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 storage diseases result in conditions ranging from difficulty exercising to cardiac and respiratory failure.
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
GSD type I is also known as von Gierke's disease, which has two subtypes, GSDIa and GSDIb. GSDIa is caused by a defect in an enzyme involved in the release of precursor components from liver glycogen stores; GSDIb is caused by a defect in a protein transporter used to transport the necessary precursor components of the pathway to the location of the enzyme. Without dietary glucose, the body is unable to access needed energy from the liver.
In times of fasting, which is essentially any time dietary glucose is not being ingested, severe hypoglycemia can result. Normal mechanisms are in effect in the body to sense a decrease in blood sugar, and respond by increasing rates of glycogen breakdown to maintain blood glucose. Because of the defect in glycogen breakdown, this does not occur and precursor molecules from the pathway accumulate. This causes liver enlargement and the protruding abdomen that is associated with the disease. In von Gierke's disease, the defects in glycogenolysis occur at a point in the pathway that causes accumulation of glucose-6-phosphate. When glucose-6-phosphate accumulates, it diverts into other metabolic pathways that form lactic acid and uric acid. The lactic acid can acidify the blood and cause a dangerous condition known as acidosis. Uric acid accumulation can cause kidney stones and kidney dysfunction. There are also alterations in blood-clotting factors that cause these individuals to bleed very easily and for prolonged periods of time. These alterations can be dangerous. Frequent nosebleeds are associated with von Gierke's disease as a result. Von Gierke's disease type Ib has other defects in blood immune system components that create susceptibility to some types of bacterial infections.
GSD type II is also known as Pompe's disease. There are three main subtypes of Pompe's disease categorized as infantile, juvenile, and adult-onset. The infantile form primarily involves defects in utilization of cardiac muscle, skeletal muscle, and respiratory muscle. This form usually presents by the age of six months and is rapidly fatal, usually due to respiratory and cardiac failure. The adult form involves muscle glycogen stores other than cardiac muscle. The adult form is a progressive disease, but there are no heart defects. However, muscle weakness often results in respiratory failure. The juvenile form includes infants and children older than six months and involves muscle weakness without cardiac defects. In general, the older a person is at the age of onset, the less the likelihood of cardiac involvement. Pompe's disease is caused by defects in an enzyme involved in a side pathway of glycogenolysis that is not critical for most glycogen degradation. The main pathway for glycogen degradation is not defective in Pompe's disease, so there is no hypoglycemia. The defect does cause an accumulation of glycogen that causes enlargement and dysfunction of the organs involved. In the infantile form of Pompe's disease, this is the cause of heart disease, respiratory deficiency, and overall muscle weakness.
GSD type III is also known as Cori's disease. Cori's disease is caused by a defect in a debranching enzyme that is responsible for breaking down the highly branched structure of glycogen in the liver, skeletal muscle, and cardiac muscle. This defect results in hypoglycemia that occurs a relatively short time after food intake. It is unknown why the defect in Cori's disease may lead to liver damage and cancers not seen in von Gierke's disease. It is known that the hypoglycemia that develops in Cori's disease is directly involved and that the liver defects improve with age. Chronic hypoglycemia also contributes to skeletal and cardiac muscle damage in Cori's disease not seen in von Gierke's disease. The enzymatic defect in Cori's disease also contributes to an increase in fat breakdown. Excessive breakdown of fatty acids leads to higher than normal levels of ketone acids, fat breakdown products, in the blood. A dangerous condition known as ketoacidosis may result in organ damage. Growth retardation is associated with Cori's disease.
