1. Congenital and Genetic Disorders
Unit 6 Human Disease
Congenital and Genetic Disorders
(additional reference – Chapter 7 of Textbook)
Pathophysiology - Borders

2. Overview
A genetic disorder is a disease caused by a variation in an individual’s DNA, or an alteration of a gene called a mutation.
Many diseases have a genetic aspect. For example, many cancers are caused by a mutation in a gene or group of genes in a person's cells. These mutations can occur randomly or because of an environmental exposure such as cigarette smoke.
Other genetic disorders are inherited. A mutated gene is passed down through a family and each generation of children can inherit the gene that causes the disease.
Still other genetic disorders are due to problems with the number of packages of genes called chromosomes. There can be extra copies of genes, missing genes, or translocated genes
(Website link)
Genetic Disorder's Interactive

3. Genetics
Genetic material, or genes, in a cell’s nucleus, contain information for all of an individual’s traits.
The genes are comprised of sequenced nucleic acids which determine all of the functions of an individual’s body cells.
There are 22 pairs of chromosomes called autosomes and a 23rd pair of sex chromosomes making a total of 46 chromosomes.
A karyotype charts these chromosomes.

4. Karyotyping A karyotype is an individual's collection of chromosomes.
The term also refers to a laboratory technique that produces an image of an individual's chromosomes.
The karyotype is used to look for abnormal numbers or structures of chromosomes.
Cells (from blood, amniotic fluid, etc) are grown in vitro (in a cell culture dish) to increase their number
Cell division is then arrested in metaphase with colchicine (prevents mitotic spindle from forming)
Cells are centrifuged and lysed to release chromosomes
Chromosomes are stained, photographed, and grouped by size and banding patterns

5. Gene Mapping
Gene mapping is the process of establishing the locations of genes on the chromosomes.
Researchers using gene maps to help cure diseases. Genetic mapping is on the cutting edge of disease prevention.

6. Genetic Testing Genetic Counseling Fetal Testing Newborn Testing
Pedigree Analysis
Blood test for proteins
Phenotype analysis
Fetal Testing
Karyotype
Amniocentesis
Chorionic villus sampling (CVS)
Newborn Testing
A phenotype is an individual's observable traits, such as height, eye color, and blood type. The genetic contribution to the phenotype is called the genotype. Some traits are largely determined by the genotype, while other traits are largely determined by environmental factors.
With genetic amniocentesis, a sample of amniotic fluid is tested for certain abnormalities — such as Down syndrome and spina bifida. With maturity amniocentesis, a sample of amniotic fluid is tested to determine whether the baby's lungs are mature enough for birth. Occasionally, amniocentesis is used to evaluate a baby for infection or other illness. Rarely, amniocentesis is used to decrease the volume of amniotic fluid.
Amniocentesis-The most common disorders that are tested for are Phenylketonuria (PKU), Congenital Hypothyroidisim, Galactosemia, Maple Syrup Urine Disease, Homocystinuria, Biotinidase, Sickle Cell Disease, Congenital Adrenal Hyperplasia and Cystic Fibrosis.
Mandated newborn testing
CH - Congenital hypothyroidism
H-HPE - Benign hyperphenylalaninemia
PKU—Phenylketonuria/hyperphenylalaninemia
HEAR - Hearing
GALT - Transferase deficient galactosemia

7. Chorionic Villus Sampling
Chorionic villus sampling (CVS) is the removal of a small piece of placenta tissue (chorionic villi) from the uterus during early pregnancy to screen the baby for genetic defects.

8. Genetic Abnormalities
Examples of Chromosomal Mutations –
Deletion –missing a gene
Duplication – sequence repeated
Translocation –chromosome attached to another one

9. Chromosomal Errors: Problems in Meiosis
Nondisjunction- Failure of paired chromosomes to disjoin (separate) during cell division so that both chromosomes go to one daughter cell and none to the other
Aneuploidy- One or a few chromosomes above or below the normal chromosome number. For example, three number 21 chromosomes or trisomy 21 is a form of aneuploidy.
• Monosomy
• Trisomy
• Polyploidy

10. Genetic Counseling
Pedigree can help us understand the past & predict the future
Thousands of genetic disorders are inherited as simple recessive traits
from benign conditions to deadly diseases
albinism
cystic fibrosis
Tay-sachs
sickle cell anemia
PKU

