Clinical Analysis of Disorders of Hearing and Balance

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The Audiology Unit continued our protocol - Normative Values in Audiovestibular Testing. This protocol is used to establish normal reference ranges and control data for comparison to results obtained for 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, sex) on normal function, and are evaluating variability of auditory and vestibular measures over time. During this past year we presented our work examining algorithms used to interpret postural stability at the American Balance Society meeting and manuscript preparation is underway (Wafa et al.). In addition, we are currently designing a sub-study to define normal ranges and evaluate test-retest reliability for tests of cochlear and otolith function. NIDCD collaborations include work with: * Dr Cunningham in her study examining the effect of statins in prevention of cisplatin ototoxicity (Fernandez et al., in submission) * Dr. Hoa in preparation and design of his translational research protocol that aims to examine characteristics of fluctuating hearing loss. This protocol is in development. * Dr. Chein in development and implementation of his longitudinal protocol examining the time course of hearing loss in patients/families with autosomal dominant nonsyndromic hearing loss (DFNA). * Dr. Griffith (NIDCD) with whom we continued analysis of auditory and vestibular data collected from patients with enlarged vestibular aqueducts. We are co-authors on a manuscript examining the influence of the SLC26A4 haplotype on the phenotype of persons with EVA (Chao et al., 2019). Additional work with Dr. Griffith included collaboration on his studies of NLRP3 and its role in the autoinflammation in the cochlea (Nakanishi et al,2020). Trans-NIH Collaborations With investigators in NHLBI, NIAID and NCI, we continue comprehensive monitoring programs for persons participating in clinical trials in which there may be risk of ototoxicity. These include aminoglycosides, anti-neoplastic compounds, and radiation therapy for brain tumors. We presented a poster on amikacin ototoxicity at a conference on ototoxicity monitoring sponsored by the National Center for Rehabilitative Auditory Research (Chisholm et al., 2019) and currently preparing a manuscript on this topic (Chisholm et al.,in preparation). With Dr. Williamson (NIAID), we evaluated and characterized auditory function in a group of previously healthy patients with cryptococcal meningitis (King et al., 2019) and are currently working on a manuscript examining clinical benefits of pulse-taper steroids in patients with non-HIV cryptococcal meningitis (Anjum et al.,in preparation) With Dr. Porter (NICHD), we continued participation in a phase 2/3a-c trial of hydroxypropyl beta cyclodextrin for treatment of Niemann Pick type C disease. Our roles included auditory monitoring, ototoxicity grading, and reporting to FDA and safety monitors. Additionally, we have worked with Dr. Porter to examine auditory function in patients with Smith-Lemli-Opitz syndrome. A manuscript on this topic is nearing completion (Zalewski et al.,in preparation). We conducted a detailed cross-sectional and longitudinal examination of hearing loss and auditory function in persons with neurofibromatosis type I (NF1)(Widemann, NCI). A manuscript on this topic is nearing completion (Idowu et al.,in preparation). 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, and genotype.We have a manuscript under review that details comprehensive balance function in the three types of Usher syndrome(Wafa et al., in submission) and another that reviews the classification of atypical Usher syndrome (Zein et al., 2020). With Dr. Guerrerio (NIAID), we continue to study auditory function in patients with Loeys Dietz syndrome and have a conference presentation and manuscript in preparation (Jeon et al). With Dr. Goldbach-Mansky (NIAMS), we continue auditory evaluation of patients with autoinflammatory disorders, including Muckle Wells syndrome and neonatal onset autoinflammatory disorder (NOMID). We have completed gathering data at a 10-year time point post initiation of anakinra in a large group of patients with NOMID. A poster was presented at the American College of Rheumatology (Alehashemi et al.) and a manuscript is in preparation. With Drs. Heiss & Cantor (NINDS), we examined vestibular function in persons with Chiari malformation. We are currently preparing a manuscript on this topic (Famili et al.). With Dr. Venditti (NHGRI), we examined the auditory phenotype of persons with methylmalonic acidemia and have a prepared a manuscript (Zalewski et al., in preparation). With Dr. Dang Do (NICHD) we participated a longitudinal study of patient with Batten disease/CLN3. A multidisciplinary manuscript is in preparation (Dang Do et al.). With Dr Huryn (NEI), we have contributed to a manuscript reporting the clinical features of Heimler syndrome (Daich Varela, et al., in press). Additionally, we presented the auditory (Brewer et al., 2020) and vestibular (Zalewski et al., 2020) manifestations of patients with spinoecerebellar ataxia type 7 at national meetings (AAS, ABS). With Dr. Muenke (NHGRI), we extensively examined auditory function, including auditory processing, in patients with sex chromosome variants. Our poster describing the auditory phenotype of patients with Klinefelter syndrome was accepted for presentation at the ASHA meeting (Zhang et al., 2020). Other Intramural Collaborations Associate investigator status on the following new protocols that are under review: *Dr. Stewart (NHGRI), Clinical, Genetic and Epidemiologic Study of Children and Adults with RASopathies. *Dr.Dowlett-McElroy (NICHD), Deep Phenotype of Women with Finding of Maternal 45,X Mosaicism Contributed to deep phenotyping protocols examining the natural history of hearing loss and vestibular function, and relationships to other aspects of diseases/disorders and genotype include: NF2 (Chittiboina, NINDS), congenital disorders of glycosylation (Wolfe & Gahl, NHGRI), gangliosidosis types 1 and 2 (Tifft, NHGRI), GATA2 (Holland, NIAID), McCune Albright Syndrome (Boyce, NIDCR), osteogenesis imperfecta (Marini, NICHD), propionic acidemia (Venditti, NHGRI), relapsing polychrondritis (Colbert, NIAID), von Hippel-Lindau disease (Heiss, NINDS), and xeroderma pigmentosum (Kraemer & Digiovanna, NCI). Examined auditory and vestibular function in patients who have experienced potential trauma to the auditory and vestibular systems (Chan, CC) and presented these results to the National Academy of Science, Engineering and Medicine. Contributed to clinical characterization of auditory and vestibular function of patients in the Undiagnosed Diseases Network (Gahl, NHGRI) and provided supportive clinical consultations to patients participating in other protocols at NIH. Intramural-Extramural Collaborations With Drs Carr & Modica (Walter Reed) Wasserman (NINDS), we examined the effect of repeated breacher explosions on the auditory and vestibular systems. A manuscript reporting hearing loss without vestibular manifestations in a group of explosive breachers is under review (Modica et al.). With Drs Duncan (UCSF) & Iannacconne (Duke)and Hufnagel (NEI), Dr. Brewer is examining the audiometric phenotype in a large group of patients with Usher syndrome type 2 caused by mutations in the USH2A gene. With Dr. Hallett (NINDS) and others, participated in development of international safety guidelines for transcranial magnetic stimulation