Question 1

What is the most likely explanation for the variability in expression of disease severity for cystic fibrosis?

Accepted Answer

The specific mutation inherited in cystic fibrosis (CF) can make a big difference in the severity of symptoms. There are well over 1,000 different mutations, and some cause milder clinical signs and symptoms. The ethnicity of the patient is not relevant. CF is an autosomal-recessive single-gene trait, making triplet repeats not relevant. Although nongenetic liver or pancreatic problems in a person with CF could make some symptoms worse, this is not a common cause of variability in the severity of CF symptoms.

Question 2

Which statement regarding Duchenne muscular dystrophy (DMD) is true?

Accepted Answer

DMD is an X-linked recessive disorder, and females with the gene mutation are carriers. These women often have reduced muscle strength and cardiac problems related to random X-inactivation in these tissues even though they only have one mutated gene allele. The disorder is not affected by advanced maternal age.

Question 3

How does the drug Endari reduce the manifestations of sickle cell disease?

Accepted Answer

Endari is a new drug that increases the amount of glutamine present in many cells. The increased glutamine appears to reduce the amount of oxidative stress the cells experience, which increases their functional life spans. The drug does not correct genetic mutations, nor does it promote faster red blood cell production or vascular smooth muscle relaxation. It does not affect the percentage of HbF within the red blood cells.

Question 4

What health advantage does cystic fibrosis confer on the person who has it?

Accepted Answer

The high frequency of the heterozygous carrier state for cystic fibrosis (CF) among Caucasians from Northern and Western Europe suggests that being a CF carrier might have a potential advantage. Scientists now believe people who are heterozygous or homozygous for specific common CFTR mutations have greater resistance to typhoid and to cholera toxin when exposed to these disease-causing microorganisms.

Question 5

How is sickle cell trait different from sickle cell disease?

Accepted Answer

When only one beta-globin allele has the mutation, the person is heterozygous for the mutation and has sickle cell trait. In this disorder, the percentage of hemoglobin S (HbS) in the red blood cells (RBCs) is usually less than 40%. When both alleles of the beta-globin gene are mutated, the person is homozygous for the mutation and has sickle cell disease. The RBCs have a high percentage, close to 90%, of HbS rather than HbA.

Question 6

Which feature or factor is the best predictor for delay of complications in a person who has sickle cell disease (SCD)?

Accepted Answer

One of the best predictors for which patients who have SCD will have delayed complications is the percentage of fetal hemoglobin (HbF) that remains in circulation. HbF is a type of hemoglobin normally expressed at high levels only during fetal life, where all oxygen is derived secondhand from the maternal circulation. It tolerates low-oxygen conditions well without sickling. Higher percentages of HbF dilute the percentage of HbS and result in better tolerance of conditions that could cause sickling.

Question 7

Which additional health problem commonly develops in boys with Duchenne muscular dystrophy?

Accepted Answer

Most boys with DMD develop cardiac muscle problems because these cells also rely on dystrophin to maintain their integrity. The most common problems are dilated cardiomyopathy and chronic heart failure. There are fewer problems with smooth muscle. Those that are present do not cause vasoconstriction. Thus, hypertension is not a common problem. The muscles rather than joints are affected, and arthritis does not develop. There is no known association of DMD with the development of diabetes.

Question 8

A 21-year-old woman who has two brothers with Duchenne muscular dystrophy asks whether carrier status testing is appropriate for her. What is the best response?

Accepted Answer

The genetic mutation for Duchenne muscular dystrophy is on the X chromosome and is transmitted in an X-linked recessive manner. Although the spontaneous mutation rate for this disease is relatively high, the fact that she has two brothers with the disorder, rather than just one, strongly suggests this mutation was inherited, not spontaneous. Thus, her mother is a carrier of an X-linked recessive genetic mutation. This young woman's risk for having inherited the mutation on her maternally derived X chromosome is 50%, not 100%. If she were a carrier, she may or may not have any symptoms of the disorder depending on which X is inactivated in her skeletal muscle and cardiac muscle tissues. The absence of symptoms does not clearly rule out a carrier status for her.

Question 9

Which type of testing is most commonly used to diagnose sickle cell disease?

Accepted Answer

Genetic mutation testing is not used to diagnose SCD. It is diagnosed based on the large percentage of hemoglobin S (HbS) seen on electrophoresis. A person who has SCD usually has 80% to 90% HbS, and a person with sickle cell trait usually has less than 40% HbS. Although hemoglobin and hematocrit levels may be abnormal, they alone are not diagnostic for sickle cell disease. Sweat chloride levels are abnormal in people with cystic fibrosis and normal in people with sickle cell disease.

Question 10

Zoe, a 20-year-old woman, shows signs of mild muscle weakness. She has two first cousins on her mother's side who died of Duchenne's muscular dystrophy (DMD).Whichexplanation regarding Zoe's situation is most likely?

Accepted Answer

Some female carriers of DMD show partial gene expression and can demonstrate symptoms of the disease. It is very likely that she is a carrier because this X-linked recessive disease has been seen in her family. It is highly unlikely that she would have received two defective dystrophin genes from her parents because men with DMD tend not to father children.

