, asthma, and hearing loss as the general population, a lower prevalence of Eustachian tube dysfunction, otitis media, headaches, and higher incidence of rhinosinusitis. Lack of patient reporting and objective testing complicate the ability to detect pediatric tinnitus. We revealed a gap in the literature regarding rhinosinusitis as a cofactor, imaging during diagnosis, and if psychiatric diagnoses are associated with tinnitus in younger children.

Tablet-Based Hearing Test Among Child Clinical Populations: Performance and Preference.

Background and Introduction: Tablet-based automated audiometry applications are a recent alternative method to perform pure-tone hearing testing. Children, in particular, might benefit from such apps because of the game-like interface. However, how children perceive this alternative approach has not been well studied. This study examined children's preference of hearing test and a relationship between their test preference and hearing test results. Materials and Methods: Forty children 6-12 years of age completed a pure-tone hearing test in both the tablet-based automated (tablet) method and the conventional method. Hearing thresholds were measured at 0.5, 1, 2, 4, 6, and 8 kHz in each ear. An exit interview was conducted to obtain each child's test preference. Results: We found that 59% of the children preferred the tablet method when compared to the conventional method. Preference to the tablet method was stronger in the younger children (6 years) than older children (7-12 years). The linear regression analyses suggest that test preference does not affect the hearing test results in the conventional method, but does negatively affect the results in the tablet method. In addition, poor performance was found among children with a clinical diagnosis, in particular, in the tablet method. Discussion: These results suggest that hearing thresholds may be overestimated in children, especially those with clinical diagnosis such as attention or behavioral issues in the tablet method. Future work is needed to determine which clinical populations have potential benefit from a tablet method. Conclusions: Children's test preference is not a good index of hearing test accuracy.

Is there a clinical application for tablet-based automated audiometry in children?

INTRODUCTION: Recent research supports the clinical use of automated audiometry for pediatric hearing screenings. However, very few studies have tested whether tablet-based automated audiometry can offer a valid alternative to traditional manual audiometry for estimation of hearing thresholds in children. This study examined the validity and efficiency of automated audiometry in school-aged children. METHODS: Hearing thresholds for 0.5, 1, 2, 4, 6, and 8 kHz were collected in 32 children ages 6-12 years using standard audiometry and tablet-based automated audiometry in a soundproof booth. Test administration time, test preference, and medical history were also collected. RESULTS: Results exhibited that the majority (67%) of threshold differences between automated and standard were within the clinically acceptable range (10 dB). The threshold difference between the two tests showed that automated audiometry thresholds were higher by 12 dB in 6-year-olds, 7 dB in 7- to 9-year-olds, and 3 dB in 10- to 12-year-olds. In addition, test administration times were similar, such that standard audiometry took an average of 12.3 min and automated audiometry took 11.9 min. CONCLUSIONS: These results support the use of tablet-based automated audiometry in children from ages 7-12 years. However, the results suggest that the clinical use of at least some types of tablet-based automated audiometry may not be feasible in children 6 years of age.

Auditory function in Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease (PMD; MIM 312080), an inherited defect of central nervous system myelin formation, affects individuals in many ways, including their hearing and language abilities. The aim of this study was to assess the auditory abilities in 18 patients with PMD by examining the functional processes along the central auditory pathways using auditory brainstem responses (ABR) and cortical auditory evoked potentials (CAEP) in response to speech sounds. The significant ABR anomalies confirm the existence of dyssynchrony previously described at the level of the brainstem in patients with PMD. Despite the significant auditory dyssynchrony observed at the level of the brainstem, CAEPs were present in most patients, albeit somehow abnormal in terms of morphology and latency, resembling a type of auditory neuropathy spectrum disorder.

Neurophysiology of hearing in patients with mucopolysaccharidosis type IV.

