Chapter 11

Question 1

Sickle cell disease (SCD)

Answer 1

-a genetic disorder caused by a single-nucleotide polymorphism (point muta- tion) in both alleles of a single gene that results in the abnormal formation of the beta chain of hemoglobin (beta globin).
-transmitted in an autosomal-recessive pattern and is most common among people with African or other equatorial ancestry
-Carrier Status, known as sickle cell trait, ill which a person has only one mutated beta globin gene allele is estimated at I in IS African Americans
-Signs and Symptoms:
The poor perfusion and oxygenation of body tissues in the person with SCD results in pain, disability, organ damage, increased infections, and early death. The short life span of the RBCs results in chronic anemia, although these patients are not iron deficient.

Question 2

sickle cell crisis.

Answer 2

-acute sickling period
-During crisis periods, extensive sickling occurs and disrupts blood flow to an entire organ(s) or body area. Severe pain in the affected area is the most common symptom during crises.
-Although some sickled RBCs resume a normal shape when tissue oxygen levels increase and the crisis is over, some cells remain sickled, and alJ are more fragile. This fragility increases the risk for repeated sickling, even when tissue oxygen levels fall only slightly below normal.

Question 3

Progressive Complications of Sick le Cell Disease

Answer 3

Pain
Priapism
Jaundice
Heart failure
Fatigue
Weakness
Joint damage
Increased susceptibility to infections, especially pneumonia Liver and spleen destruction and failure
Chronic kidney disease and kidney failure
Foot and leg ulceration
Brain infarcts, strokes, seizures

Question 4

Cystic fibrosis (CF)

Answer 4

-a monogenic disorder in which both alleles of a gene have one or more mutations that result in problems with the transmembrane transpon of chloride.
-inherited as an aurosornal- recessive single-gene trait and is most common among whites of Northern and Western European heritage, although it can be found among people of all races and ethnicities.
-Signs and Symptoms
The two main organ systems affected that involve epithelial cells are the lungs and the pancreas. The epithelial cells in these tissues produce a thick, sticky mucus due to poor chloride transport that, over time, plugs up the glands in these organs, causing glandular atrophy and organ dysfunction or failure. Other organs that are affected to a lesser degree include the liver, salivary glands, and testes.

Question 5

Duchenne muscular dystrophy (DMD)

Answer 5

• a genetic disorder of progressive muscle weakness caused by any one of a variety of mutations in an allele of the DMD gene, which codes for the protein dysrrophin. It is the most common inherited myopathy (muscle-degrading disease).
• inherited in an X-linked trans- mission pattern and is most common among males.
  -The gene for dystrophin is located on the X chromosome (locus is Xp21) (OMIM, 2016c). It is the largest gene in the human genome, and its product, dystrophin, also is large. Muscular dystrophies of several types are associated with mutations in this gene. Mutation types include large deletions, small deletions, large duplications, insertions, and base changes. The most common mutation consists of large deletions, and the disorder is exclusively genetic in origin..

Question 6

Dysrrophin

Answer 6

-a structural protein that functions to maintain muscle integrity. It is found inside skeletal, cardiac, and smooth muscle cells. A variant of dysuophin also is found in brain cells. In muscle cells, dysrrophin surrounds muscle fiber membranes and secures the contractile protein strands, especially actin, so they remain anchored in place and are stable.
-With tOO little dysrrophin (BMD) or completely nonfunctional dysrrophin (DMD), each muscle contraction loosens actin, gradually breaking down the muscle fibers and destroy- ing the integrity of individual muscle cells. Because muscles are not mirocically active after birth, damaged and dead cells are not replaced. The muscles lose muscle fibers and become filled with connective tissue and fat.

Question 7

Classic hemophilia (hemophilia A)

Answer 7

-a monogenic disorder in which the production of blood-clotting facror VIII is either absent or well below normal levels.
- inherited as an X-Linked single-gene trait and is most common among males.

