Identification and in vivo functional investigation of a HOMER2 nonstop variant causing hearing loss.

DFNA68 is a rare subtype of autosomal dominant nonsyndromic hearing impairment caused by heterozygous alterations in the HOMER2 gene. To date, only 5 pathogenic or likely pathogenic coding variants, including two missense substitutions (c.188 C > T and c.587 G > C), a single base pair duplication (c.840dupC) and two short deletions (c.592_597delACCACA and c.832_836delCCTCA) have been described in 5 families. In this study, we report a novel HOMER2 variation, identified by massively parallel sequencing, in a Sicilian family suffering from progressive dominant hearing loss over 3 generations. This novel alteration is a nonstop substitution (c.1064 A > G) that converts the translational termination codon (TAG) of the gene into a tryptophan codon (TGG) and is predicted to extend the HOMER2 protein by 10 amino acids. RNA analyses from the proband suggested that HOMER2 transcripts carrying the nonstop variant escaped the non-stop decay pathway. Finally, in vivo studies using a zebrafish animal model and behavioral tests clearly established the deleterious impact of this novel HOMER2 alteration on hearing function. This study identifies the fourth causal variation responsible for DFNA68 and describes a simple in vivo approach to assess the pathogenicity of candidate HOMER2 variants.

Predicting Outcome of Congenital Cytomegalovirus Infection by Differentiating and Revisiting Severe versus Mild Prenatal Imaging Features.

INTRODUCTION: Our objective was to evaluate the outcome of fetuses with first- and second-trimester fetal cytomegalovirus infection (CMVi) according to prenatal imaging patterns, especially fetuses presenting with mild imaging features (MF), being currently of uncertain prognosis. MATERIAL AND METHODS: In a retrospective study of 415 suspected CMVi cases, 59 cases were confirmed. Among prenatal imaging features, microcephaly, cortical disorder, and cerebellar hypoplasia as well as severe IUGR and fetal hydrops were considered as severe imaging features (SF). Other imaging features were considered as MF. Postnatal outcome was classified as "normal outcome," "mild sequelae" characterized mainly by sensorineural disorder (SND) and "severe sequelae" characterized by cognitive impairment. RESULTS: Only first-trimester (T1) and second-trimester (T2) CMVi cases were included in our study (n = 49) since all third-trimester cases (n = 10) had normal imaging and outcome. Sixteen fetuses had normal prenatal imaging and normal outcome, except one showing SND. Abnormal ultrasound findings were present in 33 fetuses, including SF noted in 16 fetuses, related exclusively to first-trimester CMVi. Termination of pregnancy was performed in 18 cases. Twelve first-trimester infected fetuses presented SF, whereas 6 fetuses (T1: n = 5, T2: n = 1) presented isolated MF. Four fetal deaths were encountered. Live-born babies with abnormal imaging included 10 fetuses with MF and one with SF. Among the 10 live babies with isolated MF, SND was encountered in 5 cases, whereas 5 children demonstrated normal outcome. Overall, 50% of our babies showing MF suffered from SND. No case of cognitive disorders was reported in babies showing only MF. CONCLUSION: SF were encountered only in first-trimester CMVi and should be distinguished from MF. Among our 10 live babies with prenatal MF following first- or second-trimester infection, 50% showed SND, whereas none presented severe sequelae. In 16 fetuses displaying normal fetal imaging, SND was encountered in one first-trimester case (6%).

High Heterogeneity of Temporal Bone CT Aspects in Osteogenesis Imperfecta Is Not Linked to Hearing Loss.

