Chapter 13

Question 1

Familial hypercholesterolemia (FH)

Answer 1

-single-gene disease that is primarily transmitted in an autosomal- dominant manner.
-The LDL receptor is a cell surface protein that binds LDL and takes it into the cell by the process of endocytosis. FH is caused by having too few working LDL receptors. Without enough working LDL receptors, cholesterol accumulates in the blood and can contribute to atheroscleroticplaques that form on the blood vessel walls.

Question 2

Fabry Disease

Answer 2

-a lysosomal storage disease that is transmitted in an X-linked recessive manner. It is caused by the inability to make the enzyme cc-galacrosidase A, which is needed so that people can metabolize lipids.

Question 3

MELAS

Answer 3

-The mitochondrial disorder mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes
-single-gene cause of stroke.
-Because it is a problem in mirochondrial DNA, it is maternally inherited
-MELAS includes a collection of symptoms that may not appear to fit together a

Question 4

Factor V Leiden

Answer 4

-Factor V Leiden
-Most people who have factor V Leiden will not develop blood clots, but their risk of having blood clots is higher than that of the general population.
-Factor V Leiden creates problems by altering factor V of the clotting cascade.
-The faeror V Leiden variation (F5) results in a protein that cannot be degraded, so the person experiences a state of “hypercoagulation.”
-

Question 5

Epistasis

Answer 5

-A gene-to-gene interaction

Question 6

channelopathies

Answer 6

problems with genes coding for ion channels (sodium, potassium, and calcium) in the heart.

Question 7

Atrial fibrillation (AF)

Answer 7

-the most common arrhythmia seen by clinicians
-Studies report that having AF in your family accounts for 40% to 60% of your risk
-however, lots of different genes can probably cause atrial fibrillation, which means that this arrhythmia has genetic heterogeneity.
-When AF is not present at birth, it is considered an acquired disease. Acquired disease can be indirectly caused by gene variants. Srrucrural changes in the heart may lead to acquired AF, and the structural changes could have a genetic cause.

Question 8

Long QT syndrome (LQTS)

Answer 8

-a group of disorders that involve a delay in repolarization during the cardiac cycle.
- This is seen on the electrocardiogram as a lengthening of the QT interval.
-This repolar- izarion delay makes the heart vulnerable to developing a potentially lethal polymorphic ventricular tachycardia called torsade de pointes (“twisting around a point”; Fig. 13-1). Triggers for developing this serious arrhythmia include electrolyte imbalances; certain activities, such as swimming; loud, sudden sounds; and bradycardia.
-Many mutations causing LQTS are considered private mutations, meaning mat they are unique to only one person or one kindred and are not found consistently in the general population.

Question 9

[congenital LQTS]
Romano-Ward syndrome

Answer 9

usually follows aurosornal-dorninanr transmission and includes QT prolongation and tachyarrhythmias.

Question 10

[congenital LQTS]
Jervell and Lange-Nielsen syndrome

Answer 10

• autosomal-recessive transmission pattern, and the QT prolongation and tachyarrhythmias are accompanied by deafness.

Question 11

cardiomyopathy

Question 12

Familial hypertrophic cardiomyopathy (HeM)

Answer 12

-most common genetic cardiac disorder worldwide.
- In HCM, the heart muscle becomes asymmetri- cally thick, and problems with ventricular filling and diastolic function occur.
-disorganization (disarray) in the cardiac myocyres. This disorganization makes transmission of electrical impulses through the heart difficult, which can lead to cardiac rhythm problems.
HCM is diagnosed based on finding left ventricular hypertrophy, without any known cause, on the elec- trocardiogram or echocardiogram. This suggests that the problem is in the heart muscle itself and is not, for example, the result of muscle growth in order to pump larger quantities of blood against a high systemic pres- sure.
-HCM is transmitted as an aurosornal-dorninanr trait, but it can also be caused by de novo mutations.

Question 13

Genetic Diseases That Can Cause Cardiomyopathy
Table 13-1

Question 14

familial dilated cardiomyopathy (DCM),

Answer 14

-the left ventricle is enlarged, and the heart pumps poorly.
-DCM often results in heart failure and is a common cause for heart transplantation.
-The heart is distended (dilated), so contraction of either ventricle is difficult (systolic dysfunction).
-DCM is most often the result of ischemic heart disease, but it can also be caused by exposure to toxins or infectious agents in susceptible people.

Question 15

Restrictive cardiomyopathy

Answer 15

-less common than the other types of cardiomyopathy, and some sources suggest that it is not a genetic disease.
-filling during diastole is decreased because of a rigid ventricle that does not expand as it should. Systolic function is usually normal.

Question 16

Arrhythmogenic right ventricular dysplasialcardiomyopatby (ARVD/C)

Answer 16

-carries a high risk of ventricular arrhythmias because of a fibro/fatty replacement of tissue in the ventricular myocardial wall.
- As the disease progresses, the left ventricle becomes more involved.
-This structural change makes the patient more likely to experience ventricular tachycardia and sudden cardiac death.

Question 17

Summary pt 1.

Answer 17

Both single-gene and multifactorial causes can result in cardiovascular diseases. Single-gene disorders tend to be rare, and multifactorial disorders tend to be common. Even so, the number of people diagnosed with cardiomyopathy seems to be on the rise. Young athletes are at particular risk of sudden death due to undiag- nosed HCM. Atherosclerosis is a major cause of coronary artery disease, stroke, and hypertension. Although the complete picture of the genes involved in these diseases has been elusive, association studies are provid- ing important information about genes that are likely to be involved. Most multifactorial disorders, such as hypertension, are probably the result of the actions of several genes working together, each contributing a small effect, combined with environmental risk facrors. We are starting to find polygenic risk factors for complex diseases such as atrial fibrillation, coronary artery disease, and stroke, bur when we will have a complete picture is still unknown.

