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Disorders of Cellular DevelopmentGenes and Genetic Disorders

University of San Francisco

Dr.M.Maag©2003 Margaret Maag

Class 1 ObjectivesClass 1 Objectives

• Upon completion of this lesson, the student will be able toß identify the basic cellular processes, which influence

our health.ß compare and contrast cellular adaptation processes.ß describe the processes associated with aging and list

the current theories.ß determine syndromes associated with chromosomal

defects.ß explain the difference between autosomal dominant

and recessive defects.

Cellular Reproduction

• Meiosis: formation of gametes– Sperm and egg cells

• Mitosis: nuclear division of somatic cells– A two-phase process:

• cellular division• cytokinesis: cytoplasmic division

• Before cell divides it has an “interphase” or “growthphase”

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Somatic Cell Cycle

• Four phases– S phase = DNA synthesis– G2 phase = RNA and protein synthesis– M phase = mitosis (nuclear and cytoplasmic

division)– G1 phase = the time between M phase &

DNA synthesis• See Fig. 1-23 McCance & Heuther (2002)

p. 25– Time: 12 to 24 hours

Do you know?

• Which adult cells do not replicate and divide?– Nerve cells– Lens cells of the eye– Muscle cells

• Which adult cells do replicate and divide?– Epithelial cells: rapidly (< 10 hrs.)– Intestinal– Lung– Skin

• Clinical implications?

Do you know?

• During which phase of pregnancy are fetal cells mostvulnerable to injury?

• Pre-Embryonic = 0 - 3 weeks– teratogens cause spontaneous abortion

• Embryonic = 3 - 8 weeks• all organ systems are formed• angiogenesis: CVS activates pump at 3rd week• critical period for morphogenesis• teratogens cause major congenital anomalies

• Fetal = 9 - 40 weeks• period of rapid growth

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See McCance & Huether Table 1-4p.26

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What Stimulates Cell Division?• “Social control genes” and protein growth factors

– Survival of the whole organism vs. survival or growth ofindividual cells

• Chemical signals, or “growth factors,” such ascytokines (peptides)– Relay messages within and between the cells– Epidermal growth factor– Insulin-like growth factor

• Clinical implications?

Cellular Adaptationsß Atrophy = decrease in cell size & proliferation• Hypertrophy = increase in cell size• Hyperplasia = increase in rate of cell division• Dysplasia = abnormal shape, size,and

organization• Metaplasia = reversible replacement of one

cell with another

Cellular Injury

• Can occur d/t hypoxia, toxins, or infections– Hypoxia: a result of ischemia (decreased

blood supply)• Low oxygen environment• Low hemoglobin or RBC• Oxidative enzymes (e.g. cytochomes)

– Anoxia: no oxygen at all– Injury d/t extreme energy sources or

chemical agents

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Cellular Injury

• Assessment:– Fever d/t PGEs and TNF

– Tachycardia d/t fever

– Pain d/t obstructions, pressure, bradykinins

• Increased cellular enzymes in blood– LDH, CK, ALT, AST, Amylase, Aldolase,

Alkaline Phosphate

Cellular Death

• Common clinical types:– Gangrene d/t severe hypoxia

• Dry, Wet, or Gas

– Fat: seen in the breast

– Caseous: seen in TB with granuloma

– Liquefaction: seen in the brain

– Coagulation: inside the heart

Necrosis

• Necrotic cell death occurs when injurious stimuli tothe cell are too intense or prolonged

• ‘Severe injury’ induced cell death initiated byinflammatory cytokines– stimulates immune & inflammatory response

– characterized by cellular swelling

– due to prolonged hypoxia or infection

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Apoptosis“A Dropping Off ”

• Important programmed capacity of genome to inducecell suicide and the elimination of ‘unwanted’ cells– e.g. preneoplastic, aged or damaged cells– Unlike necrosis; affects scattered single cells

• Controlled by intrinsic cellular mechanisms or byextra-cellular signals– Hormones, UV Radiation, Chemotherapy, Viruses– Pharmacological blockade of the calcium channels (e.g.

Nifedipine) can inhibit apoptosis

Aging• Developmental, irreversible, and a universal

programmed process on the cellular & molecularlevel– Atrophy of skeletal muscle– Loss of “elastin”– Decreased immunity, increased autoimmunity

• Aging does not always equal pathology– Primary vs. Secondary Aging

• Life span today is between 80-100 years• Women tend to outlive men

Theories

• Longevity and health between– Genetic– Sex hormones– Social Class

• General Categories of Aging– Damage accumulation– Genetic control of human lifespan

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Basics Of Genetic Inheritance

• DNA & RNA are genetic blueprints for celldevelopment

• Both are nucleic acids• What is the action of DNA vs. RNA?• DNA carries genetic code & is mainly found in the

nucleus & mitochondria• RNA transcribes genetic code from DNA & carries

the code to the cell’s cytoplasm.• RNA makes proteins

RNA

• http://www.nytimes.com/packages/html/science/20030121_RNA/sci_RNA_01.html

How Do Chromosomes Interact?

• 22 pairs of autosomes (haploid)

• Plus 1 pair of gametes– (sperm and egg cells)– (xx or xy)

• 44 + 2 = 46 (diploid)

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Plain Genetics!