GSD type IV is also known as Andersen's disease, which usually causes symptoms within the first few years of life. Andersen's disease is caused by a defect in a branching enzyme, responsible for the highly branched structure of normal glycogen. In Andersen's disease, glycogen has an abnormal, unbranched structure that cannot be properly broken down into glucose molecules, and accumulates. Most forms of Andersen's disease involve the liver. Multiple bodily organs or systems may be impacted, including the heart, gastrointestinal tract, skin, intestine, brain, blood formation, and nervous system. Andersen's disease is characterized by liver enlargement, liver-induced hypertension (portal hypertension), liver cirrhosis and failure, and often death by five years of age. Some Andersen's patients have a mild disease variant with later onset associated with a non-progressive form of liver disease. This subtype may have onset even in adulthood. Some forms of Andersen's disease have primarily muscle involvement that may include cardiac muscle. The abnormal glycogen in skeletal muscle results in weakness, exercise intolerance, and muscle wasting. Abnormal glycogen in cardiac muscle can lead to cardiac failure. The abnormal glycogen formed in Andersen's disease can also affect the nervous system by impairing mental function.
GSD type V is also known as McArdle's disease. McArdle's disease is caused by a defect in an enzyme myophosphorylase involved in initiating glycogen breakdown, specifically in skeletal muscle. As a result, glycogen is not broken down into glucose in skeletal muscle, which causes a deficit in cellular energy (ATP). Normal energy utilization in skeletal muscle involves breaking down glycogen fuel stores into glucose, and converting glucose into ATP for energy. During exercise, the amount of ATP required for performance is greatly increased. When muscle glycogen is depleted, muscle begins to use blood glucose and fat breakdown products for energy. Individuals with McArdle's disease often experience a "second wind" phenomenon in energy levels during exercise because of these secondary fuel sources. However, McArdle's disease still causes muscle cramps during exercise and exercise intolerance.
GSD type VI is also known as Hers' disease. Similar to McArdle's disease, the classic form of Hers' disease is caused by a partial defect in the phosphorylase enzyme. This form of Hers' disease involves a partial defect in liver phosphorylase, which initiates glycogen breakdown, specifically in the liver. Other forms exist that are caused by similar defects. Hers' disease includes a heterogeneous group of subtypes with mild clinical consequences. Hers' disease typically involves liver enlargement, muscle weakness, growth retardation, mild fasting hypoglycemia, and mildly elevated ketone levels during childhood that resolve by puberty. Most patients have only partial impairment of glycogenolysis, due to the incomplete deficiencies of the enzymes involved.
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.
Signs and symptoms
Von Gierke's disease
Infants born with von Gierke's disease display initial symptoms of hypoglycemia immediately following birth. These symptoms may include tremors, cyanosis (bluish tint from lack of oxygen), and seizures. Some infants are born with enlarged livers and abdomens. Onset of von Gierke's disease in an older infant may also include symptoms of fatigue, difficulty waking from long periods of sleep, tremors, extreme hunger, poor growth, short stature, and a protruding abdomen with thin limbs from liver enlargement. A doll-like facial appearance is often caused by fat deposits in the cheeks. Young children with von Gierke's disease may additionally have fat deposits called xanthomas on the elbows and knees, frequent nosebleeds, gingivitis (inflammation of the gums), and skin boils. Symptoms of severe hypoglycemia at all ages are likely to follow any illness or circumstance that causes a decrease in food intake. In later years, children may have rickets and anemia. Enlarged kidneys may be discovered by ultrasound imaging techniques. Complications that may arise from von Gierke's disease are severe hypoglycemia, liver cancer , kidney damage, fluid retention in the brain, coma, and death. In GSDIb, severe recurrent infections from immune compromise may also be a complication.
Infants born with Pompe's disease display initial symptoms of protruding abdomen due to liver enlargement, muscle enlargement, muscle weakness, and respiratory and feeding difficulty. Pneumonia is a complication. A heart murmur may be audible upon physical examination. Enlargement of the left ventricle of the heart may cause obstruction of blood flow and cardiac failure. The juvenile subtype of Pompe's disease displays symptoms of delayed motor development, weakness, and poor muscle tone. The adult subtype has symptoms of muscle weakness, especially when performing tasks such as climbing stairs or exercising. Approximately one third of cases involve respiratory complications.
