History Genetics is the study of genes. Inheritance is how traits, or characteristics,

are passed on from generation togeneration.

Chromosomes are made up of genes, whichare made up of DNA.

Genetic material (genes,chromosomes,DNA) is found inside the nucleus of a cell.

Gregor Mendel is considered The Father ofGenetics"

Mendelian Genetics Dominant traits- traits that are expressed. Recessive traits- traits that are covered up. Alleles- the different forms of a characteristic. Punnett Squares- show how crosses are made. Probability- the chances/ percentages that

something will occur. Genotype- the types of genes (Alleles) present. Phenotype- what it looks like. Homozygous- two of the same alleles. Heterozygous- two different alleles.

For each monohybrid cross, Mendel cross-fertilized true-breeding plants thatwere different in just one characterin this case, flower color. He then allowedthe hybrids (the F1 generation) to self-fertilize.

Mendel studies seven characteristics in the garden pea

:Statistics indicateda pattern.

ChromosomesHomologous chromosome: one of a matching pair ofchromosomes, one inherited from each parent.

Sister chromatids are identical

Law of DominanceIn the monohybrid cross (mating of two organisms that differ in only onecharacter), one version disappeared.

What happens when the F1s are crossed?

The F1 crossedproduced the F2generation and thelost trait appearedwith predictableratios.

This led to theformulation of thecurrent model ofinheritance.

Alleles: alternative versions of a gene.The gene for a particular inherited character resides at a specific locus(position) on homologous chromosome.

For each character, an organisminherits two alleles, one from eachparent

How do alleles differ?

Dominant - a term applied to the trait (allele) that is expressed irregardless ofthe second allele.Recessive - a term applied to a trait that is only expressed when the secondallele is the same (e.g. short plants are homozygous for the recessive allele).

Dominant allele

Recessiveallele

Recessive allele

Recessive allele

Probability and Punnett Squares

Punnett square: diagram showing the probabilities of thepossible outcomes of a genetic cross

Genotype versus phenotype.

How does agenotype ratio differfrom the phenotyperatio?

Punnett squares - probability diagram illustrating the possibleoffspring of a mating.

Ss X Ss

gametes

TestcrossA testcross is designed to reveal whether an organism that displays thedominant phenotype is homozygous or heterozygous.

Variation in Patterns of Inheritance

Intermediate Inheritance (blending): inheritance in whichheterozygotes have a phenotype intermediate between the phenotypes ofthe two homozygotes

How Does it Work?

The Importance of the EnvironmentThe environmental influences the expression of the genotype so thephenotype is altered.

Hydrangea flowers of the same genetic variety range in color from blue-violet to pink, depending on the acidity of the soil.

Multifactorial; many factors, bothgenetic and environmental,collectively influence phenotype inexamples such as skin tanning

Pedigree analysis reveals Mendelian patterns in human inheritance

In these family trees, squares symbolize males and circles representfemales. A horizontal line connecting a male and female (--) indicates amating, with offspring listed below in their order of birth, from left to right.Shaded symbols stand for individuals with the trait being traced.

Disorders Inherited as Recessive Traits

Over a thousand human genetic disorders are known to have Mendelianinheritance patterns. Each of these disorders is inherited as a dominant orrecessive trait controlled by a single gene. Most human genetic disorders arerecessive.

A particular form of deafness isinherited as a recessive trait.

Many human disorders followMendelian patterns of inheritance

Cystic fibrosis, which strikes oneout of every 2,500 whites ofEuropean descent but is much rarerin other groups. One out of 25whites (4% ) is a carrier.

The normal allele for this genecodes for a membrane protein thatfunctions in chloride ion transportbetween certain cells and theextracellular fluid. These chloridechannels are defective or absent.

The result is an abnormally highconcentration of extracellularchloride, which causes the mucusthat coats certain cells to becomethicker and stickier than normal.

Sickle-cell disease,Sickle-cell disease is caused by the substitution of asingle amino acid in the hemoglobin protein of redblood cells

Dominantly Inherited Disorders

Achondroplasia, a form of dwarfism with an incidence of one case amongevery 10,000 people. Heterozygous individuals have the dwarf phenotype.

