Mutagenesis (mutations) and Teratogenesis (congenital malformations)

1. Mutagenesis (mutations) and Teratogenesis (congenital malformations)

2. Don’t let this happen to you!!

3. MUTATIONS Changes in DNA that affect genetic information

4. Gene Mutations • Point Mutations – changes in one or a few nucleotides • Substitution • THE FAT CAT ATE THE RAT • THE FAT HAT ATE THE RAT • Insertion • THE FAT CAT ATE THE RAT • THE FAT CAT XLW ATE THE RAT • Deletion • THE FAT CAT ATE THE RAT • THE FAT ATE THE RAT

5. Gene Mutations • Frameshift Mutations – shifts the reading frame of the genetic message so that the protein may not be able to perform its function. • Insertion • THE FAT CAT ATE THE RAT • THE FAT HCA TAT ETH ERA T • Deletion • THE FAT CAT ATE THE RAT • TEF ATC ATA TET GER AT H H

6. Chromosome Mutations • Changes in number and structure of entire chromosomes • Original Chromosome ABC * DEF • Deletion AC * DEF • Duplication ABBC * DEF • Inversion AED * CBF • Translocation ABC * JKL GHI * DEF

7. Significance of Mutations • Most are neutral • Eye color • Birth marks • Some are harmful • Sickle Cell Anemia • Down Syndrome • Some are beneficial • Sickle Cell Anemia to Malaria • Immunity to HIV

8. What Causes Mutations? • There are two ways in which DNA can become mutated: • Mutations can be inherited. • Parent to child • Mutations can be acquired. • Environmental damage • Mistakes when DNA is copied

9. Chromosome Mutations • Down Syndrome • Chromosome 21 does not separate correctly. • They have 47 chromosomes in stead of 46. • Children with Down Syndrome develop slower, may have heart and stomach illnesses and vary greatly in their degree of inteligence.

10. Chromosome Mutations • Cri-du-chat • Deletion of material on 5th chromosome • Characterized by the cat-like cry made by cri-du-chat babies • Varied levels of metal handicaps

11. Sex Chromosome Abnormalities • Klinefelter’s Syndrome • XXY, XXYY, XXXY • Male • Sterility • Small testicles • Breast enlargement

12. Sex Chromosome Abnormalities • XYY Syndrome • Normal male traits • Often tall and thin • Associated with antisocial and behavioral problems

13. Sex Chromosome Mutations • Turner’s Syndrome • X • Female • sex organs don't mature at adolescence • sterility • short stature

14. Sex Chromosome Mutations • XXX • Trisomy X • Female • Little or no visible differences • tall stature • learning disabilities • limited fertility

16. Some mutations even make it on SNL!

18. Good news: coffee break  Bad news: 10 minutes 

19. Causes of Malformations(Teratogenesis or Dismorphology) ? ? ?

20. Birth defectCongenital malformationCongenital anomaly(Hereditary) abnormality

21. Types of Abnormalities : • Minor anomalies • Major anomalies • Malformation • Disruptions • Deformations • Syndromes

22. Principles of Teratology Developmental stage at the time of exposure Dose and duration of exposure to a teratogen

23. Hereditary (Genetic) causes 15-18% Environmental factors 7-10% Multifactorial 25% Unknown 50%

24. First week (Resistant period) • Embryonic period • Maximum susceptibility (organ morphogenesis) • Fetal Period • Lowered Susceptibility (functional derangement)

25. Genetic factors (Numerical Chromosomal Anomalies) Polyploidy Triploidy 69 Tetraploidy 92 Aneuploidy 13 (Patausyndrome) 18 (Edwards syndrome) 21 (Down syndrome) (Klinfeltersyndrome-XXY) Triple X (Superfemale) (Turner syndrome- 45,XO)

26. Patau Syndrome 1/20000 cleft-lip-baby

27. Edwards Syndrome 1/5000

28. Down syndrome • Maternal nondisjunction (95%) • Mosaism • Translocation

29. Monosomy • Nondisjunction in sperm (80%) • X chromosome only • Nondisjunction in mitosis (Mosaicism)

30. Structural Chromosomal Anomalies • Isochromosome • Crossing over : • Translocation 21,13,14, 15in Down syndrome • Partial Deletion Cri du chat 5(microcephal, mental, cardiovas) • Microdeletion Angelman15 (speech, mental, movement) Prader- willi15 (fatty, mental, hypogonad) • Inversion

