What are the Symptoms of Forbes Disease?
Forbes disease is one of several glycogen storage diseases in which the energy stored in the form of glycogen cannot be converted to glucose to be further processed as energy. It 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 that is inherited as an autosomal recessive trait. It 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.
Cause of Forbes Disease
Forbes disease is a genetic disorder with female to male ratio being 1:1. Its main etiological factor can be attributed to the mutation of AGL gene located on chromosome 1p21. 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. 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 leading to insufficient energy production. The incompletely broken down glycogen structure is known as limit dextrin and is stored in liver and muscle (skeletal and cardiac) tissues.
What are the Symptoms of Forbes Disease?
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. Due to the absence of amylo-1, 6-glucosidase enzyme there is incomplete breakdown of glycogen to glucose, which constitutes most of the symptoms of Forbes disease. Liver, skeletal and cardiac muscle abnormalities characterize Forbes disease as these are the places where the incomplete broken down compound of glycogen is stored.
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. Other symptoms of Forbes disease include slowed childhood growth, delayed puberty, retarded growth, failure to thrive, underdeveloped midface, deep set eyes, depressed nose bridge, broad nose tip, upturned nose tip, bow shaped lips, muscle weakness that progressively worsens with age, wasting of muscles of hands and feet (seen late in life), myopathy (also seen late in life) and fasting intolerance.
Diagnosis and Treatment of Forbes Disease
The diagnoses of Forbes disease include enlarged liver, low blood sugar, high ketone, transaminase, lipids and creatine kinase levels. It can further be confirmed by genetic testing for mutation of AGL gene.
The foundation for the treatment of Forbes disease is dietary modification, which includes high protein diet and avoiding fasting to keep hypoglycemia at bay. Nocturnal nasogastric feeding tube may be required for the prevention of hypoglycemia (low blood sugar level) during sleep. Patients should take frequent meals and consume uncooked starch supplements such as cornstarch. The patient should also monitor his/her blood glucose level and ketone level. The dietary modification is known to limit and prevent heart and/or muscular disease. In patients with severe hepatic cirrhosis, liver failure and hepatocellular carcinoma, liver transplantation is the only option.