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產前診斷 Prenatal Diagnosis

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

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產前診斷 Prenatal Diagnosis

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  1. 產前診斷Prenatal Diagnosis 鄭博仁副教授

  2. Prenatal Screening • History • Maternal serum screening • Ultrasound • Invasive testing

  3. Genetic History • Previous history • Family history • Ethnic group • Maternal Age

  4. Prior History • Previous aneuploid fetus • Known balanced translocation carrier • Known inversion carrier • History of recurrent miscarriage • History of stillbirth • Previous anomalous fetus

  5. Family History • Autosomal dominant conditions • Autosomal recessive conditions • X-linked recessive conditions • Mental retardation • Congenital cardiac disease

  6. Ethnic Background • African American • Italian, Greek or Mediterranean • Southeast Asian • Eastern European Jewish • French Canadian • Cajun

  7. 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

  8. Cystic Fibrosis • Carrier Detection

  9. 1/10 1/20 1/40 1/50 1/100 1/1000 Maternal Age

  10. OSCAR - A One Stop Clinic for Assessment of Risk for fetal anomalies. Kevin Spencer

  11. Developments & Innovations Leading to OSCAR • Ultrasound markers of chromosomal anomalies - fetal nuchal translucency thickness at 10-13 weeks.

  12. Increased fetal nuchal translucency thickness in a case of T21 Upper limbs Head Lower limbs NT

  13. Developments & Innovations Leading to OSCAR • 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.

  14. Maternal Serum Screening • Second Trimester • AFP, hCG, UE3 • Detection rate for aneuploidy and screen-positive rate vary with maternal age

  15. 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%

  16. 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 Tuner’s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

  17. New Possibilities • Fetal cells in the maternal circulation • Fetal DNA in the maternal circulation

  18. 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

  19. Ultrasound • Major anomalies

  20. 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

  21. 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

  22. Ultrasound • “Soft signs”

  23. 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

  24. 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

  25. 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

  26. Invasive Testing • Ways to obtain fetal cells for karyotype and DNA testing • Chorionic villus sampling (CVS) • Amniocentesis (amnio)

  27. Fetus (10-12 weeks) Invasive Testing • CVS

  28. 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

  29. Invasive Testing • Amniocentesis

  30. Invasive Testing • Amniocentesis • 15-20 weeks • Amniotic fluid AFP also obtained • Procedure-related risk of 1:200

  31. 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

  32. 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

  33. 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

  34. 遺傳病治療(Gene Therapy) 鄭博仁副教授

  35. 基因 基因產物 代謝作用 功能作用 構造作用

  36. 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

  37. In Vitro Fertilization Diagnosis: genetic defect Diagnosis: genetic defect ***moral dilemma*** what is a fetus?

  38. In Vitro Fertilization Diagnosis: genetic defect ***moral dilemma*** what is a fetus? Cystic fibrosis - life expectancy 20-30 yrs - medical advances - offspring will be carriers

  39. In Vitro Fertilization Diagnosis: genetic defect ***moral dilemma*** what is a fetus? Tay-Sachs disease - Ashkenazi Jewish descent - hexosaminidase deficiency - invariable fatal during infancy

  40. Treatment of Genetic Diseases No effect on genetic makeup • phenylketonuria — low phenylalanine diet • familial hypercholesterolemia — low cholesterol diet • hemophilia — injection of clotting factors • diabetes — injection of insulin Problems: - adherence to dietary restrictions - repeated injections - side effects - inadequate/excessive dosages - contamination (HIV, HBV, etc.)

  41. Gene Transfer In vivo – cells treated inside the body Ex vivo – cells taken out, treated, replaced Duration of effect: incorporated DNA >> free DNA DNA

  42. Viral Replication 100s - 1000s of progeny virions 1 virion + 1 cell

  43. Adenovirus Retrovirus

  44. Retroviruses     Problem: requires dividing cells for integration Packaging vectors: can’t replicate but can still insert DNA

  45. Adenoviruses “stealth” functions - help virus evade immune attack HEK293 cells - transformed with HAd5 E1 DNA E1 proteins

  46. 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

  47. 基因新科技 鄭博仁副教授

  48. Human Genome Project http://www.ncbi.nlm.nih.gov/genome/seq/

  49. 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

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