A B A B

A A B A

A B B B

Male Female

A = Recessive B = Dominant

Eye Color

• http://www.athro.com/evo/gen/genefr2.html

Principle of Dominance

• One gene may “mask” another gene when the 2 are foundtogether on a heterozygote

• The “dominant” gene’s characteristics are observable

• The concealed gene is called “recessive”

• Genes for a “recessive” occur in heterozygotes who carry1 copy of the gene, but do not express the disease.

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Normal Female Karotype

Normal Male Karotype

Chromosomal Defects

• Causes miscarriages (1 in 12 conceptions and 50% offirst trimester spontaneous abortions)

• Turner’s Syndrome: 1: 2,500 births; females with shortstature (4ft, 8”); abnormal sexual development;intelligence not effected

• Klinefelter’s Syndrome:1:500 BIRTHS Tall stature;delayed puberty; (47: xxy); moderate mentalimpairment; small firm testes; gynecomastia

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Turner’s Syndrome

Kleinfelter’s Syndrome

Autosomal Dominant Defects

•• HuntingtonHuntington’’s Choreas Chorea– Abnormal motor function as a result of degeneration

of the basal ganglia & cortical neurons

– 1:10,000; occurs in middle adulthood

– Defective gene inherited from one parent

– http://www.kumc.edu/hospital/huntingtons/

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Autosomal Dominant Defects

• Marfan Syndrome: genetic disorder affecting theconnective tissue

• Chromosome 15: “Fibrillin gene” is affected– skeleton, lungs, eyes, heart and blood vessels can be

affected

– 200,000 in USA

– 25% of the cases are “de novo” cases

– 50:50 chance of passing it on to offspring

Autosomal Recessive Defects

• Largest category of mendelian disorders

•• Cystic FibrosisCystic Fibrosis: : 1: 2,500 WHITES IN U.S.;abnormal sodium transport fi airway & pancreaticduct obstruction

•• Sickle Cell DiseaseSickle Cell Disease 1: 400 African Americans

•• PKUPKU:: 1:12,000 worldwide; Lack enzyme to convertphenylalanine to tyrosine; can lead to mentalretardation; screened at birth: Guthrie’s test

Hematological SlideSickle Cell

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Sex-Linked Defects

•• Hemophilia Hemophilia ““AA””:: X-linked recessive disorder resulting from an error in thegene coding for coagulation factor 8– boys inherit defective gene on the X chromosome from mother– mother is heterozygous for disorder (without symptoms)– spontaneous bleeding after a minor wound– BLEEDING INTO JOINTS CAUSING PAIN & DISABILITY– factor 8 replacement: frozen plasma concentrate

• Hemophilila “B”: X-linked disorder– lack of factor 9

Sex Genetics!

X Y X X

X X X Y

X Y X X

Male Female

e.g. Hemophilia A

Sex-Linked Defects

•• DuchenneDuchenne’’s muscular dystrophys muscular dystrophy: : a defect in a single protein in

the muscle fibers

• Causes progressive muscle weakness fi muscle cells breakdown

& are lost

• Is seen before age 11

• Mainly males

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See McCance & Huether Table 1-4p.26

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What Stimulates Cell Division?• “Social control genes” and protein growth factors

– Survival of the whole organism vs. survival or growth ofindividual cells

• Chemical signals or “growth factors” such ascytokines (peptides)– Relay messages within and between the cells– Epidermal growth factor– Insulin-like growth factor

• Clinical implications?

Case StudyA 6-month old is admitted to the ER with adiagnosis of recurrent pneumonia. The nursenotes a resp. rate of 50, heart rate of 170, andtemperature of 102 F. The client is retractingsubsternally with bilateral wheezes andrhonchi. The mother states that this is herson’s 3rd admission since birth forpneumonia. She also mentions that he hasn’tbeen gaining weight liker her older child had a6-months of age.

NCLEX Questions

1. A child with progressive cystic fibrosis for 2years is in the ER with significantrespiratory distress. What physicalcharacteristics would the nurse anticipate tosee in this client?

a) Low-set earsb) Gray appearancec) Clubbed fingernailsd) Jaundice

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NCLEX Question

2. The nurse involved in genetic counseling for the family of amother with Huntington’s Disease is asked if they have achance of developing the same disease process? What wouldbe the nurse’s best response?

a. If the mother alone has the disease, they have a 2:4 chanceof inheriting the disease.

b. Both parents must have the disease for the offspring to inheritthe disease.

c. The disorder is a spontaneous disruption of theneurotransmitters with no inheritance principles.

d. If the mother has the disease, they a 1:4 chance of inheritingthe same disorder.

NCLEX Question

3. Which response is best when a nurse is asked by afamily member why a client with Huntington’sChorea would be given thickened liquids?

a. The client is at risk for dehydration.

b. The client is at risk for aspiration.

c. The client may have difficulty chewing.

d. The client may have pain on swallowing.

References• Hansen, M. (1998). Pathophysiology:

Foundations of disease and clinicalintervention. Philadelphia, PA: Saunders.

• Hogan, M., & Hill, K. (2004). Pathophysiology:Reviews and rationales. Upper Saddle River:New Jersey, NJ: Prentice Hall.

• Huether, S. E., & McCance, K. L. (2002).Pathophysiology. St. Louis, MO: Mosby.