医学课件产前诊断

產前診斷 Prenatal Diagnosis,鄭博仁副教授,Prenatal Screening,History Maternal serum screening Ultrasound Invasive testing,Genetic History,Previous history Family history Ethnic group Maternal Age,Prior History,Previous aneuploid fetus Known balanced translocation carrier Known inversion carrier History of recurrent miscarriage History of stillbirth Previous anomalous fetus,Family History,Autosomal dominant conditions Autosomal recessive conditions X-linked recessive conditions Mental retardation Congenital cardiac disease,Ethnic Background,African American Italian, Greek or Mediterranean Southeast Asian Eastern European Jewish French Canadian Cajun,Thalassemia,DOH ,Taiwan, now recommend offering screening to all prenatal and preconception patients Carrier frequency and carrier detection rate vary based on on ethnic background,Cystic Fibrosis,Carrier Detection,Maternal Age,1/10 1/20 1/40 1/50 1/100 1/1000,Kevin Spencer,OSCAR - A One Stop Clinic for Assessment of Risk for fetal anomalies.,Ultrasound markers of chromosomal anomalies - fetal nuchal translucency thickness at 10-13 weeks.,Developments & Innovations Leading to OSCAR,Head,Upper limbs,Lower limbs,NT,Increased fetal nuchal translucency thickness in a case of T21,Ultrasound markers of chromosomal anomalies - fetal nuchal translucency thickness at 10-13 weeks. Biochemical markers of chromosomal anomalies - free hCG & PAPP-A at 10-13 weeks.,Developments & Innovations Leading to OSCAR,Maternal Serum Screening,Second Trimester AFP, hCG, UE3 Detection rate for aneuploidy and screen-positive rate vary with maternal age,Maternal Serum Screening,First Trimester Free b-hCG and PAPP-A Combined with nuchal translucency screening Detection rate 82-91% False positive rate 3.3-7.9%,孕婦血清甲型胎兒蛋白昇高可能之原因,妊娠年齡低估 先兆性流產 多胞胎 胎兒異常 無腦兒 開放性神經管缺損 Tuners症 腸阻塞 皮膚缺損 遺傳性孕婦持續性甲型胎兒蛋白 胎盤血管瘤,New Possibilities,Fetal cells in the maternal circulation Fetal DNA in the maternal circulation,Ultrasound,Major anomalies are frequently associated with chromosomal abnormalities The incidence of chromosomal abnormalities varies greatly with the type of anatomic defect 80% for fetal hydrops early in gestation 2% for facial clefts,Ultrasound,Major anomalies,Ultrasound Soft Signs,“Soft signs” are ultrasound findings that do not represent anatomic abnormalities but are associated with karyotypic abnormalities If fetal karyotype is normal, these findings do not have clinical significance,Ultrasound Soft Signs,These findings are used to increase suspicion for karyotypic abnormalities Different findings are associated with different risks of aneuploidy 5% for a thickened nuchal fold in a high risk patient 0.2% for a choroid plexus cyst in a low risk patient,Ultrasound,“Soft signs”,產前遺傳診斷技巧,超音波 安全 妊娠中期操作 羊水穿刺 操作危險性0.5% 妊娠中期操作 廣泛使用 絨毛切片 操作危險性0.1% 妊娠初期操作 高難度 臍帶穿刺 操作危險性1% 妊娠中期操作 極高難度 胎兒組織切片 操作危險性3% 妊娠中期操作 非常高難度 胚胎切片 發展中,產前診斷的一般準則,高遺傳危險性 嚴重性疾病 無法治療 可靠的產前診斷測試 妊娠終止可被接受,產前診斷的應用,孕婦血清 篩檢 甲型胎兒蛋白（AFP）測定 超音波 構造異常 羊水穿刺 甲型胎兒蛋白測定 染色體分析 生化分析 絨毛切片 DNA分析 染色體分析 生化分析 臍血採樣 染色體分析 DNA分析,Invasive Testing,Ways to obtain fetal cells for karyotype and DNA testing Chorionic villus sampling (CVS) Amniocentesis (amnio),Invasive Testing,CVS,Invasive Testing,CVS 10-12 weeks Transabdominal or transcervical Procedure-related loss rate of 1:125-1:175 No information obtained regarding neural tube defects,Invasive Testing,Amniocentesis,Invasive Testing,Amniocentesis 15-20 weeks Amniotic fluid AFP also obtained Procedure-related risk of 1:200,Fetal Cells in the Maternal Circulation,Non-invasive compared with Amnio and CVS Involves 2nd trimester maternal blood Preferable for male fetuses, due to difficulty in distinguishing maternal from female fetal cells at this time Remains investigational,Preimplantation Genetic Diagnosis (PGD),Requires in vitro fertilization (IVF) Alternative to CVS or Amnio Success rate and risks of IVF may be barriers to PGD for some couples,PGD,PGD is based on ability to remove nucleus of one cell in an early embryo (8 or 16 cells), when all cells are totipotent, ie, the loss of a single cell does not compromise development Has been carried out for MCAD deficiency, Tay-Sachs disease and sickle cell disease,遺傳病治療 (Gene Therapy),鄭博仁副教授,基因 基因產物 代謝作用 功能作用 構造作用,Genetic diagnosis,Direct enzyme analysis,Phenylketonuria - absence of phenylalanine hydroxylase - inadequate tyrosine synthesis - mental retardation, etc.,Treatment: controlled diet - low in meat, cheese, eggs - high in fruits, grains, vegetables,In Vitro Fertilization,Diagnosis: genetic defect,*moral dilemma* what is a fetus?,Diagnosis: genetic defect,In Vitro Fertilization,*moral dilemma* what is a fetus?,Diagnosis: genetic defect,Cystic fibrosis - life expectancy 20-30 yrs - medical advances - offspring will be carriers,In Vitro Fertilization,*moral dilemma* what is a fetus?,Diagnosis: genetic defect,Tay-Sachs disease - Ashkenazi Jewish descent - hexosaminidase deficiency - invariable fatal during infancy,Treatment of Genetic Diseases,No effect on genetic makeup,Problems: - adherence to dietary restrictions - repeated injections - side effects - inadequate/excessive