Question 8

von Willebrand disease (VWD)

Answer 8

• a monogenic disorder in which the affected person produces less-than- normal amounts of von Willebrand factor (vWf).
  -nherited as an autosomal-dominant trait and is the most common inherited blood-clotting disorder worldwide.
  -Because the VWF gene is located on chromosome 12, the most common forms of the disorder are from mutations inherited in an autosomal-dominant parrern. However, because of reduced penerrance, a family pedigree can sometimes give the appearance of an autosomal-recessive parrern, although without a true carrier status. However, with reduced penetrance, a person who does nor manifest the disorder can transmit the affected gene to his or her children, who then may express the disorder. In addition, the rarest form of the disorder, which is also the most severe, is autosomal recessive.

Question 9

Achondroplasia

Answer 9

-a monogenic disorder of human short-limbed dwarfism that occurs because of a mutation in the FGFR3 gene that codes for the fibroblast growth factor receptor 3. It is the most common disorder of dwarfism and occurs in all races and ethnicities.
-The word achondroplasia literally means “without cartilage.” This designation is not accurate because people with achondroplasia do have normal cartilage in appropriate locations. However, bone formation starts with cartilage in the embryonic stage, which then hardens (ossifies) to become bone. Problems in the formation and growth of the long bones result from mutations in the FGFR3 gene.
-

Question 10

Complex disorders

Answer 10

-require both genetic and environmental input to develop.
-The genetic input increases the individual’s suscepribiliry co developing the health problem, but unless one or more specific environmental triggers occurs at the right time, the problem may never develop.

Question 11

hyperglycemia).

Answer 11

blood glucose levels are elevated

Question 12

Diabetes mellitus type 1

Question 13

autoimmune disease

Answer 13

-one of inflammation and immune action excess in which components of a person’s immune system no longer recognize the person’s own cells, tissues, and organs as “self” and attack them as if they were invading organisms.

Question 14

Positive Physiological Responses to the Presence of Adequate Insulin Levels

Answer 14

Prevention of hyperglycemia
Increased amino acid uptake by cells
Increased production of cellular proteins
Decreased muscle cell breakdown
Increased cell division
Increased liver storage of excess glucose as glycogen
Movement of fats, especially triglycerides and cholesterol, out of the blood and into fat cells (reduced blood lipid levels)

Question 15

insulitis

Answer 15

infiltration of the islet cells by white blood cells, resulting in inflammation of these cells.

Question 16

Asthma

Answer 16

-a chronic inflammatory disease of the airways that is usually characterized by intermittent periods of reversible airflow obstruction. (For some people, some degree of airway obstruction is always present, but this is nor common.)
-The intermittent episodes are commonly called asthma attacks.
-Asthma can result from one or a combination of three possible mechanisms:
(I) constriction of the smooth muscles surrounding the smaller airways, (2) swelling of the mucous membranes lining the airways, or (3) excessive mucus collecting in and plugging the airways.
-The most common type of asthma is atopic asthma, which is a hypersensitivity reaction (allergic response) involving the release of immunoglobulin E (IgE). This type of asthma can have anyone or even all three mechanisms occurring at the same time.

Question 17

Summary pt 1.