OBJECTIVES: To determine whether temporal bone computed tomography (CT) features are linked to the presence and type of hearing loss in osteogenesis imperfecta (OI) when considering hearing-impaired OI patients and normally hearing (NH) OI ones. A secondary objective was to assess whether other factors influence CT features in a large sample: age, type of mutation, or bone mineral density (BMD). METHODS: A total of 41 adults with OI underwent CTs and pure-tone audiometry in 82 ears. Hearing thresholds were normal in 64 out of 82 ears, and most had not been operated on for stapedectomy or stapedotomy. Ossicle density, footplates, oval and round windows, retrofenestral peri- and endolabyrinths, and temporal pneumatization were analyzed twice by an experienced radiologist. CT features were compared to hearing, age, collagen mutations, and bone mineral density. RESULTS: Unexpectedly a high prevalence of footplate, ossicle, and otic capsule anomalies was observed, even in NH ears. Footplate hypodensity or thickening was mostly found in ears without conductive hearing loss. There were significantly more retrofenestral anomalies or window obstruction in ears with a sensorineural hearing loss component than in ears without. Age was significantly higher in ears with middle layer hypodensity than in ears without. Patients with mutations were expected to have reduced collagen quantity and had significantly more footplate or retrofenestral anomalies than those with qualitative mutations. BMD was significantly higher in ears without temporal hyperpneumatization. CONCLUSION: Temporal bone CT features in OI are present in a large proportion of patients, had they hearing loss or not, and might be determined more by collagen mutation type than by age or BMD.

PRPS1 loss-of-function variants, from isolated hearing loss to severe congenital encephalopathy: New cases and literature review.

We describe two sporadic and two familial cases with loss-of-function variants in PRPS1, which is located on the X chromosome and encodes phosphoribosyl pyrophosphate synthetase 1 (PRS-1). We illustrate the clinical variability associated with decreased PRS-1 activity, ranging from mild isolated hearing loss to severe encephalopathy. One of the variants we identified has already been reported with a phenotype similar to our patient's, whereas the other three were unknown. The clinical and biochemical information we provide will hopefully contribute to gain insight into the correlation between genotype and phenotype of this rare condition, both in females and in males. Moreover, our observation of a new family in which hemizygous males display hearing loss without any neurological or ophthalmological symptoms prompts us to suggest analysing PRPS1 in cases of isolated hearing loss. Eventually, PRPS1 variants should be considered as a differential diagnosis of mitochondrial disorders.

Long-Term Cognitive Prognosis of Profoundly Deaf Older Adults After Hearing Rehabilitation Using Cochlear Implants.

OBJECTIVES: To analyze long-term cognitive status and function after cochlear implantation in profoundly deaf individuals. DESIGN: Prospective observational longitudinal study. SETTING: Ten academic medical centers referent for cochlear implantation. PARTICIPANTS: Individuals aged 65 and older who qualified for cochlear implantation (N=70). MEASUREMENTS: Cognitive tests were administered before cochlear implantation and 1 and 5 or more years after cochlear implantation. Evaluation consisted of 6 tests assessing attention, memory, orientation, executive function, mental flexibility, and fluency. Cognitive status was determined as normal, mild cognitive impairment (MCI), or dementia. Speech perception in quiet and noisy conditions was assessed using disyllabic words, and quality of life was assessed using the Nijmegen Cochlear Implant Questionnaire. RESULTS: Mean follow-up was 6.8 years (range 5.5-8.5 years). Speech perception scores and quality of life remained stable from 1 to 7 years after cochlear implantation. Of 31 participants (45%) with MCI before cochlear implantation, 2 (6%) developed dementia during follow-up, 19 (61%) remained stable, and 10 (32%) returned to normal cognition. None of the 38 with normal cognition developed dementia during follow-up, although 12 (32%) developed MCI. CONCLUSION: MCI is highly prevalent in older adults with profound hearing loss. Nevertheless, we observed a low rate of progression to dementia, and cognitive function improved in some individuals with MCI at baseline. These results highlight that cochlear implantation should be strongly considered in profoundly deaf individuals, even those with MCI, who may have a specific subtype of MCI, with a possible positive effect of hearing rehabilitation on neurocognitive functioning.

Improvement of cognitive function after cochlear implantation in elderly patients.

