听神经病谱系障碍人工耳蜗植入疗效及其与基因的相关性分析

发布时间：2018-01-19 14:40

本文关键词： 听神经病谱系障碍听神经病人工耳蜗植入听觉言语评估基因　出处：《中国人民解放军医学院》2016年硕士论文　论文类型：学位论文

【摘要】：听神经病谱系障碍(auditory neuropathy spectrum disorder,ANSD)又叫做听神经病(auditory neuropathy, AN),听力学特点即听觉脑干诱发反应引不出或严重异常,但是耳声发射可以正常引出,纯音听闻可正常或伴有损伤,但言语理解能力表现为损伤明显,而且与纯音听闻的损伤度不成比例。初步推测ANSD属于蜗后病变,是内毛细胞以及听神经突触异常所导致,可以合并听神经本身功能不良。由于其发病部位的不确定性,目前仍无明确的公认的治疗手段。对于人工耳蜗植入(cochlear implantation,Cl)的方案治疗ANSD在以往的临床病例中,有些证实有效,有些则证实无效,推测疗效可能与病变部位的不同而产生了不同的差异。ANSD可有不同的病变部位,会表现不同的临床症状,当然也相应有不同的病理生理机制。2008年Starr等根据病损部位对ANSD进行分型：“听神经病变”(auditory nerve disorder),顾名思义,即听神经异常,而内毛细胞、听神经突触未见异常;“听突触病变”(auditory synaptic disorder),与前者相反,即内毛细胞或者听神经突触受累,听神经未见异常。按照病变部位分类,有利于为临床干预即CI提供指导。近年来,随着分子生物学的进步,在分子水平上发现了ANSD的病理机制,提示可以根据不同基因突变镇定不同的病变部位,特别对于非综合征性ANSD有意义。为了探寻Cl对ANSD患者的疗效,我们借助于基因手段做指导。本研究将选取我科2008-2015年来收集的明确诊断并行CI的23例ANSD患者,对CI后的疗效进行评估,并进一步对其中13例进行ANSD相关基因筛查,分析不同的基因突变与CI预后的相关性。本研究共分二个部分：第一部分听神经病谱系障碍患者的人工耳蜗植入干预及疗效选取我科2009年-2015年确诊为ANSD并行CI的患者23例(语前聋19例,语后聋4例),同时选取相当听力损失并行Cl的非ANSD患者与病例组按照1：1两两配对作为对照组,用纯音听阚、言语可懂度分级标准(SlR)、听觉行为分级标准(CAP)、有意义听觉整合量表(MAIS)对病例组与对照组患者进行术后效果评估,并对得出的结果进行统计学分析。研究发现：12例病例组患者即ANSD患者术后平均听阈(250HZ、500HZ、1KHZ、 2KHZ、4KHZ)为38.75±6.08 dB HL。病例组语前聋患者术后发声情况得分以及声音的自发性察觉能力得分与对照组语前聋患者术后相应得分比较,差异无统计学意义(P0.05),而声音的理解能力得分、MAIS,总分,病例组与对照组差异有统计学意义(P0.05),即病例组得分小于对照组对应得分。病例组语后聋患者术后SIR评分、CAP评分与对照组语后聋患者评分相比,差异无统计学意义(P0.05)。重度或极重度听力损失的语前聋ANSD患者CI后的发声情况、声音的自发性觉察能力与无综合征相应听力损失的语前聋患者CI后相应得分无明显差异,但在声音的理解能力方面,ANSD患者明显低于无综合征的相应听力损失的语前聋患者。重度或极重度听力损失的语后聋ANSD患者CI后的听觉言语能力与无综合征的相应听力损失的语后聋患者CI后相对比,无明显差异。第二部分听神经病谱系障碍患者人工耳蜗植入后疗效与基因的相关性分析本部分研究选取2009年10月-2014年3月于中国人民解放军总医院耳鼻咽喉头项外科行CI并确诊为ANSD的患者11例,及2012年2月-2014年8月于中国人民解放军总医院海南分院耳鼻咽喉头颈外科行CI的确诊为ANSD的患者2例,共13例。适量采集外周的静脉血液,用以提取基因组DNA,采用目标区域捕获+高通量测序技术对PJVK基因、OTOF基因、DIAPH3基因等ANSD相关基因的突变情况进行检测。针对发现的可能致病突变位点,从言语康复效果的角度分析不同的ANSD相关的基因突变的CI的疗效。研究发现：在5例语前聋ANSD患者中共检测出OTOF基因位于外显子区域的可能致病突变10种。13例患者中均未检测出PJVK基因、AIFM1基因、DIAPH3基因等ANSD相关基因的突变。在5名ANSD患者中检测到1个患者携带OTOF基因p.E793X和c.765+1 GC突变：1个患者携带OTOF基因p.N727S杂合突变：另1个患者携带OTOF基因p. Y1133X和c.5833delG复合杂合突变;另1个患者携带OTOF基因pG558A fsX21、p.0994V fsX6和p.Q265L复合杂合突变,剩余一个患者携带p.G541 S和p.L795S fsX5复合杂合突变。其5名OTOF基因阳性突变语前聋ANSD患者Cl后MAIS评分与其配对的无明确病因的重度或极重度感音神经性耳聋患者CI后MAIS评分比较,差异无统计学意义(P0.05),而7名OTOF基因阴性突变语前聋ANSD患者CI后MAIS评分与其配对的无明确病因的重度或极重度感音神经性耳聋患者Cl后MAIS评分比较,差异无统计学意义(P0.05)。在本研究中13例ANSD,患者中发现可能的致病突变有10种,且均于中国ANSD人群中发现,提示OTOF基因与我国人群ANSD的发生有较大的相关性。5名携带OTOF基因突变的语前聋ANSD患者、7名无OTOF基因突变的语前聋ANSD患者CI后言语康复水平的恢复方面与各自对照组患者CI后无明显差异。
[Abstract]:Auditory neuropathy spectrum disorder (auditory neuropathy spectrum disorder, ANSD) also known as auditory neuropathy (auditory neuropathy, AN), namely the audiological characteristics of auditory brainstem response was absent or severely abnormal, but can lead to normal otoacoustic emission, can be normal or with pure tone hearing damage, but verbal comprehension ability were damaged obviously, and the damage degree and pure tone heard. Disproportionately speculated that ANSD belongs to retrocochlear lesions, inner hair cells and auditory nerve is caused by synaptic abnormalities, nerve dysfunction can be combined to itself. Because of the disease location uncertainty, there is still no generally accepted treatment clear. For cochlear implant (cochlear implantation, Cl) regimen