新遺傳證據顯示精神分裂症不是單一種疾病


  【24drs.com】一篇新研究認為,根據帶有新穎或罕見的破壞性變種的一組基因,精神分裂症不是單一種疾病,而是由多種症狀的不同亞型組成。
  
  紐約市紐約大學Langone醫學中心的研究者表示,他們已在四個有影響力的基因發現突變,與四個不同的精神分裂症表型清楚對映,奠定了邁向更加個人化治療之基礎。與這四種基因突變有關之精神病患者,彼此在症狀、智力程度和其他疾病特徵方面都有差異。
  
  這篇研究發表於四月的EBioMedicine期刊。
  
  第一作者Dolores Malaspina醫師表示,有許多基因被發現會增加精神疾病,包括精神分裂症的易感性。她解釋,他們是透過大型的GWASs[genome-wide association studies]研究發現,不過,它們不是很具體。所以,問題是,如何聚焦於可能會更直接影響疾病的基因呢?
  
  NYU Langone精神科名譽教授Malaspina醫師在新聞稿中表示,我們的生物學研究促成開始回答在該領域已長期存在的問題,為何任兩個診斷有精神分裂者的患者可能有著完全不同的症狀?我們首度在機制上定義了四個症候群。
  
  這些研究結果是根據非常良好的特點和不同種族群體的48個精神病患者,對四個中樞神經系統的信號基因進行了目標性的外顯子定序,因為這幾個基因曾在偶發之精神分裂症案例的新突變中顯示有破壞性,這四個基因都與神經迴路的生長或調節有關。
  
  48名患者中有15人(31.25%)帶有這四個基因之一種或多種的罕見或新型的突變,這幾個亞型的患者有明顯不同的症狀。
  
  其中一個基因是PTPRG (受體型酪氨酸蛋白磷酸酶γ/receptor-type tyrosine-protein phosphatase gamma),其編碼的蛋白質讓神經細胞連接而構成神經網絡。這個基因出現罕見突變的患者,更早發生相對嚴重的精神病、以及學習障礙史。研究者表示,儘管有一些患者有高智能,她們在操作記憶上表現出認知障礙。
  
  另一個受到影響的基因是SLC39A13 (鋅轉運蛋白家族39編號13/ zinc transporter family 39 member 13)。這個基因出現罕見突變的患者,也經歷了提早發作的精神分裂症,但他們表現出整個打亂的認知和最嚴重的精神病理,包括負性症狀和嚴重的自殺企圖。研究者報告指出,他們有最低的智能和最低教育程度,並有發育障礙。
  
  患者如有第三個受影響的基因ARMS/KIDINS220 (富含錨蛋白重複結構之跨膜蛋白/ankyrin repeat-rich membrane-spanning protein)之變異,顯示出早期前景,很多讀到大學,然後,他們經歷了與退化過程一致的認知能力下降。
  
  患者如有第四個受影響的基因TGM5 (轉谷氨酰酶5/transglutaminase 5)之變異,童年時症狀較輕,但童年時往往經歷了注意力缺陷障礙,且這些患者的處理速度比較慢。
  
  第一作者、NYU Langone博士後研究員Thorsten Kranz博士在發表時表示,我們的研究結果認為,新的治療方法應該 -同時解決核心精神病-也應聚焦於TGM5案例的處理速度、PTPRG案例的操作記憶、SLC39A13案例的鋅增強、ARMS/KIDINS220突變者的神經細胞保護。沒有可以對所有患者都有用的治療,但是可以在某些患者非常有效。
  
  舉例來說,對於鋅轉運蛋白SLC39A13有突變的患者,Malaspina醫師表示,在一個鋅轉運蛋白缺陷的大鼠模式中,補充鋅可以補救行為表型,所以我們認為這確實建構了在症候群和特定治療內對特定實體啟動照護的舞台。
  
  Malaspina醫師結論表示,當然,還要有更大型的樣本驗證,但是,根據受影響的基因、可能還有更多種基因,它建構了更佳地定義疾病亞型的舞台,數百種基因巧妙地增加任何數量之精神疾病的可變性。
  
  資料來源:http://www.24drs.com/
  
  Native link:Schizophrenia Not One Disease, New Genetic Evidence Shows

Schizophrenia Not One Disease, New Genetic Evidence Shows

By Megan Brooks
Medscape Medical News

Schizophrenia is not a single disease but rather is a group of distinct subtypes with varying symptoms based on a set of genes harboring novel or rare disruptive variants, a new study suggests.

