本文關鍵詞： 聽神經病譜系障礙 聽神經病 人工耳蝸植入 聽覺言語評估 基因　出處：《中國人民解放軍醫(yī)學院》2016年碩士論文　論文類型：學位論文

【摘要】：聽神經病譜系障礙(auditory neuropathy spectrum disorder,ANSD)又叫做聽神經病(auditory neuropathy, AN),聽力學特點即聽覺腦干誘發(fā)反應引不出或嚴重異常,但是耳聲發(fā)射可以正常引出,純音聽聞可正�；虬橛袚p傷,但言語理解能力表現(xiàn)為損傷明顯,而且與純音聽聞的損傷度不成比例。初步推測ANSD屬于蝸后病變,是內毛細胞以及聽神經突觸異常所導致,可以合并聽神經本身功能不良。由于其發(fā)病部位的不確定性,目前仍無明確的公認的治療手段。對于人工耳蝸植入(cochlear implantation,Cl)的方案治療ANSD在以往的臨床病例中,有些證實有效,有些則證實無效,推測療效可能與病變部位的不同而產生了不同的差異。ANSD可有不同的病變部位,會表現(xiàn)不同的臨床癥狀,當然也相應有不同的病理生理機制。2008年Starr等根據(jù)病損部位對ANSD進行分型：“聽神經病變”(auditory nerve disorder),顧名思義,即聽神經異常,而內毛細胞、聽神經突觸未見異常;“聽突觸病變”(auditory synaptic disorder),與前者相反,即內毛細胞或者聽神經突觸受累,聽神經未見異常。按照病變部位分類,有利于為臨床干預即CI提供指導。近年來,隨著分子生物學的進步,在分子水平上發(fā)現(xiàn)了ANSD的病理機制,提示可以根據(jù)不同基因突變鎮(zhèn)定不同的病變部位,特別對于非綜合征性ANSD有意義。為了探尋Cl對ANSD患者的療效,我們借助于基因手段做指導。本研究將選取我科2008-2015年來收集的明確診斷并行CI的23例ANSD患者,對CI后的療效進行評估,并進一步對其中13例進行ANSD相關基因篩查,分析不同的基因突變與CI預后的相關性。本研究共分二個部分：第一部分聽神經病譜系障礙患者的人工耳蝸植入干預及療效選取我科2009年-2015年確診為ANSD并行CI的患者23例(語前聾19例,語后聾4例),同時選取相當聽力損失并行Cl的非ANSD患者與病例組按照1：1兩兩配對作為對照組,用純音聽闞、言語可懂度分級標準(SlR)、聽覺行為分級標準(CAP)、有意義聽覺整合量表(MAIS)對病例組與對照組患者進行術后效果評估,并對得出的結果進行統(tǒng)計學分析。研究發(fā)現(xiàn)：12例病例組患者即ANSD患者術后平均聽閾(250HZ、500HZ、1KHZ、 2KHZ、4KHZ)為38.75±6.08 dB HL。病例組語前聾患者術后發(fā)聲情況得分以及聲音的自發(fā)性察覺能力得分與對照組語前聾患者術后相應得分比較,差異無統(tǒng)計學意義(P0.05),而聲音的理解能力得分、MAIS,總分,病例組與對照組差異有統(tǒng)計學意義(P0.05),即病例組得分小于對照組對應得分。病例組語后聾患者術后SIR評分、CAP評分與對照組語后聾患者評分相比,差異無統(tǒng)計學意義(P0.05)。重度或極重度聽力損失的語前聾ANSD患者CI后的發(fā)聲情況、聲音的自發(fā)性覺察能力與無綜合征相應聽力損失的語前聾患者CI后相應得分無明顯差異,但在聲音的理解能力方面,ANSD患者明顯低于無綜合征的相應聽力損失的語前聾患者。重度或極重度聽力損失的語后聾ANSD患者CI后的聽覺言語能力與無綜合征的相應聽力損失的語后聾患者CI后相對比,無明顯差異。第二部分 聽神經病譜系障礙患者人工耳蝸植入后療效與基因的相關性分析本部分研究選取2009年10月-2014年3月于中國人民解放軍總醫(yī)院耳鼻咽喉頭項外科行CI并確診為ANSD的患者11例,及2012年2月-2014年8月于中國人民解放軍總醫(yī)院海南分院耳鼻咽喉頭頸外科行CI的確診為ANSD的患者2例,共13例。適量采集外周的靜脈血液,用以提取基因組DNA,采用目標區(qū)域捕獲+高通量測序技術對PJVK基因、OTOF基因、DIAPH3基因等ANSD相關基因的突變情況進行檢測。針對發(fā)現(xiàn)的可能致病突變位點,從言語康復效果的角度分析不同的ANSD相關的基因突變的CI的療效。研究發(fā)現(xiàn)：在5例語前聾ANSD患者中共檢測出OTOF基因位于外顯子區(qū)域的可能致病突變10種。13例患者中均未檢測出PJVK基因、AIFM1基因、DIAPH3基因等ANSD相關基因的突變。在5名ANSD患者中檢測到1個患者攜帶OTOF基因p.E793X和c.765+1 GC突變：1個患者攜帶OTOF基因p.N727S雜合突變：另1個患者攜帶OTOF基因p. Y1133X和c.5833delG復合雜合突變;另1個患者攜帶OTOF基因pG558A fsX21、p.0994V fsX6和p.Q265L復合雜合突變,剩余一個患者攜帶p.G541 S和p.L795S fsX5復合雜合突變。其5名OTOF基因陽性突變語前聾ANSD患者Cl后MAIS評分與其配對的無明確病因的重度或極重度感音神經性耳聾患者CI后MAIS評分比較,差異無統(tǒng)計學意義(P0.05),而7名OTOF基因陰性突變語前聾ANSD患者CI后MAIS評分與其配對的無明確病因的重度或極重度感音神經性耳聾患者Cl后MAIS評分比較,差異無統(tǒng)計學意義(P0.05)。在本研究中13例ANSD,患者中發(fā)現(xiàn)可能的致病突變有10種,且均于中國ANSD人群中發(fā)現(xiàn),提示OTOF基因與我國人群ANSD的發(fā)生有較大的相關性。5名攜帶OTOF基因突變的語前聾ANSD患者、7名無OTOF基因突變的語前聾ANSD患者CI后言語康復水平的恢復方面與各自對照組患者CI后無明顯差異。
[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.

【學位授予單位】：中國人民解放軍醫(yī)學院
【學位級別】：碩士
【學位授予年份】：2016
【分類號】：R764.9

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