Question 11

Which tissues are most commonly affected by mutation of the CFTR gene?

Accepted Answer

The two main organ systems affected involve epithelial cells and are the lungs and the pancreas. The epithelial cells in these tissues produce a thick, sticky mucus as a result of 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 far lesser degree include the liver, salivary glands, and testes.

Question 12

Which type of testing is most commonly used to diagnose cystic fibrosis (CF)?

Accepted Answer

Genetic testing is not used to diagnose the homozygous expression of CF. It is diagnosed on the basis of physical manifestations and the results of the sweat chloride test. Positive results are those indicating a high concentration of sodium chloride in the person's sweat (60 to 200 mEq/L or mmol/L) compared with the normal value (5 to 35 mEq/L). Genetic testing by direct sequencing of the CFTR gene is useful for establishing carrier status, identifying affected children prenatally, and, to some degree, predicting disease severity but is not used as primary diagnostic testing.

Question 13

Which ethnic group has the highest incidence of sickle cell disease (SCD)?

Accepted Answer

The disorder is inherited as an autosomal-recessive single-gene trait and is most common among people with African or other equatorial ancestry. The incidence of SCD in the United States among African Americans is about 1 in 400 live births. Carrier status, in which a person has only one mutated beta-globin gene allele, is estimated at 1 in 15 African Americans. Both SCD and sickle cell trait have a far greater incidence in East Africa and other equatorial countries.

Question 14

Which ethnic group has the highest incidence of cystic fibrosis (CF)?

Accepted Answer

The disorder is inherited as an autosomal-recessive single-gene trait and is most common among Caucasians of Northern and Western European heritage, although it can be found among people of all races and ethnicities. The incidence of CF in the United States among Caucasians is about 1 in 3,000 live births. Carrier status, in which a person has only one mutated gene allele, is estimated at 1 in 20 to 30 Caucasian Americans.

Question 15

What health advantage does sickle cell trait or disease confer on the person who has it?

Accepted Answer

The hemoglobin change caused by the genetic mutation of SCD does reduce the susceptibility to severe malaria on exposure to or infection with the organism. This benefit occurs in both those who are homozygous for the gene mutation and in those who are heterozygous. The disorder does not provide a benefit or reduce risk for development of type 1 diabetes, hypercholesterolemia, or cholera.

Question 16

What is the explanation for creatine kinase (CK) levels in a 14-year-old boy with Duchenne muscular dystrophy being much lower now than they were 5 years ago?

Accepted Answer

Children with DMD have hugely elevated blood levels of the enzyme creatine kinase (CK) and the protein myoglobin during their early childhood years. Both are normally present inside intact muscle cells. When the cells are damaged or die, CK and myoglobin are released into the blood. These levels decrease as the child ages because there is a limit to how much muscle is available to be destroyed. Therefore, lower levels in older children indicate disease progression, not disease improvement. Switching to passive exercise does not decrease muscle damage. BMD has a slower rate of muscle destruction with a more consistent level of blood CK over time.

Question 17

Why does Duchenne muscular dystrophy (DMD) have poor reproductive fitness?

Accepted Answer

Most patients with DMD will die in the late teenage years or early adulthood, and they do not typically have children. There is little variability in the severity of DMD. Those with milder cases are thought to have Becker muscular dystrophy. Although deletions are possible, the dystrophin gene is so large that it is an easy target for a variety of mutations. Adhesion proteins are not involved.

Question 18

Which specific type of genetic problem causes sickle cell disease?

Accepted Answer

Sickle cell disease (SCD) is a genetic disorder caused by a single-nucleotide polymorphism in both alleles of a single gene, which results in the abnormal formation of the beta chain of hemoglobin (beta globin). In the classic form of sickle cell disease, both beta-globin alleles have a mutation in which the DNA triplet coding for glutamic acid has adenine substituted for thymine (instead of CTC, the triplet now reads CAC). This mutation results in valine as the sixth amino acid in the protein sequence. There is no deletion of introns or exons, nor is there a translocation (balanced or unbalanced).

Question 19

Which relative of a patient who has cystic fibrosis has the correct risk for being a cystic fibrosis carrier?

Accepted Answer

Cystic fibrosis is inherited as an autosomal-recessive single-gene trait. Therefore, in virtually all cases, both parents are carriers. A patient's brother and sister would each have a 50% risk for being carriers.

Question 20

Awoman whose hemoglobin S levels are less than 1% has a brother with sickle cell disease, and both parents have been diagnosed as carriers for the disorder. She asks what her risks are of having a child with sickle cell disease. What is the best response?

Accepted Answer

Sickle cell disease is an autosomal-recessive genetic disorder. This woman does not have either sickle cell disease or sickle cell trait, as evidenced by the fact that her HbS levels are less than 1%. Thus, regardless of her partner's sickle cell status, she will not have a child with actual sickle cell disease. However, if her partner is a carrier, any child she has with this partner has a 50% risk of having sickle cell trait. If her partner has sickle cell disease, any child she has will be a carrier of sickle cell trait.

Quiz 11: Common Childhood-Onset Genetic Disorders