BACKGROUND: Hearing impairment is a common problem in patients with mucopolysaccharidosis IV (MPS IV) throughout their life. Many of the adult patients with MPS IV exhibit permanent or severe hearing loss. However, there has been no systematic review of detailed audiological test results in MPS IV. MATERIALS AND METHODS: Fourteen individuals with MPS IV (13 MPS IVA and 1 MPS IVB; aged between 12 and 38 years old) participated in the current study. We obtained auditory neurophysiological responses (auditory brainstem responses and otoacoustic emissions test) in addition to pure-tone audiometry and middle ear function tests (tympanometry and acoustic reflexes). RESULTS: The results indicated various levels and types of hearing loss with abnormal neurophysiological responses even in those patients with MPS IVA with normal pure tone thresholds. We also found a strong relationship between height (short stature is an indicator of skeletal severity) and hearing sensitivity as well as a strong relationship between height and outer hair cell function in the inner ear (measured by otoacoustic emissions) among MPS IVA patients. CONCLUSION: The strong correlation between reduced height and hearing loss indicates that patients with severe skeletal dysplasia may be at higher risk of developing more severe hearing loss. More importantly, the spectrum of hearing disorders indicates that MPS IV patients should have annual neurophysiological hearing tests in addition to audiometric testing from an early age regardless of their skeletal severity to more carefully monitor disease progression.

Cochlear Nerve Deficiency and Brain Abnormalities in Pediatric Patients.

HYPOTHESIS: To investigate the intracranial abnormalities present in children with cochlear nerve deficiency (CND), including abnormalities of other cranial nerves, and to describe their auditory abilities. BACKGROUND: The prevalence of CND has increased with the development of high resolution magnetic resonance imaging (MRI). There are varying degrees of CND from true aplasia to hypoplasia. The etiology of CND remains unclear and it may be associated with intracranial abnormalities in some instances. CND needs to be identified as early as possible to ensure prompt and adequate management of hearing loss since hearing aids and cochlear implants may not be an option. METHODS: A retrospective chart review of 56 ears of pediatric patients with CND was conducted between August 2006 and November 2014 at a tertiary care pediatric hospital. RESULTS: 27.6% of children had cochlear abnormalities and 48.9.8% had concomitant vestibular anomalies. Five patients had absent or abnormal facial nerves and two patients had aplastic bilateral olfactory nerves. In the 27 ears with an absent nerve that were functionally tested, eight (29.6%) had partial hearing which indicates the presence of an extremely small nerve whose size is below the limits of spatial resolution of the MRI. CONCLUSION: MRI is becoming the initial imaging choice for children with sensorineural hearing loss to identify CND and other brain anomalies. Concomitant vestibular and cochlear abnormalities were observed in respectively half and one-third of the pediatric patients with CND. The incidence of vestibular malformation suggests that balance testing should be recommended for most if not all CND patients.

Prevalence of Auditory Processing Disorder in School-Aged Children in the Mid-Atlantic Region.

BACKGROUND: Although auditory processing disorder (APD) is a widely recognized impairment, its prevalence and demographic characteristics are not precisely known in the pediatric population. PURPOSE: To examine the demographic characteristics of children diagnosed with APD at a tertiary health-care facility and the prevalence of pediatric APD. RESEARCH DESIGN: A cross-sectional study. STUDY SAMPLE: A total of 243 children (149 boys and 94 girls) who were referred to the Nemours Audiology Clinics in the Delaware Valley for an APD evaluation. The mean ages were 9.8 yr for boys and 9.7 yr for girls. Out of 243 children referred for an APD evaluation, 94 children exhibited one or more auditory processing deficits in the areas of auditory closure, auditory figure ground, binaural integration, binaural separation, and temporal processing. DATA COLLECTION AND ANALYSIS: Demographic and audiological data, clinical history (parental reports on prenatal and postnatal information, birth weight and height, medical and developmental history, otologic/audiological history, education information, behavioral characteristics), and results of the APD test battery were retrospectively obtained from the electronic medical records of each participant. The prevalence of APD was estimated using the total number of students enrolled in the same school attended by each participant in the 2011 academic year as cohort. RESULTS: The prevalence of APD was 1.94 per 1,000 children in this study. We found that prevalence of APD among the children who attended private schools was more than two times higher than the children who attended public schools. The results also revealed that the majority of children referred to the clinics were Caucasian (85.6%), whereas minority groups were underrepresented for this geographical area with only 3.7% of Hispanic or Latino children and 5.8% of Black or African American children. CONCLUSIONS: The estimated prevalence of APD in the current study was lower than the previously published estimates. The difference might be due to the diagnosis criteria of APD among studies as well as the use of school enrollment number as the referenced population to estimate prevalence in our study. We also found a significant difference in APD prevalence depending on the school types. The findings of higher prevalence rates among the children attending private schools and higher proportion of Caucasians children referred for APD evaluation suggest that more children among those in public schools and in the Hispanic and African American groups should have been referred for an APD evaluation. Hence, the current estimate is likely an underestimate of the actual APD prevalence. The low percentage of Hispanic or African American children referred to the clinic for APD evaluations may be related to the socioeconomic status and linguistic differences among the concerned families. The results of this study raise the importance of adapting the APD test battery for children with a different linguistic background as well as increasing awareness of available clinical resources to all families in our area.