IMPORTANCE: The association between hearing impairment and cognitive decline has been established; however, the effect of cochlear implantation on cognition in profoundly deaf elderly patients is not known. OBJECTIVE: To analyze the relationship between cognitive function and hearing restoration with a cochlear implant in elderly patients. DESIGN, SETTING, AND PARTICIPANTS: Prospective longitudinal study performed in 10 tertiary referral centers between September 1, 2006, and June 30, 2009. The participants included 94 patients aged 65 to 85 years with profound, postlingual hearing loss who were evaluated before, 6 months after, and 12 months after cochlear implantation. INTERVENTIONS: Cochlear implantation and aural rehabilitation program. MAIN OUTCOMES AND MEASURES: Speech perception was measured using disyllabic word recognition tests in quiet and in noise settings. Cognitive function was assessed using a battery of 6 tests evaluating attention, memory, orientation, executive function, mental flexibility, and fluency (Mini-Mental State Examination, 5-word test, clock-drawing test, verbal fluency test, d2 test of attention, and Trail Making test parts A and B). Quality of life and depression were evaluated using the Nijmegen Cochlear Implant Questionnaire and the Geriatric Depression Scale-4. RESULTS: Cochlear implantation led to improvements in speech perception in quiet and in noise (at 6 months: in quiet, 42% score increase [95% CI, 35%-49%; P < .001]; in noise, at signal to noise ratio [SNR] +15 dB, 44% [95% CI, 36%-52%, P < .001], at SNR +10 dB, 37% [95% CI 30%-44%; P < .001], and at SNR +5 dB, 27% [95% CI, 20%-33%; P < .001]), quality of life, and Geriatric Depression Scale-4 scores (76% of patients gave responses indicating no depression at 12 months after implantation vs 59% before implantation; P = .02). Before cochlear implantation, 44% of the patients (40 of 91) had abnormal scores on 2 or 3 of 6 cognition tests. One year after implant, 81% of the subgroup (30 of 37) showed improved global cognitive function (no or 1 abnormal test score). Improved mean scores in all cognitive domains were observed as early as 6 months after cochlear implantation. Cognitive performance remained stable in the remaining 19% of the participants (7 of 37). Among patients with the best cognitive performance before implantation (ie, no or 1 abnormal cognitive test score), 24% (12 of 50) displayed a slight decline in cognitive performance. Multivariate analysis to examine the association between cognitive abilities before implantation and the variability in cochlear implant outcomes demonstrated a significant effect only between long-term memory and speech perception in noise at 12 months (SNR +15 dB, P = .01; SNR +10 dB, P < .001; and SNR +5 dB, P = .02). CONCLUSIONS AND RELEVANCE: Rehabilitation of hearing communication through cochlear implantation in elderly patients results in improvements in speech perception and cognitive abilities and positively influences their social activity and quality of life. Further research is needed to assess the long-term effect of cochlear implantation on cognitive decline.

One-Year Follow Up of Auditory Performance in Post-Lingually Deafened Adults Implanted with the Neurelec Digisonic(®) SP/Saphyr(®) Neo Cochlear Implant System.

This study aimed to quantify outcomes in a group of patients who were implanted with an Oticon Medical Neurelec (Vallauris, France) cochlear implant system, the Digisonic(®) SP/Saphyr(®) Neo. Ten participants took part in this preliminary study. Their speech perception capacities were evaluated at 3, 6, and 12-months after cochlear implant activation and compared to pre-implantation scores and to scores observed with former versions of the sound processor. Compared to former versions of the sound processor, patients using the Saphyr(®) Neo processor obtained better speech perception scores for sentences in silence at each tests session (3 months: 79%, 6 months: 82% and 12 months: 94%) compared to Digisonic(®) users (respectively: 58%, 69% and 75%) and Convex sound processor users (resp. 39%, 59% and 51%). These observations confirm that the technological improvements made in the Saphyr(®) Neo sound processor coupled with the Digisonic(®) implant, provided quantifiable benefits in speech perception in Quiet compared to former versions of the processor Convex and Digisonic(®) SP.

Predictive factors of cochlear implant outcomes in the elderly.

