Question

Question 8:

Julia had a sibling who died because of a genetic disease as an infant. Before having children, she and her husband Tobias get genetic testing and counseling. They are unlucky.
For the GAA gene, Julia has one normal allele and one totally non-functional allele. Tobias has one normal allele and one totally non-functional allele.
Imagine you are their genetic counselor. Explain to the parents, what causes the disease and explain how it affects the body and how the treatment for Pompe will work.
Use this checklist to make sure your answer is complete:
How is the DNA of an offspring with Pompe different than the DNA of somewhat without the disease?
What function is being disrupted at the cellular level ?
Why does having this disease lead to death (what happens to the body)?
What is the treatment that is used to help Pompe patients?
How does it "fix" the problem?
Are offspring with Pompe cured for life once they receive a dose of the medicine? Explain why or why not.

Answer 1

(How is the DNA of an offspring with Pompe different than the DNA of somewhat without the disease?)

Pompe disease is also known as the glycogen storage disease type II and it is an autosomal recessive metabolic disorder. People suffering of these disease have a mutation in one of the alleles of the GAA (glucosidase alpha, acid) gene. In order to have this disease, both copies of the gene need to be defective, as it is autosomal. Both you Julia and Tobias are healthy due to the presence of a normal allele.

(What function is being disrupted at the cellular level ?)

The enzyme known as acid alpha-glucosidase is produced due to the GAA gene which provides the instructions for its production. Due to mutations, one of the amino acids within the gene changes. This leads to the protein to be less effective in its job. As this enzyme is responsible for the hydrolysis of glycogen to glucose, Pompe disease will cause the accumulation of this substance in the body.

(Why does having this disease lead to death (what happens to the body?)

In time glycogen will accumulate inside the lysosomes up to toxic levels. This will lead to myopathy that is a weakening of the muscles in which the muscle fibers do not function properly. The heart is mostly affected and is the main cause behind the death of individuals suffering from Pompe's disease. Other organs and tissues throughout the body will suffer from increasing damage as well.

(What is the treatment that is used to help Pompe patients?)

Currently there is no cure for this disease. The only treatment is Myozyme, which is an enzyme replacement therapy (ERT). This special form called rhGAA, is obtained from modified animal cells.

(Does this "fix" the problem?) & (Are offspring with Pompe cured for life once they receive a dose of the medicine? Explain why or why not.)

This works through infusions of this drug in order to supplement the defective enzyme produced by the body. This however is not a cure. Myozyme IV infusions are required every other week. As it is currently impossible to repair the defective gene, the body will still be unable to break down glycogen effectively. Thus, continuous infusions of rhGAA are required.

Answer 2

Checklist: 1

Each healthy individual possesses among these genes a functional alpha galactosidase acid gene as an enzyme that contributes to carbohydrate metabolism.

The DNA of an individual with Pompe disease has in his alpha galactosidase acid gene a loss of function due to a mutation which has made the encoded protein non-functional.

Checklist: 2

Pompe disease is a progressive and often fatal genetic disease related to an abnormal functioning of acidic alpha-1,4-glucosidase, a lysosomal enzyme that hydrolyzes glycogen to glucose.

This disease is responsible for muscle damage by abnormal glycogen metabolism. Since the defective enzyme is localized at the level of the lysosome, it is often classified as a lysosomal overload disease.

Checklist: 3

The accumulation of glycogen in the lysosomes of the skeletal muscles and the heart can cause lysosomal overload and lysosome destruction, leading eventually to cell destruction. This pathology can also affect other cells like the liver cells or the nerve cells.

The symptoms are different, it depends on the age. The most commonly observed signs are heart disease and breathing abnormalities leading to death if no care is taken.

Checklist: 4 and 5.

The available treatment is Enzyme Replacement Therapy

Enzyme Replacement Therapy (ERT) provides patients with a special form of alpha-glucosidase to replace the missing enzyme. This special form, called rhGAA, is produced from modified animal cells (a way to produce a large quantity of a quality enzyme needed for ERT).

Checklist: 6.

Unfortunately, the replacement therapy does not treat the disease itself, it only makes it possible to fill the enzymatic deficit caused by the disease, in order to improve the quality of life and prolong the life of the patient, because the cells will always remain incapable to synthesize the enzyme to the functional state by themselves.

The transplantation of bone marrow (in order to correct the deficit in the blood cells) has not been successful.