Glycogen Storage Diseases
Glycogen is a form of stored glucose that the body uses as an energy source. Glycogen storage disease (GSD) involves defects that cause an abnormal accumulation of glycogen, usually found in the liver, muscle, or both. When accumulation occurs in the liver, glycogen storage diseases result in liver enlargement and in conditions ranging from mild hypoglycemia to liver failure. When the accumulation occurs in muscle, glycogen
Glucose is a simple sugar that functions as a critical energy source for most bodily functions. Glucose can be acquired through the diet or formed within the bodily cells. Levels of glucose in the blood are maintained in a very narrow range, before and after the ingestion of food. Eating a meal supplies a high level of dietary glucose. Hormones, such as insulin, assist in the removal of glucose from the blood and into cells to be used as energy. Excess glucose is accumulated in the form of glycogen as a type of easily mobilized energy storage for use when food is not plentiful. Even while sleeping, glycogen stores are available to maintain blood glucose levels and energy for life.
The process of the formation of glycogen sheets is termed glycogenesis, and is stimulated by hormones, such as insulin. The process of the breakdown of sheets of glycogen into usable glucose is termed glycogenolysis, and is also under tight control. Hormones that stimulate glycogenolysis control enzymes to remove only the necessary amount of glucose from glycogen stores. With an average daily food intake, glycogen stores are constantly being built up and broken down based on the needs of the body. Average glycogen stores serve as a short-term supply of glucose, and need to be replenished daily. Glycogen serves as energy storage in every organ, but the liver and skeletal muscles are the main sites of glycogen deposition. The brain is dependent upon glucose for energy, and so requires a certain level of blood glucose to be available at all times. Because the brain has only minimal glycogen stores, it is mainly dependent on glycogen from other organs, such as the liver.
Glycogen has separate functions in liver and muscle. Muscle uses glycogen as a fuel source with which to produce energy during activity. As muscle is being used, glycogen stores are being broken down into glucose, turned into cellular energy called ATP, and depleted. In the liver, glycogen is mainly used as a maintenance energy source for the entire body, and is responsible for keeping blood glucose levels in a stable range. After ingestion of dietary glucose, the liver takes up many food breakdown products from the bloodstream, converts them into glucose, and stores them as glycogen. Some time after a meal, when blood glucose levels naturally fall, the liver uses its glycogen stores to replenish the blood with glucose. Organs that cannot create enough glycogen of their own are thus supplied.
Glycogen storage diseases may involve defects in glycogen breakdown or formation in muscle, liver, or both muscle and liver. Some classic features of GSDs that primarily involve muscle are muscle cramps, exercise intolerance, and easy fatigability. Some classic features of GSDs that primarily involve liver are liver enlargement, liver function defects, and hypoglycemia. Most GSDs can have subtypes with onset at different stages of life. There are many types of GSD that involve different defects in glycogen utilization. The types of GSD that are best described are types I through VIII, each with a distinct name and profile.
Von Gierke's disease
Von Gierke's disease is diagnosed through various types of testing. Characteristically, blood tests will reveal low blood sugar and the presence of lactic acid. Tests may also be performed to assess blood glucose levels after various challenges, such as administration of hormones that normally cause glycogen breakdown into glucose. Tests are done to assess for the presence of uric acid in the blood, kidney function, and liver function. GSDIa has a normal white blood cell (immune cells) level in the blood
Blood tests are performed that can assess whether muscle disease is present by assessing for various factors, such as the enzyme creatine kinase, that are normally present inside muscle cells but not in the blood. The release of high levels of these factors into the bloodstream indicates a complication. Tests for the function of the enzyme alpha-glucosidase are performed to attain a definite diagnosis. This test may be done on white blood cells, but in infants it requires an amount of blood drawn that might not be practical. Instead, a skin biopsy is usually performed to test for the enzyme. Ultrasound imaging and tests that assess the heart's response to electrical stimulation are performed to diagnose the presence or extent of cardiac muscle defects.
Blood tests are done to assess blood glucose and uric acid levels. Liver function studies are performed to determine the presence or extent of liver damage. Tests may also be performed to assess blood glucose levels after various challenges such as administration of hormones that normally cause glycogen breakdown into glucose. Both blood and urine are tested for the presence of ketone bodies, products of fat breakdown that can lead to dangerously acidic blood. Ultrasound imaging can assess for heart and liver enlargement or the presence of disease. Ultrasound imaging is also used to assess for polycystic ovaries in females, a common occurrence in Cori's disease that does not seem to affect fertility. A definite diagnosis involves tests that demonstrate abnormal, unbranched glycogen along with a debrancher enzyme deficiency in liver and muscle tissues.
