翻譯: 瑾心 www.autismawakening.org

中東家庭幫助科學家尋索自閉症的基因突變, 正在慢慢地進行當中, 主要是因自閉症含概了廣範的失常症狀, 這也是為什麼要發現是否基因突變導致自閉症.

現在，霍華德・休斯醫療學院 (Howard Hughes Medical Institute) 調查員, 克里斯托弗.華斯 (Christopher Walsh), 與在美國、土耳其、沙特阿拉伯、巴基斯坦和科威特的科學家和醫師合作，，使用一個新的戰略辨認，是否當六個基因產生突變時，會造成自閉症; 藉著集中於兩個父母分享一個近血緣祖先的大家庭，克里斯托弗.華斯和他的同事能精密地探索早先研究但依然是無頭緒的基因變化.

克里斯托弗.華斯，堯雲永(Seung-Yun Yoo譯音)和他們的同僚分別在,以色列女執事醫療中心(Beth Israel Deaconess Medical Center)、波士頓兒童醫院(Children's Hospital Boston),和在麻薩諸塞綜合醫院(Massachusetts General Hospital)服務的遺傳學家,艾力克.莫羅(Eric Morrow),一起在2008年7月11日的科學學報(the journal Science)報告他們的研究結果.

克里斯托弗.華斯 (Christopher Walsh) 引用作者里歐拓斯吐 (Leo Tolstoy) 小說 “Anna Karenina”中的一句話, “所有快樂的家庭享有同樣的幸福，但每個不快樂的家庭在他們自己不同的道路上怏怏不樂” (where all happy families are the same, but every unhappy family is unhappy in their own way.) 如同自閉兒享有共同的三個關鍵特徵：他們的語言能力發展遲緩, 他們很難進入社交互動, 他們會一直重覆不當的行為反應; 但是除此之外, 自閉症的形態仍是難以捉摸的, 在不同的功能上產生摧殘作用.

變異 (variation) 是多種基因造成混亂的証據, 而且要發現這些基因是極度困難的, 光用一個基因來研讀所有個體會被改變以致於失常是不可能的, 所以科學家同意自閉症的起因是牽涉廣泛的基因，他們對這個因素的認識還很陌生, 華斯 (Christopher Walsh) 說, “當時, 我們能瞭解基因造成自閉症的起因只有15%到20%, 剩餘的80%仍是無法解釋的”.

華斯和他的同事試圖從兄弟姐妹的染色體中, 來辨別自閉症的基因和沒自閉症的基因.在美國，這項研究非常困難, 因這個國家是由典型小型的多數家庭組成，所以華斯與中東的自閉症研究員合作, 因中東大多數是有六個孩子的大家庭, 相形下美國和歐洲大多數是只有二到三個孩子的小家庭, 在中東的家庭血緣內比較基因容易了許多.

華斯和他的同事採取另一個不同的步驟, 使發現自閉症基因更加容易: 他們具體地瞄準了母親和父親分享一個近親血緣的家庭.華斯解釋 “這共有的祖先會大致加倍子孫的機會受影響…當風險機率增加會使研究容易觀察, 例如比較40歲生的孩子和在年齡20歲時生的孩子，但更加重要的是，擁有共同祖先的血緣能提供一個線索, 使跟蹤繼承變化的蹤影更加容易”.

華斯和他的同事從八個國家： 喬丹、沙特阿拉伯、科威特、阿曼、巴基斯坦、卡塔爾、土耳其和阿拉伯聯合酋長國 (Jordan, Saudi Arabia, Kuwait, Oman, Pakistan, Qatar, Turkey, and the United Arab Emirates) 中, 來研究88個這樣的家庭，從五個家庭中有自閉症，他們發現一個大段的個體染色體的是不見的, 而其他沒有自閉症的家員仍保有這個大段的個體染色體.

華斯說, “許多這些不見的基因關係學習的功能…具體而言, 這些不見的基因幫助腦神經細胞執行突觸 (synapses) 的物理變動, 為要加強學習和新記憶的形成…這在對自閉症的發展是一個重大發現…因有許多證據建議對突觸神經的認識, 是明白了解自閉症的關鍵.”

華斯和他的同事非常受激勵, 因為他們發現了基因的減除會改變原有功能活動的方式。他說「僅這個刪除完全地除去一個基因…其他不見的基因區域緊挨著擁有 (學習) 開關功能的基因”.

華斯說, “這會影響如何治療某些自閉症癥狀的新可能性…當自閉症是由一個缺掉基因時造成的，唯一的選擇也許是使用基因療法(gene therapy)替換它,但當起因是一個殘破的(基因)開關時， 有其中一些基因可以被其他方式激活的,如研究顯示，將許多自閉症兒童安置在加重的學習環境中,會幫助他們克服學習障礙; 這加重學習的環境能在腦內啟動通過殘破開關(基因)的路，為了能描繪更多關於多種形態自閉症中的基因突變,我們也許能預言哪些孩子需要基因療法，和哪些孩子只需要某種方法的訓練”.

