1. We continue to acquire normative data for various aspects of auditory and vestibular function. This data is used to develop normal reference ranges for test interpretation and as control data for comparison to results obtained in various patient groups in our collaborative research endeavors. We are also examining the effects of various methodologies, stimulus characteristics, test equipment, and subject characteristics (e.g., age, gender) on normal function, and are evaluating variability of auditory and vestibular measures over time. To date we have focused on the development of normative and comparative data for tests of otolith function. 2. We extended our work examining heritability of auditory processing abilities using a twins paradigm with Drs. Griffith & Friedman (NIDCD), Dr. Moore (Cincinnati Childrens Hospital), and Dr. Zobay (Institute for Hearing Research, UK). Initially, we showed heritability of several speech based auditory processing skills. Recently, we published findings demonstrating heritability for skills related to frequency discrimination and perception of signals in the presence of masking sounds (Brewer et al., 2016). This work has implications for those interested in the genetic underpinnings of auditory processing. 3. We initiated development of a test protocol to determine the stability of the auditory nerve action potential and otoacoustic emissions over time in a group of healthy volunteers. The goals are to determine feasibility of these physiologic measures as markers of damage to the auditory system from noise or ototoxic agents and to determine hearing safety following prolonged exposure to MRI noise while using hearing protection in support of research being conducted by Drs. Duyn & Picchioni (NINDS). 4. In collaboration with Dr. Griffith (NIDCD), we continued auditory and vestibular phenotypic assessments of individuals with enlarged vestibular aqueducts (EVA) as well as their siblings and parents. To date, over 100 probands and their families have been ascertained. We published one manuscript on vestibular characteristics (Zalewski et al., 2015) and have submitted another that examines longitudinal progression of hearing in persons with EVA and 1 or 2 mutated alleles in the SLC26A4 gene. 5. In collaboration with Dr. Griffith (NIDCD), we evaluated auditory function in 2 families with NLRP3 mutations and examined the effects of interleukin-1 beta blockade therapy on hearing acuity. This work has been submitted for publication. 6. In collaboration with Drs. Friedman & Griffith (NIDCD) and Dr. Zein (NEI), we continue to study hearing and balance function in persons with Usher syndrome. We are interested in postural balance skills and their relationship to vestibular and visual function, type of Usher syndrome, genotype, and the progression/decline of these skills over time. We have one manuscript in preparation that details comprehensive balance function in the three types of Usher syndrome. 7. In collaboration with Dr. Friedman (NIDCD), we reviewed and interpreted audiograms collected from outside facilities, and assisted in preparation of a manuscript reporting variability in presentation of recessively inherited hearing loss suggesting a prominent role of genetic and environmental modifiers (Naz et al., 2016). 8. In collaboration with Dr. Porter (NICHD), we are participating in phase 1 and phase 2/3a trials of hydroxypropyl beta cyclodextrin for treatment of Niemann Pick type C disease. Our roles include auditory monitoring, ototoxicity grading, and reporting to FDA and safety monitors. We are preparing a manuscript with Dr. Porter. 9. In collaboration with Dr. Gahl (NHGRI), we identified progressive auditory dysfunction, similar to auditory neuropathy, as a characteristic of the newly described NGLY1 deficiency. This work was presented at the American Auditory Society meeting in 2016 (Brewer et al.) and was included in a recently published manuscript (Lam et al., 2016). 10. In collaboration with Dr. Alter (NCI), we published a manuscript detailing the auditory characteristics of persons with Fanconi Anemia and other inherited bone marrow failure syndromes (Kalejaiye et al., 2016). 11. In collaboration with A. Smith (NHGRI), we characterized hearing in persons with Smith Magenis Syndrome and currently have a manuscript under review. 12. In collaboration with Dr. Biesecker, we evaluated patients with and without mutations in the MYO1A gene in an effort to determine and challenge the association of this gene with non-syndromic deafness. Our manuscript is currently in review. 13. In collaboration with Drs. Hallett (NINDS) & Damiano (CC) we investigated hearing before and after exposure to transcranial magnetic stimulation in a group of adolescents; our manuscript is currently in review. 14. In collaboration with Dr. Gunay-Aygun (NHGRI) we are preparing a manuscript describing the auditory phenotype and progression of hearing loss in persons with Alstrom syndrome. Preliminary data were presented at the Alstrom Syndrome International Conference in 2016 (Gunay-Aygun). 15. In collaboration with Dr. Chittiboina (NINDS), we are investigating auditory and vestibular function in persons with neurofibromatosis type 2. We are interested in the relationship of these measures to tumor size and sensitivity of these assessments in early detection of tumor growth with the goal of improving clinical management. We are analyzing progression of auditory and vestibular findings in a subgroup with small tumors to better understand the relative timing of clinical versus anatomical changes. 17. In collaboration with Dr. Goldbach-Mansky (NIAMS) we continued auditory evaluation of patients with autoinflammatory disorders, including Muckle Wells syndrome and neonatal onset autoinflammatory disorder. We are preparing a manuscript examining the course of hearing over a 5-year monitoring period for those who have been treated with anakinra. The initial description of this data was presented at COSM in 2016 (Gao et al.). 18. In collaboration with Dr. M. Collins (NIDCR) we have initiated an in-depth analysis of hearing and middle ear function as well as otology and imaging findings in persons with McCune Albright Syndrome. The initial analysis of this data will be presented at the ASBMR in Sept. 2016 (Boyce et al.). 19. In collaboration with other NIH investigators, we are evaluating auditory function in persons with oculocutaneous albinism (Adams, NHGRI), neurofibromatosis type 1 (Widemann, NCI), congenital disorders of glycosylation (Wolfe & Gahl, NHGRI), Moebius syndrome (Mannoli, NHGRI), and gangliosidosis types 1 and 2 (Tifft, NHGRI). We are interested in the auditory phenotype, including auditory processing of dichotic and other complex sounds, and relationships to other aspects of the disease/disorder and genotype. 20. We continue to evaluate natural history of auditory function in persons with von Hippel-Lindau disease (Heiss, NINDS), WHIMS (McDermott, NIAID), osteogenesis imperfecta (Marini, NICHD), sex-chromosome variants (Muenke, NHGRI), xeroderma pigmentosum (Kraemer & Digiovanna), Smith-Lemli-Optiz syndrome (Porter, NICHD) and the Undiagnosed Diseases Program (Gahl, NHGRI). We are interested in auditory phenotype, natural history of hearing, and relationships to other aspects of disease/disorder and genotype. 21. In collaboration with Wasserman & LoPresti (NINDS), we are examining the effects of repeated breacher explosions on the auditory/vestibular systems. 22. In collaboration with other NIH investigators, we continue our comprehensive monitoring program for persons participating in clinical trials in which there may be risk of ototoxicity. These include aminoglycosides, antineoplastic compounds and radiation therapy for brain tumors.
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