Huntingtons disease, a degenerative disease of the nervous system, iscaused by a lethal dominant allele that has no obvious phenotypic effectuntil the individual is about 35 to 45 years old.

Sex-Linked Disorders in HumansDuchenne muscular dystrophy, affects about one out of every 3,500 malesborn in the United States. People with Duchenne muscular dystrophy rarelylive past their early 20s. The disease is characterized by a progressiveweakening of the muscles and loss of coordination. Researchers have tracedthe disorder to the absence of a key muscle protein called dystrophin andhave tracked the gene for this protein to a specific locus on the Xchromosome.

Posture changes duringprogression of Duchennemuscular dystrophy.

Hemophilia is a sex-linked recessive trait defined by the absence of one ormore of the proteins required for blood clotting.

Color Blindness In Humans: An X-Linked TraitNumbers That You Should See If You Are In One Of The FollowingFour Categories: [Some Letter Choices Show No Visible Numbers]

Sex-Linked Traits:1. Normal Color Vision:

A: 29, B: 45, C: --, D: 26

2. Red-Green Color-Blind:A: 70, B: --, C: 5, D: --

3. Red Color-blind:A: 70, B: --, C: 5, D: 6

4. Green Color-Blind:A: 70, B: --, C: 5, D: 2

Pattern Baldness In Humans: A Sex Influenced TraitBaldness is an autosomal trait and is apparently influenced by sex hormonesafter people reach 30 years of age or older.

In men the gene is dominant, while in women it is recessive. A man needsonly one allele (B) for the baldness trait to be expressed, while a bald womanmust be homozygous for the trait (BB).

What are the probabilities for the children for a bald man andwoman with no history of baldness in the family?

DNA DNA is often

called theblueprint of life.

In simple terms,DNA contains theinstructions formaking proteinswithin the cell.

Why do we study DNA?

We study DNA formany reasons:

its centralimportance toall life on Earth

medical benefitssuch as curesfor diseases

better foodcrops.

Chromosomes and DNA

Chromosomesare made up ofgenes.

Genes are madeup of a chemicalcalled DNA.

The Shape of the Molecule

DNA is a verylong molecule.

The basic shapeis like a twistedladder or zipper.

This is called adouble helix.

One Strand of DNA

The backbone ofthe molecule isalternatingphosphate anddeoxyribose, asugar, parts.

The teeth arenitrogenousbases.

phosphate

deoxyribose

bases

The Double Helix Molecule

The DNA doublehelix has twostrands twistedtogether.

(In the rest of thisunit we will lookat the structureof one strand.)

DOUBLEHELIX OF DNA

The Nucleus DNA is located in the nucleus

Nucleotides

C C

COPhosphate

O

O -P OO

O

O -P OO

O

O -P OO

O One deoxyribose together withits phosphate and base make anucleotide.

Nitrogenousbase

Deoxyribose

The Basics Stucture Each side of the ladder

is made up of nucleicacids.

The backbone is aphosphate and a sugar

The rung of the ladderis the nitrogen base.

Hydrogen Bonds When making

hydrogen bonds,cytosine alwayspairs up withguanine,

And adeninealways pairs upwith thymine.

(Adenine andthymine are shownhere.)

C

C

C

C

N

N

O

O

C

Four nitrogenous bases

Cytosine C Thymine T Adenine A Guanine G

DNA has four different bases:

Two Stranded DNA Remember, DNA

has two strandsthat fit togethersomething like azipper.

The teeth are thenitrogenousbases but whydo they sticktogether?

Important

Adenine and Thyminealways join together

A -- T Cytosine and Guanine

always join togetherC -- G

Types of nitrogen bases

A= adenine G= guanine C= cytosine T= thymine

Copying DNA Step 1- DNA unwinds

and unzips Step 2- Once the

molecule is separatedit copies itself.

The new strand ofDNA has basesidentical to theoriginal

DNA by the numbers Each cell has about 2

m of DNA. The average human

has 75 trillion cells. The average human

has enough DNA to gofrom the earth to thesun more than 400times.

