Glycogen storage diseases

Dr. Samah Kotb 2015

Cellular Biochemistry and

Metabolism2(CLS 333)

GLYCOGEN STORAGE DISEASES

CHAPTER 6

Glycogen

• Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals and fungi. The polysaccharide structure represents the main storage form of glucose in the body.

Disorders of glycogen metabolism

Disorders of glycogen metabolism

• The most common disease in which glycogen metabolism becomes abnormal is diabetes, in which, because of abnormal amounts of insulin, liver glycogen can be

abnormally accumulated or depleted. Restoration of normal glucose metabolism usually normalizes glycogen

metabolism, as well.

• In hypoglycemia caused by excessive insulin, liver glycogen levels are high, but the high insulin levels prevent the glycogenolysis necessary to maintain normal blood sugar levels. Glucagon is a common treatment for this type of hypoglycemia.

• Various inborn errors of metabolism are caused by deficiencies of enzymes necessary for glycogen synthesis or breakdown. These are collectively referred to as glycogen storage diseases .

Glycogen depletion endurance exercise

• Long-distance athletes, such as marathon runners, cross-country skiers, and cyclists, often experience glycogen depletion, where almost all

of the athlete's glycogen stores are depleted after long periods of exertion without enough

energy consumption. This phenomenon is referred to as hitting the wall.

Glycogen depletion can be forestalled in three possible ways.

First, during exercise, carbohydrates with the highest possible rate of conversion to blood glucose (high glycemic index) are ingested continuously. The best possible outcome of this strategy replaces about 35% of glucose consumed at heart rates above about 80% of maximum.

• The glycemic index is a number associated with a particular type  of  carbohydrate-containing  food  that  indicates  the food's effect on a person's blood glucose (also called blood sugar  ) level.

• Second, through endurance training adaptations and specialized regimens (e.g. fasted low-intensity endurance training), the body can condition type I muscle fibers to improve both fuel use efficiency and workload capacity to increase the percentage of fatty acids used as fuel, sparing carbohydrate use from all sources.

• Third, by consuming large quantities of carbohydrates after depleting glycogen stores as a result of exercise or diet, the body can increase storage capacity of intramuscular glycogen stores. This process is known as carbohydrate loading.

• When experiencing glycogen debt, athletes often experience extreme fatigue to the point that it is difficult to move. As a reference, the best professional cyclists in the world will usually finish a 4 to 5 hr stage race right at the limit of glycogen depletion using the first three strategies.

• When athletes ingest both carbohydrate and caffeine following exhaustive exercise, their

glycogen is replenished more rapidly

Glycogen storage diseases

• Glycogen storage diseases (GSDs) are a group of inherited genetic disorders. They cause glycogen to be improperly formed or released in the body. This results in a build up of abnormal amounts or types of glycogen in tissues.

• The main types of GSDs are categorized by number and name and include:

• Type I (Von Gierke disease, defect in glucose-6-phosphatase) most common type of GSD; accounts for 90% of all GSD cases.

• Type II (Pompe’s disease, acid maltase deficiency).

• Type III (Cori’s disease, debrancher enzyme deficiency)

• Type IV (Andersen’s disease, brancher enzyme deficiency).

• Type V (McArdle’s disease, muscle glycogen phosphorylase deficiency).

• Type VI (Hers’ disease, liver glycogen phosphorylase deficiency).

• Type VII (Tarui’s disease, muscle phosphofructokinase deficiency).

• Type IX (liver glycogen phosphorylase kinase deficiency).

• Glycogen is mainly stored in the liver or muscle tissue. As a result, GSDs usually affect functioning of the liver, the muscles, or both.

• Liver: The GSDs that mainly affect the liver are types I, III, IV, VI, and IX.

• Muscles: The GSDs that mainly affect muscles are types V and VII.

• Type II affects nearly all organs including the heart.