OBJECTIVE: To analyze predictive factors of cochlear implant outcomes and postoperative complications in the elderly. STUDY DESIGN: Prospective, longitudinal study performed in 10 tertiary referral centers. METHODS: Ninety-four patients aged 65-85 years with a profound, postlingual hearing loss were evaluated before implantation, at time of activation, and 6 and 12 months after cochlear implantation. Speech perception and lipreading were measured using disyllabic word recognition in quiet and noise, and lipreading using disyllabic words and sentences. The influence of preoperative factors on speech perception in quiet and noise at 12 months was tested in a multivariate analysis. Complications, presence of tinnitus and of vestibular symptoms were collected at each evaluation. RESULTS: The effect of age was observed only in difficult noisy conditions at SNR 0 dB. Lipreading ability for words and sentences was negatively correlated with speech perception in quiet and noise. Better speech perception scores were observed in patients with shorter duration of hearing deprivation, persistence of residual hearing for the low frequencies, the use of a hearing aid before implantation, the absence of cardiovascular risk factors, and in those with implantation in the right ear. General and surgical complications were very rare, and the percentage of vestibular symptoms remained stable over time. CONCLUSION: This study demonstrates that cochlear implantation in the elderly is a well-tolerated procedure and an effective method to improve communication ability. Advanced age has a low effect on cochlear implant outcome. Analyses of predictive factors in this population provide a convincing argument to recommend treatment with cochlear implantation as early as possible in elderly patients with confirmed diagnosis of a severe-to-profound hearing loss and with only limited benefit from hearing aid use in one ear.

Non-USH2A mutations in USH2 patients.

We have systematically analyzed the two known minor genes involved in Usher syndrome type 2, DFNB31 and GPR98, for mutations in a cohort of 31 patients not linked to USH2A. PDZD7, an Usher syndrome type 2 (USH2) related gene, was analyzed when indicated. We found that mutations in GPR98 contribute significantly to USH2. We report 17 mutations in 10 individuals, doubling the number of GPR98 mutations reported to date. In contrast to mutations in usherin, the mutational spectrum of GPR98 predominantly results in a truncated protein product. This is true even when the mutation affects splicing, and we have incorporated a splicing reporter minigene assay to show this, where appropriate. Only two mutations were found which we believe to be genuine missense changes. Discrepancy in the mutational spectrum between GPR98 and USH2A is discussed. Only two patients were found with mutations in DFNB31, showing that mutations of this gene contribute to only a very small extent to USH2. Close examination of the clinical details, where available, for patients in whom no mutation was found in USH2A, GPR98, or DFNB31, showed that most of them had atypical features. In effect, these three genes account for the vast majority of USH2 patients and their analysis provide a robust pathway for routine molecular diagnosis.

Strategies of active middle ear implants for hearing rehabilitation in congenital aural atresia.

OBJECTIVE: To describe our surgical and audiometric experience using different active middle ear implant strategies facing various anatomic situations in aural atresia. STUDY DESIGN: Retrospective case review. SETTING: Tertiary academic referral center. PATIENTS: Five patients with congenital aural atresia, (3 unilateral and 2 bilateral), with mean age of 22.4 years (range, 12-44 yr), referred for hearing rehabilitation. INTERVENTION: Active middle ear implant on stapes capitulum. MAIN OUTCOME MEASURES: Description of surgical implantation with different active middle ear implants. Preoperative and postoperative air conduction, bone conduction, and aided and unaided thresholds and speech scores were measured, at mid to long term. Subjective benefit analysis was determined through the Abbreviated Profile of Hearing Aid Benefit questionnaire. RESULTS: After activation and fitting of the devices, a mean functional gain of 32.5 dB hearing level was measured. Speech tests in quiet showed a mean functional gain of 20.2 dB. Patients had a mean follow-up period of 12 months. No intraoperative or postoperative complications were noted. Furthermore, we reflected on new coupling possibilities, especially in a difficult case with stapes-footplate fixation where no approach of the round window was feasible because of aberrant facial nerve course. CONCLUSION: Facing anatomic variations in congenital aural atresia, active middle ear implants can provide substantial hearing improvement in safe conditions and open new strategies for hearing rehabilitation.

Four-year follow-up of diagnostic service in USH1 patients.

