Richard T. Miyamoto

A Mosaic Activating Mutation in AKT1 Associated with the Proteus Syndrome

BACKGROUND The Proteus syndrome is characterized by the overgrowth of skin, connective tissue, brain, and other tissues. It has been hypothesized that the syndrome is caused by somatic mosaicism for a mutation that is lethal in the nonmosaic state. METHODS We performed exome sequencing of DNA from biopsy samples obtained from patients with the Proteus syndrome and compared the resultant DNA sequences with those of unaffected tissues obtained from the same patients. We confirmed and extended an observed association, using a custom restriction-enzyme assay to analyze the DNA in 158 samples from 29 patients with the Proteus syndrome. We then assayed activation of the AKT protein in affected tissues, using phosphorylation-specific antibodies on Western blots. RESULTS Of 29 patients with the Proteus syndrome, 26 had a somatic activating mutation (c.49G→A, p.Glu17Lys) in the oncogene AKT1, encoding the AKT1 kinase, an enzyme known to mediate processes such as cell proliferation and apoptosis. Tissues and cell lines from patients with the Proteus syndrome harbored admixtures of mutant alleles that ranged from 1% to approximately 50%. Mutant cell lines showed greater AKT phosphorylation than did control cell lines. A pair of single-cell clones that were established from the same starting culture and differed with respect to their mutation status had different levels of AKT phosphorylation. CONCLUSIONS The Proteus syndrome is caused by a somatic activating mutation in AKT1, proving the hypothesis of somatic mosaicism and implicating activation of the PI3K-AKT pathway in the characteristic clinical findings of overgrowth and tumor susceptibility in this disorder. (Funded by the Intramural Research Program of the National Human Genome Research Institute.).

Language Development in Profoundly Deaf Children with Cochlear Implants

Although cochlear implants improve the ability of profoundly deaf children to understand speech, critics claim that the published literature does not document even a single case of a child who has developed a linguistic system based on input from an implant. Thus, it is of clinical and scientific importance to determine whether cochlear implants facilitate the development of English language skills. The English language skills of prelingually deaf children with cochlear implants were measured before and after implantation. We found that the rate of language development after implantation exceeded that expected from unimplanted deaf children (p < .001) and was similar to that of children with normal hearing. Despite a large amount of individual variability, the best performers in the implanted group seem to be developing an oral linguistic system based largely on auditory input obtained from a cochlear implant.

Mutations in a novel cochlear gene cause DFNA9, a human nonsyndromic deafness with vestibular dysfunction

DFNA9 is an autosomal dominant, nonsyndromic, progressive sensorineural hearing loss with vestibular pathology. Here we report three missense mutations in human COCH (previously described as Coch5b2), a novel cochlear gene, in three unrelated kindreds with DFNA9. All three residues mutated in DFNA9 are conserved in mouse and chicken Coch, and are found in a region containing four conserved cysteines with homology to a domain in factor C, a lipopolysaccharide-binding coagulation factor in Limulus polyphemus. COCH message, found at high levels in human cochlear and vestibular organs, occurs in the chicken inner ear in the regions of the auditory and vestibular nerve fibres, the neural and abneural limbs adjacent to the cochlear sensory epithelium and the stroma of the crista ampullaris of the vestibular labyrinth. These areas correspond to human inner ear structures which show histopathological findings of acidophilic ground substance in DFNA9 patients.

Effects of age at implantation in young children.

This study examined the effects of age at implantation on the development of communication abilities in children with early implantation. The 73 participants were prelingually deafened, received a cochlear implant before 5 years of age, and used current cochlear implant technology. The children were administered a battery of speech and language outcome measures before implantation and again at successive 6-month postimplant intervals. A mixed model analysis was used to examine the rate of growth in word recognition and language skills as a function of age at time of implantation. The results revealed significant improvements in communication skills over time. Spoken word recognition improved at a faster rate in the oral children with early implantation. However, the children who underwent implantation before 3 years of age had significantly faster rates of language development than did the children with later implantation. The oral children demonstrated more rapid gains in communication abilities than did the children who used total communication.

Cochlear implants and spoken language processing abilities: Review and assessment of the literature

Cochlear implants (CIs) process sounds electronically and then transmit electric stimulation to the cochlea of individuals with sensorineural deafness, restoring some sensation of auditory perception. Many congenitally deaf CI recipients achieve a high degree of accuracy in speech perception and develop near-normal language skills. Post-lingually deafened implant recipients often regain the ability to understand and use spoken language with or without the aid of visual input (i.e. lip reading). However, there is wide variation in individual outcomes following cochlear implantation, and some CI recipients never develop useable speech and oral language skills. The causes of this enormous variation in outcomes are only partly understood at the present time. The variables most strongly associated with language outcomes are age at implantation and mode of communication in rehabilitation. Thus, some of the more important factors determining success of cochlear implantation are broadly related to neural plasticity that appears to be transiently present in deaf individuals. In this article we review the expected outcomes of cochlear implantation, potential predictors of those outcomes, the basic science regarding critical and sensitive periods, and several new research directions in the field of cochlear implantation.