DNA has a diameter ofonly 0.000000002 m.

The earth is 150 billion mor 93 million miles fromthe sun.

Whats the main difference between DNAand RNA

RNA

In RNA Thymineis replaced byUracil

A-U (RNA) not A-T (DNA)

Transcription

When a secretarytranscribes a speech,the language remainsthe same. However,the form of themessage changesfrom spoken towritten

Transcription

Transcription- RNAis made from aDNA template inthe nucleus.

This type of RNA iscalled messengerRNA or mRNA

Transcription

DNA is protectedinside the nucleus.

mRNA carries themessage of DNAinto the cytoplasmto the ribosome's

Translation To translate Englishinto Chineserequires aninterpreter.

Some person mustrecognize theworlds of onelanguage andcovert them intothe other.

tRNA Transfer RNA

The cellsinterpreter

tRNA translated thethree-letter codonsof mRNA to theamino acids thatmake up protein.

Translation Genetic translationconverts nucleicacid language intoamino acidlanguage.

Codon

The flow ofinformation fromgene to protein isbased on codons.

A codon is a three-base word thatcodes for oneamino acid

Codon

The flow ofinformation fromgene to protein isbased on codons.

Information Flow: DNA to RNA to Protein

Hereditaries Terminology hereditary = derived from parents familial = transmitted in the gametes through

generations congenital = present at birth (not always genetically

determined - e.g. congenital syphilis, toxoplasmosis) ! not all genetical diseases are congenital - e.g.

Huntington disease - 3rd to 4th decade of life

Classification 3 groups of genetic diseases

1. Disorders with multifactorial inheritance(polygenic)

2. Monogenic (mendelian) disorders 3. Chromosomal aberrations

1. Disorders with multifactorialinheritance (polygenic)

influence of multiple genes + environmental factors relatively frequent Diabetes mellitus (see Endocrine pathology) Hypertension (see Circulation) Gout (discussed here + see Crystals) Schizophrenia (Psychiatry) Congenital heart disease - certain forms (see Heart) Some types of cancer (ovarian, breast, colon) (seeNeoplasms) often familial occurrence - probability of disease is in 1stdegree relatives about 5-10%; 2nd degree relatives - 0,5-1%

Gout genetically impaired metabolism of uric acid (end

product of purine metabolism) tissue accumulation of excessive amounts of UA

crystals recurrent episodes of acute arthritis - precipitation of

monosodium urate crystals inside the joints formation of large crystalline aggregates - tophi chronic destruction of joints - joint deformity renal injury M>F

Primary gout (90% of cases) unknown enzymatic defect

Secondary gout (10%) known cause of hyperuricemia (increasedturnover of nucleic acids - e.g. leukemias;chronic renal disease; increased intake -game, red wine)

Morphology Acute arthritis any joint, mostly hallux - abrupt and intense pain reason??? - lower temperature? Chronic arthritis permanent precipitation - tophi - inflammation(lymphocytes, histiocytes) destruction of cartilage, fibrosis of synovialmembrane, ankylosis Kidneys - 3 forms medulla (papillae), tophi, kidney stones

tophi are formed in the vicinity of joints, bursa olecrani, bursapreapatellaris, auricle less frequently kidneys, other tissues urate crystals are soluble in water! - fixation in absolute alcohol(biopsy!!!) turns polarized light patients with gout - obese, increased risk of hypertension,arteriosclerosis Clinical presentation - 3 stages 1. asymptomatic hyperuricaemia 2. acute arthritis - attacks of acute pain (days-weeks), silentperiods (months-years) 3. chronic changes - tophi, ankylosis, in 20% chronic renalfailure

2. Monogenic (mendelian) disorders mutation of 1 gene, mendelian type ofinheritance

today about 5000 diseases Autosomal dominant Autosomal recessive X-linked

Autosomal dominant disorders both homozygotes and heterozygotes areaffected

usually heterozygotes (inherited from oneparent)

both males and females are affected transmission from one generation to the other 50% of children are affected

