PATHOPHYSIOLOGY Name Introduction to Pathophysiology and Chapter 2 Genetic Diseases PART 1: INTRODUCTION 1. Pathophysiology is the study of the functional changes produced by disease processes. For example: the pathophysiology of insulin dependent diabetes mellitus (IDDM) includes things such as inadequate uptake of glucose into body cells, elevated blood glucose, destruction of tissue capillaries by excessive glucose, ketoacidosis from fat catabolism, and tissue ischemia and necrosis. 2. Homeostasis is one of the most fundamental ideas in physiology. Homeostasis is the maintenance of a constant internal environment, even though external conditions may be continually changing. - It is a state of dynamic equilibrium, where there is constant controlled change. Cells die and are replaced, and there is a constant flux of nutrients and other chemicals, but throughout life, balance is maintained. - Disease upsets homeostasis, and treatment seeks to restore it. 3. Differential diagnosis includes: - Identifying the disease responsible for the observed signs and symptoms, and - Distinguishing that disease from other diseases that may produce similar signs and symptoms. 4. The etiology of a disease includes all the factors that cause the disease. For example: The etiology of Insulin Dependent Diabetes Mellitus (IDDM) is the destruction of beta cells in the pancreas by autoimmune disease, leading to a deficiency of insulin. 5. Prognosis is the outcome that can be expected for persons with a particular disease. - This may include discussion of expected outcomes with and without treatment. - It will also include a description of changes in the quality of life individuals might experience, as well as changes in life expectancy. 6. Symptoms are the characteristics of the disease that are observed by the individual having the disease. - For example, pain is a common symptom of disease. 7. Signs are characteristics of the disease that can be observed by a clinician or can be measured with laboratory tests. - For example, elevated blood glucose cannot be directly felt by the individual, but it can be measured in the laboratory. 8. A case history is the story of a person presenting with a disease. The case history may include family background, signs and symptoms, test results, and clinical observations. 9. Treatment is what is done to cure a disease or to alleviate its symptoms. Since this is a pathophysiology course, and not a clinical course, we will focus on the physiological basis of treatment. In other words, what does the treatment do to restore homeostasis? 10. A sequela is the result or outcome of a disease process or, perhaps, of a treatment. The plural is sequelae. (Don t ask me why sequel and sequels would not suffice, but medical people seem to like it this way!) - For example, among the possible sequelae of diabetes mellitus are: blindness, heart disease, and peripheral neuropathy.
2 PART 2: CHAPTER 2 GENES AND GENETIC DISEASES Review the information at the beginning of Chapter 2. I. DNA Mutation Any inherited alteration of genetic material. A. Chromosome aberrations (see below) - leading known cause of mental retardation and miscarriage. B. Base pair substitution - one base pair is substituted for another C. Frameshift mutation Insertion or deletion of one or more base pairs Causes a change in the entire reading frame The resulting protein sequence will be wrong D. Spontaneous mutation Mutation that occurs in absence of exposure to known mutagens [10-4 to 10-7 /gene/generation] E. Mutational hotspots Areas of the chromosomes that have high mutation rates A cytosine base followed by a guanine is known to account for a disproportionately large percentage of disease-causing mutations F. Mutagen Agent known to increase the frequency of mutations o Radiation o Chemicals II. Chromosomes Somatic cells o Contain 46 chromosomes (23 pairs) o Called diploid cells Gametes o Contain 23 chromosomes - one member of each chromosome pair o Called haploid cells A. Chromosomal Replication 1. Meiosis Formation of haploid cells (23 individual chromosomes) from diploid cells (23 pairs) Occurs in ovaries and testes to form the ova and sperm Two divisions occur, so a total of four daughter cells are formed 2. Mitosis Formation of daughter cells identical to parent (diploid cells) Forms somatic cells
