罕見病從溶酶體病說起-2014高級醫(yī)學遺傳學

1、罕見病 ---從溶酶體病說起,@黃昱北京大學醫(yī)學部醫(yī)學遺傳學系huangyu@bjmu.edu.cnhttp://blog.sina.com.cn/medgeneticsQQ: 1115868344,第47期 科學家與媒體面對面活動關(guān)注罕見病,2014-9-19,故事從一個罕見病說起…….,溶酶體貯積癥 LSDsLysosomal Storage Disorders,由于基因突變或染色體畸變導(dǎo)致的，溶酶體發(fā)揮其正常功

2、能所需的一種或多種酶類分子，或調(diào)控分子，功能減弱或喪失引起的疾病成為溶酶體病。由于該類疾病常?？梢娤鄳?yīng)的底物或／和其衍生物在溶酶體內(nèi)大量累積，因此通常稱之為溶酶體貯積癥。在遺傳病分類上屬于遺傳代謝性疾病。,Clathrin-coated lysosome,貯積物的性質(zhì)和形態(tài)可以作為鑒別診斷的依據(jù),NCL1,NCL2,NCL3,Neuronal Ceroid Lipofuscinosis (NCL),溶酶體貯積癥分類,Mucopolys

3、accaridoses 粘多糖貯積病Glycoproteinoses 糖蛋白貯積病Glycogen storage 糖原貯積病Sphingolipidoses 神經(jīng)鞘脂貯積病Lipid storage disorders 脂質(zhì)貯積病Multiple enzyme defects 多酶缺陷Transport defects 轉(zhuǎn)運缺陷,Fabry Disease,Anderson-Fabry Disease,Dr Johanne

4、s Fabry,Dr William Anderson,Fabry Disease,Angiokeratoma Corporis Diffusum彌漫性軀體性血管角化瘤,Fabry Disease,X-linked Lysosomal Storage DisorderDeficiency of α- galactosidase A (GLA)Accumulation of globotriaosylceramide (Gb3),

5、Fabry Disease,More than 250 kinds of GLA DNA mutationsMajority of them are point mutations,Fabry Disease,Frequency?1/55,000 male JAMA. 1999; 281: 249-541/3,100 male Am. J. Hum. Genet. 2006; 79: 31-40,,Based on th

6、is result, Fabry became the most common lysosomal storage disorder.,Classification by Clinical Features,TypicalAtypical, Cardiac variant,Typical disease course in a classically affected male hemizygote with Fabry disea

7、se.,Fabry Disease,Recessive?,Wang et al. Genet. Med. 9: 34-45, 2007.,Dr Wang reported that ss many as 76 percent of carrier women experience symptoms of the disease. So he suggested that Fabry disease should not be consi

8、dered an X-linked recessive disorder and that heterozygous Fabry women should not be called carriers because they experience significant life-threatening conditions requiring medical treatment and intervention.,肥厚型心肌病患者中

9、 3-6% 為Fabry,,,腎透析病患者中 0.2% 為Fabry,18-55歲腦中風病人中 2 - 5% 為Fabry,常見的病，罕見的病因。,罕見病的定義,罕見病 Rare Diseases,“A disease is rare if fewer than 200,000 people in the United States have it. There are close to 7,000 rare diseases and

10、 about 25 million people in the U.S. have one. Many rare diseases are caused by changes in genes and are called genetic diseases.” From Medline：http://www.nlm.nih.go

11、v/medlineplus/rarediseases.html 總發(fā)病率：~ 8.3％ 發(fā)病率：200,000/300,000,000 < 1/1500的為罕見病。 平均發(fā)病率：25,000,000/7,000*300,000,000 = 1/120,000,罕見病是病種細分后的必然結(jié)果,疾病的分類和命名現(xiàn)代醫(yī)學的發(fā)展必然使得疾病的種類越來越多每種疾病所占的比例也就越來越小小到足以稱之為“罕見病”。,ht

12、tp://blog.sina.com.cn/s/blog_698a79070100pgc8.html,面對“罕見病時代”我們準備好了嗎？,,,http://omim.org/statistics/entry,2011,2012,2010,2013,罕見病有多少種？,2014,,,,“Soon there will be no disease called breast cancer,” says Draghia-Akli. Inste