PURPOSE: The purpose of this study was to establish the mutation spectrum of an Usher type I cohort of 61 patients from France and to describe a diagnostic strategy, including a strategy for estimating the pathogenicity of sequence changes. METHODS: To optimize the identification of Usher (USH)-causative mutations, taking into account the genetic heterogeneity, preliminary haplotyping at the five USH1 loci was performed to prioritize the gene to be sequenced, as previously described. Coding exons and flanking intronic sequences were sequenced and, where necessary, semiquantitative PCR and multiplex ligation-dependent probe amplification (MLPA) were performed to detect large genomic rearrangements. RESULTS: Four years ' experience confirms that the chosen approach provides an efficient diagnostic service. Sixty-one patients showed an abnormal genotype in one of the five USH1 genes. Genetic heterogeneity was confirmed, and, although MYO7A remains the major gene, involvement of other genes is considerable. Distribution of missense, splicing, premature termination codons (PTCs; due to point substitution and small deletions/ or insertions), and large genomic alterations was determined among the USH genes and clearly highlights the need to pay special attention to the diagnostic approach and interpretation, depending on the mutated gene. CONCLUSIONS: Over the 4 years of a diagnostic service offering USH1 patient testing, pathogenic genotypes were identified in most cases (>90%). The complexity and heterogeneity of mutations reinforces the need for a comprehensive approach. Because 32% of the mutations are newly described, the results show that a screening strategy based on known mutations would have solved less than 55% of the cases.

Speech perception performance for 100 post-lingually deaf adults fitted with Neurelec cochlear implants: Comparison between Digisonic® Convex and Digisonic® SP devices after a 1-year follow-up.

CONCLUSION: Patients implanted with the Digisonic® SP device showed better identification scores than those implanted with the Convex device, with skills continuing to improve over a longer time period. Technological improvements were beneficial in terms of speech perception in quiet. OBJECTIVE: To compare speech perception skills for post-lingually deaf patients implanted with a previous Neurelec device, the Digisonic® Convex, with those implanted with a more recent one, the Digisonic® SP, which provides more electrodes and a faster stimulation rate. METHODS: This was a retrospective study of 100 implanted patients, 45 with the Digisonic® Convex implant and 55 with the Digisonic® SP. Speech perception (dissyllabic words and sentences, in open set) was evaluated until 1 year after implantation. RESULTS: Patients fitted with the Digisonic® SP implant showed significantly better scores after 3, 6, and 12 months (mean scores: 53%, 62%, and 68% for words; 58%, 69%, and 75% for sentences) than those fitted with the Convex implant (34%, 42%, and 43% for words; 38%, 59%, and 51% for sentences). The improvement in speech perception after implantation for SP patients continued throughout the 12 months for words and 6 months for sentences, versus 6 months for words and 3 months for sentences for Convex patients.

Screening to detect permanent childhood hearing impairment in neonates transferred from the newborn nursery.

OBJECTIVES: The focus of this report is hearing screening of newborns transferred from the regular nursery to a specialized area. The purpose of the study undertaken was: (1) to determine whether screening coverage in this population was achieved; (2) to establish whether the linkage between neonatal screening and the diagnostic follow-up was carried out correctly; (3) to better determine the incidence of permanent childhood hearing impairment (PCHI) in this at-risk population. METHODS: Six population centres averaging 12,000 births annually participated (Bordeaux, Lille, Paris, Marseille, Toulouse and Lyon). Automated auditory brainstem response (AABR) (Natus ALGO 3i) screening was performed in two stages: i.e. infants with initial "positive" results were screened a second time using the same technique. Of the 117,103 babies born during the study period, 4972 neonates were "transferred" and comprised the population for this report (4.2% of the total births). RESULTS AND DISCUSSION: Screening results for 4972 "transferred" neonates were compared with those of non-transferred neonates (N=112,131). Screening coverage of eligible infants was significantly lower (75.4%) in "transferred" neonates (3750 infants screened) compared to 97.5% coverage of non-transferred neonates (109,349 infants screened). The rate of positive results after the first stage AABR was higher in the "transferred" population (11.1%) than in the non-transferred population (6.5%). Of the 415 "transferred" newborns with initial positive screens, 91.3% were rechecked as stipulated in the project protocol. The second pre-discharge AABR ascertained that in half of the cases auditory function had normalized in the day. Of the 183 "transferred" infants whose result remained suspect at the conclusion of both stages of the neonatal screen (4.9% of the tested population), only 70.5% returned to the audiology centre for diagnostic follow-up. The incidence of bilateral PCHI was markedly higher (4/1000) in "transferred" infants than in the non-transferred population (1.08/1000). CONCLUSIONS: The difficulty of obtaining universal screening coverage in "transferred" infants was, unfortunately, verified in this prospective, multicentre study. Further, the diversity of our "transferred" population was not much greater than that revealed by careful analysis of published hearing screening studies in neonatal intensive care unit (NICU) infants. The influence of risk factors and their more or less complex combinations is apparent.

