Glycogen Storage Disease type III is consider to be an autosomal recessive disorder that is caused by the deficiency of the glycogen debrancher enzyme. This deficiency causes there to be a mutation on exon three and it causes abnormally structured glycogen to be present in the body. This disease can be diagnosed by multiple tolerance tests and it also can be diagnosed by analyzing the muscle tissues. This disease causes problems in the liver and in the muscles. The tolerance tests are used to test for liver diseases and the analysis of the muscles is used in order to determine if a patient has myopathy. This disease affects a large range of ages. This ages can range from early childhood to adulthood usually between ages one and sixty-two. Children and adults usually experience different symptoms. The symptoms in children are most commonly growth and muscle retardation. The symptoms in adults usually vary in comparison to children. Adults usually have myopathy in there calf muscles. Adults also usually develop fatigue and weakness. Also some of the tolerance test cannot be performed on children due to blood glucose levels. There are multiple types of Glycogen Storage Disease. The types of this disease depends on which part of the glycogen debrancher enzyme is missing. Some types of this disease are caused by the deficiency in amylo-1, 6-glucosydase and some other types of this disease are caused by a deficiency in 4-α-glucantransferase. One of the main treatments for this disease is dietary management. This treatment typically only works on patients who are younger in age due to their metabolism. This treatment consists of a high protein diet, which will help with the development of hypoglycemia. This treatment is commonly ineffective in adults because most adults with this disease already have hypoglycemia therefore the high protein diet treatment would not help prevent that development.
Literature review
The debrancher enzyme is an enzyme that helps break down glycogen in the body. The debrancher enzyme consists of amylo-1, 6-glucosydase and 4-α-glucantransferase. The debrancher enzyme is an amino acid chain. It is also known as AGL. Glycogen is an important molecule in the body because it is a polysaccharide of glucose that stores energy in the body. When there is a deficiency of the debrancher enzyme, it causes there to be an abnormally structured glycogen in the body. These abnormally structured glycogens can accumulate in tissues which then causes the disease known as the Glycogen Storage Disease type III as indicated in Lucchiari (2007). This deficiency most commonly occurs in the liver and in muscles. It can also occur only in one part of the body. For example someone can have an enzyme deficiency in just their liver and not in there muscles. When this disease occurs in the muscles it is referred to as myopathy. Glycogen Storage Disease type III is also commonly called Cori-Forbes Disease.
It was determined that Glycogen Storage Disease type III affects the liver and muscles by an experiment which is discussed in Chen (1987). In this experiment they took a fold of skeletal muscle from a patient and compared it to a purified rabbit muscle enzyme. This enzyme in the rabbit muscle was the debranching enzyme. They placed both the fold of skeletal muscle and the rabbit enzyme and put them in a gel electrophoresis and compared the migration paths of each of them to each other. This helped to show the defected activity of the debranching enzyme in the muscle.
Glycogen Storage Disease is a disease that affects multiple phenotypes. According the tests, experiments, and data provided in Kiechl (1999) four of those phenotypes include adult onset distal and severe generalized myopathy. They also include minimal variant myopathy and subacute myopathy of the muscles in the respiratory system. These phenotypes were determined during an experiment on four patients. The first patient was a sixty-two year old man who always believed he was a healthy man. He then started to realize that he was developing muscle weakness in his calves and peroneal muscles. The second patient was a healthy forty-five year old who always exercised. She then was diagnosed with cardiomyopathy. The third patient was a sixty year old man who was diagnosed with hypoglycemia as a child. At the age of forty-five this man developed muscle wasting. The fourth and final patient was a male who was diagnosed with muscular hypotonia, hypoglycemia, and hepatomegaly. This patient was diagnosed with these diseases when he was only eight months old. He was diagnosed with Glycogen Storage Disease type III after a liver biopsy was performed. This disease affects a wide variety of ages with multiple phenotypes. The age range of patients with Glycogen Storage Disease is between one and sixty-two years of age.
The studies found in Kiechl (1999) show that depending on the age at which Glycogen Storage Disease was developed, clinical appearance, and a patient’s phenotype will determine how severe a patients’ symptoms will be. It will also determine how well a patient will respond to any therapy. It can also determine any other complications or symptoms that might develop as the patients’ age increases.
In the information provided in Shen (1996) a study was performed on three patients who had Glycogen Storage Disease type IIIb. They performed many studies such as DNA sequencing, single-strand conformation polymorphism, and family studies. After these studies they determined that these patients were in fact heterozygotes for two mutations. The first mutation was in exon three for all the patients. In exon three the mutation was at the amino acid codon six of the glycogen debranching enzyme. One of these patients had a transition at nucleotide 16. This transition caused the Glutamine codon to change into a stop codon. This transition was from C to T. The other two patients had a change in their amino acid sequence due to a deletion in two of their nucleotides. These deletions occurred at nucleotide seventeen and eighteen. There deletion was an AG deletion. The second mutation found in this study consisted of R864X, R1228X, and W68OX according to Shen (1996). These mutations cause a premature stop codon to form. So it was determined that mutation in exon three causes stop codons to form which then causes problems with the glycogen debranching enzyme which then leads to Glycogen Storage Disease. According to Lucchiari (2007), who performed multiple genetic screenings in multiple populations, it was concluded that the most common mutation shared between Caucasians is R864X.