To assess for liver complications, blood tests are performed to check for the presence of enzymes that are normally present in healthy liver cells and not in significant quantities in the blood. Distinct signs of liver cirrhosis or dysfunction may also be found in the blood. Ultrasound imaging can assess for liver enlargement, liver cirrhosis, and cardiac abnormalities. Cases in which there are primarily muscle, nervous system, or cardiac defects may have no sign of liver dysfunction. Blood glucose levels are tested to assess for hypoglycemia. To confirm a diagnosis of Andersen's disease, a defect in glycogen-branching enzyme activity must be demonstrated from tissue samples. Most cases can be assessed from a variety of different tissue types. A biopsy of the liver or other affected organs, such as the heart, may be taken for microscopic examination and to assess enzyme activity. In Ashkenazi Jews, deficient glycogen-branching enzyme activity is only seen in white blood cells and nerve cells. Prenatal enzyme testing can be done from amniotic samples.
Blood tests in McArdle's cases show elevated levels of enzymes, such as creatine kinase, that are normally present inside muscle cells but not in the blood. The release of high levels of these factors into the bloodstream indicates a complication. Exercise does not produce an increase in blood lactic acid in McArdle's disease. An electromyogram (EMG) is a graphic record of a muscle contraction in response to electrical stimulation. Half of all McArdle's cases have abnormalities in EMG. A muscle tissue biopsy may be assayed for muscle glycogen phosphorylase enzyme activity.
The extent of abnormal blood testing results are variable and usually mild in Hers' disease. There may be some hypoglycemia, ketone bodies in blood and urine, elevated blood triglycerides, or enzyme levels that indicate liver complications. Ultrasound imaging may be used to assess liver enlargement. Tests may also be performed to assess blood glucose levels after various challenges, such as administration of hormones that normally cause glycogen breakdown into glucose. To confirm a diagnosis of Hers' disease, a liver biopsy is taken to assess to liver glycogen phosphorylase activity.
The GSDs are autosomal recessive diseases, which are caused by the inheritance of two defective copies of a gene. Each parent contributes one copy of the gene for the enzymes or transporters involved in GSDs. If both copies are defective, the result is disease. If only one defective copy is present, the disease does not occur, but the defective gene can still be passed on to subsequent generations. If both parents are carrying a defective gene, then each offspring has a one in four, or 25%, chance of inheriting the disease. Populations with a high frequency of healthy individuals carrying defective genes will also have higher prevalence of offspring with the disease.
Von Gierke's disease GSDIa and GSDIb are caused by mutations on chromosomes 17 and 11, respectively. GSDIa is caused by deficient activity of the enzyme glucose-6-phosphatase, both negatively impacting glycogenolysis. Pompe's disease is caused by mutations on chromosome 17 that result in different types of dysfunction of the enzyme glucosidase. Mutations in Pompe's disease may cause the complete absence of the enzyme, a normal amount of enzyme with reduced activity, or a reduced amount of enzyme with normal activity. The infantile subtype usually displays an absence of enzyme activity, whereas the other forms involve enzyme levels or functionality. Cori's disease may involve many different mutations in chromosome one, and any combination of defective genes may lead to the disease. There may be a generalized debrancher enzyme deficiency in Cori's disease, or genetic mutations in only some of the tissue-specific enzyme types.
All forms of Andersen's disease result from mutations on chromosome 3 in the genes for glycogen-branching enzymes. The branched structure of glycogen is necessary for compaction and breakdown. The mutations seen in Andersen's disease cause an abnormal, unbranched form of glycogen. Mutations may be generalized for all types of branching enzyme or tissue-specific. McArdle's disease can be caused by multiple types of mutations on chromosome 11 for the muscle-specific form of the phosphorylase enzyme. Most cases involve the functional absence of the enzyme. Hers' disease is due to mutations in multiple genes on multiple chromosomes that cause defects in liver phosphorylase enzyme pathways. Some types of the Hers' form are autosomal recessive, like other GSDs. Some subtypes have been reported that display X-linked recessive inheritance. In this mode of inheritance, mothers carrying defective X-linked genes can pass one copy to each offspring. However, because female offspring also receive a normal X-linked gene from the father, female offspring do not actually develop the disease. Male offspring who receive their only X chromosome from the mother can develop the disease.
GSDs are autosomal recessive inheritance and so occur with equal frequency in both sexes. GSDs as a group have a frequency of one per 20,000–25,000 births internationally. Approximately 80% of all GSD cases are a combination of von Gierke's, Cori's, and Hers' diseases, with each contributing equally. All three subtypes of Pompe's disease combined are estimated to occur at a rate of one per 40,000 individuals in the United States, and account for approximately 15% of GSD cases worldwide. Cori's disease is prevalent among Sephardic Jews of North African descent. In this population, the frequency is approximately one per 5,400 individuals. Even within the same mutation type, the physical effects of Cori's disease in this population are variable. Andersen's disease is uncommon, responsible for only 3% of all GSD cases. Andersen's disease is prevalent among the Ashkenazi Jews. McArdle's disease is also rare, with only a few hundred cases reported in the United States. McArdle's disease may be underdiagnosed because of its mild disease course. Only a few cases of early-onset McArdle's disease have been reported. Classic McArdle's disease has an adolescent onset. However, cases have been reported with onset in the sixth decade of life. Hers' disease is responsible for approximately 30% of GSD cases, while approximately 75% of Hers' disease are the X-linked form. Hers' disease is prevalent in the Mennonite population, with a frequency of 0.1%. X-linked recessive forms of Hers' disease are expressed primarily in affected males. Some breakthrough expression has still been reported in carrier females with mild symptoms.
