Type III Glycogen Storage Disease

Synonyms:
Debrancher Deficiency, Cori Disease, Forbes Disease, Limit Dextrinosis

Type III GSD is caused by a deficiency of glycogen debrancher enzyme (GDE) activity. Glycogen debranching enzyme along with another enzyme, phosphorylase, helps break down the branches of glycogen to release free glucose. Deficiency of GDE results in glycogen with short outer chains in liver, muscle, and heart tissues. The abnormal glycogen is not soluble and causes damage to tissues where it collects (liver and/or muscle). This can be compared having a piece of sand in your shoe that, although small, irritates the foot. This partial breakdown of glycogen into glucose also causes hypoglycemia (low blood sugar) because glucose sugar can not be released. The body is unable to properly metabolize glycogen (a complex form of sugar). Because of improper processing, glycogen is stored in the organs of the body.

Glucose, a simple form of sugar, is our bodies' main source of energy. After a person eats, there is too much glucose in the blood, so the body stores the extra glucose in the form of glycogen in the liver and muscles (much like one might deposit extra money in a bank). When the body needs more energy, certain enzymes convert the glycogen back to glucose and withdraw it from the liver and the muscles (just like one can withdraw spending money from the bank). One of the enzymes that helps break glycogen down into glucose in the muscles is called debranching enzyme. Individuals with GSD III either have a defective enzyme or lack a sufficient amount of this important enzyme. As a result, glycogen is not broken down completely and accumulates in the liver and/or muscle tissue. Accumulation of abnormal glycogen in the liver tissue causes it to become enlarged and not function properly.

GSD III is a genetic disorder and it is inherited as an autosomal recessive disease. This means it is caused by a change in a part of an individual's genetic information. Genetic information is stored on genes. Genes serve as the instruction manual for our bodies. They tell the body how to grow and function. They also determine physical features, such as hair color and eye color. A person has around a 30,000 genes in every cell of their body. Two sets of every gene are inherited, one set from the mother and one set from the father.

If there is a change in the genetic information contained on one of these genes, the body is unable to read the instructions. Therefore, it may cause a difference in the way the body functions. This is similar to having a page missing out of an instruction manual for putting an appliance together. Without that page, one would be unable to properly assemble the appliance and it would not be able to work. The gene responsible for making debranching enzyme (GDE) is called the amylo-1,6-glucosidase, 4-alpha-glucoanotransferase gene (AGL) gene. If one copy of the AGL gene is altered but the second copy is not, then the body can follow the instructions on the second copy in order to produce enough debranching enzyme. This is like having a second instruction manual to refer to. When both copies of an individual's AGL gene are altered, the body is unable to read any instructions on how to make the proper amount of debranching enzyme. As a result, the individual has GSD III.

There are two types of GSD III known as type IIIa and type IIIb. Most patients with Type III GSD have enzyme deficiency in liver and skeletal muscle. Patients that have enzyme deficiency in liver and muscle (including sometimes the heart muscle) have what is known as GSD IIIa. Some patients (<15%) have debranching enzyme deficiency only in the liver - this is known as GSD IIIb. During early years of infancy and childhood, the disease may present clinically just like Type I GSD: small stature, large liver, poor muscle tone (hypotonia) and hypoglycemia. Some liver symptoms (enlarged liver) often improve with age and may disappear after puberty. However, in some patients liver cirrhosis (damage to liver cells) can occur due to accumulation of abnormal glycogen.

Children with GSD III are often first diagnosed because they have distended abdomens (swollen belly) due to a very large liver. Some children have problems with low blood sugars when fasting (not eating for 4 hours) but this is not as common or as severe as in GSD I. Growth may be delayed or slow during childhood but most individuals reach a normal adult height. Muscle weakness (GSD IIIa) is commonly present in childhood and can, at times, become severe in adult age (requiring use of a wheel chair for mobility by 50-60 years). Although the enzyme defect does not go away, the liver often returns to a smaller size at puberty.

Elevated glycogen content is present in liver and muscle cells. A definite diagnosis and sub-typing (determining IIIa versus IIIb type) requires either liver biopsies or DNA based genetic testing. Biopsy of the liver shows inflammatory changes (swollen liver cells) with great elevations of abnormal-structured glycogen content and a deficiency of the debrancher enzyme (GDE). In GSD IIIa, biopsy of muscle and liver shows an accumulation of abnormal-structured glycogen and deficiency of debrancher enzyme. However, if only the liver is examined, the type of GSD cannot be determined. If genetic testing is performed and the person has a gene change in the area associated with GSD IIIb, a doctor may be able to use the mutation information and clinical information to determine the GSD III sub-type (type a versus type b).

Other complications associated with Type III GSD can include radiographic (X-ray) evidence of osteopenia (weak bones) and fractures. Often, a DEXA bone scan will be required to measure bone density. Also, chemical analysis of the blood usually shows low blood sugar and elevated levels of fat (cholesterol/lipids). However, uric acid and lactic acid levels, which are usually elevated in GSD I patients, are usually normal.

Currently, there is no effective treatment for this disease. Hypoglycemia (low blood sugar) can be controlled by frequent meals high in carbohydrates. Researchers have proven the storage of glycogen leads to liver cirrhosis progressing to liver failure. Patients with myopathy (weak muscles) have been tried on a diet high in protein, with some improvement; however, no long-term data is currently available.

Type III GSD is considered a muscular dystrophy because of the weakness of the muscle. As a result, people with GSD III may qualify for services offered by the Muscular Dystrophy Association (MDA).

People with debrancher deficiency have lived well into late adulthood. Muscle disorders seem to be an increasing problem with age in those persons with Type IIIa. Muscle weakness, though minimal during childhood, may become more evident in adults with onset in the third or fourth decade. These patients have slowly progressive weakness and distal muscle deterioration, and some patients eventually may require the use of a wheelchair for mobility. The heart may be mildly enlarged, but its function is typically normal. In rare instances, the heart muscle can thicken and result in heart failure and heart rhythm disturbances.

Additional Support:
Muscular Dystrophy Association [MDA] Resources: www.mdausa.org
MDA information on Type III GSD
Metabolic Diseases of Muscle
”Living With Metabolic Myopathies”

Guidelines

“Glycogen Storage Disease Type III Diagnosis and Management Guidelines”,
 created by the AGSD and the American College of Medical Genetics and Genomics