Genetic defects in glycogen metabolism can result in disease. The symptoms are often useful diagnostic indicators of the underlying genetic defect. Here are some cases that present typical symptoms of various glycogen storage diseases.
6 week old male infant; low weight;
weakness and lethargy; difficulty in nursing.
Normal delivery; parents healthy
Very noticeable muscle laxity; slightly
enlarged liver; mild cyanosis and rapid, shallow breathing.
|BUN & creatinine||Normal|
Imaging shows enlarged heart (3 times normal) and liver; congestive heart failure.
Micropathological exam of biopsy samples shows extensive glycogen deposits in heart muscle, liver, kidney.
1. What is the defective enzyme in Pompe's disease? What is the "common" name for this enzyme?
2. What is unusual about the cellular location of this enzyme?
3. What are the biochemical consequences of a deficiency in this enzyme?
4. Pompe's disease is referred to as a generalized type of glycogen storage disease. Contrast it with McArdle's disease (a myopathic type of glycogen storage disease), in terms of tissue specificity.
5. Explain why the laboratory results reported above all were normal.
6. Why is there enlargement of the heart and the liver here?
7. Explain the generalized lethargy and muscle laxity.
8. What therapy is available for Pompe's disease?
Pompe's disease is due to a deficiency in lysosomal -1,4 glucosidase, also known as "acid maltase". Lysosomes are normally responsible for breaking down macromolecules like proteins and nucleic acids, but they can incidentally take up and digest glycogen as well. The interior of the lysosome is typically more acidic than the surrounding cytosol; the lysosomal enzymes are more active under acid pH conditions than at neutral pH; hence the designation of this particular glucosidase as the "acid" maltase.
In Pompe's disease, the lack of the lysosomal enzyme results in a buildup of undigested glycogen in the lysosomes, interfering with their proper functioning. The increasing loss of lysosomal function then affects the whole cell. Since lysosomes are distributed throughout all types of tissue, this disease affects all major organ systems.
The onset of the disease is early and severe, and affected infants generally do not survive past 24 months. Therapy can only be palliative.Back to the Clinical Cases Homepage
14 year old male, nonsmoker; easily
fatigued, experiencing muscle cramps after windsprints and calisthenics in high
school gym class.
Generally sedentary habits; avoided
physical activity throughout grade school and junior high school. Noticed that
exercise "hurt", so tended to avoid it if at all possible.
About 10 pounds overweight.
No gross abnormalities noted.
1. What is the enzyme activity that is deficient here?
2. What biochemical reaction does it catalyze?
3. What are the biochemical consequences of a deficiency in its activity? Explain why this patient complains that it "hurts" when he exercises. Why is he easily fatigued?
4. Is this enzyme (and the biochemical reaction it catalyzes) essential for sustaining life?
5. As alternative causes, could this disease also be caused by a deficiency in phosphorylase kinase? Could it be caused by excessive activity by protein phosphatase?Review of glycogen biochemistry
McArdle's disease is due to a deficiency in glycogen phosphorylase, principally in skeletal muscle. Since it is muscle tissue that is mainly affected, this disease is referred to as a myopathic type of glycogen storage disease.
Glycogen phosphorylase a is the phosphorylated, tetrameric form of the enzyme which is responsible for breaking down glycogen into phosphorylated monomer units (glucose 1-P, which then is converted to glucose 6-P for further metabolism). The b form of the enzyme is de-phosphorylated and inactive; phosphorylase kinase catalyzes the activation by transferring a phosphoryl group from ATP onto a specific serine residue of the phosphorylase monomer, and a protein phosphatase catalyzes the de-phosphorylation reaction.
Low or negligible levels of glycogen phosphorylase activity will result in a general inability to break down glycogen quickly; it will be hard for the body's muscles to draw on glycogen as a quick source of energy, and other sources of glucose must be utilized instead. Thus, sudden demands for energy (for example, climbing several flights of stairs, or moving furniture) can cause painful cramps and weakness, due to a buildup of lactic acid. Patients with this disease are usually otherwise in good health, though in later life they may develop persistent muscular weakness.Back to the Clinical Cases Homepage
6 year old boy with frequent episodes of weakness
Weakness accompanied by sweating, feeling of dizziness; weakness had been noticed since about age 4, but had become more noticeable when child entered school and was challenged by other children during recess.
Enlarged abdomen, due to grossly enlarged liver. Kidneys also enlarged. Poor musculature. Normal heart.
Fasting blood sample:
|Glucose||3.0 mmol/L||(normal, 3.9 to 5.6)|
|Lactate||7.1 mmol/L||(normal, 0.56 to 2.0)|
|Pyruvate||0.4 mmol/L||(normal, 0.05 to 0.10)|
|Free fatty acids||1.6 mmol/L||(normal, 0.3 to 0.8)|
|Triglycerides||3.0 g/L||(normal, 1.5)|
|Total ketone bodies||380 mg/L||(normal, 30)|
|pH||7.25||(normal, 7.35 to 7.44)|
|Total CO2||12 mmol/L||(normal, 24 to 30)|
Liver biopsy results
|Glycogen||10 g/ 100g of tissue||(normal, up to 6 g)|
|Lipid||20 g/100g of tissue||(normal, less than 5 g)|
|Glucose 6-phosphatase||20 units per gram of liver nitrogen||(normal, 214 ± 45)|
|Phosphorylase||20 units per gram of liver nitrogen||(normal, 22 ± 3)|
|Fructose 1,6-Bisphosphatase||9 units per gram of liver nitrogen||(normal, 10 ± 6)|
1. What is the enzyme defect here?
2. Why is the liver enlarged?
3. Why did the child complain of weakness?
4. What is the significance of the fasting blood sample test results?
5. Why is blood pH on the acidic side? Is this related to the serum CO2 level? If so, how? If not, why not?
6. What is the significance of the high levels of glycogen in the liver biopsy test results?
7. What do the enzyme test results tell you about this patient?
8. What therapy do you recommend for this patient?
Von Gierke's disease is caused by a deficiency in glucose 6-phosphatase, the enzyme that removes the phosphoryl group from glucose and permits it to be released from the cell (where it was presumably stored as glycogen, or synthesized via gluconeogenesis). Passage of the phosphorylated sugar through the cell membrane is negligible; only the de-phosphorylated form can be exported. Thus, when exercise raises energy demands on the body, glycogen stores cannot be adequately mobilized as glucose into the bloodstream to provide the needed energy. The result is a severe hypoglycemia and general weakness. Furthermore, since the glycogen in the liver is not being broken down, it tends to accumulate and to then interfere with the proper functioning of the liver cells in which it is stored. This causes an enlarged liver.
Instead of the customary glucose as a source of energy, the body now tends to use more fatty acids and ketone bodies for energy production. This results in elevated serum levels of triglycerides, free fatty acids, and ketone bodies. This is typically accompanied by a metabolic acidosis.