Answer 17

-Common monogenic disorders that usually manifest in childhood include sickle cell disease, cystic fibrosis, Duchenne muscular dystrophy, hemophilia, Von Willebrand disease, and achondroplasia. Those that have obvious anatomic manifestations, such as achondroplasia, or those that show other problems early, such as sickle cell disease, cystic fibrosis, and hemophilia, may be diagnosed within the first few weeks or months of life. Patterns of inheritance are clear, although disease expression can vary considerably. Some of these disorders have such severe associated problems that death in childhood was common. At present, even though most disorders cannot be cured, berter supportive care has resulted in people with these disorders living into adulthood.
The complex disorders of diabetes mellitus type I and atopic asthma have less identifiable genetic origins and considerable variability in susceptibility. They both require an interaction with environmental factors for disease expression.
• Sickle cell disease (SCD) and sickle cell trait have a far greater incidence in East Africa and other equatorial countries.
• SCD results in most of a person’s hemoglobin being HbS instead of normal adult hemoglobin (HbA).
• HbS does bind oxygen in the same way that HbA does; however, HbS is very sensitive to low tissue levels of oxygen and makes the red blood cell pull inward, forming a sickle shape when tissue oxygen
levels decrease.
• A person with sickle cell trait can form sickled red blood cells, but the degree of hypoxia must be severe
and prolonged for this to occur.
• The genetic mutation that causes SeD is the same for every person who has the disease, does not arise
spontaneously, and is the most stable of the disease-causing mutations.
• Genetic testing is not needed for the diagnosis of SeD.
• Pain is the most common symptom associated with SeD.
• Two additional genetic factors that moderate SeD effects are a higher percentage of fetal hemoglobin
(HbF) and the coexisting presence of alpha-thalassemia, another genetic disease.
• Carriers for SeD have an inherent reduced susceptibility to death from malarial infection.
• Cystic fibrosis (CF) is most common among Caucasians from Northern and Western Europe, although
it can be found in any race or erhniciry,
• More than 1,700 mutations in the cystic fibrosis gene (CFTR) have been identified and are thought to
be responsible for the extreme variation in expression of disease severity.
• The most common clinical test used to diagnose CF is the sweat chloride test, Genetic testing is used
to identify carrier status, specific mutations, and an affected fetus.
• Carriers of CF appear to have an inherent reduced susceptibility to death from typhoid and cholera.
• Duchenne muscular dystrophy (DMD) is the most common inherited muscle-degrading disease; a milder form is Becker muscular dystrophy (BMD).
• DMD is an X-linked recessive disorder that affects males more severely and more commonly than females.

Question 18

Summary pt 2.

Answer 18

• The DMD gene is the largest gene in the human genome and is very susceptible to mutation, including a high percentage of spontaneous mutations.
• The spontaneous mutation rate for the large gene responsible for classic hemophilia (the F8 gene) is high.
• Many different mutations of F8 can cause hemophilia, and these may vary trom family to family, making
genetic testing for hemophilia more difficult.
• Most forms of von Willebrand disease (VWD) are inherited as an autosomal-dominant trait, and it is
the most common inherited blood-clotting disorder worldwide.
• Most people who have VWD have the mildest form and commonly have never been diagnosed with
the disorder.
• Two specific point mutations in the FGFR3 gene are responsible for 99% of all cases of achondroplasia.
• The FGFR3 gene is very large, and at least 80% of achondroplasia is a result of spontaneous new mutations associated with advanced paternal age.
• Most children with achondroplasia have delayed motor development and normal intellectual development.
• Obstructive sleep apnea is a potentially lethal complication of achondroplasia.
• Diabetes mellitus type I is an autoimmune disease that results from an increased genetic susceptibility coupled with an environmental trigger, most commonly a viral infection.
• The tissue types most associated with diabetes mellitus typr I, asthma, and other autoimmune diseases
are the HLA-DR and HLA-DQ tissue types.
• People who have the HLA-DR and HLA-DQ tissue types are twice as likely to develop an autoimmune
disease than the general population, but the risk is still low (2%).
• A person with diabetes mellitus type 1 has a loss of pancreatic islet cells and produces no insulin.
• Unlike type 2 diabetes, obesity and a sedentary lifestyle have no role in the development of diabetes
mellitus type I.
• The chronic hyperglycemia and hyperlipidemia associated with any type of diabetes are responsible for
pathological changes starring at the blood vessel level in almost all tissues and organs.
• Asthma is an airway disease problem and does not cause changes in the alveoli.
• Genome-wide association studies link variations in 50 to 100 genes to increased risk for developing
atopic asthma.
• Gene variations most strongly associated with asthma differ among races and erhnicities.
• The major genetic/genomic issues of asthma are an increased responsiveness of airway tissues when contacted with an environmental irritant (hyperresponsiveness) and an increased amount of the mediators of inflammation, especially immunoglobulin E (IgE).