Infants born with Cori's disease may be healthy for the first few months of life, then present with initial symptoms of tremors, sweating, irritability, difficulty feeding, respiratory complications, seizures, coma, and sudden death. Older infants may also present with difficulty waking from sleep, poor growth, increased appetite, and dizziness. The level of hypoglycemia associated with this disease ranges from mild to severe. An enlarged liver may or may not be present. Some patients with Cori's disease have improvement in the liver complications as they get older, but others develop liver cirrhosis, liver failure, and liver cancer after puberty. Approximately 85% of patients with Cori's disease have significant involvement of both the liver and skeletal muscles. During childhood, complications with muscle are often minimal, but progressively get worse with age to the point of disability. Some patients may develop an enlarged heart but, otherwise, cardiac defects are rare. Often, Cori's disease causes poor growth with a short stature in children. If blood glucose levels are appropriately maintained, the attainment of normal growth is possible.
Infants born with Andersen's disease usually fail to thrive during the first year of life. In some cases, liver enlargement may lead to a protruding abdomen, liver cirrhosis, jaundice, hypertension, fatigue, bruising or bleeding easily, and liver failure. In other cases, the muscles may primarily be affected, causing weakness, fatigue, and muscle wasting. Muscle complications may extend to cardiac muscle and cause defects in function. If damage to the nervous system occurs in addition to muscular deficits, there may be decreased reflexes, sensory loss, and gait disturbances. Mild mental impairment may occur.
McArdle's disease usually has a primary symptom of exercise intolerance, with muscle weakness and fatigue. The symptoms occur during strenuous or sustained exercise and usually resolve with rest. Often there is a "second wind" of energy from glucose and fat breakdown products supplied by the blood. Symptoms may range from mild fatigue to temporarily incapacitating fatigue with muscle cramping. Late-onset cases may begin showing symptoms of progressive muscle weakness at 60–70 years of age. Other cases may present symptoms in the first year of life and become severely progressive. Even in the absence of exercise, one third of patients experience weakness. This symptom is especially common in older age. One half of cases filter blood in the urine after intense exercise, which may be indicative of impending kidney failure. A small percentage of McArdle's cases have seizures.
Hers' disease usually has onset between the first and fifth year of life. Classic symptoms include a protruding abdomen due to enlarged liver, delay in growth with childhood short stature, and delayed motor development. Mild hypoglycemia may also be present, but many patients develop no other symptoms. Normal growth may be eventually achieved, along with a complete resolution in liver size to normal. Muscle strength in adults is usually normal.
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 because the immune system is unaffected in this subtype. However, in subtype GSDIb, the immune system is impaired and has lower than normal blood levels of white blood cells. Most cases also involve a defect in blood coagulation, and tests are performed to assess bleeding times in a controlled setting. Ultrasound imaging of the abdomen is performed to assess liver and kidney size. To confirm a diagnosis, a biopsy of liver tissue is used to assess the function of the glucose-6-phosphatase enzyme that presents as defective in von Gierke's disease.
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.
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 can sustain blood glucose levels. Any illness or condition that reduces the amount of food intake requires supple-mental injections of simple sugars, such as dextrose, or intravenous administration of glucose. Caregivers need to be educated in inserting feeding tubes, dietary control, and recognizing and managing hypoglycemia.
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 prognosis of the GSDs described is with Hers' disease. Hers' disease has a mild course with risk of growth retardation, mild fasting hypoglycemia, and delayed motor development in early childhood. However, these clinical features usually normalize by the time of puberty, along with liver enlargement and muscle weakness. Adult patients usually have normal stature and motor functions. Hers' disease may have an excellent prognosis, even without childhood dietary management.