Hydroxyapatite versus titanium ossiculoplasty.

OBJECTIVE: To compare the results of ossicular chain reconstruction using hydroxyapatite (HA) and titanium (TI) prostheses. STUDY DESIGN: Retrospective study and case series. SETTING: Tertiary referral center. PATIENTS: One hundred sixty-eight patients presenting chronic otitis media with or without cholesteatoma. INTERVENTION: Ossiculoplasty using partial or total HA and TI ossicular replacement prostheses (TORP and PORP, respectively). MAIN OUTCOME MEASURES: Patients were assessed at 2 months postoperatively to establish short-term results. Results of treatment for conductive hearing loss were reported according to guidelines. Available audiometric data at 1, 2, 3, and 5 years were used to assess prosthesis stability. Average postoperative air-conduction gain, air-bone gap, and sensorineural hearing level were measured at four frequencies: 0.5, 1, 2, and 4 kHz. Statistical analyses compared outcomes for HA TORP versus TI TORP and HA PORP versus TI PORP. RESULTS: Postoperative air-bone gap of less than 20 dB was obtained in 50% of HA TORP versus 45.8% of TI TORP cases and in 63.2% of HA PORP versus 72% of TI PORP cases. Preoperative middle ear status and presence/absence of malleus significantly influenced postoperative audiometric results. All types of prosthesis demonstrated significant postoperative air-conduction gain decrease on follow-up. Prosthesis exclusion was observed in three cases (1.78%). CONCLUSION: Prostheses using both types of biomaterial gave good functional results and stability with low exclusion rates, with no statistically significant differences between the two. Trends could be observed for slightly better results for HA in total reconstruction and for TI in partial reconstruction. The degradation in postoperative functional gain seemed to be independent of prosthesis type.

Effects of oral alendronate on BMD in adult patients with osteogenesis imperfecta: a 3-year randomized placebo-controlled trial.

UNLABELLED: A 3-year, randomized, double-blind, placebo-controlled trial evaluated the effect of oral alendronate on the BMD of 64 adult patients with osteogenesis imperfecta. The mean increases in the lumbar spine BMD were 10.1 +/- 9.8% (p < 0.001) and 0.7 +/- 5.7% in the alendronate and placebo groups, respectively. Oral alendronate increases BMD in adult patients with osteogenesis imperfecta. INTRODUCTION: This study evaluated the effect of oral alendronate on the BMD of adult patients with osteogenesis imperfecta. MATERIALS AND METHODS: We carried out a 3-year, randomized, double-blind, placebo-controlled trial of oral alendronate in 64 adult patients with osteogenesis imperfecta. The primary endpoint was the difference between the groups in the mean percent change in lumbar spine BMD at 3 years. Secondary outcomes included changes in BMD of total hip, vertebral and peripheral fracture incidence, pain, hearing loss, and bone turnover biochemical markers. Patients were treated daily with either placebo or 10 mg alendronate. All received 1 g of calcium and 800 IU of vitamin D daily. RESULTS: The mean +/- SD increases in the lumbar spine BMD were 10.1 +/- 9.8% (p < 0.001) and 0.7 +/- 5.7% in the alendronate and placebo groups, respectively. Hip BMD increased in the alendronate group by 3.3 +/- 0.5% (p = 0.001) and decreased in the placebo group by 0.3 +/- 0.6%. The sample size was not sufficient to determine an effect of alendronate on fracture rate. A significant increase of the pain score was noted in the alendronate group (p = 0.04) in the intent-to-treat analysis but not in the per protocol analysis. There was no change in hearing in either group. Bone resorption and formation biochemical markers were significantly decreased in the alendronate group (p < 0.001). There were no differences in severe adverse effects between the groups, but there was an increase in nonsevere upper gastrointestinal effects in the alendronate group (p = 0.003). CONCLUSIONS: Oral alendronate increases BMD and increase nonsevere gastrointestinal adverse effects but does not modify the hearing loss in adult patients with osteogenesis imperfecta. More studies are needed to evaluate an effect on the fracture rate.