3 B. Autosomes The first 22 of the 23 pairs of chromosomes in males and females The two members are virtually identical and thus said to be homologous C. Sex Chromosomes Remaining pair of chromosomes In females, it is a homologous pair (XX) In males, it is a nonhomologous pair (XY) D. Karyotype Ordered display of chromosomes E. Abnormalities in Chromosome Number 1. Euploid cells have a multiple of the normal number of chromosomes Haploid and diploid cells are euploid forms When a euploid cell has more than the diploid number, it is called a polyploid cell o Triploidy: a zygote having three copies of each chromosome (69) o Tetraploidy: four copies of each (92 total) Neither triploid nor tetraploid fetuses survive 2. Aneuploidy A somatic cell that does not contain a multiple of 23 chromosomes A cell containing three copies of one chromosome is trisomic (trisomy) Monosomy is the presence of only one copy of any chromosome Monosomy is often lethal, but infants can survive with trisomy of certain chromosomes It is better to have extra than less 3. Chromosome Separation a. Disjunction o Normal separation of chromosomes during cell division b. Nondisjunction o Usually the cause of aneuploidy o Failure of homologous chromosomes or sister chromatids to separate normally during meiosis or mitosis 4. Autosomal Aneuploidy Partial trisomy o Only an extra portion of a chromosome is present in each cell Chromosomal mosaics o Trisomies occurring only in some cells of the body o Usually results in a milder form of the disease caused by trisomy of the gene Down syndrome o Best known example of aneuploidy
4 o Trisomy 21 o 1:800 live births o Mentally retarded, low nasal bridge, epicanthal folds, protruding tongue, poor muscle tone o Risk increases with maternal age >35 o Usually caused by nondisjunction in ovum 5. Sex Chromosome Aneuploidy One of the most common is trisomy X. This is a female that has three X chromosomes. Termed metafemales o Symptoms are variable: sterility, menstrual irregularity, and/or mental retardation o Symptoms worsen with each additional X a. Turner syndrome Females with only one X chromosome Characteristics o Absence of ovaries (sterile) o Short stature (~ 4'7") o Webbing of the neck o Edema o Underdeveloped breasts; wide nipples o High number of aborted fetuses o X is usually inherited from mother b. Klinefelter syndrome Individuals with at least two Xs and one Y chromosome Characteristics o Male appearance o Develop female-like breasts o Small testes o Sparse body hair o Long limbs Some individuals can be XXY or XXXY The abnormalities increase with each X F. Abnormalities in Chromosome Structure 1. Chromosome breakage If a chromosome break does occur, physiologic mechanisms will usually repair the break, but the breaks often heal in a way that alters the structure of the chromosome Clastogens o Ionizing radiation, chemicals, and viruses
5 2. Deletions of DNA Cri du chat syndrome o Cry of the cat o Deletion of short arm of chromosome 5 o Low birth weight, mental retardation, microcephaly, and heart defects 3. Duplication - presence of a repeated gene or gene sequence. 4. Inversions - reversal of the gene order; can occur if there are two breaks on a chromosome and the region is reversed during reattachment. Affected individuals usually have no physical defect, but inversions may cause chromosomal aberrations in the offspring of the carrier. 5. Translocations - the interchanging of material between nonhomologous chromosomes. 6. Fragile sites Fragile sites are areas on chromosomes that develop distinctive breaks or gaps when cells are cultured. Fragile X syndrome o Site on the long arm of the X chromosome o Associated with mental retardation; second in occurrence to Down syndrome o Higher incidence in males because they have only one X chromosome III. Genetics A. Terminology 1. Locus - position of a gene along a chromosome 2. Allele - a different form of a particular gene at a given locus Example: Hgb A vs. Hgb S 3. Polymorphism - a locus that has two or more alleles that occur with appreciable frequency 4. Homozygous - loci on a pair of chromosomes have identical alleles Example - O blood type (OO) 5. Heterozygous - loci on a pair of chromosomes have different alleles Example - AB blood type (A and B genes on pair of loci) 6. Genotype ( what they have ) - the genetic makeup of an organism 7. Phenotype ( what they demonstrate ) - the observable, detectable, or outward appearance of the genetics of an organism Example - a person with the A blood type could be AA or AO. A is the phenotype; AA or AO is the genotype. B. Dominance and Recessiveness 1. If two alleles are found together, the allele that is observable is dominant, and the one whose effects are hidden is recessive 2. In genetics, the dominant allele is represented by a capital letter, and the recessive by a lowercase letter 3. Alleles can be codominant (trait is modified by both alleles)