Activity of daily living for Morquio A syndrome.

The aim of this study was to evaluate the activity of daily living (ADL) and surgical interventions in patients with mucopolysaccharidosis IVA (MPS IVA). The factor(s) that affect ADL are age, clinical phenotypes, surgical interventions, therapeutic effect, and body mass index. The ADL questionnaire comprises three domains: "Movement," "Movement with cognition," and "Cognition." Each domain has four subcategories rated on a 5-point scale based on the level of assistance. The questionnaire was collected from 145 healthy controls and 82 patients with MPS IVA. The patient cohort consisted of 63 severe and 17 attenuated phenotypes (2 were undefined); 4 patients treated with hematopoietic stem cell transplantation (HSCT), 33 patients treated with enzyme replacement therapy (ERT) for more than a year, and 45 untreated patients. MPS IVA patients show a decline in ADL scores after 10years of age. Patients with a severe phenotype have a lower ADL score than healthy control subjects, and lower scores than patients with an attenuated phenotype in domains of "Movement" and "Movement with cognition." Patients, who underwent HSCT and were followed up for over 10years, had higher ADL scores and fewer surgical interventions than untreated patients. ADL scores for ERT patients (2.5years follow-up on average) were similar with the-age-matched controls below 10years of age, but declined in older patients. Surgical frequency was higher for severe phenotypic patients than attenuated ones. Surgical frequency for patients treated with ERT was not decreased compared to untreated patients. In conclusion, we have shown the utility of the proposed ADL questionnaire and frequency of surgical interventions in patients with MPS IVA to evaluate the clinical severity and therapeutic efficacy compared with age-matched controls.

Ganglioside GM3 is essential for the structural integrity and function of cochlear hair cells.

GM3 synthase (ST3GAL5) is the first biosynthetic enzyme of a- and b-series gangliosides. Patients with GM3 synthase deficiency suffer severe neurological disability and deafness. Eight children (ages 4.1 ± 2.3 years) homozygous for ST3GAL5 c.694C>T had no detectable GM3 (a-series) or GD3 (b-series) in plasma. Their auditory function was characterized by the absence of middle ear muscle reflexes, distortion product otoacoustic emissions and cochlear microphonics, as well as abnormal auditory brainstem responses and cortical auditory-evoked potentials. In St3gal5(-/-) mice, stereocilia of outer hair cells showed signs of degeneration as early as postnatal Day 3 (P3); thereafter, blebs devoid of actin or tubulin appeared at the region of vestigial kinocilia, suggesting impaired vesicular trafficking. Stereocilia of St3gal5(-/-) inner hair cells were fused by P17, and protein tyrosine phosphatase receptor Q, normally linked to myosin VI at the tapered base of stereocilia, was maldistributed along the cell membrane. B4galnt1(-/-) (GM2 synthase-deficient) mice expressing only GM3 and GD3 gangliosides had normal auditory structure and function. Thus, GM3-dependent membrane microdomains might be essential for the proper organization and maintenance of stereocilia in auditory hair cells.

CODAS syndrome is associated with mutations of LONP1, encoding mitochondrial AAA+ Lon protease.

