GENETIC ABNORMALITY.pptx

8/14/2019 GENETIC ABNORMALITY.pptx

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Dr. Triwani, M.Kes


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Mendel did not know what the physicalproperties of his particles were when heproposed his laws of inheritance.

August Weismann suggested thatchromosomes (discovered in 1882) werethe location of hereditary material.

Genes are located on chromosomes The idea that genes are located onchromosomes is known as thechromosome theory of inheritance.


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The physical location of a gene on achromosome is called a locus.

Chromosomes that pair duringmeiosis and contain the same geneloci and structure are calledhomologous chromosomes.

See Figure below for a diagram ofhomologous chromosomes.


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Chromosomes that determine gender are called sexchromosomes; all other chromosomes are calledautosomes.

Autosomes are homologous pairs.

Sex chromosomes can be homologous or non-homologous pairs (see Figure 13.2). Sex determination in humans Human females have two X chromosomes, and all their

gametes contain one X chromosome. Human males have one X and one Y chromosome; half

their gametes contain an X chromosome, and the otherhalf contain a Y chromosome.

The chromosome carried by the sperm determines sexin humans.

Genetic anomalies such as XY females and XX males canoccur because of chromosomal mutations.


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Crossing-over disrupts genetic linkage If the linkage between two genes on a

chromosome were complete, all offspringwould be of a parental type.

Morgans experiments showed that completelinkage was not occurring as a result of thepresence of nonparental genotypes (see Figure13.3).

To explain the appearance of nonparental

genotypes in linked genes, Morgan proposedthat genes are physically exchanged betweenhomologous chromosomes during meiosis.


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The exchange of genes betweenhomologous chromosomes is calledcrossing-over (see Figure 13.4).

Genes that are far from each other ona chromosome are more likely to beseparated by crossing-over than aregenes that are close to each other.

Genes that are very distant from oneanother on a chromosome will assortindependently.


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1)Single gene disorders autosomal dominan autosomal ressif X-linked2) Chromosomal abnormalities3) Common disorders with appreciable geneticcomponent/multifactorial4) Congenital malformations


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Autosomal traits the genetic informationfor the trait is found on chromosome 1-22,not on one of the sex chromosomes Autosomal disorders may be:

Recessive Co-dominant blood type Dominant


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Several thousand human geneticdisorders are inherited as recessivecharacters, most of which are causedby recessive mutations of genes onautosomes (Figure 13.6).

For genetic disorders caused by arecessive allele (a), only homozygous(aa) individuals get the disease.


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Heterozygous individuals (Aa) are calledcarriers because they have one copy ofthe disease-causing allele but do not get

the disease. If two carriers of a recessive geneticdisorder (Aa) mate, there is a 25 percentchance that their offspring will get the

disease (see Figure 13.7). If a genetic disorder is dominant (A), thenAA and Aa individuals are symptomaticfor the disease.


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Either parent can carry the recessiveallele on an autosomal chromosome. Heterozygotes are symptom-free;homozygotes have the disorder.

Two heterozygous parents have a 25percent chance of producing a childwith the disorder.

When both parents are homozygous,all children can be affected.


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More than 2 alleles for a given trait Some versions of the gene aredominant over others But they are not dominant over all ofthe alleles

Both dominant alleles are expressed inheterozygotes


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There are 3 alleles for blood type A (IA) and B (IB) are co-dominant Both A and B are dominant over type O

blood Writing alleles for blood type

A = IA B = IB O = i


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X-linked: genetic information for the traitis located on the X chromosome no genetic info about the trait on theY chromo Examples: Hemophilia, colorblindness, Duschenne musculardystrophy

Y-linked (not many known) Allele for hairy ears is Y-linked


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Genes located on the X or Ychromosome are called sex-

linked. Genes on the X chromosome arecalled X-linked.


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Males are more likely thanfemales to have recessive X-

linked genetic disorders, becausethey need to inherit only one copyof the disease-causing allele to beaffected.