Familial hypercholesterolemia (= subgroup of hyperlipoproteinemia) most frequent mendelian disorder - 1:500 mutation of gene encoding LDL-receptor (70% of plasmacholesterol) heterozygotes 2-3 elev. of plasma cholesterol levels homozygotes 5 elevation of plasma cholesterol levels heterozygotes asymptomatic until adulthood - xanthomasalong tendon sheets, coronary AS homozygotes - xanthomas in childhood, death due to MI bythe age of 15Y

Marfan syndrome French pediatrician Marfan - 1896 - young girlwith typical habitus

abnormal protein fibrillin - secreted byfibroblasts, part of ECM

impairment of collagenous and elastic tissue -decreased firmness of connective tissue

principal clinical manifestations - 3 systems

1. skeleton slender, elongated habitus long legs, arms and fingers (arachnodactyly) -El Greco!

high, arched (Gothic) palate hyperextensibility of joints spinal deformities, pectus excavatum, pigeonbreast - pres. Lincoln???

2. ocular changes dislocation or subluxation of the lens(weakness of suspensory ligaments)

3. cardiovascular system fragmentation of elastic fibers in tunica media

- aorta aneurysmal dilatation - aortic dissection -

rupture (35-45% of pts.) incompetence (dilatation) - aortic valve tricuspidal and/or mitral valve - floppy valve

Ehlers-Danlos syndrome similar to Marfan syndrome genetic defect of collagen fibrils - several types- both autosomal dominant and recessive

hyperextensibility of skin, hypermobility ofjoints - contortionist!

joint dislocations, vulnerability rupture of large vessels, colon, cornea

2. Autosomal recessive majority of mendelian disorders only homozygotes are affected, heterozygotes

(parents) are only carriers 25% of descendants are affected if the mutant gene occurs with low frequency - high

probability in consanguineous marriages onset of symptoms often in childhood frequently enzymatic defect testing of parents and amnial cells

Cystic fibrosis 1:2000 live births - most common lethal genetic

disease in white population defect in the transport of chloride ions across

epithelia - increased absorption of Na+ and water tothe blood

widespread defect in the exocrine glands -abnormally viscid mucous secretions

blockage of airways, pancreatic ducts, biliary ducts

Pancreatic abnormalities (85%) - dilatation ofducts, atrophy of exocrine part, fibrosis Pulmonary lesions - dilatation of bronchioles,mucus retention, repeated inflammation,bronchiectasis, lung abscesses, emphysema andatelectasis (100%), cor pulmonale chronicum GIT - meconium ileus (newborns) (25%), biliarycirrhosis (2%) Male genital tract - sterility (obstruction of vasdeferens, epididymis, seminal vesicles) (95%)

Clinical symptomatology recurrent pulmonary infections pancreatic insufficiency, malabsorption syndrome

(large, foul stool), hypovitaminosis A, D, E, K, poorweight gain

high level of sodium in the sweat - "salty" children -mother's diagnosis

death usually in 3. decade due to respiratory failure

Phenylketonuria (PKU) absence of enzyme phenylalanine-hydroxylase (PAH) Phe ->Tyr increase of plasmatic Phe since birth - rising levels - impairsbrain development after 6M - severe mental retardation - IQ under 50 decreased pigmentation of hair and skin - absence of Tyr EARLY SCREENING TEST!!! DIET!!! mothers with PKU - increased levels of Phe - transplacentaltransport - child with severe mental defect (althoughheterozygous!) - maternal PKU - DIET!!!

Galactosemia defect of galactose metabolism lactose -> Gal+Glc Gal -> Glc - defect - accumulation of Gal in blood liver, eyes, brain are affected hepatomegaly (fatty change - fibrosis - cirrhosis) lens - opacification - cataracts brain - loss of neurons, gliosis, edema Symptomatology - from birth vomiting, diarrhea, jaundice, hepatomegaly later - cataracts, mental retardation DIET!