華斯說, 研究團隊將繼續從單純的研究, 進一步到辨認更多與自閉症相關的基因，但他強調另一個更大的訊息: “其中一個最扣人心弦的調查, 是設法瞭解這些自閉症的突變化在告訴我們, 基因是如何在學習機能範圍內被調控, 我們若能可以瞭解關於這些基因控制越多，我們就可以幫助許多特殊兒越多”.

Middle Eastern Families Help Scientists Pinpoint Autism Genes

Medical News Today by Jennifer Michalowski (Howard Hughes Medical Institute)

The hunt for gene mutations that contribute to autism has proceeded slowly, largely because autism encompasses a spectrum of diseases. Just as its symptoms vary widely among individuals, so do the genetic mutations that cause them.

Now, Howard Hughes Medical Institute investigator Christopher Walsh, in collaboration with scientists and physicians in the United States, Turkey, Saudi Arabia, Pakistan, and Kuwait, has used a new strategy to identify six genes that, when mutated, contribute to autism. By focusing on large families in which both parents share a recent ancestor, Walsh and his colleagues were able to hone in on rare mutations that had remained elusive in previous studies.

Walsh, who is at Beth Israel Deaconess Medical Center and at Children's Hospital Boston, geneticist Eric Morrow of Massachusetts General Hospital, Seung-Yun Yoo, and their colleagues report their findings on July 11, 2008, in the journal Science.

Walsh likens autism to Leo Tolstoy's novel Anna Karenina, "where all happy families are the same, but every unhappy family is unhappy in their own way." Autistic children share three key traits: they're slow to develop language, they are poor at social interactions, and they repeat stereotyped behavior over and over. But that's where the similarities end; some forms of autism are subtle, whereas others devastate every aspect of functioning.

This variation is evidence of the wide variety of genes that can contribute to the disorder, Walsh says, and makes finding those genes difficult. It's not possible to look for a single gene that is mutated in all individuals with the disorder, as has been done with diseases such as cystic fibrosis or Huntington's disease. So while scientists agree that the causes of autism are largely genetic, they are far from understanding those factors. "At the moment, we understand the genetic causes of 15 to 20 percent of autism," Walsh said. "The remaining 80 percent remain unexplained."

Walsh and his colleagues have been attempting to identify autism genes by comparing the genomes of autistic and non-autistic siblings. In the United States, the task is particularly difficult due to the typically small size of most families, Walsh said.

So Walsh collaborated with researchers from the Middle East, where families are typically larger. The average of six children per family - versus two or three in the United States and Europe - makes it much easier to compare genes within a family.

Walsh and his colleagues took another step to make finding autism genes easier: they specifically targeted families in which the mother and father shared a recent ancestor. "This shared ancestry roughly doubles the chance of offspring being affected," he explained. "This increase in risk is modest - about the same as having a child at age 40 versus at age 20 - but more importantly, the shared ancestry provides a trace that makes it easier to track inherited mutations."

Walsh and his colleagues studied 88 such families, from eight countries: Jordan, Saudi Arabia, Kuwait, Oman, Pakistan, Qatar, Turkey, and the United Arab Emirates. In five of those families, they found that large segments of individuals' genomes were missing. While family members who retained one functional copy of these segments did not have autism, those with both copies missing had the disorder.

Many of these deletions inactivated genes involved in learning, Walsh said. Specifically, they help nerve cells carry out the physical changes to their synapses that underlie learning and the formation of new memories. Walsh said that in a developmental disorder like autism, that was an important find. "There's lots of evidence to suggest that this process of synaptic learning is key to autism," he said.

But he and his colleagues are also excited because of the way in which the deletions they found alter gene activity. "Only one of these deletions completely removed a gene," he said. The others removed areas close to the genes that contain the genes' "on/off switches."

Walsh said that raises new possibilities about how to treat some forms of autism. When autism is caused by a missing gene, the only option may be to replace it using gene therapy, he said. But when the cause is a broken on/off switch, "there are other ways in which some of these genes can be activated," he said. For instance, studies have shown that placing many autistic children in enriched learning environments helps them move past the disease. These environments can activate pathways in the brain that bypass the broken on/off switches, Walsh said. "By being able to characterize more about the genetic mutations at work in various forms of autism, we may be able to predict which kids need gene therapy, and which just need some form of training," he said.

Walsh says the team will continue to sift through data from the study to identify more autism-related genes, but he stressed that there is also a larger message. "One of the most exciting areas of investigation is trying to understand what these autism mutations are telling us about how genes are regulated in the context of learning," he said. "The more we can understand about the control of these genes, the more we can help a lot of different kids."