11. Chromosomal Sex-linked Disorders
Fragile X Syndrome
Occurs in about 1 of 1,200 males and 1 of 2,500 females. Results from a breakage of the tip of an X chromosome.
Klinefelter Syndrome (XXY, XXXY, XXXXY)
Occurs in about 1 of 1,000 males. It is caused by an extra X chromosome

12. Turner Syndrome Nondisjunction of the X
Occurs in about 1 of 10,000 females.
This condition occurs in about 1 in 2,500
More common among pregnancies that do not survive to term (miscarriages and stillbirths).
These women have immature female appearance, do not develop secondary sex characteristics, and lack internal reproductive organs.
Turner syndrome is a chromosomal condition that affects development in females. The most common feature of Turner syndrome is short stature, which becomes evident by about age 5. An early loss of ovarian function (premature ovarian failure) is also very common. The ovaries develop normally at first, but egg cells (oocytes) usually die prematurely and most ovarian tissue degenerates before birth. Many affected girls do not undergo puberty unless they are treated with the hormone estrogen. A small percentage of females with Turner syndrome retain normal ovarian function through young adulthood.
About 30 percent of people with Turner syndrome have extra folds of skin on the neck (webbed neck), a low hairline at the back of the neck, puffiness or swelling (lymphedema) of the hands and feet, skeletal abnormalities, and/or kidney problems. One third to one half of people with Turner syndrome are born with a heart defect, such as a narrowing of the large artery leaving the heart (coarctation of the aorta) or abnormalities of the valve that connects the aorta with the heart (the aortic valve).
Most girls and women with Turner syndrome have normal intelligence. Developmental delays, nonverbal learning disabilities, and behavioral problems are possible, although these characteristics vary among affected individuals. Studies show that many women with Turner syndrome have higher-than-average educational achievements.

13. Chromosomal Sex-linked Disorders
Superfemale Syndrome (XXX, XXXX, XXXXX)
Occurs in about 1 of 1,000 females. Women appear normal, but tend to score slightly below average in intelligence.
Supermale Syndrome (XYY, XYYY, XYYYY)
Occurs in about 1 0f 1,000 males. The men tend to be taller than average, with a greater incidence of acne and minor skeletal abnormalities.

14. Recessive autosomal disease
Phenylketonuria PKU
Recessive autosomal disease
Inability to produce enzyme to break down specific amino acid
Build up of amino acid leads to mental retardation if it is not avoided.
PKU testing of babies
Phenylketonuria (PKU) is a rare condition in which a baby is born without the ability to properly break down an amino acid called phenylalanine.
Phenylketonuria (PKU) is inherited, which means it is passed down through families. Both parents must pass on the defective gene in order for a baby to have the condition. This is called an autosomal recessive trait.
Babies with PKU are missing an enzyme called phenylalanine hydroxylase, which is needed to break down an essential amino acid called phenylalanine. The substance is found in foods that contain protein.
Without the enzyme, levels of phenylalanine and two closely-related substances build up in the body. These substances are harmful to the central nervous system and cause brain damage.
Phenylalanine plays a role in the body's production of melanin, the pigment responsible for skin and hair color. Therefore, infants with the condition often have lighter skin, hair, and eyes than brothers or sisters without the disease.
Other symptoms may include:
Delayed mental and social skills
Head size significantly below normal
Hyperactivity
Jerking movements of the arms or legs
Mental retardation
Seizures
Skin rashes
Tremors
Unusual positioning of hands
If the condition is untreated or foods containing phenylalanine are not avoided, a "mousy" or "musty" odor may be detected on the breath and skin and in urine. The unusual odor is due to a build up of phenylalanine substances in the body.
PKU is a treatable disease. Treatment involves a diet that is extremely low in phenylalanine, particularly when the child is growing. The diet must be strictly followed. This requires close supervision by a registered dietitian or doctor, and cooperation of the parent and child. Those who continue the diet into adulthood have better physical and mental health. “Diet for life” has become the standard recommended by most experts. This is especially important before conception and throughout pregnancy.
Phenylalanine occurs in significant amounts in milk, eggs, and other common foods. The artificial sweetener NutraSweet (aspartame) also contains phenylalanine. Any products containing aspartame should be avoided.
The outcome is expected to be very good if the diet is closely followed, starting shortly after the child's birth. If treatment is delayed or the condition remains untreated, brain damage will occur. School functioning may be mildly impaired.
If proteins containing phenylalanine are not avoided, PKU can lead to mental retardation by the end of the first year of life.