CODAS syndrome is a multi-system developmental disorder characterized by cerebral, ocular, dental, auricular, and skeletal anomalies. Using whole-exome and Sanger sequencing, we identified four LONP1 mutations inherited as homozygous or compound-heterozygous combinations among ten individuals with CODAS syndrome. The individuals come from three different ancestral backgrounds (Amish-Swiss from United States, n = 8; Mennonite-German from Canada, n = 1; mixed European from Canada, n = 1). LONP1 encodes Lon protease, a homohexameric enzyme that mediates protein quality control, respiratory-complex assembly, gene expression, and stress responses in mitochondria. All four pathogenic amino acid substitutions cluster within the AAA(+) domain at residues near the ATP-binding pocket. In biochemical assays, pathogenic Lon proteins show substrate-specific defects in ATP-dependent proteolysis. When expressed recombinantly in cells, all altered Lon proteins localize to mitochondria. The Old Order Amish Lon variant (LONP1 c.2161C>G[p.Arg721Gly]) homo-oligomerizes poorly in vitro. Lymphoblastoid cell lines generated from affected children have (1) swollen mitochondria with electron-dense inclusions and abnormal inner-membrane morphology; (2) aggregated MT-CO2, the mtDNA-encoded subunit II of cytochrome c oxidase; and (3) reduced spare respiratory capacity, leading to impaired mitochondrial proteostasis and function. CODAS syndrome is a distinct, autosomal-recessive, developmental disorder associated with dysfunction of the mitochondrial Lon protease.

Ear effect and gender difference of spontaneous otoacoustic emissions in children with auditory processing disorder.

Spontaneous otoacoustic emissions (SOAEs) are found in most healthy ears, and can be used to measure the health of the cochlear structures and feedback mechanism. According to existing literature, right ears tend to exhibit greater numbers of SOAEs than left ears (Bilger et al., 1990) and females tend to show higher incidence of SOAEs than males (Moulin et al., 1993). The SOAE prevalence has not been extensively studied in children with Auditory Processing Disorder (APD), a disorder with unknown etiology that reduces one's ability to process auditory information. This study examined the prevalence and ear advantage of SOAEs between genders in children diagnosed with APD. SOAEs were investigated in 19 children (7 girls and 12 boys) with APD and 2 4 typically developing children (14 girls and 10 boys) aged 7-12. Right ear advantage was more prevalent in control (71%) than APD subjects (42 %). However, over 30% more females exhibited a right ear advantage than males in each group. Although the results are not significant, our findings indicate that the lack of right ear advantage for SOAE is more prevalent in children with APD, particularly in males, suggesting that cochlear mechanisms or their control might be somehow affected in APD.

A homozygous SLITRK6 nonsense mutation is associated with progressive auditory neuropathy in humans.

OBJECTIVES/HYPOTHESIS: SLITRK family proteins control neurite outgrowth and regulate synaptic development. In mice, Slitrk6 plays a role in the survival and innervation of sensory neurons in the inner ear, vestibular apparatus, and retina, and also influences axial eye length. We provide the first detailed description of the auditory phenotype in humans with recessive SLITRK6 deficiency. STUDY DESIGN: Prospective observational case study. METHODS: Nine closely related Amish subjects from an endogamous Amish community of Pennsylvania underwent audiologic and vestibular testing. Single nucleotide polymorphism microarrays were used to map the chromosome locus, and Sanger sequencing or high-resolution melt analysis were used to confirm the allelic variant. RESULTS: All nine subjects were homozygous for a novel nonsense variant of SLITRK6 (c.1240C>T, p.Gln414Ter). Adult patients had high myopia. The 4 oldest SLITRK6 c.1240C>T homozygotes had absent ipsilateral middle ear muscle reflexes (MEMRs). Distortion product otoacoustic emissions (DPOAEs) were absent in all ears tested and the cochlear microphonic (CM) was increased in amplitude and duration in young patients and absent in the two oldest subjects. Auditory brainstem responses (ABRs) were dys-synchronised bilaterally with no reproducible waves I, III, or V at high intensities. Hearing loss and speech reception thresholds deteriorated symmetrically with age, which resulted in severe-to-profound hearing impairment by early adulthood. Vestibular evoked myogenic potentials were normal in three ears and absent in one. CONCLUSION: Homozygous SLITRK6 c.1240C>T (p.Gln414Ter) nonsense mutations are associated with high myopia, cochlear dysfunction attributed to outer hair cell disease, and progressive auditory neuropathy.