聽覺神經病變在臺灣的現況與遺傳研究

Abstract

研究背景及目的 聽力損失是各種感覺系統缺陷中最常見的。據估計，每1000名新生兒中就有一名患有先天性兩側重度聽力損失需接受聽能復健。由於聽力對於語言發展、學習過程乃至於生活的適應均扮演著重要的角色；所以有關先天性聽損，早期診斷、早期治療目前已形成一種主流趨勢。 一般而言，先天性聽損大多源於耳蝸病變，然而一些聽損兒具有正常耳聲傳射，顯然他們的聽損原因不同於一般，後證實其為 - 聽覺神經病變，而且最近證實其和OTOF基因的突變有關，雖然國內的首例病例報告由台大醫院耳鼻喉部於西元1999年提出；但迄今為止，醫界對此病仍感十分陌生。因此我們致力於此一特殊的新興疾病 -“聽覺神經病變”之流行病學與遺傳之研究，進而評估是否可對高危險群的病人應用基因檢查做聽覺神經病變的篩檢、治療和復健的計劃及預後的預測。 研究設計及方法 本研究包涵流行病學及基因研究。首先我們採用回溯性流行病學研究，收集自西元2000至2006年在台大醫院診斷為先天性聽損之患者共706例，研究聽覺神經病變之盛行率；接著自台大醫院和其他醫院共計收集了22例聽覺神經病變患者，我們收集所有病例之臨床資料，並加以整理分析病人的：「家族史」、｢過去病史」、｢理學檢查結果」、｢聽力檢查結果」、｢影像檢查結果」以及｢復健治療結果」等資料，以比較分析其臨床表徵。而在基因研究方面，我們篩檢17個聽覺神經病變家族，並研究其基因型和表現型間之相關性。 成果 從西元2000至2006年，在台大醫院耳鼻喉科門診總共有706名接受完整聽力檢查之聽損兒童患者，其中13例診斷為聽覺神經病變，故其在習語前聽障兒之盛行率為1.8%。連同他院轉介之病例共計22例，其聽力喪失形式大部分為習語前、漸進性、兩側對稱之感覺神經性聽障，純音聽閾為正常至重度聽損皆有，聽力圖圖形多為平坦型，且顳骨之高解析度電腦斷層掃瞄檢查結果大部分為正常。多數病人未能追溯到明顯之家族史。於17位接受基因研究之初始受試者中，

3名患者(18%)發現有OTOF基因的突變，且全都是一新突變E1700Q(5098G>C)之同型合子。由於E1700Q未出現於50名正常受試者之100個對偶基因、分離分析証明其和聽損之表現型有關且發生在演化上高度保留之胺機酸基，故可推論其是導致聽覺神經病變之突變。目前我們正在基因定型此突變點附近之單一核甘酸多型性變異，以驗證他們是否可能來自共同的祖先。 結論 聽覺神經病變在台灣先天性聽障兒童中並不是一個少見的疾病，且有一部分導因於OTOF基因的突變，在我們的研究中發現了一新突變E1700Q(5098G>C)，再次證實了國人在OTOF基因突變上亦具有種族特異性。

Background and Objective Hearing loss is the most common congenital sensory defect: approximately 1/1000 newborns are affected by severe hearing impairment. Congenital hearing loss (CHL) is composed of a plethora of disease entities. Of which, auditory neuropathy (AN) is of specific interest because of its unique clinical manifestations. Recently, AN has been documented to be associated with mutations in OTOF gene. Although the first AN case in Taiwan was reported by NTUH in 1998, largely remains unknown regarding its prevalence and etiology in Taiwanese patients with CHL. According, we conducted the present study to clarify the epidemiologic significance of AN and inspect the genetic characteristics in Taiwanese patients with AN. Study design and Methods The present project includes an epidemiologic study and a genetic study. In the epidemiologic study, we retrospectively reviewed the clinical data in 706 CHL children who were diagnosed at NTUH from 2000 to 2006. We investigated the prevalence of AN in the cohort, and analyzed the clinical features associated with AN. In the genetic study, we screened mutations in OTOF gene in 17 AN families and explored the genotype-phenotype correlations. Results Among the 706 CHL children at our clinic, 13 (1.8%) revealed positive otoacoustic emissions (OAEs) and abnormal auditory brainstem response (ABR), thus fulfilling the diagnostic criteria of AN. In total, 22 subjects were recruited in this study, including another 9 subjects referred from other hospitals. The associated audiologic features included progressive, prelingual, bilateral moderate to severe sensorineural hearing loss with a flat-type audiogram configuration. Among the probands of the 17 AN families enrolled for genetic study, mutations in OTOF gene were identified in 3 (18%) probands. All the 3 probands were homozygous for a novel mutation, E1700Q (5098G>C). E1700Q was not identified in a panel of 50 normal

controls, co-segregated with the phenotype of deafness in the 3 pedigrees and is evolutionarily highly conserved, conferring its pathogenicity for AN. We are currently genotyping SNPs in the vicinity of E1700Q to elucidate whether the mutation arises from a common ancestor or not. Conclusion Auditory neuropathy (AN) is not rare in Taiwanese children with CHL, and a portion of the AN patients can be attributed to mutations in OTOF gene. A novel OTOF mutation, E1700Q, was identified in the present study, implicating a distinct OTOF mutation spectrum in Taiwanese patients with AN.