Clinical Analysis Of Disorders Of Hearing And Balance

听力和平衡障碍的临床分析

• 批准号: 6814194
• 负责人: Andrew J Griffith
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6814194
• 关键词: Fabry's disease; Usher syndrome; adolescence (12-20); auditory pathways; balance; bone marrow disorder; child (0-11); clinical research; craniofacial dysostosis; deafness; diagnosis design /evaluation; diagnosis procedure safety; ear disorder; gene mutation; genetic disorder; hearing disorders; hearing tests; human subject; medical complication; neurogenetics; neuromuscular disorder; sensorineural hearing loss; transcranial magnetic stimulation

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).

1.与NINDS的Schiffman博士合作，我们在一个大型法布里病患者队列中描述了与α-半乳糖苷酶突变相关的听觉和前庭表现。我们目前正在进行我们的表型数据与基因型和酶活性水平数据的相关性分析。2.与NHGRI的Biesecker博士合作，我们继续对与GLI 3突变相关的Pallister-Hall或Greig头多并指综合征患者进行耳鼻喉科表型表征。我们观察到，严重的感音神经性听力损失是Pallister-Hall综合征的一个表型特征。这是一个新的发现，对于理解GLI 3在听觉系统中的作用，GLI 3疾病的诊断和遗传咨询具有重要意义。3.与NIDCD人类遗传学部（SHG）的Friedman博士合作，我们提供了有助于以下研究的临床表型特征：鉴定一种普遍存在的PCDH 15创始突变，该突变在德系犹太人的1型Usher综合征中占很大比例; MYO 6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; MYO 6作为非综合征隐性耳聋DFNB 37的潜在基因的定位克隆;以及ESPN作为隐性耳聋DFNB 36的潜在基因的定位克隆。4.在与SHG的Morell和Friedman博士的合作中，我们的听力学单位在开发用于单卵双胞胎和双卵双胞胎的大型队列的中央听觉和语言处理测试电池方面取得了重大进展，以测试这些现象的一个或多个可测量参数是可遗传的假设，因此，适合于分子遗传学方法来鉴定这些表型变异的潜在基因。5.在分子遗传学实验室的Drayna博士的合作下，我们的听力学单位正在开发一系列听力学测试，试图检测与音调耳聋相关的听觉生理异常。6.与NINDS的Hallett和Garvey博士合作，听力学部门参与了两项不同的安全性研究的设计，实施和数据分析，这些研究分别针对成人和儿童暴露于经颅磁刺激（TMS）后的听觉系统（和听力）。TMS是一种广泛使用的临床神经生理学技术，其对许多器械或儿童听力的影响尚未得到充分表征。7.听力科继续积极参与听力损失和前庭水管扩大（伊娃）患者及其兄弟姐妹和父母的听觉表型评估。近50个先证者和他们的家庭现已确定，听力学数据揭示了相关的听力表型与潜在的SLC 26 A4（PDS）基因型。8.一项主要伊娃项目的推论研究已经检查了先天性巨细胞病毒（CMV）感染在伊娃中的潜在病因作用。虽然轶事报道和单一出版物假设CMV在伊娃病因学中的作用，但我们的研究表明CMV在伊娃病因学中的作用可以忽略不计。9.我们与其他NIH研究所的研究人员合作，继续评估Von Hippel-Landau病（Linehan博士，NCI）、Turner综合征（邦迪博士，NICHD）、范可尼贫血和其他遗传性骨髓衰竭综合征（Alter博士）以及新生儿发作性多系统炎性疾病（Goldbach-Mansky博士，NIAMS）的听力和平衡表现。