What is Glycogen Storage Disease?
Glycogen storage diseases (GSDs) are genetically inherited diseases that affect the way your body processes carbohydrates, specifically a substance called glycogen. These disorders happen when your body isn’t able to properly store or use glycogen due to problems with specific enzymes. Enzymes are proteins that help speed up chemical reactions in the body.
Glycogen is a type of sugar that your body uses for energy. After you eat, any extra glucose (another type of sugar) in your body gets stored as glycogen. Most glycogen is stored in your liver, although your muscles can store a smaller amount as well. When your body needs energy, it breaks down the stored glycogen back into glucose for use. However, in GSDs, this process doesn’t work properly.
Depending on the particular kind of GSD, either the body can’t break down the glycogen to use it for energy, or it can’t prevent a buildup of glycogen which can be harmful. The onset of GSDs can happen at any age, from infancy all the way through adulthood.
There are many different types of GSDs, each associated with a specific enzyme defect. Some GSDs primarily affect the liver, including types like GSD type 0a (glycogen synthase-2 deficiency), type Ia (glucose-6-phosphatase deficiency), and others. Some primarily affect the muscles, like GSD type V (muscle phosphorylase deficiency) and type VII (phosphofructokinase deficiency). And some affect both the muscles and the heart, like GSD type IIa (lysosomal acid maltase deficiency) and type IIb (lysosome-associated membrane protein 2 deficiency).
Most of these diseases are very rare, and more are being identified as research continues. They used to be named after the doctors who first described them, but now they are often referred to according to the specific enzyme defect and gene involved.
What Causes Glycogen Storage Disease?
Glycogen storage diseases (GSDs) are understood by looking at the process through which the body creates and breaks down a carbohydrate called glycogen. When we eat more glucose (sugar) than our bodies need right away, it gets stored as glycogen. This process is managed by an enzyme called glycogen synthase (GS). Your body has two types of GS – one in the liver, and one in your muscles. Both versions of GS add glucose to the growing chain of glycogen.
In a healthy glycogen molecule, there are two types of links binding the glucose together. Most of the links, about 95%, are one type (called alpha-1,4). But some are a different type (alpha-1,6).
However, some people have mutations in the gene that makes liver GS (GYS2) or muscle GS (GYS1). If their liver GS doesn’t work properly (due to a GYS2 mutation) then their liver can’t make glycogen. This causes GSD type 0a. If their muscle GS doesn’t work (due to a GYS1 mutation), then their muscles can’t make glycogen. This causes GSD type 0b.
Making the second, less common type of linkage (alpha-1,6) needs a different enzyme called glycogen branching enzyme (GBE1). If this enzyme has any mutations, it can cause the glycogen to have a strange shape. This is the cause of GSD type IV. These abnormally shaped glycogen molecules, named polyglucosan bodies, build up in liver and muscle cells. They can’t be properly broken down, causing muscle weakness and an enlarged liver.
Most of the time, GSDs happen because the body can’t properly break down glycogen, resulting in too much glycogen stored in the body. The first step in breaking down glycogen into glucose requires an enzyme called glycogen phosphorylase. GSD type V happens when there’s a mutation in the muscle-specific phosphorylase gene (PYGM), and GSD type VI is due to a mutation in the liver-specific version of the gene (PYGL).
Muscles can’t release glucose into the blood because they lack a key enzyme called glucose-6-phosphatase that’s needed in the last step of breaking down glycogen. Instead, muscles use the glucose directly. Some GSDs (type I) occur when the body can’t use glucose-6-phosphatase. GSD type Ia, also known as von Gierke disease, happens due to mutations in the G6PC gene, which creates glucose-6-phosphatase. GSD type Ib is caused by mutations in the gene SLC37A4 that provides a passage for glucose-6-phosphate.
Another type of GSD, called Fanconi-Bickel disease, is rare and caused by a deficiency in the GLUT2 gene, leading to the failure of releasing glucose and an accumulation of it, resulting in increased glycogen storage and an enlarged liver.