Causes

Causes

1) GSDs are caused by a genetic enzyme defect. It is inherited from both parents.

2) Normally, enzymes help convert glucose into glycogen for storage. Other enzymes convert the glycogen back to glucose when energy is needed. This happens during activity like exercise. With GSD, some of these enzymes are defective, deficient, or absent.

• The abnormal glycogen build up in the liver and/or muscle tissues.

The main risk factor for GSDs is having a family member with this disease. The risk varies with the type of GSD.

Risk Factors

• Parents with one child with GSD have a 25% of having another child with GSD. In a few of the GSD types, the risk rises to 50%. In this case only male children are affected.

Symptoms

• The most common symptoms of GSDs include:

* Low blood sugar.* Enlarged liver.* Slow growth.* Muscle cramps.

• Signs and symptoms of specific types of GSDs include:

• Type I:• 1) Large and fatty liver and kidneys.• 2) Low blood sugar.• 3) High levels of lactate, fats, and uric acid in the blood• 4) Impaired growth and delayed puberty.• 5) Osteoporosis.• 6) Increased mouth ulcers and infection.

• Type II:• 1) Enlarged liver and heart.• 2) In severe cases, muscle weakness and heart

problems develop.• 3) In severe cases, infants may suffer fatal heart failure

by the age of 18 months.• 4) Milder forms of type II may not cause heart

problems.

• Type III:• 1) Swollen abdomen due to an enlarged liver.• 2) Growth delay during childhood.• 3) Low blood sugar.• 4) Elevated fat levels in blood.• 5) Possible muscle weakness.

• Type IV:• 1) Growth delay in childhood.• 2)Enlarged liver Progressive cirrhosis of the liver

(which may lead to liver failure). • 3) May affect muscles and heart in late-onset type.

• Type V:• 1) Muscle cramps during exercise.• 2) Extreme fatigue after exercise.• 3) Burgundy-colored urine after exercise.

• Type VI, IX:• 1) Liver enlargement occurs, but diminishes with age.• 2) Low blood sugar.

• Type VII:• 1) Muscle cramps with exercise.• 2) Anemia.

Diagnosis

• The doctor will ask about symptoms and medical history. A physical examination will be done. Diagnosis of GSDs usually occurs in infancy or childhood. It is often done by the symptoms listed above.

Tests may include

• Biopsy of the affected organs. • Blood and urine samples.• MRI (Magnetic Resonance Imaging) scan: a test that

uses magnetic waves to make pictures of the inside of the body.

Treatment

Treatment

Treatment will depend on the type of GSD and the symptoms. Your doctor will develop a plan based on your specific symptoms.

Treatment of GSDs that affect the liver

• These general guidelines apply to people with types I, III, IV, VI, and IX.

• The goal of treatment is to maintain normal blood glucose levels. This may be done with:

• Nasogastric infusion of glucose for infants and children under age two.

• Dietary changes, including: • Children over age two frequent small carbohydrate

feedings throughout the day; may include uncooked cornstarch (provides a steady slow-release form of glucose)

• Type I only elimination of foods that are high in fructose or lactose.

• Allopurinol (Aloprim, Zyloprim) reduces uric acid levels in the blood to prevent gout and kidney stones.

Type IV sometimes treated with liver transplantation.

Treatment of GSDs That Affect the Muscles

• These general guidelines apply to people with types V and VII:

• The goal of treatment is to avoid muscle fatigue and/or cramps induced by exercise. This is done by:

• 1) Regulating or limiting strenuous exercise to avoid fatigue symptoms.

2) Improving exercise tolerance by oral intake of glucose or fructose (fructose must be avoided in people with type I), or an injection of glucagon.

• 3) Eating a high protein diet.

Prevention

• There is no way to prevent GSDs. However, early treatment can help control the disease once a person has it.

• If you have a GSD or a family history of the disorder, you may want to consult a genetic counselor. They can help determine the risk for your children.