Brittnee A.

Williams
September 15, 2015
HUN 3230
Case Study 1

40 points

Please answer the questions thoroughly. Your answers should be in essay format and they should
include a certain level of detail as covered in class. Please do not exceed one third to one half
page per answer (single space).” Make sure to include the questions with the answers right below
them.

Note: You will likely need to find research articles to help you answer the questions. Please make
sure you cite the references according to AMA guidelines while answering the questions. You
should also include the bibliography at the end of the page.

Case Presentation 1: A patient complained of muscle cramps and was unable to perform
strenuous exercise. He had elevated levels of creatine phosphokinase, aldolase, and myoglobin
in his blood. The release of enzymes and other proteins from muscle cells is indicative of muscle
cell damage. He was diagnosed with type V glycogen storage disease (McArdle disease), which
is caused by an absence of muscle glycogen phosphorylase.

1. Would you expect glycogen to accumulate in the muscle of this patient? Why or
why not? (5 points) If insulin production and sensitivity to insulin is normal in a person
with type V glycogen storage disease, then blood glucose is being transported into the
muscle tissues as normal via GLUT 4 translocation. Once it is inside the muscle tissues,
these glucose molecules are phosphorylated by hexokinases, into glucose 6-phosphate,
which traps the glucose inside the muscle cells. From here, the glucose can be oxidized
for energy or stored as glycogen. If it is to be stored as glycogen, glucose 6-phosphate is
converted to UDP-glucose which is incorporated into glycogenin by glycogen synthase at
carbons 1 and 4. Branches of 5 to 7 glucose molecules are cleaved and bonded to
carbons 1 and 6 of the glucose molecules on the glycogen chain by branching enzyme
forming the glycogen stores. For the muscle tissues to be able to access this stored
glycogen to be utilized for energy, individual units of glucose 1-phosphate, need to be
cleaved from the branches of glycogen. The enzyme that cleaves these individual units
at the 1 to 4 carbon bonds is called phosphorylase. In the absence of muscle glycogen
phosphorylase these bonds cannot be broken and the individual molecules of glucose
cannot be cleaved from the glycogen molecules. Therefore the glycogen molecules stay
intact while glycogenesis continues, although most likely at a slower rate, yet causing
glycogen to accumulate in the muscle of this patient. 1

2. Would you expect lactate to accumulate in the muscle or blood of this patient during
exercise? Why or why not? (5 points) In the presence of sufficient oxygen, glucose
molecules can be oxidized aerobically, and the product of glycolysis, pyruvate, is able to
enter the mitochondria of the muscle cells where a series of reactions converts the 3
carbon pyruvate into a 2 carbon acetyl group and joins it with coenzyme A. This newly
formed acetyl-CoA can now enter the TCA cycle and ultimately generate energy for the
cells in the form of ATP. Lactate is this product of glycolysis, pyruvate, in the absence of
sufficient oxygen. Pyruvate does not enter the mitochondria and instead is reduced to
form lactate which is released back into the bloodstream to be sent to the liver and
converted back into pyruvate to reenter the energy pathways as glucose, known as the
Cori Cycle. Therefore lactate should not be accumulating in the blood or muscles of this
patient, it is being recycled. The deficiency of muscle phosphorylase that is characteristic
 Brittnee A. Williams
September 15, 2015
HUN 3230
of this disease causes the accumulation of glycogen whereas a deficiency of oxygen
available to the cells would be the cause of lactate accumulation. The fatigue experienced
by this patient would be due to a lack of pyruvate available to even enter the TCA cycle
and a subsequent lack of oxygen being used by the cells.1 Therefore, even with the limited
amount of pyruvate production from limited access to glucose supplies, any lactate
molecules produced should be sent back to the liver to be converted to glucose through
gluconeogenesis which is why you would therefore not expect to see lactate accumulate
in the muscle or blood of this patient.

3. What fuels would you expect this patient to use during exercise? (10 points) The
patient is not accessing his glycogen stores from the muscles, therefore, I would expect
he is oxidizing the glucose molecules as soon as they are transported from the blood to
the muscle cells and trapped inside as glucose 1-phosphate. However, because blood
glucose levels will soon be depleted, two other sources of fuel could be the glucose
provided by the liver and kidneys. Liver glycogen stores, from gluconeogenesis of lactate,
glucogenic amino acids, and glycerol, can be broken down by liver phosphorylase and
because the liver (and kidneys) has the enzyme glucose 6-phosphatase, it can convert
glucose 6-phospate into glucose which can be sent back out into the bloodstream and
picked up by the muscle cells for immediate oxidation. There is, however, a lapse in the
time (6-8 minutes) where the patient may have to minimize exercise until the muscle cells
are provided with these alternative fuel sources. It is hypothesized that this lower activity
level timeframe is the time it takes for the liver glycogen stores and fatty acid oxidation to
reach the muscle cells so the patient can resume exercise. 2