4. Carriers A carrier is someone that has a disease gene but is phenotypically normal 6 For a person to demonstrate a recessive disease, the pair of recessive genes must be inherited Example IV. Single-Gene Disorders o Ss = sickle cell anemia carrier o ss = demonstrates sickle cell disease A. Autosomal Dominant Disorders 1. Abnormal allele is dominant, normal allele is recessive, and the genes exist on a pair of autosomes Example - Huntington disease has a delayed age of onset, so dementia symptoms appear later in life. 2. Recurrence risk - The probability that parents of a child with a genetic disease will have yet another child with the same disease. Recurrence risk of an autosomal dominant trait - when one parent is affected by an autosomal dominant disease and the other is normal, the occurrence and recurrence risks for each child are one half (50%) ACTIVITY 1: Fill in the following Punnett square diagram for the children of a couple in which the woman is genetically normal and the father has the gene for Huntington disease (H), which is autosomal dominant: H h h h Mother's genotype = hh (normal) Father's genotype = Hh (Huntington) What percentage of their offspring will be genotype Hh? Will any of their children be phenotypically normal, but carry the gene for Huntington? (See last page for answers.) 3. Penetrance - the percentage of individuals with a specific genotype who also express the expected phenotype Incomplete penetrance - individual who has the genotype for a disease but does not express it. Retinoblastoma (eye tumor in children) demonstrates incomplete penetrance (90%) 4. Expressivity - the variation in a phenotype associated with a particular genotype This can be caused by modifier genes Example - neurofibromatosis type 1 (von Recklinghausen s disease) o Autosomal dominant o Long arm of chromosome 17 o Disease varies from dark spots on the skin to malignant neurofibromas, scoliosis, gliomas, neuromas, etc.
7 5. Epigenetics Same DNA sequence can produce different phenotypes due to chemical modification that alters expression of genes 6. Genomic imprinting One parent imprints (inactivates) the gene during transmission to offspring B. Autosomal Recessive Disorders 1. Abnormal allele is recessive and a person must be homozygous for the abnormal trait to express the disease 2. The trait usually appears in the children, not the parents, and it affects the genders equally because it is present on a pair of autosomes 3. Recurrence risk of an autosomal dominant trait - when two parents are carriers of an autosomal recessive disease, the occurrence and recurrence risks for each child are 25% 4. Consanguinity (mating of two related individuals) dramatically increases the occurrence risk of recessive disorders, because each parent is more likely to carry the same recessive allele than the general population. 5. Examples: cystic fibrosis, phenylketonuria, sickle cell anemia ACTIVITY 2: Fill in the following Punnett square diagram for the children of a couple in which both parents carry the gene for cystic fibrosis (c), which is autosomal recessive: C c C c Mother's genotype = Cc (carrier) Father's genotype = Cc (carrier) What percentage of their offspring will be genotype cc? What percentage of their offspring will be carriers for cystic fibrosis? C. Sex-Linked Disorders 1. The Y chromosome contains only a few dozen genes, so most sex-linked traits are located on the X chromosome and are said to be X-linked 2. Sex-linked (X-linked) disorders are usually expressed by males because females have another X chromosome to mask the abnormal gene 3. X-linked recessive o Most X-linked disorders are recessive o Affected males cannot transmit the genes to sons, but they can to all daughters o Sons of female carriers have a 50% risk of being affected 4. Examples: hemophilia A, muscular dystrophy, red-green color blindness
8 ACTIVITY 3: Fill in the following Punnett square diagram for a woman who carries the gene for muscular dystrophy (X m ) any her normal husband. X M Y X M X m Mother's genotype = X M X m (normal muscles) Father's genotype = X M Y (normal muscles) What percentage of their children will inherit muscular dystrophy? Which genotype will be a carrier who could pass it on to the next generation? Will it be a boy or a girl? V. Multifactorial Inheritance Many traits and disorders are not caused by single genes, but by a combination of multiple genes interacting with other factors. Polygenic trait - trait that results from several genes acting together. Multifactorial trait - variation in a trait is caused by a combination of genetic and environmental or lifestyle factors Examples - height, weight, skin color, intelligence. Diseases such as hypertension, heart disease, and diabetes are influenced by multifactorial inheritance.