31. Gene Mutation Anomalies • Marphan syndrome • Crigler-Najjarsyndrome • Roberts syndrome • Alportsyndrome • Aarskog-Scott syndrome • Savant syndrome • Treacher-Collinssyndrome • Niemann–Pick disease • Cystic Fibrosis • DMD

32. Environmental factors • Infectious Agents (& other disease) • Drugs Agents (& Hormonic Agents) • Chemical Agents • Physical Agents

33. Infectious Agents • A) Viral infections • Rubella virus (German Measles) 1month-From placenta- atrioventricularseptsl defect, cataract. Weight ↓ • Cytomegalovirus(CMV) From Placenta,Cervix,Vagina (& Lactation) - microephaly, deafness, mental retardation, hepatospleenomegally ,cardiac defect,cerebral calcification, blue spot on skin • Herpes simplex virus(HSV) From Placenta,Vagina(85%)-Defect in CNS,liver, pancreas,ren,suprarenal glands, infection on skin, Eyes or mouth – no treatment=40-50% death • Varicella-zoster virus(VZV)first 3 month-From Placenta- limb hypoplasia & parasis., hydrocephaly. Mental retardation, cataract • HIV After 35th week- Systematic Chronic infection(fungus,bacterial,viral,protozoan)

35. Infectious Agents • B)Nonviral infections • Toxoplasma in each three munth - death, microcephaly, hydroceohaly, cerebral calcification • Treponemapallidum Syphilis, rhinitis, eye defect (cataract), icterus,abnormal teeth, splenohepatomegaly

36. Chronic Diseases • Diabetes Coudaldisgenesis, death • PKU mental retardation, microcephaly, cardiac defect • Nutrient deficiency Iodine deficiency coused cretinism • Obesity ONTD, cardiac defect, … • Hypoxy

37. Drugs Agents • Category X drugs • Category D drugs

38. Category X drugs • Clomiphen • Diethylstilbestrol • Ethisterone • Norethindrone • Nicotine • Alcohol • Thalidomide • Aminopterin • methotrexate • Busulfan • Phenytoin • Triazolam • Warfarin • Isotretinoin

39. Category X drugs • Thalidomide antinauseant drug داروی ضد تهوع • limb defect (Amelia,Meromelia) • Cardiac defect • GIT atresy • Optic & otic defect

40. Thalidomide

41. Category X drugs • Aminopterin • Methotrexate • Busulfan • Used in chemotererapy • Dawerfism • Myelomeningocele • palate clef • Growth retardation • ophtalmic defect

42. Category X drugs • Aminopterin • Methotrexate • Busulfan • Used in chemotererapy • Dawerfism • Myelomeningocele • palate clef • Growth retardation • ophtalmic defect

43. Category X drugs • Phenytoin • Antileptic drug • microcephaly • Growth & mental retardation • palate clef • Finger & nail Hypoplesia • Skull defect

44. Category X drugs • Warfarin • Anti couagulant drug • Mental retardation • microcephaly • optic n. atrophy • Fetal bleeding

45. Category X drugs • Clomiphen • Non-steroidal drug • Used for stimulus ovulation • Maybe Malformatin

46. Category X drugs isotretinoin, 13-cis-retinoic acid • Retinoids (vitamin A) • Used for Cystic acne • severe craniofacial defects • cardiac defects • neural tube defects (NTD) • Palate cleft tretinoin (Retin-A)

47. Category X drugs • Nicotine • Mental retardation • Wheight loss • Fetal Hypoxy • Premature Parturition

48. Category X drugs • Alcohol • Fetal Alcholic Syndrome (FAS) • Mental retardation • microcephaly • Cardivascular defect • Limb & Face malformation • Hairsutism

49. Valsuroicacid • Diazepam • lorazepam • Lithium • Hydrochlorothiazide Category D drugs • Tetracycline • doxycycline • Streptomycin • Phenobarbital • Pentobarbital

50. Category D drugs • Phenobarbital & Pentobarbital • paliative drug • Fetal malformation