What is the Main Cause of Forbes Disease?
Humans utilize energy from three main sources carbohydrates (glucose), fats and proteins. Carbohydrates are stored mainly in the liver and muscles in the form of glycogen; fats are stored in adipose tissues and other organs and proteins are stored mainly in the muscles. There are thirteen types of glycogen storage diseases in which the energy stored in the form of glycogen cannot be converted to glucose to be further processed as energy. Forbes disease is a type of glycogen storage disease that has various names such as glycogen storage disease type III, Cori’s disease, amylo-1,6-glucosidase deficiency, AGL deficiency, glycogenosis type III, limited dextrinosis, glycogen debrancher deficiency and GSD-III. Forbes disease is a rare hereditary disease, which affects 1 in 100,000 people all around the world, 1 in 40,000 in the United States, but is common in the Inuit population of Canada, Faroese and North African Jews.
What is the Main Cause of Forbes Disease?
The main cause of glycogen storage disease type III or Forbes disease is the mutation of AGL gene located on chromosome 1p21. It is a genetic disorder that is inherited as an autosomal recessive trait. The mutation of AGL gene is responsible for the production of amylo-1,6-glucosidase debranching enzyme and this leads to incomplete conversion of glycogen to glucose, which is the main source of energy for the body. Glucose is stored in the liver and muscles in the form of glycogen. At the time of energy need (such as during fasting or exercising) by the body, glycogen is converted to glucose for energy. The debranching enzyme has two catalytic (active) sites known as amylo-1,6-glucosidase and 4-alpha-glucanotransferase. These sites, along with phosphorylase and phosphorylase kinase enzyme are responsible for the complete breakdown of glycogen to glucose.
Without the normal function of debranching enzyme (lack of amylo-1,6-glucosidase enzyme), glycogen is only broken down partially, thus there is insufficient production of glucose in the body, thus insufficient energy is produced. The incompletely broken down glycogen structure is known as limit dextrin and is stored in liver and muscle (skeletal and cardiac) tissues. Thus, liver, skeletal and cardiac muscle abnormalities characterize Forbes disease. The risk is the same for males and females. The risk also increases when both the parents are closely related than in unrelated parents.
What are the Types of Glycogen Storage Disease Type III?
Glycogen storage disease type III is classified into four subtypes in which GSD-IIIa subtype is the most common affecting nearly 85% of individuals and affects both the liver and muscles (cardiac and/or skeletal). GSD-IIIb affects about 15% of all individuals and affects only the liver. GSD-IIIc is extremely rare and is believed to be caused by a loss of activity of glucosidase catalytic site of glycogen debranching enzyme. GSD-IIId is also considered extremely rare and is suspected to be caused by loss of activity of transferase catalytic site of the glycogen debranching enzyme.
What are the Symptoms of Glycogen Storage Disease Type III?
Generally, Forbes disease starts to show symptoms at very early age (as early as one year of age) since it is a genetic disorder. The most common symptoms of the disease are hepatomegaly (enlarged liver in about 98% cases), hypoglycemia (low blood sugar in about 53% cases), failure to grow (in about 49% cases) and recurrent illness and/or infection (in about 17% of all cases). There is also protrusion of abdomen due to hepatomegaly along with weak/flaccid muscles during childhood. Hepatomegaly, starts subsiding with age as the child becomes adult; however, it may progress to liver cirrhosis and hepatic carcinoma.
Forbes disease causes short stature along with hypoglycemia and hyperlipidemia as a child. Patients also have frequent nosebleeds as well as difficulty fighting infections. Cardiac hypertrophy is common in patients with GSD-IIIa, although the heart function is normal. The signs and symptoms usually improve with dietary changes; however, muscular disease gets worse even with dietary changes.