Researchers from New York University Langone Medical Center, in New York City, say they have uncovered mutations in four "influential" genes that clearly align with four different schizophrenia phenotypes, paving the way toward more personalized treatments. Patients with psychoses associated with mutations in each of the four genes differed from each other with respect to symptoms, intelligence level, and other disease features.

The study was published in the April issue of EBioMedicine.

Genes That Matter

"A large number of genes have been discovered that increase the vulnerability for psychiatric disorders, including schizophrenia," lead author Dolores Malaspina, MD, told Medscape Medical News. "They were found through large GWASs [genome-wide association studies], and they're not very specific. So the question is, how can we zero in on the genes that are likely to influence the disease more directly?" she explained.

"Our biologically driven study begins to answer long-standing questions in the field about why any two people diagnosed with schizophrenia may have drastically different symptoms. For the first time, we have defined four syndromes mechanistically," Dr Malaspina, the Anita Steckler and Joseph Steckler Professor in the Department of Psychiatry at NYU Langone, added in a news release.

The findings are based on an "exceptionally well-characterized" and ethnically diverse group of 48 individuals with psychosis for whom targeted exome sequencing was conducted with regard to four central nervous system signaling genes that have previously been shown to harbor disruptive de novo mutations in sporadic cases of schizophrenia. All four genes are involved in the growth or regulation of nerve circuits.

Fifteen of the 48 patients (31.25%) carried rare or novel variants in one or more of the four genes, and these subgroups of patients had significantly different symptoms.

One gene is PTPRG (receptor-type tyrosine-protein phosphatase gamma), which encodes a protein that allows nerve cells to connect as they form nerve networks. Patients with rare variants in this gene experienced earlier onset of relatively severe psychosis and had a history of learning disabilities. Despite high intelligence in some, they showed cognitive deficits in working memory, the researchers say.

Another influential gene is SLC39A13 (zinc transporter family 39 member 13). Patients with mutations in this gene also experienced early onset of schizophrenia, but they showed globally disrupted cognition and the most severe psychopathology, including negative symptoms and severe suicide attempts. They had the lowest intelligence and the least educational attainment, consistent with a developmental disorder, the researchers report.

Patients with variants in a third influential gene, ARMS/KIDINS220 (ankyrin repeat-rich membrane-spanning protein), showed early promise, and many attended college. They then experienced cognitive decline, consistent with a degenerative process.

Patients with variants in a fourth influential gene, TGM5 (transglutaminase 5), had less severe symptoms but often experienced attention-deficit disorder during childhood, and processing speed was slow in these patients.

Genotype, Then Treat?

"Our results argue that new treatments should ─ while addressing core psychoses ─ also focus on processing speed in TGM5 cases, working memory in PTPRG, zinc augmentation in SLC39A13, and nerve cell protection in patients with ARMS/KIDINS220 mutations," first study author Thorsten Kranz, PhD, a postdoctoral fellow at NYU Langone, said in the release. "Treatments that do not work for all patients may be highly effective in some."

For example, for patients with mutations in the zinc transporter SLC39A13, "there is a mouse model with a defect in this zinc transporter gene that has a behavior phenotype that is rescued by zinc supplementation, so we think this does set the stage to start carving out specific entities within the syndrome and specific treatments," Dr Malaspina told Medscape Medical News.

"Of course, this needs to be replicated in larger samples, but I think it sets the stage to better define the disease subtypes based on influential genes and not just the many, many hundreds of genes that subtly increase the variability for any number of psychiatric disorders," Dr Malaspina concluded.

This research was supported by the National Institutes of Health. The authors have disclosed no relevant financial relationships.

EBioMedicine. 2016;6:206-214.

    
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