15. Cystic Fibrosis Recessive autosomal gene Effects 1 in 2,500 Whites
Caused by defective transport protein
Results in organs clogged with mucus, premature death.

16. delta F508
loss of one amino acid

17. Effect on Lungs Chloride channel Cl– Cl– bacteria & mucus build up
transports salt through protein channel out of cell
Osmosis: H2O follows Cl–
normal lungs
airway
Cl–
Cl– channel
H2O
cells lining lungs
cystic fibrosis
Cl–
In people without cystic fibrosis, working cystic fibrosis proteins allow salt (chloride) to enter the air space and water follows by osmosis. The mucus layer is dilute and not very sticky.
In people with cystic fibrosis, non-working cystic fibrosis proteins mean no salt (chloride) enters the air space and water doesn't either. The mucus layer is concentrated and very sticky.
People with cystic fibrosis have lung problems because:
Proteins for diffusion of salt into the airways don't work. (less diffusion)
Less salt in the airways means less water in the airways. (less osmosis)
Less water in the airways means mucus layer is very sticky (viscous).
Sticky mucus cannot be easily moved to clear particles from the lungs.
Sticky mucus traps bacteria and causes more lung infections.
Therefore, because of less diffusion of salt and less osmosis of water, people with cystic fibrosis have too much sticky mucus in the airways of their lungs and get lots of lung infections. Thus, they are sick a lot.
H2O
bacteria & mucus build up
thickened mucus hard to secrete
mucus secreting glands

18. Tay-Sachs Disease
Recessive autosomal disease
Caused by defective enzyme; therefore fats build up and ruin the brain
Results in nervous system deterioration and early death

19. Tay-Sachs Disease
Primarily Jews of eastern European (Ashkenazi) descent & Cajuns (Louisiana)
strikes 1 in 3600 births
100 times greater than incidence among non-Jews
non-functional enzyme fails to breakdown lipids in brain cells
fats collect in cells destroying their function
symptoms begin few months after birth
seizures, blindness & degeneration of muscle & mental performance
child usually dies before 5years old

20. Sickle Cell Anemia Recessive autosomal disease
Effects 1 in 500 African-
Americans
Causes anemia, poor blood circulation

21. Sickle Cell Anemia Primarily Africans
strikes 1 out of 400 African Americans
high frequency
caused by substitution of a single amino acid in hemoglobin
when oxygen levels are low, sickle-cell hemoglobin crystallizes into long rods
deforms red blood cells into sickle shape
sickling creates pleiotropic effects = cascade of other symptoms
Pleiotropy occurs when a single gene influences multiple phenotypic traits. Consequently, a mutation in a pleiotropic gene may have an effect on some or all traits simultaneously. This can become a problem when selection on one trait favors one specific version of the gene (allele), while the selection on the other trait favors another allele.

22. Sickle Cell Anemia Substitution of one amino acid in polypeptide chain
hydrophilic amino acid
hydrophobic amino acid

23. Doctors can use regular blood transfusions to prevent brain damage and new drugs to prevent or treat other problems.

24. Huntington’s Chorea 1872 Dominant inheritance
repeated mutation on end of chromosome 4
mutation = CAG repeats
glutamine amino acid repeats in protein
one of 1st genes to be identified
build up of “huntingtin” protein in brain causing cell death
memory loss
muscle tremors, jerky movements
called “chorea”
starts at age 30-50
early death
10-20 years after start

25. Huntington’s Disease

26. Down Syndrome Brushfield Spots Simian Crease Large gap between toes
In most cases, Down syndrome occurs when there is an extra copy of chromosome 21, or Trisomy 21. The extra chromosome causes problems with body and brain development.
Brushfield Spots
Simian Crease
Large gap between toes

27. Progeria Mutation in egg or sperm
Mutation of protein lamin A which holds nucleus together.
Uncommon: 1 in 10 million births
Results in aging rates 10 times that of normal, death usually before 18.

28. Genetics & Culture Why do all cultures have a taboo against incest?
laws or cultural taboos forbidding marriages between close relatives are fairly universal
Fairly unlikely that 2 unrelated carriers of same rare harmful recessive allele will meet & mate
but matings between close relatives increase risk
“consanguineous” (same blood) matings
individuals who share a recent common ancestor are more likely to carry same recessive alleles