in the treatment of ANSD in clinical cases in the past, some have proved effective, some are confirmed to be invalid, that efficacy may be related to different parts of the lesions had no With the difference of.ANSD can have different lesions, will show different clinical symptoms, of course, also have different pathophysiological mechanisms of.2008 Starr according to the lesion site of ANSD subtypes: "auditory neuropathy" (auditory nerve disorder), as the name suggests, the auditory nerve abnormalities, and inner hair cells, listen no abnormal synaptic; listen to synaptic lesions "(auditory synaptic disorder), in contrast, is the inner hair cells or auditory nerve synapses of auditory nerve involvement, no abnormality. In accordance with the classification of the lesion, to provide guidance for clinical intervention of CI. In recent years, with the progress of molecular biology, the pathogenesis of ANSD. Found at the molecular level, suggesting that according to different gene mutation lesion stabilization is different, especially for non syndromic ANSD sense. In order to explore the efficacy of Cl in patients with ANSD, with the help of gene Guidance means. 23 cases of ANSD patients diagnosed in our department were selected in this study 2008-2015 years of parallel CI, to evaluate the curative effect after CI, and further to 13 cases of ANSD related gene screening, analysis of different gene mutations associated with the prognosis of CI. This study is divided into two parts: listen to the first part of the cochlear implant intervention and efficacy in patients with neurological disorders in our hospital from 2009 -2015 years were diagnosed as ANSD parallel CI in 23 patients (19 cases, 4 cases were prelingually deaf postlingually deaf and hearing loss), a selection of parallel Cl patients and non ANSD patients according to 1:1 22 matched as control group Kan, listen with pure tone and speech intelligibility rating standard (SlR), standard (CAP), auditory behavior of meaningful auditory integration scale (MAIS) of patients in case group and control to assess the postoperative effect, and statistics of the results Analysis. The study found: 12 cases patients that the average hearing threshold in patients with ANSD (250HZ, 500HZ, 1KHZ, 2KHZ, 4KHZ) 38.75 + 6.08 dB HL. patients preoperative deaf patients after vocal language score and sound ability to detect and control group scores of spontaneous language of deaf patients after the corresponding preoperative scores, no statistically significant difference (P0.05), while the sound comprehension score, MAIS score, the case group and the control group had significant difference (P0.05), namely the case group scores than the control group. The corresponding score cases of postoperative language deaf patients after the SIR score, CAP score and score of deaf patients in the control group after. Compared with no significant difference (P0.05). Sound deaf ANSD CI patients after severe or extremely severe hearing loss before language, voice of spontaneous awareness and syndrome without corresponding hearing loss before language CI deaf patients after phase should be no significant