Chapter 10

Question 1

enzyme

Answer 1

-protein that acts as a biological catalyst causing one or more biochemical reactions to occur or increasing the rate of a biochemical reaction within a cell, body tissue, or organ

Question 2

Pleiotropy

Answer 2

A single-gene disorder results in problems expressed in many tissues and functions

Question 3

hyperaminoacidemias

Answer 3

one particular amino acid accumulates in the blood to toxic levels

Question 4

lysosomal storage diseases

Answer 4

-enzyme within lysosomes is defective or deficient, causing the buildup of a precursor substance that becomes toxic to the cell.

Question 5

Lysosomes

Answer 5

intracellular vesicles that contain many enzymes to degrade the protein and lipid by-products of metabolism.

Question 6

Phenylketonuria (PKU)

Answer 6

-a disorder in which a genetic mutation in the PAH gene causes the function of the enzyme phenylalanine hydroxylase (PAH) ro be reduced, and the amino acid phenylalanine cannot be enzymatically converted to the amino acid tyrosine. T
-his results in an excess of phenylalanine and a deficiency of tyrosine.
-PKU is an example of a problem that leads to hyperaminoacidemia.

Question 7

Executive functions

Answer 7

-behavioral functions associated with prefrontal lobe brain activity and include solving problems, controlling impulses, planning, and making goal-directed actions.

Question 8

Gaucher disease

Answer 8

-genetic lysosomal storage disease in which there is a deficiency of the GSA gene product, the enzyme Beta-glucocerebrosidase. It normally breaks down the metabolic glycolipid glucosylceramide (also called glucocerebroside) into sugar and fat that can be recycled for other metabolic uses.

Question 9

enzyme-replacement therapy (ERT).

Answer 9

-replacement of the missing or malfunctioning enzyme with one that has been generated artificially
-Three drugs are approved for treatment. These drugs are imiglucerase (Cerezyme), taliglucerase (ELELYSO), and velaglucerase (VPRN), which are infused intravenously every 2 weeks once a blood level has been achieved. Some patients have a dramatic reduction in liver size, spleen size, and bone pain within a few weeks of beginning the therapy, although each patient’s response is variable. This therapy is very expensive and representS only a disease-management therapy, not a cure.

Question 10

substrate restrictive therapy

Answer 10

-this type of therapy reduces the amount of glucosylceramide (glucosylcerebroside) presem in macrophages.
-Drugs in this class are eliglustat (Cerdelga) and miglustat (Zavesca).
-These oral drugs are taken daily to inhibit the enzyme that makes glucosylce- ramide, resulting in less accumulation in macrophages. Currently, the drugs are approved only for use in adults.

Question 11

Hurler syndrome
also known as mucopolysacchandosisI (MPS I),

Answer 11

-a genetic lysosomal storage disease caused by a mutation in the a-L-iduronidase gene (IDUA), which results in the deficiency of the enzyme A-L-idurorudase.
-This deficiency results in the accumulation of mucopolysaccharides (MPSs) in the lysosomes of most cells.
-The IDUA gene mutation is transmitted in an autosomal-recessive pattern and is located on chromosome 4pI6.3.

Question 12

Fabry disease

Answer 12

-a genetic lysosomal storage disease in which a mutation in the n-galacrosidase A gene (CLA) results in a deficiency of the enzyme A-galactosidase A (also known as ceramide trihexosidase).
-Without sufficient amounts of the enzyme, globotriao-sylceramide (GL-3) accumulates in the lysosomes of many tissues and organs.
-It is an X-linked recessive disorder. and CLA is located on chromosome Xq22.

Question 13

Hunter syndrome

Answer 13

-a genetic lysosomal storage disease in which a mutation in the iduronate sulfatase gene (IDS) results in a deficiency of the enzyme iduronare sulfatase.
-The enzyme deficiency results in the accumu- lation of MPSs within the lysosomes of many tissues and organs.
-This disorder is also known as mucopolysaccharidosisII (MPS II).
-Unlike Hurler syndrome, Hunter syndrome is an X-linked recessive disorder with the gene located on Xq28.