Glycogen storage diseases(glycogenoses)

deficiency of any one of the enzymes involved indegradation or synthesis depending on the type of defect - tissue distribution,type of accumulated product 12 forms - most important: type I. - von Gierke disease - hepatorenal type type II. - Pompe disease - generalized type (liver,heart, skeletal muscle) type V. - McArdle syndrome - skeletal muscle only biopsy: PAS, Best's carmine

Lysosomal storage diseases defect of lysosomal enzymes, hydrolyzingvarious substances (a.o. sphingolipids,mucopolysacharides) - storage of insolublemetabolites in lysosomes

extremely rare

Sphingolipidoses more frequent in Ashkenazi Jews

Gaucher disease defect of glucocerebrosidase - 3 types (type 1- survival, type 2 - lethal, type 3 -intermediate)

accumulation of glucocerebroside (Glc-ceramide) - kerasin

Gaucher cells - spleen (red pulp), liver(sinuses), bone marrow

Niemann-Pick disease defect of sphingomyelinase accumulation of cholesterol andsphingomyelin in spleen, liver, BM, LN, lungs -massive visceromegaly

CNS (foamy cells) - severe neurologicaldeterioration

death during first 4-5 years

Tay-Sachs disease (gangliosidosis)

neurons and glial cells of CNS - mentalretardation, blindness

Mucopolysacharidoses MP synthesized in the connective tissue by fibroblasts -part of the ground substance several clinical variants (I-VII) involvement of liver, spleen, heart (valves, coronaryarteries), blood vessels Symptoms: coarse facial features (gargoylism), cloudingof the cornea, joint stiffness, mental retardation usually death in childhood (cardiac complications) most frequent Hurler syndrome and Hunter syndrome(X-linked!)

X-linked diseases transmitted by heterozygous mother to sons daughters - 50% carriers, 50% healthy sons - 50% diseased, 50% healthy Children of diseased father - sons are healthy, all

daughters are carriers Hemophilia A (defect of Factor VIII) Hemophilia B (defect of Factor IX) Muscle dystrophy (Duchen disease)

3. Chromosomal aberrations(cytogenetic disorders)

alternations in the number or structure of chromosomes autosomes or sex chromosomes studied by cytogenetics cell cycle arrested in metaphase (colchicin) - staining by

Giemsa method (G-bands) - photographing - karyotype 2 sets of 23 chromosomes 22 pairs of autosomes, 2 sex chromosomes (XX or XY) cytogenetic disorders are relatively frequent! (1:160

newborns; 50% of spontaneous abortions)

Numerical abnormalities euploidy - normal 46 (2n) polyploidy (3n or 4n) - spontaneous abortion aneuploidy trisomy (2n+1) - 47 - compatible with life monosomy (2n-1) - autosomal - incompatible

with life - sex chromosomal -

compatible with life

Structural abnormalities breakage followed by loss or rearrangement deletion, translocationGenerally: loss of chromosomal material is more dangerous thangain abnormalities of sex chromosomes are better toleratedthan autosomal abnormalities of sex chromosomes sometimessymptomatic in adult age (e.g. infertility) usually origin de novo (both parents and siblings arenormal)

Autosomal disordersTrisomy 21 (Down syndrome) most frequent - 1:700 births; parents havenormal karyotype

maternal age has a strong influence: 45 y. 1:25 live births

most frequently is abnormality in ovum (ovumis under long-time influence of enviroment)

Clinical symptoms mental retardation (IQ 25-50) flat face + epicanthus congenital heart defects neck skin folds skeletal muscle hypotonia hypermobility of joints increased risk of acute leukemias mortality 40% until 10Y (cardiac complications)

Less frequent disorders

Trisomy 18 (Edwards syndrome) 1:8000 Trisomy 13 (Patau syndrome) 1:15000

Sex chromosomal disorders a number of karyotypes from 45(X0) to 49(XXXXY) - compatible with survival

normally - in females 1 of X is inactivated (allsomatic cells contain Barr body)

! male phenotype is encoded by Y

Klinefelter syndrome (47, XXY) 1:1000 males additional X is either of paternal or maternal origin advanced maternal age, history of irradiation ofeither of parents wide range of clinical manifestations distinctive body habitus - increase length betweensoles and pubic bone reduced body and facial hair gynecomastia testicular atrophy - impaired spermatogenesis -sterility (rarely fertility! - mosaics)