difference score, But in the sound understanding ability, ANSD patients were significantly lower than the corresponding hearing loss without syndrome of prelingual deaf patients. ANSD patients with CI after the hearing and speech ability of severe or extremely severe hearing loss and no language syndrome related hearing loss after CI language of deaf patients after compared, no significant difference correlation analysis of efficacy and gene. Cochlear neuropathy spectrum disorder patients after implantation of this part of the study from October 2009 -2014 year in March in General Hospital of PLA otolaryngology head surgery and CI of 11 patients with ANSD diagnosed in 2 cases and listen to the second part, February 2012 -2014 year in August in Hainan branch of General Hospital of PLA otolaryngology head and neck surgery for CI patients diagnosed with ANSD, a total of 13 cases. The amount of peripheral venous blood collection, used to extract genomic DNA, using target capture + high-throughput sequencing technology Operation of the PJVK gene, OTOF gene, DIAPH3 gene mutation was detected in ANSD related genes. The possible pathogenic mutations were found, analysis the effect of different ANSD related CI gene mutation from speech rehabilitation perspective. The study found: in the 5 cases of possible pathogenic prelingually deaf patients with ANSD were detected in OTOF the gene mutation in the exon region of 10.13 patients were not detected in the PJVK gene, AIFM1 gene, DIAPH3 gene mutation and ANSD gene in 5 patients with ANSD were detected in 1 patients with OTOF p.E793X and c.765+1 GC gene mutation: 1 patients with OTOF gene p.N727S heterozygous mutation the other 1 patients with OTOF gene P. Y1133X and c.5833delG compound heterozygous mutation; the other 1 patients carrying the OTOF gene of pG558A fsX21, p.0994V fsX6 and p.Q265L compound heterozygous mutation, one of the remaining patients carrying p.G541 S and p.L795S FS X5 compound heterozygous mutation. The 5 OTOF gene positive mutation of prelingual deafness in patients with ANSD Cl MAIS score after matched no definite cause severe or extremely severe sensorineural hearing loss in patients with CI after MAIS score comparison, the difference was not statistically significant (P0.05), while the 7 OTOF gene mutation negative prelingual deafness ANSD CI of patients with MAIS score after matched no definite cause severe or extremely severe sensorineural hearing loss in patients with Cl after MAIS score comparison, the difference was not statistically significant (P0.05). In this study, 13 cases of ANSD, there are 10 possible pathogenic mutations found in patients, and were Chinese ANSD populations showed that this suggested that the OTOF gene and ANSD in Chinese population with.5 correlated carrying OTOF gene mutation in prelingual deafness in patients with ANSD, 7 patients without OTOF mutations in patients with ANSD after CI prelingually deaf speech rehabilitation level recovery and their patients in the control group after CI ignorance Difference.

【学位授予单位】：中国人民解放军医学院
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R764.9

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