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Maria Basile, PhD
Glycogen Storage Diseases
Glycogen Storage Diseases
Glycogen serves as the primary fuel reserve for the body's energy needs. Glycogen storage diseases, also known as glycogenoses, are genetically linked metabolic disorders that involve the enzymes regulating glycogen metabolism. Symptoms vary by the glycogen storage disease (GSD) type and can include muscle cramps and wasting, enlarged liver, and low blood sugar. Disruption of glycogen metabolism also affects other biochemical pathways as the body seeks alternative fuel sources. Accumulation of abnormal metabolic by-products can damage the kidneys and other organs. GSD can be fatal, but the risk hinges on the type of GSD.
Most of the body's cells rely on glucose as an energy source. Glucose levels in the blood are very stringently controlled within a range or 70-100 mg/dL, primarily by hormones such as insulin and glucagon. Immediately after a meal, blood glucose levels rise and exceed the body's immediate energy requirements. In a process analogous to putting money in the bank, the body bundles up the extra glucose and stores it as glycogen in the liver and muscles. Later, as the blood glucose levels begin to dip, the body makes a withdrawal from its glycogen savings.
The system for glycogen metabolism relies on a complex system of enzymes. These enzymes are responsible for creating glycogen from glucose, transporting the glycogen to and from storage areas within cells, and extracting glucose from the glycogen as needed. Both creating and tearing down the glycogen macromolecule are multistep processes requiring a different enzyme at each step. If one of these enzymes is defective and fails to complete its step, the process halts. Such enzyme defects are the underlying cause of GSDs.
The enzyme defect arises from an error in its gene. Since the error is in the genetic code, GSDs can be passed down from generation-to-generation. However, all but one GSD are linked to autosomal genes, which means a person inherits one copy of the gene from each parent. Following a Mendelian inheritance pattern, the normal gene is dominant and the defective gene is recessive. As long as a child receives at least one normal gene, there is no risk for a GSD. GSDs appear only if a person inherits a defective gene from both parents.
The most common forms of GSD are Types I, II, III, and IV, which may account for more than 90% of all cases. The most common form is Type I, or von Gierke's disease, which occurs in one out of every 100,000 births. Other forms, such as Types VI and IX, are so rare that reliable statistics are not available. The overall frequency of all forms of glycogen storage disease is approximately one in 20,000-25,000 live births.
Causes and symptoms
GSD symptoms depend on the enzyme affected. Since glycogen storage occurs mainly in muscles and the liver, those sites display the most prominent symptoms.
There are at least 10 different types of GSDs which are classified according to the enzyme affected:
- Type Ia, or von Gierke's disease, is caused by glucose-6-phosphatase deficiency in the liver, kidney, and small intestine. The last step in glycogenolysis, the breaking down of glycogen to glucose, is the transformation of glucose-6-phosphate to glucose. In GSD I, that step does not occur. As a result, the liver is clogged with excess glycogen and becomes enlarged and fatty. Other symptoms include low blood sugar and elevated levels of lactate, lipids, and uric acid in the blood. Growth is impaired, puberty is often delayed, and bones may be weakened by osteoporosis. Blood platelets are also affected and frequent nosebleeds and easy bruising are common. Primary symptoms improve with age, but after age 20-30, liver tumors, liver cancer, chronic renal disease, and gout may appear.
- Type Ib is caused by glucose-6-phosphatase translocase deficiency. In order to carry out the final step of glycogenolysis, glucose-6-phosphate has to be transported into a cell's endoplasmic reticulum. If translocase, the enzyme responsible for that movement, is missing or defective, the same symptoms occur as in Type Ia. Additionally, the immune system is weakened and victims are susceptible to bacterial infections, such as pneumonia, mouth and gum infections, and inflammatory bowel disease. Types Ic and Id are also caused by defects in the translocase system.
- Type II, or Pompe's disease or acid maltase deficiency, is caused by lysosomal alpha-D-glucosidase deficiency in skeletal and heart muscles. GSD II is subdivided according to the age of onset. In the infantile form, infants seem normal at birth, but within a few months they develop muscle weakness, trouble breathing, and an enlarged heart. Cardiac failure and death usually occur before age 2, despite medical treatment. The juvenile and adult forms of GSD II affect mainly the skeletal muscles in the body's limbs and torso. Unlike the infantile form, treatment can extend life, but there is no cure. Respiratory failure is the primary cause of death.