Turner syndrome (45, X0) 1:3000 females primary hypogonadism in phenotypic female growth retardation (short stature, webbing ofthe neck, low posterior hairline, broad chest,cubitus valgus)

streak ovaries - infertility, amenorrhea,infantile genitalia, little pubic hair

Prenatal diagnostics amniocentesis - analysis of amniotic fluid cytogenetic analysis (karyotype - e.g. Down) biochemical activity of various enzymes (e.g. Tay-

Sachs) analysis of various specific genes (CF gene - PCR) sex of the fetus (X-linked disorders - hemophilia)

Pediatric diseases infants and children first year of life - high mortality highest mortality - neonatal period (first 4W;perinatal first 1W)

between 1Y and 15Y of age - the leading causeof death = injuries from accidents

Congenital malformations structural defects present at birth - some may

become apparent later! etiology is either genetic or environmental viral infections (rubella, CMV) - during first 3M other infectious (toxoplasmosis, syphilis, HIV) drugs (thalidomide, alcohol, cytostatics) irradiation in 40-60% is the cause unknown!

Perinatal infections

ascending (transcervical) - in utero orduring birth (HSV, HIV)

transplacental - syphilis, toxoplasmosis,rubella, CMV

Prematurity higher morbidity and mortality than in full term babies before 37.-38. W high risk - weight

Tumors benign vs. malignant benign (hemangioma - nevus flammeus - portwine stains, lymphangioma - hygroma collicysticum, sacrococcygeal teratoma)

malignant (hematopoietic - malignantlymphomas, leukemias - see Hematopathology;neurogenic (neuroblastoma, Ewing sarcoma,primitive neuroectodermal tumor - PNET, CNS-medulloblastoma), sarcomas (rhabdo-, osteo-),kidneys (Wilms' tu), thyroid (papillary ca)

A congenital anomaly is a structuralabnormality of any type that is present atbirth.

Congenital anomalies may be induced bygenetic or environmental factors. Mostcommon congenital anomalies, however, showthe family patterns expected of multifactorialinheritance (determined by a combination ofgenetic and environmental factors).

About 3% of all liveborn infants have anobvious major anomaly.

The incidence is about 6% in 2-year-oldsand 8% in 5-year-olds.

Congenital anomalies may be single ormultiple and of minor or major clinicalsignificance.

During the first 2 weeks of development,teratogenic agents usually kill the embryo orhave no effect.

During the organogenesis period (3rd 8thweeks), teratogenic agents disruptdevelopment and may cause major congenitalanomalies.

During the fetal period (9th week 9thmonth) teratogens may producemorphological and functional abnormalities,particularly of the brain and eyes.

Causes of congenital anomalies

1-Genetic factors such as chromosomalabnormalities and mutant genes.

2-Environmental factors e.g.: themother had German measles in earlypregnancy will cause abnormality inthe embryo.

3-Combined genetic and environmentalfactors (mutlifactorials factors).

Types of abnormalities1-Malformations: this occurs during the formation

of the structures of the organ (duringorganogenesis) results in partial or complete nonformation or alterations in the normal structure.This occurs in the 3rd to the 8th week of gestation.Ex. Cleft lip and or cleft palate.

2-Disruptions: results in morphological change ofthe already formed structure due to exposure todestructive process. e.g.: vascular accidentsleading to intestinal atresia, amniotic banddisruption.

3-Deformations: due to mechanical forces thataffect a part of the fetus over a long period. Ex:talipes equinovarus deformity.

4-Syndrome: is a group of anomalies occurringtogether due to a common cause .

The genetic factors leading to congenitalanomalies may be due to chromosomalabnormalities, gene mutations or may bemultifactorial.

Chromosomal abnormalities occur due to:- late maternal age at the time of

pregnancy(leads to chromosomal non-disjunction),- radiation (causes chromosome deletions,translocations or breaks),- viruses as German measles,- autoimmune diseases,- and some chemical agents as anti-mitotic drugs.

- Chromosomal abnormalities are classified into numerical andstructural.