While majority of the glucose in glycogen is linked via alpha-1,4 linkages, at the branching points, glucose is linked via alpha-1,6 links. These branch points require a different enzyme – the glycogen debranching enzyme (GDE). So, if the gene that makes GDE (called AGL) is mutated, it causes GSD type III.
Lastly, GSD type II is also referred to as a lysosomal storage disease. That’s because it is caused by mutations in a gene called GAA, which makes an enzyme that breaks down glycogen in a part of the cell called the lysosome. If this enzyme doesn’t function properly, glycogen builds up in the lysosome. This can be harmful to the cell.
Risk Factors and Frequency for Glycogen Storage Disease
Figuring out the exact number of metabolic diseases is challenging because not all babies are uniformly screened at birth all over the world. Additionally, pinpointing the incidence of specific types of Glycogen Storage Diseases (GSDs) is tricky because symptoms often overlap and specific tests are not standardized in many parts of the world. In a study conducted in British Columbia in the 1990s, about 30 out of every 100,000 newborns were found to have some form of metabolic disorders. This included GSDs, but was not limited to them; about 2.3 out of every 100,000 newborns were estimated to have a GSD. But the latest research points to approximately 1 case of GSD per every 20,000 to 43,000 live births.
Signs and Symptoms of Glycogen Storage Disease
Glycogen storage diseases (GSDs) are a group of rare genetic disorders that affect the way the body stores and uses sugar. These disorders can vary in severity, even among those of the same type. Familial history may provide clues to the inheritance pattern of the disease. Most GSDs are inherited in an autosomal recessive pattern, but some, like GSD type IX, are X-linked. Symptoms often seen in these disorders include poor growth or weight gain in children, fatigue during exercise, low blood sugar, enlarged liver, weak muscle tone, high acid levels in the body, and increased fats in the blood. However, symptoms most commonly observed are low blood sugar and fatigue during exercise.
Different GSD types are characterized by various symptoms. For instance, patients with certain types of GSDs that affect the liver often have low blood sugar and high levels of ketones, substances made when the body breaks down fats for energy, especially when fasting. Their symptoms can usually be improved by taking glucose. On the other hand, patients with GSDs that affect the muscles often become tired and find it hard to carry out moderate to strenuous exercise within a short period. This contrasts with people who have disorders affecting fat metabolism, who only develop symptoms after long periods of exercise. Moreover, people with muscle-related GSDs can experience muscle cramps and, in some cases, muscle breakdown (rhabdomyolysis) or presence of a muscle protein (myoglobin) in the urine. Rarely, progressive weakness may be seen in certain GSD types (type 0, II, and IV).
Very rarely, other types of GSDs (type III, V, and VII) may lead to weakness rather than muscle cramps, which can develop into fixed weakness over time. Patients with some types of GSDs that affect the heart muscles may show symptoms of heart muscle disease (cardiomyopathy) and, rarely, abnormalities in heart rhythm.
It’s important to measure and track children’s growth when dealing with GSDs. Short stature or lack of growth, especially in a child with low blood sugar, may suggest the presence of a glycogen storage disorder. Also, the inability to properly convert stored glucose (glycogen) back into glucose can lead to an abnormal build-up of glycogen. In the liver, this can cause an enlarged liver and, possibly, scarring of the liver (cirrhosis).
Testing for Glycogen Storage Disease
Hypoglycemia, or low blood sugar, is when symptoms related to low blood sugar improve after eating or drinking something with glucose. It’s worth noting that newborns often experience temporarily low blood sugar in the first two days of life, and during this time, it’s challenging to diagnose hypoglycemia related diseases called Glycogen Storage Disorders (GSDs).
The length of time a person can go without food before experiencing symptoms of low blood sugar is a crucial factor that your doctor will consider. If symptoms occur after a short time without food, it may suggest a particular type of GSD (type I or III). In contrast, symptoms that appear after an overnight fast could point towards a different kind of GSD (type 0, VI, IX).
