罕见病从溶酶体病说起-2014高级医学遗传学

罕见病 -从溶酶体病说起,黄昱北京大学医学部医学遗传学系/medgeneticsQQ: 1115868344,第47期 科学家与媒体面对面活动关注罕见病,2014-9-19,故事从一个罕见病说起.,溶酶体贮积症 LSDsLysosomal Storage Disorders,由于基因突变或染色体畸变导致的，溶酶体发挥其正常功能所需的一种或多种酶类分子，或调控分子，功能减弱或丧失引起的疾病成为溶酶体病。由于该类疾病常常可见相应的底物或和其衍生物在溶酶体内大量累积，因此通常称之为溶酶体贮积症。在遗传病分类上属于遗传代谢性疾病。,Clathrin-coated lysosome,贮积物的性质和形态可以作为鉴别诊断的依据,NCL1,NCL2,NCL3,Neuronal Ceroid Lipofuscinosis (NCL),溶酶体贮积症分类,Mucopolysaccaridoses 粘多糖贮积病Glycoproteinoses 糖蛋白贮积病Glycogen storage 糖原贮积病Sphingolipidoses 神经鞘脂贮积病Lipid storage disorders 脂质贮积病Multiple enzyme defects 多酶缺陷Transport defects 转运缺陷,Fabry Disease,Anderson-Fabry Disease,Dr Johannes Fabry,Dr William Anderson,Fabry Disease,Angiokeratoma Corporis Diffusum弥漫性躯体性血管角化瘤,Fabry Disease,X-linked Lysosomal Storage DisorderDeficiency of - galactosidase A (GLA)Accumulation of globotriaosylceramide (Gb3),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 this 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 disease.,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 considered 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 3-6% 为Fabry,肾透析病患者中 0.2% 为Fabry,18-55岁脑中风病人中 2 - 5% 为Fabry,常见的病，罕见的病因。,罕见病的定义,罕见病 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 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：/medlineplus/rarediseases.html 总发病率： 8.3 发病率：200,000/300,000,000 1/1500的为罕见病。 平均发病率：25,000,000/7,000*300,000,000 = 1/120,000,罕见病是病种细分后的必然结果,疾病的分类和命名现代医学的发展必然使得疾病的种类越来越多每种疾病所占的比例也就越来越小小到足以称之为“罕见病”。,/s/blog_698a79070100pgc8.html,面对“罕见病时代”我们准备好了吗？,/statistics/entry,2011,2012,2010,2013,罕见病有多少种？,2014,“Soon there will be no disease called breast cancer,” says Draghia-Akli. Instead, 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 曲妥珠单抗 治疗 HER-2阳性乳腺癌,Gefitinib Tablet 吉非替尼 治疗EGFR具有敏感突变的局部晚期或转移性非小细胞肺癌,遗传性罕见病的治疗现状这么惨吗？,/n/2013/0225/c14739-20586389.html,1%？,1680万？,10%,探究36种遗传代谢性疾病在中国进行新生儿筛查的必要性与可行性的前期理论研究,根据查阅36种疾病的相关文献，按其预后我们将他们分为了以下四类。筛后能治愈（16）：枫糖尿病，同型胱氨酸尿症，酪氨酸血症型，酪氨酸血症III型，鸟氨酸氨甲酰基转移酶缺乏症，酪氨酸血症I型，甲基丙二酸血症，2-甲基丁酰辅酶A脱氢酶缺乏症，3-甲基巴豆辅酶A羧化酶缺乏症，多种辅酶A羟化酶缺乏症，线粒体乙酰乙酰辅酶A硫解酶缺乏症，肉碱吸收障碍，肉碱棕榈酰转移酶缺乏型，肉碱棕榈酰转移酶缺陷，短链酰基辅酶A脱氢酶缺陷，中链酰基辅酶A脱氢酶缺陷筛后也完全不能治（1）：戊二酸血症II型筛后治疗还会有后遗症（15）：精氨基琥珀酸尿症，瓜氨酸血症I型，瓜氨酸血症II型，精氨酰琥珀酸尿症，精氨酸血症，氨甲酰磷酸合成酶缺乏症，丙酸血症，异戊酸血症，戊二酸血症I型，肉碱/酰基肉碱转运酶缺陷，长链L-3-羟酰基辅酶A脱氢酶缺陷，线粒体三功能蛋白缺乏症，乙基丙二酸脑病，长链酰基辅酶A脱氢酶缺陷，极长链酰基辅酶A脱氢酶缺陷当前报道不足无法清楚该病具体情况（3）：3-甲基戊烯二酰辅酶A水解酶缺乏症，异丁酰基辅酶A脱氢酶缺乏症，2,4-二烯酰辅酶A还原酶缺乏症,Current 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 natural selection.,Current State of Treatment of Genetic Disease Single-Gene Diseases,2152,3032,2009年,2014年,2个/天,325,2008,2013,350,2014年第三届DMD康复与治疗国际研讨会,Jes Ranbek教授丹麦的神经肌肉疾病功能康复中心,2014年8月23-24日,“丹麦DMD病人生存时间提高到50-60岁！”,罕见病公共政策制定的策略问题,罕见病不是与常见病对立的概念，而是解决常见病的分型诊