Drug therapy and enzyme supplementation are not standard parts of treatment for the GSDs. Treatment focuses on maintaining blood glucose levels and treating the symptoms of complications that may arise from the disease. In most cases, this may involve frequent daytime feedings and, for infants, overnight use of a specialized nasogastric feeding tube equipped with an alarm. In most GSDs, children two years of age and older can be switched to cornstarch feeding at bedtime. Raw cornstarch, but not other types of starch, can sustain blood glucose for 4–6 hours if mixed with water at room temperature. Hot water significantly reduces the timeframe in which cornstarch
Diet is a critical component of treatment for most GSDs, and must be closely monitored by highly specialized nutritionists. Von Gierke's disease requires dietary avoidance of excessive carbohydrates, fat, or calories. All contact sports should be avoided because of the potential for excessive bleeding and liver damage. Iron supplementation is advised because of liver deficiencies. In GSDIb, an immune cell booster called granulocyte colony-stimulating factor (GCSF) is administered because of the depressed immune system. Dental and oral health needs to be actively maintained in GSDIb, to prevent infections. Cori's disease does not involve the same carbohydrate restrictions, but avoiding excessive fat intake is advised. Cori's disease is also treated with a high protein diet to supplement muscle function. Cori's disease does not involve sports restrictions past the personal limits of the individual's energy and blood glucose levels. Rupture of the liver from contact sports has not been reported in Cori's disease. The infantile subtype of Pompe's disease may not improve with dietary changes and may become fatal. A high protein diet may assist with muscle functioning in people affected with McArdle's disease and with adults with Pompe's disease. Supplementation with B vitamins may make muscles less prone to fatigue in McArdle's disease. McArdle's cases are advised to avoid sustained, strenuous, or weight-bearing exercise to prevent kidney damage. While Hers' disease requires avoiding long periods of fasting, most cases do not require significant dietary intervention or exercise reduction unless there is significant liver enlargement.
Blood glucose monitoring is done with specialized home kits called glucometers, which provides an exact reading of blood glucose. A test strip is used to collect a small drop of blood obtained by pricking the finger with a small needle called a lancet. The test strip is placed in the meter and results are available within 30–45 seconds. Testing is done on a regular basis to monitor the balance between food intake and blood sugar levels. If hypoglycemic episodes occur, drinking fruit juice or taking a few teaspoons of sugar may bring blood glucose levels back to normal. If 15 minutes have passed and blood sugar has not returned to normal, a second dose is administered.
Specialists are frequently consulted to monitor liver complications that arise in some GSDs. Andersen's disease often requires liver transplantation for effective treatment. However, some cases of Andersen's disease still result in a poor outcome after liver transplant. Specialists also monitor and provide symptom-specific management of cardiac and nervous system complications that arise from GSDs. Parents of children with GSDs are given genetic counseling regarding the risk of GSD to future pregnancies. There is a 25% recurrence risk for each subsequent pregnancy in most GSDs. There is a 50% of male offspring having X-linked forms of Hers' disease.
The prognosis of GSD is highly varied. Overall, the long-term prognosis depends on the extent, severity, and progression of the disease. GSDs are generally multisystem diseases, with many potential complications. With von Gierke's disease and Cori's disease, many patients receiving proper treatment do not encounter life-threatening hypoglycemia and have a reasonable lifespan. However, some patients may develop liver cirrhosis, liver cancer, or liver failure. Pompe's disease is also variable in prognosis. The infantile form is usually fatal within the first year of life. Death results from cardiac and respiratory failure. The juvenile (intermediate) form progresses more slowly, but is generally fatal by the second or third decade of life. Most deaths are from respiratory failure. The adult form may afford survival for several decades after onset. However, muscle weakness may interfere with normal daily activities, and death may result from respiratory failure.
Andersen's disease has a very poor prognosis, with the classic infantile form causing progressive liver cirrhosis and death by five years of age in the absence of a liver transplant. Liver transplantation still does not guarantee improvement. Cases involving non-progressive liver disease do not require liver transplantation, but are still at increased risk of liver cancer. Cases involving cardiac complications often lead to heart failure, despite medical intervention. Andersen's disease involving nervous system and skeletal muscle complications may not be life-threatening, but may be progressive and debilitating.
The prognosis of McArdle's disease is comparatively better than many other forms of GSDs. The primary complications are muscle weakness, cramping, and fatigue, which can interfere with normal daily activities. Some patients are able to adapt exercise to take advantage of the second wind phenomenon, as long as it is not too strenuous. Prognosis remains good as long as sustained, strenuous, and weight-bearing exercises are avoided, which can lead to acute renal failure. The infantile form of McArdle's disease has a poor prognosis, with death caused severe and rapidly progressive muscle weakness that leads to respiratory failure. The best
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Maria Basile, PhD