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hereditary = derived from parents familial = transmitted in the gametesthrough generations congenital= present at birth (notalways genetically determined - e.g.congenital syphilis, toxoplasmosis) not all genetical diseases arecongenital - e.g. Huntington disease -3rd to 4th decade of life


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3 groups of genetic diseases1. Disorders with multifactorialinheritance (polygenic)2. Monogenic (mendelian) disorders3. Chromosomal aberrations


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influence of multiple genes +environmental factors relativelyfrequent Diabetes mellitus Hypertension Gout (discussed here + see Crystals) Schizophrenia (Psychiatry)


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Congenital heart disease - certainforms (see Heart) Some types of cancer (ovarian, breast,colon) (see Neoplasms)

often familial occurrence - probabilityof disease is in 1stdegree relativesabout 5-10%; 2nddegree relatives -0,5-1%


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mutation of 1 gene, mendeliantype of inheritance today about 5000 diseases Autosomal dominant Autosomal recessive X-linked


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both homozygotes and heterozygotesare affected usually heterozygotes (inherited fromone parent)

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


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(= subgroup ofhyperlipoproteinemia) most frequent mendelian disorder -1:500

mutation of gene encoding LDL-receptor (70% of plasma cholesterol) heterozygotes 2-3 elev. of plasmacholesterol levels


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homozygotes 5 elevation ofplasma cholesterol levels heterozygotes asymptomatic untiladulthood - xanthomas alongtendon sheets, coronary AS homozygotes - xanthomas inchildhood, death due to MI by theage of 15Y


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French pediatrician Marfan - 1896 - younggirl with typical habitus abnormal protein fibrillin - secreted byfibroblasts, part of ECM impairment ofcollagenous and elastic tissue - decreasedfirmness of connective tissue

principal clinical manifestations - 3systems


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slender, elongated habitus long legs, arms and fingers(arachnodactyly) - El Greco high, arched (Gothic) palate hyperextensibility of joints spinal deformities, pectusexcavatum, pigeon breast - pres.Lincoln???


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dislocation or subluxationof the lens (weakness ofsuspensory ligaments)


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3. cardiovascular system

fragmentation of elastic fibers intunica media - aortaaneurysmal dilatation - aortic

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


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similar to Marfan syndrome genetic defect of collagen fibrils -several types - both autosomaldominant and recessive

hyperextensibility of skin,hypermobility of joints - contortionist joint dislocations, vulnerabilityrupture of large vessels, colon, cornea


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1:2000 live births - most common lethalgenetic disease in white population defect in the transport of chloride ionsacross epithelia - increased absorptionof Na+ and water to the blood

widespread defect in the exocrineglands - abnormally viscid mucoussecretions blockage of airways, pancreatic ducts,biliary ducts


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Pancreatic abnormalities (85%) - dilatationof ducts, atrophy of exocrine part, fibrosis Pulmonary lesions - dilatation ofbronchioles, mucus retention, repeatedinflammation, bronchiectasis, lungabscesses, emphysema and atelectasis(100%), cor pulmonale chronicum

GIT - meconium ileus (newborns) (25%),biliary cirrhosis (2%) Male genital tract - sterility (obstruction ofvas deferens, epididymis, seminal vesicles)(95%)


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recurrent pulmonary infections pancreatic insufficiency, malabsorptionsyndrome (large, foul stool),hypovitaminosis A, D, E, K, poor weightgain

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

death usually in 3. decade due torespiratory failure


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absence of enzyme phenylalanine-hydroxylase(PAH) Phe ->Tyr increase of plasmatic Phe since birth - rising levels- impairs brain development after 6M - severe mental retardation - IQ under 50 decreased pigmentation of hair and skin - absenceof Tyr EARLY SCREENING TEST DIET mothers with PKU - increased levels of Phe -transplacental transport - child with severe mentaldefect (although heterozygous ) - maternal PKU -DIET


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defect of galactose metabolism lactose -> Gal+Glc Gal -> Glc - defect - accumulation of Gal inblood 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