Question 19

For which genetic problem does the heterozygous state confer an advantage?
a. Achondroplasia
b. Diabetes mellitus eype 1
c. Classic hemophilia
d. Sickle cell trait

Answer 19

D

Question 20

Which of the autosomal-dominant genetic disorders has the highest penetrance?
a. Achondroplasia
b. von Willebrand type I
c. Diabetes mellitus type 1
d. Duchenne muscular dystrophy

Answer 20

A

Question 21

A 16-year-old girl whose older sister just had a baby boy diagnosed with hemophilia is pregnant with
a male fetus. Her boyfriend (the baby’s father) does not have hemophilia and does not have any relatives with the disorder. She asks what the chances are that her son could be affected. What is your best response?

A. “Because it is likely that you are a carrier and your boyfriend does not have any affected relatives, only your daughters can develop the disease.”
B.”Because you may be a carrier and your boyfriend does not have any affected relatives, your son will not have the disease but could also be a carrier.”
C. “Because your sister’s baby has hemophilia, the risk for your children having the disorder is 50% with each pregnancy.”
D. “Because we do not know your carrier status for the disease, we cannot predict whether your son will have hemophilia.”

Answer 21

D

Question 22

Why are some women who are carriers for Duchenne muscular dystrophy (DMD) at risk for cardiac disease, especially cardiomyopathy?
a. They have more fatty tissue in the heart than do men.
b. The DMD gene is located very close to the main gene for cardiac function.
c. Cardiac muscle requires 80% active dysrrophin to maintain cardiac muscle function.
d. Having a child with DMD who is not very mobile increases the workload on the mothers’ hearts.

Answer 22

C

Question 23

A son with classic hemophilia is born to parents with no family history of the disease. Genetic testing reveals that the mother does not have the mutation on either of her X chromosomes. What is the most likely explanation for the son’s disorder?
a. The son is not biologically related ro the mother.
b. One of the mother’s ova had a spontaneous mutation of the X chromosome.
c. One of the father’s sperm had a spontaneous mutation of the X chromosome.
d. The son’s DNA underwent a spontaneous mutation during the second trimester of pregnancy.

Answer 23

B

Question 24

What is the most likely cause of a child with achondroplasia being born to a couple with a normal- stature phenotype?
a. Expansion of maternal trinucleotide repeat sequences within the FGFR3 gene during gametogenesis
b. Incomplete penetrance of the autosomal-dominant FGFR3 gene
c. Random X-chromosome inactivation in a carrier mother
d. Advanced parental age at conception

Answer 24

B

Question 25

Which common childhood disorder requires a genetic contribution and a significant environmental contribution to develop fully?
a. Achondroplasia
b. Sickle cell disease
c. Diabetes mellitus type 1
d. von Willebrand disease

Answer 25

C

Question 26

Which factor or condition suggestS a strong genetic contribution to the development of diabetes mellitus rype I?
a. Monozygotic twins show a high concordance of the disease.
b. Most individuals with the disease are diagnosed before age 20 years.
c. A large percentage of affected individuals are both obese and have a sedentary lifesryle.
d. The disorder occurs most often in children born to parents who are advanced in age at the time
of conception.

Answer 26

A

Question 27

Which types of genes have been implicated in the development of childhood asthma?
a. Genes controlling mucus production
b. Genes involved in inflammatory responses
c. Genes important in the growth of lung alveoli
d. Genes that produce proteins needed to break down inhaled pollutants

Answer 27

B

Question 28

Edward is a 32-year-oldman who has had diabetes mellitus type 1 since he was 8 years old. His identical twin brother also has the disease, as did his paternal grandmother. Edward’s wife, Ellen, had gestational diabetes when she was pregnant with their son (Frank),who is now 5 years old. Ellen’s older sister and her mother also had gestational diabetes. Her mother now has diabetes mellitus type 2. Frank is being evaluatedyearly by his pediatricianfor signs and symptoms of diabetes. Currently,he has no indication of the disease,
1. Draw the pedigree and indicate any obvious pattern of inheritance.
2. Does Ellen’sfamily history of gestational diabetes and type 2 diabetes increase Frank’srisk for
development of diabetes mellitus type 1? Explainyour response.
3. Isthe concernthat Edward’sandEllen’ssonmaydevelopdiabetesmellitustype 1valid? 4. Can Frank’sparents do something to prevent the development of diabetes mellitus type 1?