13、ad, the catch-all term will be replaced by “a large number of rare diseases, each of which causes malignant growth in breast tissue and requires individual treatment”.,Trastuzumab 曲妥珠單抗 治療 HER-2陽性乳腺癌,Gefitinib Tablet

14、 吉非替尼 治療EGFR具有敏感突變的局部晚期或轉(zhuǎn)移性非小細胞肺癌,遺傳性罕見病的治療現(xiàn)狀這么慘嗎？,http://health.people.com.cn/n/2013/0225/c14739-20586389.html,1%？,1680萬？,10%,,,,《探究36種遺傳代謝性疾病在中國進行新生兒篩查的必要性與可行性的前期理論研究》,根據(jù)查閱36種疾病的相關(guān)文獻，按其預(yù)后我們將他們分為了以下四類。篩后能治愈（16）：楓糖尿病

15、，同型胱氨酸尿癥，酪氨酸血癥Ⅱ型，酪氨酸血癥III型，鳥氨酸氨甲酰基轉(zhuǎn)移酶缺乏癥，酪氨酸血癥I型，甲基丙二酸血癥，2-甲基丁酰輔酶A脫氫酶缺乏癥，3-甲基巴豆輔酶A羧化酶缺乏癥，多種輔酶A羥化酶缺乏癥，線粒體乙酰乙酰輔酶A硫解酶缺乏癥，肉堿吸收障礙，肉堿棕櫚酰轉(zhuǎn)移酶缺乏Ⅰ型，肉堿棕櫚酰轉(zhuǎn)移酶Ⅱ缺陷，短鏈酰基輔酶A脫氫酶缺陷，中鏈酰基輔酶A脫氫酶缺陷篩后也完全不能治（1）：戊二酸血癥II型篩后治療還會有后遺癥（15）：精氨基琥珀酸

16、尿癥，瓜氨酸血癥I型，瓜氨酸血癥II型，精氨酰琥珀酸尿癥，精氨酸血癥，氨甲酰磷酸合成酶缺乏癥，丙酸血癥，異戊酸血癥，戊二酸血癥I型，肉堿/?；鈮A轉(zhuǎn)運酶缺陷，長鏈L-3-羥?；o酶A脫氫酶缺陷，線粒體三功能蛋白缺乏癥，乙基丙二酸腦病，長鏈?；o酶A脫氫酶缺陷，極長鏈?；o酶A脫氫酶缺陷當前報道不足無法清楚該病具體情況（3）：3-甲基戊烯二酰輔酶A水解酶缺乏癥，異丁?；o酶A脫氫酶缺乏癥，2,4-二烯酰輔酶A還原酶缺乏癥,Curren

17、t State of Treatment of Genetic Disease,Now it is the turn of so-called genetic diseases to enter this arena of hopeHomo sapiens is the only species on earth which intentionally modifies experience, thereby modifying n

18、atural selection.,Current State of Treatment of Genetic Disease Single-Gene Diseases,,,2152,3032,2009年,2014年,2個/天,,,,325,2008,2013,350,2014年第三屆DMD康復(fù)與治療國際研討會,,,,Jes Ranbek教授丹麥的神經(jīng)肌肉疾病功能康復(fù)中心,2014年8月23-24日,“丹麥DMD病人生存時間提高到5

19、0-60歲！”,罕見病公共政策制定的策略問題,罕見病不是與常見病對立的概念，而是解決常見病的分型診斷和個體化治療之路。罕見病人不是社會的負擔，而是財富。罕見病是未來衛(wèi)生經(jīng)濟領(lǐng)域國際間競爭的重要方向，我們國家必須后來追上，否則，落后就會挨打。,面對“罕見病”時代，我們準備好了嗎？,病友會的重要作用,北醫(yī)三院 樊東升教授,《中文罕見病數(shù)據(jù)庫》,@黃昱北京大學醫(yī)學部醫(yī)學遺傳學系huangyu@bjmu.edu.cnhttp:/