mutagenesis (mutations) and teratogenesis (congenital malformations)
Post on 22-Jan-2016
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Don’t let this happen to you!!
Changes in DNA that affect genetic information
Gene MutationsPoint Mutations – changes
in one or a few nucleotidesSubstitution
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
Gene MutationsFrameshift 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
Chromosome MutationsChanges in number and structure of entire
chromosomes Original Chromosome ABC * DEFDeletion AC * DEFDuplication ABBC * DEFInversion AED * CBFTranslocation ABC * JKL
GHI * DEF
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
What Causes Mutations?There are two ways in which DNA can
become mutated:Mutations can be inherited.
Parent to childMutations can be acquired.
Environmental damage Mistakes when DNA is copied
Chromosome MutationsDown 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.
Chromosome MutationsCri-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
Sex Chromosome AbnormalitiesKlinefelter’s
SyndromeXXY, XXYY, XXXYMaleSterilitySmall testiclesBreast enlargement
Sex Chromosome AbnormalitiesXYY Syndrome
Normal male traitsOften tall and thinAssociated with antisocial and behavioral
problems
Sex Chromosome MutationsTurner’s
SyndromeXFemalesex organs don't
mature at adolescence
sterilityshort stature
Sex Chromosome MutationsXXX
Trisomy XFemaleLittle or no visible differencestall staturelearning disabilitieslimited fertility
Some mutations even make it on SNL!
Good news: coffee break Bad news: 10 minutes
Causes of Malformations(Teratogenesis or Dismorphology)
Birth defect
Congenital malformation
Congenital anomaly
(Hereditary) abnormality
Types of Abnormalities :
MalformationDisruptionsDeformationsSyndromes
• Minor anomalies
• Major anomalies
Principles of Teratology
Developmental stage at the time of exposure
Dose and duration of exposure to a teratogen
Hereditary (Genetic) causes 15-18%Environmental factors 7-10%Multifactorial 25%Unknown 50%
First week (Resistant period)Embryonic period
Maximum susceptibility (organ morphogenesis)
Fetal Period Lowered Susceptibility (functional derangement)
Genetic factors
(Numerical Chromosomal Anomalies) Polyploidy
Triploidy 69 Tetraploidy 92
Aneuploidy 13 (Patau syndrome)
18( Edwards syndrome) 21( Down syndrome)
(Klinfelter syndrome-XXY) Triple X (Superfemale)
(Turner syndrome- 45,XO)
Patau Syndrome 1/20000
cleft-lip-baby
Edwards Syndrome 1/5000
Maternal nondisjunction (95%)MosaismTranslocation
•Monosomy•Nondisjunction in sperm (80%)•X chromosome only•Nondisjunction in mitosis (Mosaicism)
Structural Chromosomal AnomaliesIsochromosomeCrossing over : Translocation
21,13,14, 15 in Down syndromePartial Deletion
Cri du chat 5(microcephal, mental, cardiovas) Microdeletion
Angelman 15 (speech, mental, movement) Prader- willi 15 (fatty, mental, hypogonad)Inversion
Gene Mutation Anomalies
Marphan syndromeCrigler-Najjar syndromeRoberts syndromeAlport syndromeAarskog-Scott syndromeSavant syndromeTreacher-Collins syndromeNiemann–Pick diseaseCystic FibrosisDMD
Environmental factors
• Infectious Agents (& other disease)
• Drugs Agents (& Hormonic Agents)
• Chemical Agents
• Physical Agents
A) Viral infectionsRubella virus (German Measles)
1month-From placenta- atrioventricular septsl 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)
Infectious Agents
Infectious AgentsB) Nonviral infections
Toxoplasma in each three munth - death, microcephaly, hydroceohaly, cerebral calcification
Treponema pallidum Syphilis, rhinitis, eye defect (cataract), icterus,a bnormal teeth, splenohepatomegaly
Chronic DiseasesDiabetes
Coudal disgenesis, death
PKUmental retardation, microcephaly, cardiac defect
Nutrient deficiency Iodine deficiency coused cretinism
ObesityONTD, cardiac defect, …
Hypoxy
Drugs AgentsCategory X drugs
Category D drugs
Category X drugs Thalidomide
Aminopterin
methotrexate
Busulfan
Phenytoin
Triazolam
Warfarin
Isotretinoin
Clomiphen
Diethylstilbestr
ol
Ethisterone
Norethindrone
Nicotine
Alcohol
Category X drugs
Thalidomide
Category X drugsAminopterin MethotrexateBusulfan
Used in chemotererapy
Dawerfism Myelomeningocele palate clef Growth retardation ophtalmic defect
Category X drugs
Aminopterin MethotrexateBusulfan
Used in chemotererapy
Dawerfism Myelomeningocele palate clef Growth retardation ophtalmic defect
Category X drugs
Phenytoin
Antileptic drug microcephalyGrowth & mental
retardationpalate clefFinger & nail
HypoplesiaSkull defect
Category X drugsWarfarin
Anti couagulant drugMental retardation microcephaly optic n. atrophy Fetal bleeding
Category X drugs
Clomiphen
Non-steroidal drug Used for stimulus ovulation
Maybe Malformatin
Category X drugs
Retinoids (vitamin A)
Used for Cystic acne
severe craniofacial defects
cardiac defects
neural tube defects (NTD)
Palate clefttretinoin (Retin-A)
isotretinoin, 13-cis-retinoic acid
Category X drugs
Nicotine
Mental retardationWheight lossFetal HypoxyPremature Parturition
Category X drugs
Alcohol
Fetal Alcholic Syndrome (FAS)Mental retardationmicrocephalyCardivascular defectLimb & Face malformationHairsutism
Category D drugsTetracycline
doxycycline
Streptomycin
Phenobarbital
Pentobarbital
Valsuroic acid
Diazepam
lorazepam
Lithium
Hydrochlorothiazid
e
Category D drugs
Phenobarbital &
Pentobarbital
paliative drug
Fetal
malformation
Category D drugs
Diazepam,
Lorazepam ,
Chlorodiazepoxide
antianxiety drug palate & lip clef specially in first 3
months
Category D drugs
Lithium ,Phenothiazine
Antiedepressive
CardioVascular defect
Chemical Agents(heavy metals)
Physical Agents
Male-mediated Teratogenesis
Chromosomal defects & Mutation in germ cells
Environmental agent : transmission of paternal mediated toxicity through seminal fluid
Ultrasonography
Maternal Serum Screening (AFP,hCG)
AFP : Trisomy↓- NTD,GIT atresia,amniotic band↑
Amniocentesis
Chorionic Villus Sampling (CVS)
Prenatal Diagnosis
Fetal Transfusion
Fetal Medical Treatment
Fetal Surgery
Stem Cell Transplantation and Gene Therapy
Befor 18th week (activation of immune system)
Fetal Therapy
Thank you!
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