Cochlear Implantation in Auditory Neuropathy

Objective: Auditory neuropathy is a recently described clinical entity characterized by sensorineural hearing loss in which the auditory evoked potential (ABR) is absent but otoacoustic emissions are present. This suggests a central locus for the associated hearing loss. In this study the results observed in a child with auditory neuropathy who received a cochlear implant are presented and compared with those of a matched group of children who were recipients of implants. Methods: A single‐subject, repeated‐measures design, evaluating closed‐set and open‐set word recognition abilities was used to assess the subject and a control group of matched children with implants who had also experienced a progressive sensorineural hearing loss. Results: The subject demonstrated improvements in vowel recognition (82% correct) by 1 year after implantation, which were only slightly lower than the control group. Consonant recognition and open‐set word recognition scores were significantly lower. Conclusion: Caution should be exercised when considering cochlear implantation in children with auditory neuropathy. As with conventional hearing aids, less than optimal results may be seen.

Phase III clinical trial results with the Vibrant Soundbridge implantable middle ear hearing device: A prospective controlled multicenter study

OBJECTIVES : The goal of the study was to evaluate the performance of a semi-implantable middle ear hearing device (Vibrant Soundbridge System [VSB]; Symphonix Devices, Inc). STUDY DESIGN : A prospective, single-subject, repeated-measures multicenter study was conducted to determine the safety and efficacy of the VSB using analog and digital external processors. Measures included residual hearing, functional gain, speech recognition, acoustic feedback, occlusion, and patient self-assessment to determine satisfaction, perceived performance, and device preference compared with an appropriately fit acoustic hearing aid. Fifty-three adult subjects with moderate to severe sensorineural hearing loss were evaluated at 4 or more intervals after implantation. RESULTS : Improvements in satisfaction, performance, and preference were statistically significant with the VSB, as was functional gain across all test frequencies (P < 0.001). Occlusion and feedback were virtually eliminated. Aided speech recognition was comparable between VSB and the hearing aid. Residual hearing was unchanged. CONCLUSION : The VSB is a safe and effective treatment option for adults with moderate to severe sensorineural hearing loss.

Independent evaluation of the speech perception abilities of children with the nucleus 22-channel cochlear implant system

The performance of 28 children with the Nucleus multichannel cochlear implant, who had used the device an average of 1.7 yr, was examined on a battery of speech perception measures. All children demonstrated better speech perception skills with the implant than they had in the preimplant condition with hearing aids. With the Nucleus implant, 61% of the children demonstrated some open-set speech recognition and another 14% demonstrated closed-set speech recognition. Scores on the tests were corrected for guessing and a hierarchy of test difficulty was developed. The results revealed systematic differences in performance as a function of perception task and test format. The results of regression analyses, which were performed to identify predictors of success, showed that communication mode made a significant unique contribution to the variance in performance among subjects on an open-set word recognition test. When the scores of the children who used oral or total communication were compared on the full battery of tests, however, there were few significant group differences.

Enhancement of expressive language in prelingually deaf children with cochlear implants.

Expressive language skills were assessed in two groups of prelingually-deafened children using the Reynell Developmental Language Scales (RDLS). Results from a group of 89 unimplanted subjects provided cross-sectional data which suggested that profoundly deaf children without implants, on average, could only be expected to make 5 months of expressive language growth in one year. Twenty-three children who received cochlear implants made up the second group of subjects and were administered the RDLS at three intervals: preimplant, 6-, and 12-months postimplant. The scores obtained at the post-implant intervals were then compared to scores that would be predicted on the basis of maturation alone, without the implant (these predictions were formulated based on the data obtained from the unimplanted subjects). At the 12-month postimplant interval, the observed mean language score was significantly higher than the predicted score. Although the mean group data were extremely encouraging, wide inter- subject variability was observed. Although the implant subjects, as a group, were substantially delayed compared with their normal hearing peers, their rate of language growth was found to match that of hearing peers, following implantation. Thus, the gap between chronological age and language age, which normally widens over time in deaf children, remained constant. Preliminary analyses over the first 2.5 years post-implant are consistent with this trend. These results suggest that early implantation (before age 3) might be beneficial to profoundly deaf children because the language delays at the time of implantation would be much smaller.

Communication Skills in Pediatric Cochlear Implant Recipients

Detailed longitudinal studies of speech perception, speech production and language acquisition have justified a significant change in the demographics of congenitally and prelingually deaf children who receive cochlear implants. A trend toward earlier cochlear implantation has been justified by improvements in measures assessing these areas. To assess the influence of age at implantation on performance, age 5 years was used as a benchmark. Thirty-one children who received a Nucleus cochlear implant and use the SPEAK speech processing strategy and two children who received a Clarion cochlear implant and use the CIS strategy served as subjects. The subjects were divided into three groups based on age at implantation. The groups comprised children implanted before the age of 3 years (n = 14), children implanted between 3 years and 3 years 11 months (n = 11) and those implanted between 4 years and 5 years 3 months (n = 8). The children were further divided according to whether they used oral or total communication. The earlier-implanted groups demonstrated statistically significant improvements on measures of speech perception. Improvements in speech intelligibility as a function of age at implant were seen but did not reach statistical significance. The results of the present study demonstrate that early implantation promotes the acquisition of speaking and listening skills.