Case Presentation 2: Two genetic defects in fructose metabolism are known: fructose
intolerance and essential fructosuria. Fructose intolerance is caused by an autosomal recessive
defect in the liver fructose 1-phosphate aldolase (aldolase B) gene. The symptoms of hereditary
fructose intolerance are absent in infancy if the infant is breast-fed. However, the introduction of
sweetened milk formulas or the later introduction of fruits and vegetables provokes the symptoms
of this disorder due to exposure to fructose. The deficiency in aldolase B leads to the buildup of
fructose 1-phosphate and the depletion of Pi for ATP production in liver. The accumulation of
fructose 1-phosphate blocks both glycogenolysis, owing to inhibition of glycogen phosphorylase
by fructose 1-phosphate, and gluconeogenesis, owing to inhibition of the fructose bisphosphatase
aldolase and phosphoglucose isomerase reactions in the reversal of glycolysis. Furthermore, the
depletion of Pi and ATP leads to a series of imbalances, including the inhibition of protein
synthesis, that cause liver cell damage and a decline in liver function. In contrast to fructose
intolerance, the symptoms of essential fructosuria are essentially those of a “nondisease”.
Essential fructosuria is caused by a defect in fructokinase, which is normally found in liver, kidney,
and intestinal mucosa. This relatively harmless disorder results in the excretion of fructose in the
urine, as well as some metabolism of fructose to fructose 6-phosphate by hexokinase in adipose
and muscle tissue.

1. In normal individuals, the capacity of the liver to phosphorylate fructose

(fructokinase activity) greatly exceeds the liver's capacity to split fructose 1-
phosphate (aldolase B activity). Why is a deficiency of fructokinase a less serious
genetic defect than a deficiency of fructose 1-phosphate aldolase? Consider what
happens to fructose in each case and what effect this has on hepatic metabolism.
(20 points)
 Brittnee A. Williams
September 15, 2015
HUN 3230
The initial phosphorylation of fructose by fructokinase is what traps the fructose inside the
liver cells. The deficiency of fructokinase means the fructose never, or far less frequently,
enters the liver cells and is instead filtered out of the blood by the kidneys and excreted in
urine as waste. If fructose is continuously phosphorylated and therefore trapped inside
the cell, it must also have a means to leave the cell. Fructose 1-phosphate aldolase b is
this means in the liver as it splits the fructose 1-phosphate molecule so that it may enter
the glycolytic pathway. The absence of Fructose 1-phosphate aldolase means the now
trapped Fructose 1-phosphate has no exit and will accumulate in the liver cells. If this
accumulation of trapped fructose is also inhibiting the enzymes needed to breakdown
glycogen stores and create new glucose molecules for glycogen storage the liver will be
severely limited in its ability to function normally and the individual will most likely suffer
from symptoms such as nausea and vomiting which with repeated exposure could
progress to jaundice, cirrhosis and liver or kidney failure.3 This accumulation of
phosphorylated fructose is also monopolizing the liver’s supply of the inorganic phosphate
needed to make ATP and the reduction of ATP leads to more cell damage/death. Fructose
is modified to enter the glycolytic pathway as glyceraldehyde 3-phosphate and the muscle
cells can even convert fructose into fructose 6-phosphate so there are alternative
pathways for the metabolism of fructose but these do not aid in the removal of fructose
from accumulating in the liver. The capacity to phosphorylate fructose greatly exceeds the
supply of fructose that the liver would even need, therefore, excretion of fructose in the
urine due to a deficiency in fructokinase is a far less serious genetic defect than
accumulation of fructose in its phosphorylated form due to a deficiency in fructose 1-
phosphate aldolase for the series of imbalances and damage the accumulation can cause.

References

1. Sharma N, Suva MA. A brief review on McArdle Disease (Glycogen Storage Disease Type

V). Pharma Science Monitor. 2014;5(3):110-121.

2. Scalco RS, Chatfield S, Godfrey R, et al. From exercise intolerance to functional

improvement: The second wind phenomenon in the identification of McArdle Disease. Arq

Neuropsiquiatr. 2014;72(7):538-541.

3. Valadares ER, Cruz AFd, Adelino TER, et al. Hereditary fructose intolerance in Brazilian

patients. Molecular Genetics and Metabolism Reports. 2015;4:35-38.