1. In collaboration with Dr. Schiffman of the NINDS, we have characterized the auditory and vestibular manifestations associated with alpha-galactosidase mutations in a large cohort of patients with Fabry disease. We are currently performing a correlative analysis of our phenotypic data with the genotypic and enzyme activity level data. 2. In collaboration with Dr. Biesecker of the NHGRI, we have continued our otolaryngologic phenotypic characterization of patients with Pallister-Hall or Greig Cephalopolysyndactyly syndromes associated with GLI3 mutations. We have observed that severe sensorineural hearing loss is a phenotypic feature of Pallister-Hall syndrome. This is a novel finding with important implications for understanding the role of GLI3 in the auditory system, diagnosis of GLI3 disorders, and genetic counseling. 3. In collaboration with Dr. Friedman of the Section on Human Genetics (SHG), NIDCD, we have provided clinical phenotypic characterizations contributing toward the following studies: Identification of a prevalent founder mutation of PCDH15 that accounts for a large proportion of type 1 Usher syndrome in Ashkenazi Jews; the novel association of a MYO6 mutation with dominant progressive sensorineural hearing loss and hypertrophic cardiomyopathy; positional cloning of MYO6 as the gene underlying nonsyndromic recessive deafness DFNB37; and positional cloning of ESPN as the gene underlying recessive deafness DFNB36. 4. In collaboration with Drs. Morell and Friedman of the SHG, our audiology unit has made significant progress in developing a battery of tests of central auditory and speech processing for use in a large cohort of monozygotic and dizygotic twins in order to test the hypothesis that one or more measurable parameters of these phenomena are heritable and, therefore, amenable to molecular genetic approaches to identify the genes underlying variation of these phenotypes. 5. In collaboration with Dr. Drayna of the Laboratory of Molecular Genetics, our audiology unit is developing a battery of audiologic tests to attempt to detect auditory physiologic abnormalities associated with tune deafness. 6. In collaboration with Drs. Hallett and Garvey of the NINDS, the audiology unit has been involved in the design, implementation, and data analysis for two different safety studies on the auditory system (and hearing) after exposure to transcranial magnetic stimulation (TMS) in adults and children, respectively. TMS is a widely utilized clinical neurophysiologic technique whose effects on hearing have not been adequately characterized for many of the devices, or for children. 7. The Hearing Section continues to be actively involved in the auditory phenotypic assessment of individuals with hearing loss and enlarged vestibular aqueducts (EVA), as well as their siblings and parents. Nearly 50 probands and their families have now been ascertained, and the audiologic data reveals a correlation of the auditory phenotype with the underlying SLC26A4 (PDS) genotype. 8. A corollary study of the main EVA project has examined the potential etiologic role of congenital cytomegalovirus (CMV) infection in EVA. Although anecdotal reports and a single publication postulate a role for CMV in the etiology of EVA, our study has demonstrated that CMV plays a negligible, if any, role in the etiology of EVA. 9. In collaboration with investigators from other NIH institutes, we continue to evaluate hearing and balance manifestations in Von Hippel-Landau disease (Dr. Linehan, NCI), Turner syndrome (Dr. Bondy, NICHD), Fanconi anemia and other inherited bone marrow failure syndromes (Dr. Alter), and neonatal onset multi-system inflammatory disorder (Dr. Goldbach-Mansky, NIAMS).
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