dosages - contamination (HIV, HBV, etc.), phenylketonuria low phenylalanine diet familial hypercholesterolemia low cholesterol diet hemophilia injection of clotting factors diabetes injection of insulin,Gene Transfer,In vivo cells treated inside the body Ex vivo cells taken out, treated, replaced,Duration of effect: incorporated DNA free DNA,DNA,Viral Replication,1 virion,1 cell,+,100s - 1000s of progeny virions,Adenovirus,Retrovirus,Retroviruses,Packaging vectors: cant replicate but can still insert DNA,Problem: requires dividing cells for integration,Adenoviruses,“stealth” functions - help virus evade immune attack,HEK293 cells - transformed with HAd5 E1 DNA,E1 proteins,Problems Associated with Viral Gene Therapy,Immune response Targeting of specific tissues Toxic effect of viral vectors Inadequate or limited time response Integration into cell DNA,基因新科技,鄭博仁副教授,Human Genome Project,/genome/seq/,Human Genome Project,Initiated 1990 Completion originally planned for 2005 Anticipate completion prior to deadline Results Complete sequencing of the Human Genome New branch of science and medicine - Genomics,What Is a Genome?,Genome: All of the DNA for an organism Human Genome Nucleus: 3.2 billion base pairs packaged into chromosomes Mitochondrion: 16,600 base pairs packaged in one circular chromosome,“Central Dogma” of Modern Genetics,DNA RNA Protein Metab ,Genomics: Derivative Studies,Transcriptomics Trascript is an RNA copy of a gene Transcriptome is all RNA gene copies in a cell, tissue or individual Proteomics Proteome is all proteins in a cell, tissue or individual,Genomics: Derivative Studies,Metabolomics Metabolome is all of the small molecule components of a cell, tissue or individual that are produced by the proteins of the proteome,Genomics and Derivative Studies,Will generate the complete parts lists and the parts assembly directions for a fully functioning organism,Promise of the Human Genome Project,Improved diagnosis and treatment through the application of genetic information and technologies Predictive medicine Individualized medical care Population screening,Genomic Medicine,Predictive rather than reactive Preventive rather than responding only after acute presentation Screening of populations, sub-populations and individuals Pharmacogenomics,Screening: Examples,Prenatal: MSAFP for Spina Bifida Neonatal: PKU for prevention of Mental Retardation Selected sub-populations: Ashkenazim for Tay-Sachs Disease carrier status,Genetics in the News,Genetic Banking,Down Syndrome,Prenatal Diagnosis,Newborn Screening,/amsci/articles/02articles/millingtoncap3.html,Genetic Variation,Genetics in Medicine,Birth,genetic liability,environmental factors,prenatal,presymptomatic,disease,Models,Genotype,Phenotype,Environment,Medicine in Transformation,Two Convergent Forces,Information Technology,Genetics,Predictive testing and prevention Stratification of disease and targeted treatments Pharmacogenetics,“Individualized Medicine”,syncope,sudden death,CAD age 57,2000,Cardiomyopathy,Kamisago et al. New Engl. J. Med. 2000;343 (23): 1688,syncope,sudden death,CAD age 57,2005,J.L. is admitted to Faulkner Hospital. He rules out for myocardial infarction by enzymes and electrocardiography. Blood is sent for a DNA test and J.L. is found to have a mutation in the b cardiac myosin heavy chain gene. A.L. is found to have the same mutation, but it is not present in B.L. or C.L. A.L. is started on a program of regular monitoring by echocardiography.,A.L.,B.L.,C.L.,J.L.,2010,sudden death,CAD age 57,A.L.,B.L.,C.L.,A.L.s pediatrician learns of a family history of sudden death on his fathers side. He arranges for a blood specimen to be sent to the laboratory for a panel of tests involving genes associated with cardiac dysfunction. A.L. is found to have a mutation in the b cardiac myosin heavy chain gene. The same mutation is found in J.L. A.L. is started on a program of monitoring by echocardiography. An echocardiogram done in J.L. reveals signs of advanced hypertrophic cardiomyopathy. He is started on a new b blocker medication, and is advised to consider implantation of a defibrillator.,J.L.,2015,In the course of a routine primary care visit, D.L. is noted to have a family history of early unexplained death (her mother and maternal aunt). She is tested for a set of risk factors known to predispose to early death and is found to have a mutation in the b cardiac myosin heavy chain gene. She is started on a new class of medication known to prevent the occurrence of hypertrophic cardiomyopathy. Four of her children are also found to carry the mutation. They, too, are started on medication and a program of regular monitoring.,D.L.,Clinicians will use family history and genetic testing to identify patients who need further evaluation and/or management,Screening,Disease Stratification Targeted Therapy,hypertension,ALOX5 Polymorphism and Asthma,Trial of ABT-761, an ALOX5 (leukotriene pathway) inhibitor in asthma. Drazen et al. Nature Genetics 1999;22:168.,Targeted Therapy,Goldman JM, Melo JV. N Engl J Med 2001;344:1084-1086.,Avoidance of Adverse