NAM tutorial glycogen storage disease PDF

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Metabolism & Nutrition Block

Biomolecular Tutorial worksheet 4 XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX

Metabolism

Glycogen Storage Disease William, a 19-year-old science student, had consulted the College Health service, because of leg muscle pains and cramps after attempting to play for a five-a-side football team during freshers’ week. During his school years, William had managed to avoid playing an active role in team sports or PE, after early experiences had shown him that he tired very easily and developed cramp after running for a few minutes. He had also observed in the past that, when the severe pain occurred, if he carried on with gentle exercise such as walking, the cramps seemed to disappear after 15 – 30 mins and he could continue with a moderate level of activity. Now he wanted to get involved in College activities and sort out whether there was a genuine problem or whether he was merely unfit and out of condition. A physical examination revealed no obvious joint or skeletal problems. A fasting blood sample was taken which indicated a normal blood glucose concentration (4.2 mM), normal blood lipid levels and normal insulin and thyroid hormone levels. After William carried out a moderate and controlled amount of work on the exercise bicycle for 15 minutes, (which caused a mild degree of discomfort in his leg muscles), another blood sample was taken. This sample showed that his blood glucose level had dropped slightly to 3.9 mM, but also showed a very low level of blood lactate, despite the sensation of cramp. The blood analysis showed that there was a significant amount of the protein myoglobin in the plasma, as well as abnormally increased levels of three enzymes, creatine kinase (MM isoform), aldolase and lactate dehydrogenase (muscle isoform). A carefully controlled study of forearm muscle work using a hand dynamometer showed that William produced very little lactic acid compared with the results from a group of normal individuals, and a provisional diagnosis of McArdle’s disease (muscle glycogen phosphorylase deficiency) was made. William was given advice on the best approach to controlling the symptoms of muscle pain, such as glucose drinks or tablets before starting exercise, and optimising his physical exertion strategies to allow the muscles to use fatty acids as the predominant fuel. A muscle biopsy later confirmed the diagnosis of muscle phosphorylase deficiency, with less than 20% of the normal level of the enzyme. (NB: McArdle’s disease was first described at Guy’s Hospital) Questions 1.

In which two tissues or organs of the body is glycogen an important store of carbohydrate?

2.

What is the reaction catalysed by the enzyme glycogen phosphorylase?

3.

Outline the series of enzyme reactions responsible for the breakdown of glycogen to glucose-6-phosphate, (including enzymes acting on the α-1, 6 glycoside links).

4.

What might be the subsequent metabolic fate of glucose-6-phosphate in the following tissues: a) liver b) fast (white/glycolytic) skeletal muscle (with high % of type 2 fibres) c) slow (red/oxidative) skeletal muscle (with high % of type 1 fibres)

5.

Outline the reaction catalysed by the enzyme lactate dehydrogenase , and explain why lactate is the end product of glycolysis in normal muscles performing high intensity exercise

6.

Explain why very little lactate was detected in William’s blood even when he carried out standard exercise procedures as part of his investigation.

7.

What may be the explanation for the painful cramps experienced by William after short bursts of exercise, even though his muscles are producing very little lactic acid?

8.

This inherited condition is known as McArdle’s Syndrome (glycogen storage disease type V). Many patients with this condition experience a ‘second wind’ or ability to continue exercising after an interval of 10 – 15 minutes after the pain first starts. What blood-borne fuel molecules might be providing a delayed alternative to glycogen as a source of ATP for muscle contraction?

9.

The clinical chemistry investigations of the patient reported high levels of the enzymes creatine kinase, aldolase and lactate dehydrogenase in his plasma. What do these findings indicate?

10.

What signs and symptoms would you expect in a patient with an inherited defect in the liver isoform of glycogen phosphorylase? Why is this likely to be more life threatening condition than the muscle enzyme defect?

11.

Name one other ‘glycogen storage disease’ and indicate the affected enzyme...