Question 14

Tay-Sachs disease

Answer 14

-a genetic lysosomal storage disease in which the HEXA gene responsible for producing the enzyme B-hexosaminidase A is mutated.
-The enzyme deficiency results in the accumulation of GM2-ganglioside in brain cells. The HEXA gene is located on chromosome 15q23 to q24, and the disorder is transmitted in an autosomal-recessive pattern (OMIM, 2013).

Question 15

Collagen

Answer 15

-a group of glycoprotein fibers that forms the major component of the connective tissue found in nearly all body tissues.
-It starts out as procollagen and is the most abundant protein in humans and other mammals.
-Procollagen is processed or modified in various ways to form different types of mature collagen fibers that work with other fibrous tissues to form cables that add
strength and structure to most tissues
- In addition, collagen fibers are part of the extracellular matrix between cells and tissues that functions to hold tissues together and promote communication between and among cells.

Question 16

five main types of collagen within the human body are as follows (many minor types also exist):

Answer 16

• Type 1 collagen is the most common and is a major component of bones, the dermal layer of skin, tendons, ligaments, corneas, intervertebral disks, and the walls of arteries and other blood vessels. It is coded for by the COL2A1 gene located on chromosome 17q21.33.
• Type 2 collagen is the major type of collagen found in cartilage and is coded for by the COL2A1 gene located on chromosome 12q.13.11.
• Type 3 collagen is a major component of connective tissue in the skin, lungs, intestinal walls, and the walls of blood vessels. It is coded for by the COL3A1 gene located on chromosome 2q31.
• Type 4 collagen is a major component of connective tissue in the kidney and inner ear. Several subgroups of type 4 collagen are coded for by the COL4A genes 1 to 6, which are located on chromosomes 2 and 13 and the X chromosome.
• Type 5 collagen works with other collagen types to provide strength to connective tissues in the skin, ligaments, bones, tendons, muscles, and the extracellular matrix. It is coded for mainly by the COL5A1 gene located on chromosome 9q34.2-q34.3.3.

Question 17

Genetic mutations

Answer 17

Genetic mutations in any of the collagen genes usually affece more than one type of tissue (pleiotropy) and are involved in many genetic disorders (Table 10–3). The collagen disorders discussed in this chapter are the osteogenesis irnperfecra and Ehlers-Oanlos syndromes. In addition, Marfan syndrome, which is a problem of fibrillin production that normally interacts with collagen for connective tissue strength and flexibility, is also discussed.

Question 18

Osteogenesis imperfecta (01)

Answer 18

-a group of genetic disorders in which collagen formation is impaired, resulting in bones that fracture easily.
-Many different mutations, especially in the genes for type 1 collagen, result in great variation in disease severity. With some mutations, bone fractures occur in the fetal period and are lethal (osteogenesis imperfecra type II).
-Other mutations result in milder disease expression in which bones are brittle and fracture more easily, but bone deformity does not occur. -Four major types of 01 occur because of mutations in a gene for type 1 collagen. All follow an autosomal- dominant transmission pattern, although spontaneous mutations are responsible about 35% of the time

Question 19

Ehlers-Danlos syndrome

Answer 19

-a group of six different inherited disorders that occur because of mutations in the genes responsible for collagen formation or modification.
-The genes are located on different chromosomes and are responsible for problems in the production of different collagen types.
-These disorders vary in severity and the tissues most involved.
-In classical Ehlers-Danlos, the skin and joints are most commonly involved. These tissues are hyperextensible and stretchier than normal because of abnormal collagen (Fig. 10-3). Wide scars develop in areas of injury or skin stress. The skin is fragile and bruises easily.