- Type III, or Cori's disease, is caused by glycogen debrancher enzyme deficiency in the liver, muscles, and some blood cells, such as leukocytes and erythrocytes. About 15% of GSD III cases only involve the liver. The glycogen molecule is not a simple straight chain of linked glucose molecules, but rather an intricate network of short chains that branch off from one another. In glycogenolysis, a particular enzyme is required to unlink the branch points. When that enzyme fails, symptoms similar to GSD I occur; in childhood, it may be difficult to distinguish the two GSDs by symptoms alone. In addition to the low blood sugar, retarded growth, and enlarged liver causing a swollen abdomen, GSD III also causes muscles prone to wasting, an enlarged heart, and heightened levels of lipids in the blood. The muscle wasting increases with age, but the other symptoms become less severe.
- Type IV, or Andersen's disease, is caused by glycogen brancher enzyme deficiency in the liver, brain, heart, skeletal muscles, and skin fibroblasts. The glycogen constructed in GSD IV is abnormal and insoluble. As it accumulates in the cells, cell death leads to organ damage. Infants born with GSD IV appear normal at birth, but are diagnosed with enlarged livers and failure to thrive within their first year. Infants who survive beyond their first birthday develop cirrhosis of the liver by age 3-5 and die as a result of chronic liver failure.
- Type V, or McArdle's disease, is caused by glycogen phosphorylase deficiency in skeletal muscles. Under normal circumstances, muscles cells rely on oxidation of fatty acids during rest or light activity. More demanding activity requires that they draw on their glycogen stockpile. In GSD V, this form of glycogenolysis is disabled and glucose is not available. The main symptoms are muscle weakness and cramping brought on by exercise, as well as burgundy-colored urine after exercise due to myoglobin (a breakdown product of muscle) in the urine.
- Type VI, or Hers' disease, is caused by liver phosphorylase deficiency, which blocks the first step of glycogenolysis. In contrast to other GSDs, Type VI seems to be linked to the X chromosome. Low blood sugar is one of the key symptoms, but it is not as severe as in some other forms of GSD. An enlarged liver and mildly retarded growth also occur.
- Type VII, or Tarui's disease, is caused by muscle phosphofructokinase deficiency. Although glucose may be available as a fuel in muscles, the cells cannot metabolize it. Therefore, abnormally high levels of glycogen are stockpiled in the muscle cells. The symptoms are similar to GSD V, but also include anemia and increased levels of uric acid.
- Types VIII and XI are caused by defects of enzymes in the liver phosphorylase activating-deactivating cascade and have symptoms similar to GSD VI.
- Type IX is caused by liver glycogen phosphorylase kinase deficiency and, symptom-wise, is very similar to GSD VI. The main differences are that the symptoms may not be as severe and may also include exercise-related problems in the muscles, such as pain and cramps. The symptoms abate after puberty with proper treatment. Most cases of GSD IX are linked to the X chromosome and therefore affect males.
- Type X is caused by a defect in the cyclic adenosine monophosphate-dependent (AMP) kinase enzyme and presents symptoms similar to GSDs VI and IX.
Diagnosis usually occurs in infancy or childhood, although some milder types of GSD go unnoticed well into adulthood and old age. It is even conceivable that some of the milder GSDs are never diagnosed.
The four major symptoms that typically lead a doctor to suspect GSDs are low blood sugar, enlarged liver, retarded growth, and an abnormal blood biochemistry profile. A definitive diagnosis is obtained by biopsy of the affected organ or organs. The biopsy sample is tested for its glycogen content and assayed for enzyme activity. There are DNA-based techniques for diagnosing some GSDs from more easily available samples, such as blood or skin. These DNA techniques can also be used for prenatal testing.
