Clinical Analysis Of Disorders Of Hearing And Balance

1. 与美国国家疾病研究所的Schiffman博士合作，我们在一大批法布里病患者中描述了与α -半乳糖苷酶突变相关的听觉和前庭表现。我们目前正在进行表型数据与基因型和酶活性水平数据的相关分析。2. 我们与NHGRI的Biesecker博士合作，继续研究与GLI3突变相关的Pallister-Hall或Greig头多指综合征患者的耳鼻喉学表型特征。我们观察到，严重感音神经性听力损失是帕利斯特-霍尔综合征的表型特征。这是一个新的发现，对理解GLI3在听觉系统中的作用、GLI3疾病的诊断和遗传咨询具有重要意义。3. 与NIDCD人类遗传学（SHG）部门的Friedman博士合作，我们为以下研究提供了临床表型特征：确定了占德系犹太人1型Usher综合征很大比例的PCDH15的普遍创始人突变；MYO6突变与显性进行性感音神经性听力损失和肥厚性心肌病的新关联；MYO6基因在非综合征性隐性耳聋DFNB37中的定位克隆以及ESPN作为隐性耳聋DFNB36基因的定位克隆。4. 在与博士合作。SHG的Morell和Friedman，我们的听力学部门在开发一系列中央听觉和语言处理测试方面取得了重大进展，这些测试用于单卵和异卵双胞胎的大型队列，以验证这些现象的一个或多个可测量参数是可遗传的假设，因此，适用于分子遗传学方法来识别这些表型变异的基因。5. 与分子遗传学实验室的Drayna博士合作，我们的听力学部门正在开发一系列听力学测试，试图检测与调性耳聋相关的听觉生理异常。6. 在与博士合作。听力学部门的Hallett和Garvey参与了两项不同的安全性研究的设计、实施和数据分析，分别针对成人和儿童接受经颅磁刺激（TMS）后的听觉系统（和听力）。经颅磁刺激是一种广泛应用的临床神经生理学技术，其对许多设备或儿童听力的影响尚未得到充分的表征。7. 听力科继续积极参与听力损失和前庭导水管（EVA）扩大的个体及其兄弟姐妹和父母的听觉表型评估。目前已经确定了近50个先证及其家族，听力学数据揭示了听觉表型与潜在的SLC26A4 （PDS）基因型的相关性。8. 主要EVA项目的一项推论研究已经检查了先天性巨细胞病毒（CMV）感染在EVA中的潜在病因学作用。尽管坊间报道和单一出版物假设巨细胞病毒在EVA病因学中起作用，但我们的研究表明，巨细胞病毒在EVA病因学中的作用可以忽略不计，如果有的话。9. 与其他NIH研究所的研究人员合作，我们继续评估Von Hippel-Landau病（Linehan博士，NCI）、Turner综合征（Bondy博士，NICHD）、Fanconi贫血和其他遗传性骨髓衰竭综合征（Alter博士）以及新生儿发病的多系统炎症性疾病（Goldbach-Mansky博士，NIAMS）的听力和平衡表现。

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).