-Classical Ehlers-Danlos is caused by gene mutations for type I or type 5 collagen and is transmitted in an autosomal-dominant pattern. Hypermobility Ehlers-Danlos is transmitted as an autosomal-dominant disorder, although no specific collagen mutation has been identified. Vascular Ehlers-Danlos is caused by a gene mutation for type 3 collagen and is transmitted in an autosomal-dominant pattern, although spontaneous new mutations (de novo) can occur. Kyphoscoliosis Ehlers-Danlos is caused by a mutation in a gene responsible for modifying collagen and is transmitted in an autosomal-recessive pattern. Classical Ehlers-Danlos syndrome is the mildest form. Vascular Ehlers-Danlos and kyphoscoliosis Ehlers- Danlos syndrome have more severe complications and are associated with early death. The incidence of all types of Ehlers-Danlos syndrome collectively is about I in 5,000 births.

Question 20

Marfan syndrome (MFS)

Answer 20

• an inherited genetic connective tissue disorder in which rhe FBN1 gene for the glycoprotein fibrillin is mutated.
  -Fibrillin, like collagen, is a glycoprotein that assembles into long Strands of microfibrils and is an essential component of specific connective tissues, especially rhose mat respond by stretching when a force is applied. It is most abundant in tendons, muscles, the connective tissue that surrounds large arteries, and heart valves

Question 21

Summary

Answer 21

-At the present, collagen disorders and connective tissue diseases cannot be cured. Thus, accurate diagnosis and early preventive intervention strategies are needed to delay complications and promote quality of life. Many of these disorders are inherited in an aurosomal-dorninanr fashion; however, some also have a relatively high rate of occurrence because of spontaneous new mutations. Health oversight by a knowledgeable health-care professional and appropriate genetic counseling are essential components of patient and family care.
-• All enzymes are gene products.
• A mutation in a gene coding for a specific enzyme usually reduces the enzyme’s activity and results in
one or more physiologic problems related to the toxic accumulation of the precursor substance.
• People with phenylketonuria must adhere to a low-phenylalanine diet to prevent or slow the central
nervous system complications of the disease.
• Enzyme-replacement therapy (ERT) for lysosomal storage diseases reduces the progression of the disease
and must be regularly continued for life.
• Of the three types of Gaucher disease, type I is most common, does not affect the central nervous
system, and can be managed with ERT.
• Signs and symproms of Gaucher disease type 1 may not be present until adulthood.
• The phenotypes of Hurler syndrome and Hunter syndrome are very similar, although Hunter syndrome
has a slower onset and a less detrimental effect on intellectual function.
• The incidence of Tay-Sachs disease is 100 times greater among Ashkenazi Jewish populations than
among most non-Jewish populations.
• Many enzyme disorders can be cured by hematopoietic stem cell transplantation (HSCT), but the
procedure is both costly and dangerous.
• No therapy exists to prevent progression ofTay-Sachs disease.
• Collagen is the most abundant protein found in humans and provides both structure and strength to
many tissues.
• In mild forms of osteogenesis imperfecra, collagen is normal but is present in reduced amounts.
• In moderate and severe forms of osteogenesis imperfecra, the type 1 collagen produced is abnormal.
• About 35% of the cases of osreogenesis imperfecra occur because of a new spontaneous mutation.
• The FBNl gene for fibrillin isvery large, and many different mutations can lead to Marfan syndrome. • The most serious and life-threatening complications of Marfan syndrome occur in the cardiovascular
system.

Question 22

A 37-year-old female nurse was diagnosed with Marfan syndrome last year when her older brother was diagnosed with the disorder at the time he had heart valve replacement surgery. Their father is still livingat age 75 and is 6’ tall.Their mother, who was 5’ 11”, died of a ruptured aortic aneurysm while giving birth to her third child.This nurse is 6’ 1” tall, 50 Ib overweight, and works as a labor and delivery nurse. She has long fingers and enjoys playing the piano. She is blond with blue eyes and very near-sighted. Six months ago, she broke her wrist when she fell on the ice and tried to break her fall.Two years ago, she had a total hysterectomy for uterine fibroids and endometriosis. She also has scoliosis and high blood pressure. Her leisure activities include swimming, bowling, and knitting.
1. Draw the pedigree and identify probable affected individuals.
2. What physical attributes and health problems could be associated with Marfan syndrome? Explain
your choices.
3. Are her work and leisure-time activities placing her at any particular risk? Support your choices. 4. Would genetic counseling be of any benefit to her? Explain why or why not.