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deficiency of any one of the enzymesinvolved in degradation or synthesis depending on the type of defect - tissuedistribution, type of accumulated product 12 forms - most important: type I. - von Gierke disease - hepatorenaltype type II. - Pompe disease - generalized type(liver, heart, skeletal muscle) type V. - McArdle syndrome - skeletalmuscle only biopsy: PAS, Best's carmine


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defect of lysosomal enzymes, hydrolyzingvarious substances (a.o. sphingolipids,mucopolysacharides) - storage of insolublemetabolites in lysosomes extremely rareSphingolipidoses more frequent in Ashkenazi Jews


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defect of glucocerebrosidase - 3types (type 1 - survival, type 2 -lethal, type 3 - intermediate) accumulation of glucocerebroside(Glc-ceramide) - kerasin Gaucher cells - spleen (red pulp),liver (sinuses), bone marrow


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defect of sphingomyelinase accumulation of cholesterol andsphingomyelin in spleen, liver, BM,LN, lungs - massive visceromegaly CNS (foamy cells) - severeneurological deterioration death during first 4-5 years


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neurons and glial cells ofCNS - mental retardation,blindness


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MP synthesized in the connective tissue byfibroblasts - part of the ground substance several clinical variants (I-VII) involvement of liver, spleen, heart (valves,coronary arteries), blood vessels Symptoms: coarse facial features (gargoylism),clouding of the cornea, joint stiffness, mentalretardation usually death in childhood (cardiaccomplications) most frequent Hurler syndrome and Huntersyndrome (X-linked )


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transmitted by heterozygous motherto sons daughters - 50% carriers, 50% healthy sons - 50% diseased, 50% healthy Children of diseased father - sons arehealthy, all daughters are carriers Hemophilia A (defect of Factor VIII) Hemophilia B (defect of Factor IX) Muscle dystrophy (Duchen disease)


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Inversion Translocation


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Deletion Duplication


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alternations in the number or structureof chromosomes autosomes or sex chromosomes studied by cytogenetics cell cycle arrested in metaphase(colchicin) - staining by Giemsa method(G-bands) - photographing - karyotype


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2 sets of 23 chromosomes 22 pairs of autosomes, 2 sexchromosomes (XX or XY) cytogenetic disorders are relativelyfrequent (1:160 newborns; 50% ofspontaneous abortions)


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Aneuploidy - One extra or one lesschromosome

Polyploidy - Three or more of eachchromosome Nondisjunction causes changes in

chromosome number


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Nondisjunction:

Aneuploidy: Monosomy Trisomy Polyploidy


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euploidy - normal 46 (2n) polyploidy (3n or 4n) - spontaneous

abortion Aneuploidytrisomy (2n+1)- 47- compatible with lifemonosomy (2n-1)

- autosomal - incompatible with life- sex chromosomal - compatible with life


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Down Syndrome - Trisomy 21


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Age ofMother

Frequency of DownSyndrome

30

35

36

37

3839

40

45

1 in 800

1 in 384

1 in 307

1 in 242

1 in 1891 in 146

1 in 112

1 in 32


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Turner Syndrome X0 KlinefeltersSyndrome XXY XYY Condition


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Categories of chromosomeaberrationDeletionDuplication InversionTranslocation


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breakage followed by loss or rearrangement deletion, translocationGenerally: loss of chromosomal material is more dangerous

than gain abnormalities of sex chromosomes are bettertolerated than autosomal abnormalities of sex chromosomes sometimes

symptomatic in adult age (e.g. infertility) usually origin de novo (both parents and siblingsare normal)


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Trisomy 21 (Down syndrome) most frequent - 1:700 births; parentshave normal karyotype maternal age has a strong influence:45 y. 1:25live births most frequently is abnormality inovum (ovum is under long-timeinfluence of enviroment)


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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 (cardiaccomplications)


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


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a number of karyotypes from 45(X0)to 49 (XXXXY) - compatible withsurvival normally - in females 1 of X isinactivated (all somatic cells containBarr body) male phenotype is encoded by Y


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1:1000 males additional X is either of paternal ormaternal origin advanced maternal age, history ofirradiation of either of parents wide range of clinical manifestations

distinctive body habitus - increase lengthbetween soles and pubic bone reduced body and facial hair gynecomastia testicular atrophy - impairedspermatogenesis - sterility (rarely fertility