Numericalchromosomal anomaliesare divided into:1- polyploidy as triploidy ( a fetus

with 69 chromosomes) andtetraploidy where the fetus has 92chromosomes. Polyploidy leads tosevere congenital anomalies andearly abortion.

2- Aneuploidy (one or more chromosomes is added ormissed) as in:Down syndrome (trisomy 21),

Edward syndrome (trisomy 18), Patau syndrome (trisomy 13),

Turner syndrome ((45,X or a female missing one X), andKlinefelter syndrome (47,XXY or a male person with an extra Xchromosome).

Structural chromosomal anomaliesinclude chromosomal deletion,duplication, translocation, inversion, ring and iso chromosomes.

It may also lead to severe congenitalanomalies or fetal death.

Environmental factors1) Infectious Agents:1-Infectious agents include a number of viruses: Rubella used to be a major problem. It causescataract, glaucoma, heart defects and deafness. Cytomegalovirus :The infection is often fatal and ifnot meningoencephalitis produce mentalretardation. Herpes simplex, varicella and humanimmunodeficiency viruses are other examples.2- Toxoplasmosis3- Syphilis : leads to congenital deafness and mentalretardation.

Environmental factors Cont.2)Radiation :Ionizing radiation kills rapidly proliferating cells, producing any

type of birth defect depending upon dose and stage ofdevelopment. Ex. Atomic bomb on Hiroshima and Nagasaki.

Exposure of the pregnant woman to a large dose of x- ray canlead to microcephaly, spina bifida or cleft palate.

Environmental factors Cont.3) Chemical agents:There are many dangerous drugs, if have given to thepregnant female, can produce congenital anomalies. Ex.:- Thalidomide (antinauseant sleeping pills) produce limbdefects (phocomelia) and heart malformations.- Diphenylhydantoin produce facial defects and mentalretardation. Tetracycline (bone and teeth anomalies) Aspirin may cause harm in large doses. Cocaine cause birth defect possibly to its effect as avasoconstrictor that cause hypoxia. Alcohol cause fetal alcohol syndrome.

Environmental factors Cont.5)Hormones: Androgenic agents (synthetic progestin to prevent

abortion) cause masculinization of the genitalia offemale embryos.

Endocrine hormones as Diethylstilbestrol causemalformation of the uterus, uterine tubes, upper vagina,vaginal cancer and malformed testes.

Insulin which treat diabetes of the mother congenitalanomalies.

Cortisone (in large doses) may cause cleft palate.

Environmental factors Cont.6)Maternal Disease: Diabetes cause variety of malformations asheart and neural tube defects.

7)Nutritional deficiency: particularly vitaminsdeficiency.

8)Heavy metals: Eg: organic mercury.

PRENATAL DIAGNOSISMethods of prenatal diagnosis are divided into invasive and non-invasivetechniques.Technique Time Disorders diagnosed

(in weeks)A. Non-invasive:Maternal serum screen:Alpha feto protein (AFP) 16 Neural tube defects (NTD)Triple test 16 Down syndromeUltrasound 18 Structural defects in many

organs as CNS, heart,kidney, and limbs.

B. Invasive:- Amniocentesis 14-16 Chromosomal and metabolic

abnormalities, and DNAanalysis.

- Chorionic villus sampling 10-12 As amniocentesis.- Fetal blood sample near term As amniocentesis + blood

disorders.

Technique of amniocentesis

Technique of CVS

U/S showing polydactyly

U/S showing micrognathia

U/S showing Umibilical hernia (associated with Trisomy 18 in 50% of cases)

Fetal therapy The fetus during intrauterine life can receive treatment such as:1- Fetal transfusion (administration of blood transfusion to the

anemic fetus in thalassemia).2- Medical treatment of thyroid dysfunction or congenital adrenal

hyperplasia of the fetus.3- Fetal surgery: is possible due to advanced ultrasound and surgical

procedures eg: repair of hernia of the fetus or in case ofhydrocphalus.

4- Stem cell transplantation (adults, in TDC Surabaya) and genetherapy: it is possible to transplant stem cells before 18 weeks ofgestation of the fetus without rejection because theimmunocompetence of the fetus doesnt develop yet.