Question 23

Which clinical situation best demonstrates the concept of pleiotropy?
a. A mutation in anyone of several genes can cause the same problem or disorder.
b. The problem caused by a single-gene rnutation appears at an earlier age in each succeeding generation.
c. A specific, single-gene mutation results in the phenotype of reduced cognition, absent iris, and
exstrophy of me bladder.
d. Huntington disease, caused by a single-gene mutation present at birth, does not result in symptoms
until later in life.

Answer 23

C

Question 24

Which normal physiologic process usually requires an enzyme?
A. Degradation of mucopolysaccharides (glycosaminoglycans) into sugar and proteins for recycling
B. Propagation of a nerve action potential from the point of stimulation to the axon terminal
C. Exfoliation (shedding) of dead skin cells from me stratum corneum of the epidermal layer
D. Movement of water across a cell’s plasma membrane from an area of high hydrostatic pressure to an area of lower hydrostatic pressure

Answer 24

A

Question 25

Which problems result from me gene mutation associated with phenylketonuria?
a. Excessive levels of tyrosine and deficient levels of phenylalanine
b. Excessive levels of tyrosine and normal levels of phenylalanine
c. Excessive levels of phenylalanine and deficient levels of tyrosine
d. Excessive levels of phenylalanine and normal levels of tyrosine

Answer 25

C

Question 26

How does substrate reduction therapy help manage the problems associated with Gaucher disease type I?
a. By directly decreasing the amounts of glucosylceramide present in macrophages
b. By directly decreasing the amounts of b-glucocerebrosidase present in macrophages
c. By directly increasing the amounts of glucosylceramide present in macrophages
d. By directly increasing the amounts of b-glucocerebrosidase present in macrophages

Answer 26

A

Question 27

Why is a person with Gaucher type 1 usually anemic without therapy?
a. The excess B-glucocerebroside in the macro phages of the spleen reduces its function.
b. The excess B-glucocerebroside in the macro phages of the bone marrow reduces its function.
c. The excess glucosylceramide in the macrophages of the spleen reduces its function.
d. The excess glucosylceramide in the macrophages of the bone marrow reduces its function.

Answer 27

D

Question 28

Why does enzyme-replacement therapy with laronidase in a child with Hurler syndrome have no effect on slowing the central nervous system manifestations of the disease?
a. The drug does not cross me blood-brain barrier.
b. The drug is only effective on cells that maintain the ability to divide.
c. The enlarged liver degrades the drug too quickly for it to be transported to remote body areas.
d. The type of iduronidase present in the central nervous system differs from mat in me rest of me body.

Answer 28

A

Question 29

Which ethnic groups have me highest incidence of Gaucher type I? Select all mat apply.
a. Ashkenazi Jewish people
b. Asian people from China and the Korean Peninsula
c. Celtic people from Scotland and Ireland
d. French Canadian people from me Quebec area
e. People from equatorial African countries
f. People from the Mediterranean region

Answer 29

A, d

Question 30

Which form of Ehlers-Danlos is severe and leads to premature death?
a. Kyphoscoliosis
b. Hypermobility
c. Classical
d. Vascular

Answer 30

D

Question 31

If a man with Hunter disease has children with a woman who neither has the disease nor is a carrier for the disorder, what is the expected risk pattern?
a. All sons will be unaffected; all daughters will be carriers.
b. Sons have a 50% risk for being affected; all daughters will either be affected or carriers.
c. Daughters have a 50% risk for being affected; all sons will either be affected or carriers.
d. Each child of either gender has a 50% risk of being a carrier, a 25% risk of having the disease, and
a 25% risk of neither being a carrier nor having the disease.

Answer 31

A