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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)


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infants and children first year of life - high mortality highest mortality - neonatal period(first 4W; perinatal first 1W) between 1Y and 15Y of age - theleading cause of death = injuriesfrom accidents


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structural defects present at birth - somemay become apparent later

etiology is either genetic or environmental viral infections (rubella, CMV) - during first3M

other infectious (toxoplasmosis, syphilis,HIV) drugs (thalidomide, alcohol, cytostatics) irradiation in 40-60% is the cause unknown


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ascending (transcervical) - inutero or during birth (HSV, HIV)

transplacental - syphilis,toxoplasmosis, rubella, CMV


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The earlier the abortion the more likely to bechromosomal 50% of spontanous abortion are chromosomalabnormal Mostly triploidy. 45 XO, trisomy 16 98% of fetus with turner abort Generally 6/1000 the incidence ofchromosomal abnormalities


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Presence of congenital anomalies45% have minor single anomalies9% 3 minor anomalies1.5% HAVE major anomaly

2 or more major anomalies mayrepresent genetic syndrome orchromosomal abnormalities(10%).


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Incidence 1/700 2/3 of down fetus spontaneously abort Clinical diagnosis depend on gestalt Trisomy 21 in 94% of cases with extrachromosome from mother mostly(95%) Risk correlate with maternal age 40 y/0 1/80

2% are mosaic


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Hypotonia without weakness Clinodactaly protruded tongue,smallears,brachycephaly,small up turnednose, depressed nasal bridge.

Mental retardation, socially do betterwith good environment (Happychildren)


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Cardiac and GI Hypothyriodism Transient leukemoid reaction Alzheimers disease up to 25 over40 y/o Early death relate to cardiacdysfunction


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Incidence 1/8000Overlaps with trisomy 13Sever Mental retardation>90% dead in 1styear


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Small face with prominant occiput Small sternum and pelvis Flexion deformity of the finger VSD and horseshoe kidney


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Complete extra set of chromosomes Mostly miscarriages Fetal wastage skeleton more thancephalic, 2% survive to be recognized

Large hydatidiform placenta VSD, ASD, Syndactaly Genital and CNS abnormalities


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Severe developmetal retardation Incidence 1/20000 90% dead in the 1styear


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Midline brain defectMalformed earMicroophalmos and colobomaScalp defect


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Congenital abnormalities include severemental retardation, seizures,microcephaly, scalp defects (absent skin),microphthalmia, cleft lip and/or palate,hypotelorism, simian crease, extra digits


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Characterized by short stature and the lackof sexual development at puberty
http://medgen.genetics.utah.edu/photographs/diseases/high/611.gif


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Normal IQ scale with difficulty inspatial orientation such as map Present with short stature or delaysex maturation

Hormonal therapy


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20% of aspermic adult male(blocked spermatogenesis 47 XXY in 80% and mosaic in 20% IQ is 98 (normal) with milddecrease in verbal IQ Scoliosis, decrease libido mayimprove with testesterone,gynecomastia


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Moderate to severe mental retardation Speech delay, short attention,hyperactivity Poor motor coordination andmouthing objects Poor socialization, temper tantrum Mood disorder (bipolar),schizophrenia


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Long protruding ears Long face and prominent jaw Flattened nasal bridge High arch palate Macroorchidism Genetic is complex, 80%penetration in male and 30%penetration in female


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Means: as genomes pass throughmeiosis it is normal for part of it tochange. During meiosis inactive Xchromosome become active andchanges on fragile X gene(imprinting) make it malignant


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Severe mental retardation Inappropriate laughter Decrease pigmentation of choroid or iris(pale blue eyes)

Ataxia and jerky eye movement Sever speech proplem Deletion of 15q11q13, maternal in origin Paternal uniparental disomy


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(A fat red faced boy in state ofsomnolency) Charles Diickens Early hypotonia Obesity Short stature as adult Almond shaped blue eyes Mental retardation (mild to moderate) Narrow hands

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