Some GSD types cannot be treated, while others are relatively easy to control through symptom management. In more severe cases, receiving an organ transplant is the only option. In the most severe cases, there are no available treatments and the victim dies within the first few years of life.
Of the treatable types of GSD, many are treated by manipulating the diet. The key to managing GSD I is to maintain consistent levels of blood glucose through a combination of nocturnal intragastric feeding (usually for infants and children), frequent high-carbohydrate meals during the day, and regular oral doses of cornstarch (people over age 2). Juvenile and adult forms of GSD II can be managed somewhat by a high protein diet, which also helps in cases of GSD III, GSD VI, and GSD IX. GSD V and GSD VII can also be managed with a high protein diet and by avoiding strenuous exercise.
For GSD cases in which dietary therapy is ineffective, organ transplantation may be the only viable alternative. Liver transplants have been effective in reversing the symptoms of GSD IV.
Advances in genetic therapy offer hope for effective treatment in the future. This therapy involves using viruses to deliver a correct form of the gene to affected cells. Another potential therapy utilizes transgenic animals to produce correct copies of the defective enzyme in their milk. In late 1997, a Dutch pharmaceutical company, Pharming Health Care Products, began clinical trials to treat GSD II with human alpha-glucosidase derived from the milk of transgenic rabbits. Researchers at Duke University in North Carolina are also focusing on a treatment for Pompe's disease and, aided by Synpac Pharmaceuticals Limited of the United Kingdom, plan to begin clinical trials of a recombinant form of the enzyme in 1998.
People with well-managed, treatable types of GSD can lead long, relatively normal lives. This goal is accomplished with the milder types of GSD, such as Types VI, IX, and X. As the GSD type becomes more severe, a greater level of vigilance against infections and other complications is required. Given current treatment options, complications such as liver disease, heart failure, and respiratory failure may not be warded-off indefinitely. Quality of life and life expectancy are substantially decreased.
Because GSD is an inherited condition, it is not preventable. If both parents carry the defective gene, there is a one-in-four chance that their offspring will inherit the disorder. Other children may be carriers or they may miss inheriting the gene altogether.
Through chorionic villi sampling and amniocentesis, the disorder can be detected prior to birth. Some types of GSD can be detected even before conception occurs, if both parents are tested for the presence of the defective gene. Before undergoing such testing, the prospective parents should meet with a genetic counselor and other professionals in order to make an informed decision.
American Liver Foundation. 1425 Pompton Ave., Cedar Grove, NJ 07009. (800) 223-0179. 〈http://www.liverfoundation.org〉.
Association for Glycogen Storage Disease. PO Box 896, Durant, Iowa 52747-9769. (319) 785-6038.
Amniocentesis— A medical test done during pregnancy in which a small sample of the amniotic fluid is taken from around the fetus. The fluid contains fetal cells that can be examined for genetic abnormalities.
Autosomal gene— A gene found on one of the 22 autosomal chromosome pairs; i.e., not on a sex (X or Y) chromosome.
Chorionic villus sampling— A medical test done during pregnancy in which a sample of the membrane surrounding the fetus is removed for examination. This examination can reveal genetic fetal abnormalities.
Glucose— A form of sugar that serves as the body's main energy source.
Glycogen— A macromolecule composed mainly of glucose that serves as the storage form of glucose that is not immediately needed by the body.
Glycogenolysis— The process of tearing-down a glycogen molecule to free up glucose.
Glycogenosis— An alternate term for glycogen storage disease. The plural form is glycogenoses.
Gout— A painful condition in which uric acid precipitates from the blood and accumulates in joints and connective tissues.
Mendelian inheritance— An inheritance pattern for autosomal gene pairs. The genetic trait displayed results from one parent's gene dominating over the gene inherited from the other parent.
Osteoporosis— A disease in which the bones become weak and brittle.
Renal disease— Kidney disease.
Transgenic animal— Animals that have had genes from other species inserted into their genetic code.