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Congenital and Genetic Disorders

BIO 375

Pathophysiology

Review of Genetic Control

Genetic information for each cell is stored on chromosomes:

Each body cell contains 2 sets (diploid) of chromosomes; one inherited from each parent

22 pairs of autosomes1 pair of sex chromosomes (XX or XY)

Karyotype is an arrangement of a cell’s chromosomes based on size and shape

Meiosis reduces the diploid number to haploid (1 set of autosomes + X or Y)

Human Karyotype

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Meiosis and Fertilization

Meiosis reduced the 2n chromosome number or 46 down to n chromosome number of 23.Each ovum (egg) and sperm have 23 chromosomesAll eggs have an X sex chromosomeSperm are either X or YFertilization of an egg by sperm reestablishes the diploid number of 46 and XX (female) or XY (male) sex determination.

Chromosomes and Genes

Each chromosome contains many geneswhich code for traits like hair color or metabolic enzymes.Genes are arranged in a linear fashionHumans have about 22,000 genesEach gene may exist in a population in alternative forms called allelesSome alleles code for faulty or disease causing genes

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Some Terminology

Dominant vs. recessiveGenotype vs. phenotypeHomozygous vs. heterozygousCodominanceIncomplete dominanceMultiple allelesAutosomal vs. sex linked inheritanceSex influenced vs. sex linkedPolygenic (metric) traits

More Terminology

PenetranceExpressivityCarrierAge of onsetTeratogenic agentsDevelopmental disorders

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DNA replication and Mutations

DNA is copied from generation to generation by a process called semi-conservative replicationThis is a highly accurate processEven so, occasionally, a copy error occurs resulting in a mutationMutations can arise by other processesDNA “code” is transcribed to RNA and then translated into protein structures

Gene Inheritance

Genes control:Physical structures, e.g. collagenMetabolic processes, via enzymesPatterns of behavior, e.g. schizophrenia

Both normal and disease causing genes are inherited in predictable patternsGenetic disorders may be:

Single gene traitsMultiple gene traitsDue to chromosomal defects (number or structure)

Examples of Gene Inheritance

Autosomal single gene disorder:PTC taster or cystic fibrosis

Sex linked single gene disorderRed-green colorblindness or hemophilia

Multiple allelesABO blood types

Polygenic traitIntelligence or schizophrenia

Age of onsetTay-Sachs diseaseHuntington’s disease

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Sex influenced traitPattern baldnessBaldness dominant in male heterozygote but recessive in female heterozygote

Lyon Hypothesis (1961)

Named after Mary Frances LyonSuggested that dosage compensation in mammals is by inactivation of all but one X chromosome in cells with more than one X chromosome. Inactivation occurs at about day 16.The Barr body, visible in some female mammalian cells, is an inactivated X chromosome (Murray Barr 1949)

Consequences of X-inactivation

Multisomies are more tolerated in the X-chromosomes than autosomesDosage compensationVariable expression in heterozygous females, e.g. hemophilia A

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Chromosomal number defect

Kleinfelter’s SyndromeXXY 1/1,000 male births

Turner’s Syndrome

Turner’s Syndrome XO (1 in 10,000 female births)Monosomy of sex chromosomes; Almost normal in appearance until pubertyFail to menstruate; secondary sex characteristics fail to developShield chest; webbed neck; short stature

Down’s SyndromeDown’s Syndrome Trisomy21 (1 in 600 births)Epicanthal eye folds; hypotonia of skeletal muscles; small mouth with tongue protrusion commonAtypical palm creases; pubic hair and beards sparse in males; heart malformations and low resistance to disease commonMales infertile; some females fertile; low IQ scores

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Chromosomal structure defect

Cri du chat syndrome (cat cry syndrome) deletion of part of short arm of chromosome 5

Developmental Disorders

May be due to exposure of embryo to negative environmental influences

RadiationAlcohol (fetal alcohol syndrome)Cigarette smoking (low birth weight)DrugsCocaineAbuseMaternal infections (e.g. Rubella)

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Exposure in first two weeks usually results in death of embryoFirst two months most critical

Time of rapid cell divisionTime of organogenesis

There are different critical periods for different systems

Developmental Disorders

Diagnostic tools

Pedigree analysis, e.g. in families where inherited disorders are presentScreening for carriers, e.g. Tay-Sachs

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Diagnostic tools

Amniocentesis, e.g. chromosomal disorders and come gene defectsNeonatal testing, e.g. phenylketonuria