Question 18

Summary pt. 2

Answer 18

• About 50% of the risk for atherosclerosis can be attributed to genetics.
• Familial hypercholesterolemia is a single-gene problem that greatly increases the risk of coronary artery
disease.
• Both ischemic and hemorrhagic stroke can have genetic causes.
• Less than 1% of Strokes are caused by single-gene problems, and these occur primarily in people who
have genetic disorders such as Marfan syndrome or Fabry disease.
• Most strokes are probably caused by several gene variants working together combined with environ-
mental risk factors.

• Thrombophilias increase the risk of stroke, and these can be caused by single-gene genetic diseases such as factor V Leiden.
• Hypertension is caused by several gene variants working together with environmental risk factors.
• Mutations of genes involved in the renin-angiotensin-aldosterone system pathways are commonly
implicated in hypertension.
• Different mutations in ion-channel genes can cause different arrhythmic phenotypes.
• Atrial fibrillation seems to have high genetic heterogeneity.
• The heart rhythm and conduction problems caused by genetic variations in genes that code for ion-
channel proteins are called channelopathies.
• At least eight different types of long QT syndrome (LQTS) exist.
• The gene involved in LQTS affects the likelihood of certain triggers, causing torsade de poinres.
• Some drugs can lengthen the QT interval and cause an “acquired” LQTS.
• Private mutations are common in LQTS.
• Familial hypertrophic cardiomyopathy (HeM) is transmitted as an autosomal-dominant trait.
• HeM and dilated cardiomyopathy (OeM) are caused by mutations in genes that code for proteins
in the sarcomere.
• Young people and athletes with HeM are at an increased risk of sudden cardiac death during exercise.
• Familial OeM is usually rransmirted as an autosomal-dominant trait, but it can also be transmitted as
either an autosomal-recessive or an X-linked recessive trait.
• Arrhythmogenic right ventricular dysplasia/cardiomyopathy is often caused by mutations in genes that
code for proteins in cell junctions.

Question 19

.Your patient is admitted for episodes of chest discomfort. She says that she is sure it is muscular because only the men in her family have heart disease. What do you tell her?
a. “It makes sense that only the men in your family have heart disease because most generic risk
factors are on the Y chromosome.”
b. “Let’s complete your family history. Generic risk for heart disease can affect both men and women.”
c. “It is important that you have genetic testing to idenrify any generic risk that exists in your family.”
d. “How is your diet, and do you have an exercise routine? These are the most important facrors to
reduce genetic risk.”

Answer 19

B

Question 20

You are caring for the Johnson family. Several members have been diagnosed with LQTl. You notice on the pedigree that some F.amilymembers have both the genotype and the phenotype, whereas others have the genotype but nor the phenorype. Why is this?
a. Phenotype variation
b. Reduced penetrance
c. Epistasis
d. Variable expressiviry

Answer 20

B

Question 21

Your patient has hypertension (HTN). She wants to know about genetic testing because she is concerned about her son’s risk of also being hypertensive. What do you know about genetic testing for HTN?
A. Hypertension is a complex multifactorial disease in which lots of genes contribute small amounts to risk, and it is complicated by environmental factors.
B. Genome-wide association studies can be very effective in identifying a person’s risk of hypertension.
C. Factor V Leiden (FVL) is an important contributor to hypertension risk. Genetic testing is available for FVL.
d. Genetic testing for HTN is available, but it is very expensive because it is so new.

Answer 21

A

Question 22

Yom HCM patient has given you a four-generation family history, and none of her relatives appears
to be affected. What could be going on?
a. HCM is an autosomal-dominant disease, so she has been misdiagnosed.
b. She is not providing accurate and complete information about her family history.
c. Some of her family members could have been diagnosed with asthma, anxiety attacks, or mitral
valve prolapse when they really had HCM.
d. HCM is autosomal recessive, so it may nor show up in a four-generation pedigree.

Answer 22

C

Question 23

Select a reason why the low-density lipoprotein (LDL) receptor gene could cause the LDL receptOr not to work properly.
a. The receptor might not be able to move from the endoplasmic reticulum to the Golgi apparatus.
b. The receptor could bind too easily to cholesterol molecules, clogging the cell membrane.
c. High doses of HMG-CoA reductase inhibitors could result in the production of a defective protein.
d. If a person has Tangier disease, atherosclerotic plaques cannot be properly produced.

Answer 23

A

Question 24

What is true regarding the origins of stroke?
a. Approximately 50% of strokes are ischemic in origin.
b. Monogenic or single-gene causes of stroke do not exist. It is a complex, multifactorial disease.
c. The phenotype is well defined, which makes study much easier.
d.Genes that increase the risk of atrial fibrillation have also been linked to increased risk for stroke.

Answer 24

D

Question 25

Margery’s maternal grandparents moved to Cincinnati, Ohio, from Ireland before her mother was born. Both her paternal grandparents were of Scottish ancestry. Margery recently married Sam, and they want to put oft having children until they are financially stable. She is interested in advice about birth control and asks for information about oral contraceptives during her routine physical examination. You take a family history and find out that Margery’s mother has a history of blood clots, and her paternal grandfather died from a stroke.
1. Why is the history of blood clots and stroke important to consider in Margery’s decision regarding oral contraceptives?
2. How is Margery’s Celtic background relevant to her risk of blood clots?
3. Should you suggest that she have genetic testing for factor V Leiden?
4. How could your concerns be handled in a professional manner consistent with your scope of practice?