What is Glycogen Storage disease?
Glycogen storage diseases (GSDs) are a group of inherited genetic disorders that cause glycogen to be improperly formed or released in the body. They are characterized by the accumulation of abnormal amounts or types of glycogen in tissues.
Glucose is a simple sugar, which is a form of carbohydrate. It is found in many foods and is the main source of energy for our bodies. Glycogen is the storage form of glucose in our bodies. Glycogen storage diseases are due to either a deficiency or blockage of an enzyme that is important in converting glucose to glycogen so it can be stored in the body for later use. The main places glycogen is stored in the body includes the liver and muscle cells.
The main types of GSDs are categorized by number and name. They include:
- Type I (Von Gierke disease, defect in glucose-6-phosphatase) – this is the most common type of GSD, and 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 phosphorylase deficiency)
- Type VII (Tarui’s disease, muscle phosphofructokinase deficiency)
- Type IX (liver glycogen phosphorylase kinase deficiency)
Since glycogen is primarily stored in the liver or muscle tissue, GSDs usually affect functioning of the liver, the muscles, or both.
What is phosphorylase Kinase deficiency (GSD IX)?
Phosphorylase Kinase deficiency is a disorder in which the body cannot break down (metabolize) glycogen (a complex form of sugar). When someone has GSD IX, glycogen is stored in the organs of the body (liver, muscle and rarely heart) instead of being used. To briefly review metabolism, a simple form of sugar (glucose) is the 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 storing extra food from the grocery store in the pantry to be used later, when needed). When the body needs more energy, specific proteins (enzymes) change the glycogen back to glucose and take it out of the liver and the muscles (just like taking food out of the pantry).
There are many different steps involved in breaking down glycogen into glucose. Many different enzymes help each step of breakdown happen in a sequential manner. Patients with type of GSD IX glycogen storage disease have a deficiency of the enzyme called phosphorylase kinase. Phosphorylase Kinase Deficiency, PHK, constitutes the largest subgroup (1:100,000 births) of liver glycogenosis. When phosphorylase kinase is low or deficient, glycogen cannot be broken down completely. The phosphorylase kinase enzyme is a regulatory enzyme in the breakdown of glycogen; thus, the deficiency of this enzyme results in glycogen accumulation. When there is a defect in phosphorylase kinase, the body may not be able to make enough sugar (glucose) to use, and also the incompletely digested glycogen builds up (accumulates) in the body, primarily in the liver and muscles. Although some glucose (energy) is created from the successful earlier steps in the breakdown of glycogen, not enough glucose is made for the proper function of the body.
What are the symptoms of phosphorylase kinase deficiency?
The clinical picture of Type IX glycogen storage disease is similar to that seen in Type VI GSD, liver phosphorlyase deficiency. GSD IX can cause low levels of glucose in the blood (hypoglycemia or low blood sugar), which has the potential to lead to seizures. This is more likely to happen after long periods of not eating (fasting), and can be prevented by maintaining a high carbohydrate (starchy foods) diet, adequate amounts of protein in the diet, and avoiding long periods of not eating. A deficiency in PHK causes glycogen accumulation in various tissues and organs including liver, muscle, blood cells but rarely in the heart. The liver can become irritated or inflamed from storing increased amounts of glycogen, which can cause some blood tests to be abnormal with elevated enzymes (ALT and AST) on liver function blood tests. The most common symptoms are enlarged liver, growth retardation, mild delay in motor development, and elevated blood lipids (fats). The symptoms usually improve as a child ages, and children usually reach their full potential height and weight by adulthood.
How do you get phosphorylase kinase deficiency?
Phosphorylase kinase enzyme is made up of four different pieces (subunits), which we can compare to puzzle pieces. When putting together a puzzle, the picture is not complete unless all of the pieces are placed together correctly. In the same way, all the pieces (subunits) of this enzyme must come together correctly in order for the enzyme to work properly. If a puzzle piece is missing or has the wrong shape, the puzzle cannot be completed. Likewise, if there is a change in one of the subunits, the enzyme cannot be assembled and formed properly and will not be able to perform its job in the breakdown of glycogen. The inheritance of Type IX glycogen storage disease can be either autosomal recessive or X-linked recessive.
There are multiple genes that provide the instructions to make the four pieces/subunits (i.e. alpha, beta, gamma, and delta) that make up the phosphorylase kinase enzyme. A change in a subunit is caused by a change in the gene that gives the instructions for that subunit. A definitive diagnosis of PHK deficiency requires demonstration of the enzymatic loss in certain tissues (blood (erythrocytes), muscle, heart and liver tissues). DNA testing is currently available for the subunits alpha1, alpha2, and gamma2. Not many patients have had genetic changes found in beta, delta1, and delta2.
The most common form of Type IX GSD is the X-linked form, which accounts for nearly 75% of all cases. X-linked recessive conditions mainly affect boys. The X-linked type involves genetic changes affecting the alpha-subunit of PHK genes (PHKA1 and PHKA2 genes). The main organs affected include the blood cells, muscle and liver. The clinical picture associated with these genetic changes is hepatomegaly (large liver), growth retardation, and mild to moderately elevated cholesterol and fat in blood and liver enzymes.
The most common autosomal recessive sub-types of GSD IX are caused by mutations in the PHKG2 gene or the PHKB gene. This form of GSD IX is inherited in an autosomal recessive manner. Although mutations in the PHKB gene can cause both liver and muscle glycogen accumulation, patients usually have liver complications. PHKB mutations tend to cause the mildest form of PHK deficiency. In contrast, individuals with mutations in the PHKG2 subunit of the PHK enzyme usually have more severe symptoms; PHKG2 gene changes are particularly associated with recurrent hypoglycemia, hepatomegaly and rarely liver fibrosis.
How is it diagnosed?
Several specialized tests are used to confirm a suspected diagnosis of metabolic disease:
- Blood tests can be used to detect the presence of certain chemicals in the blood that may indicate some metabolic diseases.
- An exercise test is used to monitor a person’s response to intense or moderate exercise. Blood samples are taken during exercise for testing.
- Electromyography (EMG) uses small needle electrodes to measure the electrical currents in a muscle as it contracts. While an EMG can’t definitively diagnose metabolic disease, it can be used to rule out a number of other types of neuromuscular disease that cause similar patterns of weakness.
- A muscle biopsy requires the removal of a small piece of muscle tissue for microscopic analysis. The procedure is done either surgically, with an incision to expose the target muscle, or with a needle. A skin biopsy is also sometimes performed. A muscle biopsy will show a deficiency of the muscle phosphofructokinase enzyme and a modest accumulation of glycogen found
- Other tests that may be needed include an electrocardiogram to test heart function, and brain imaging studies such as CT or MRI scans.
- Genetic tests, using a blood sample, can analyze the person’s genes for particular defects that cause metabolic disease, but these tests often aren’t necessary for diagnosis or for determining treatment.
Is there any treatment for phosphorylase kinase deficiency?
Currently, the only treatment for GSD IX is based on the symptoms of the condition. Hypoglycemia (low blood sugar) can be controlled by frequent meals high in carbohydrates with cornstarch supplements or night time stomach drip feedings if needed. As it is understood now, patients with mutations in the PHKA2 or PHKB genes typically have lessening of their symptoms by puberty. However, patients with more severe types and symptoms may need to remain on treatment regimens to avoid hypoglycemia.
As our understanding increases with GSD IX through long term research studies done on GSD IX patients, like other GSDs, the long term complications will be better understood. Research is still progressing and presenting more information about this disease. Prognosis (prediction of future health) is generally considered good for the liver forms of the disease; however, prognosis for the muscle forms is still unknown.
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