There are four types of Glycogen Storage Disease type III according to Lucchiari (2007). These types are known as type IIIa, type IIIb, type IIIc, and type IIId. These types are dependent on what activity they have a deficiency in. Glycogen Storage Disease type IIIa is when a patient does not have any activity of glucosidase and transferase in their liver and in their muscles. Type IIIb means that the patient does not have any activity of glucosidase and transferase in only the liver. These patients are different from type IIIa because they have activity of glucosidase and transferase in their muscles. Type IIIc is when someone only has selective loss of activity of glucosidase. Type IIId is a lot like type IIIc except instead of having selective loss of glucosidase, they have selective activity loss of transferase. All of these types of Glycogen Storage Disease type III have mutations on exon three.
There are many screening procedures available in order to diagnose someone with Glycogen Storage Disease type III. These procedures include tolerance tests. One test is the epinephrine tolerance test. Another test is the glucagon tolerance test. There were some issues with the glucagon tolerance test according to Fernandes (1969). This test had some issues in diagnosing liver disease because it showed that some patients had high rise in blood glucose levels. This was an issue because many normal and healthy children have high levels of blood glucose and since some of the patients they were testing were children, the results were inconclusive and could not necessarily determine if that patient had any liver glycogen diseases. So it was decided that this test only gave good results if it was used on older patients to whom they could dictate if their blood glucose levels were too high compared to a healthy adult, which would then determine if they had liver glycogen disease. Also this test could be performed after the patient performed a long fast, in order to lower their blood glucose levels. This fast is commonly eight hours.
Another screening procedure is the fructose and galactose tolerance test. This test also caused some problems. It mainly caused problems because it was considered a serious risk to perform. It was a serious risk because it caused issues with those patients who had a deficiency of the glucose-6-phosphate. It was a risk with those patients because they would convert the galactose and fructose into lactic acid instead of converting it to glucose. Since this tolerance test was considered dangerous they came up with an oral glucose tolerance test. They also have the glucagon test. Also according to Kiechl (1999), Glycogen Storage Disease can also be diagnosed with an analysis of the tissues within the skeletal muscles. Also electrophysiology examinations can be used to diagnose.
Glycogen Storage Disease type III is consider an autosomal recessive disorder because it can be passed down from your family members. Someone who has this disease has to have two copies of the abnormal gene that causes Glycogen Storage Disease type III. This disease is common to develop during childhood or early adulthood. The symptoms and reactions to therapy differ between the age differences. Those with this disease who are young in age do not show as many symptoms of liver disease. Those who are younger typically show signs of muscle tone retardation and also signs of muscle growth retardation. Also children are known to develop hypoglycemia as well. Adults typically show signs of this disease because they experience more weakness which affects their muscles. Glycogen Storage disease is also commonly known for the development of neuropathy which is a dysfunction in the peripheral nerves according to Lucchiari (2007). Other symptoms are things such as back pain and fatigue. Many adults with this disease typically experience muscle problems with their lower limbs especially in their calf muscles. Also adults commonly experience symptoms in their peroneal muscles. These symptoms in muscles are most commonly considered to be muscle weakness.
An experiment was performed where they monitored liver damage over the lifetime of multiple patients. The results in Lucchiari (2007) found that as age increases there is an inverse relationship with transferase levels. This means that as a patient increases in age, that their levels will continue to decrease. This means that as age increases, the severity of this disease will increase. This implies that age increases in a patient that their symptoms could get worse. This goes along with the fact that adults with this disease experience more muscle problems than children with this disease do. Also this means that liver damage is more severe in adults than it is in children.
Muscles weakness and disability was tested during an experiment according to Lucchiari (2007). They measured and observed lower limb weakness by using the Walton Functional Rating Scale. After performing this experiment they found that a patients’ age has a direct relationship to the severity of this disease. This means that as a patient gets older, the severity of their disease will get worse. According to their data in this experiment, they found that muscle and limb impairment was low and mild in patients around the age of thirty-five. Also their results showed that older patients had severe muscles loss.
One of the main treatments for this disease is dietary management. It is better to start dietary management as early as possible. These managements include high-protein meals. According to Lucchiari (2007) it is recommended to have frequent meals that contain 45% carbohydrates, 25% protein, and 30% fat. These dietary management changes are not as affective on adults as they are with children. Dietary management affects children more than adults because of their metabolism. Corn starch has also be proven to help children with growth and muscle retardation. This treatment in children is mainly performed in order to avoid hypoglycemia.
Future Directions and Conclusions
There will constantly be studies performed about this disease in order to learn more about the diagnosis and reasons behind why it is developed. There will continue to be studies performed on exon three in order to determine if any other mutations can cause Glycogen Storage Disease. As the data in Chen (1987) concludes, there is a similarity in the effects of the glycogen debrancher enzyme in the liver compared to the muscles. This point will continue to be researched until it is entirely understood why it can occur in both the liver and the muscles but also why it can occur in just the liver and not in the muscles or why it can occur in just the muscles and not the liver.
There are not many treatments and therapies for this disease. Most of the treatments that have been determine usually only work on those patients who are young in age due to many differences in growth, metabolism, and severity. Research and experiments will continue to be developed until a treatment is achieved that will help those patients who are older in age and who have a more severe case of this disease. A future development could be the development of a drug that could potentially control or decrease the symptoms of this disease. Since it was found that a high protein diet can help a child control their symptoms, researches could develop a drug that could potentially take place of a diet change in order to help with the symptoms. This type of drug would be beneficial because it could help those who may not have the option to eat high protein foods due to things such as allergies or other problems that the patient might have developed over the years.