When suspecting hypoglycemia, your doctor will usually measure your blood sugar levels. This is usually done through a diagnostic fasting glucose test, which must be done in a hospital setting for close monitoring.
Several GSDs (type 0, III, VI, IX) are characterized by a process called ketosis, and you’ll often have a level of a substance called beta-hydroxybutyrate above 2.5 mmol/L. High levels of fats in the blood, and abnormal liver function tests are also common in these conditions. Specific types of GSD (type III) may also cause an increase in a compound called creatine kinase, whereas others (type I) are related to high levels of lactic acid and acidosis.
Patients with the type I disorder can also have high levels in enzymes linked to the liver and uric acid, and it’s common for them to have high fat levels in the blood. Urinary myoglobin, a protein in muscle cells, can also be found in GSD patients, particularly those where GSD mainly affects the skeletal muscles.
Even though gene testing is now widely used for diagnosing most GSDs, in some cases, a tissue sample examination from the liver or muscle is still needed. The liver under the lens for GSD type 0 and type I will look different, helping make a more precise diagnosis. Fibrosis, or liver scarring, is a common finding in patients with GSDs and is particularly noted in patients with GSD type III, IV, and VI.
For GSD types IV and V, a muscle tissue sample examination can also provide clues to specific abnormalities. In type V, particular tests for chemical reactions (referred to as histochemical staining) will turn negative, and glycogen deposits, a form of energy storage, become evident with certain stains. For GSD type XV, unique features can be observed in a muscle biopsy as well.
Lastly, non-invasive genetic testing is largely available today, often eliminating the need for invasive biopsies. Such genetic tests target mutations known to cause these rare genetic disorders.
Treatment Options for Glycogen Storage Disease
Currently, no cure exists for Glycogen Storage Disease (GSD), a group of inherited conditions that affect how the body processes and stores sugar and starch from food. The main focuses of treatment are managing the symptoms and reducing the potential side effects.
Often experienced symptoms from GSD include drops in blood sugar levels (hypoglycemia), an increase in lactate (hyperlactatemia), an overload of uric acid (hyperuricemia), and high levels of lipids (hyperlipidemia). Hyopglycemia is prevented by the intake of starch. The best form of starch for this purpose is now commercially available. Hyperuricemia is managed with a medication called allopurinol and hyperlipidemia can be tackled with a category of medications called statins.
Furthermore, some types of GSDs are now managed with a method called enzyme replacement therapy (ERT) which uses an artificially created enzyme called alglucosidase alfa. This enzyme helps to break down glycogen, the complex sugar at the root of GSD. Currently, research is ongoing to expand the use of ERT to manage other types of GSDs.
Liver transplant may also be considered for patients with specific types of GSDs that have developed into severe liver disease, such as liver cancer or failure. It should be noted that while liver transplantation could address liver failures and hypoglycemia, it does not remedy heart problems (cardiomyopathy) that may come with the GSD.
In terms of immediate management of hypoglycemia, oral carbohydrates and glucose injections are used. The hormone glucagon, mainly used in other types of hypoglycemia, is not effective in cases where hypoglycemia is as a result of GSD.
Future ongoing treatments are customized based on the specific type of GSD. For instance, uncooked or modified cornstarch, allopurinol, and liver transplants are sometimes employed in severe cases of GSD type Ia or Ib. Unfortunately, there are currently no specific treatments for several other forms of GSD such as GSD type IIb, VII, X, XI, XII, XIII, XIV, XV.
Management of GSD is complex and varies according to the specific type. Therefore patients are encouraged to regularly consult with their healthcare team to adapt their treatments as necessary.
What else can Glycogen Storage Disease be?
The following are some medical conditions that could be diagnosed:
- Charcot-Marie-Tooth disease
- Congenital disorders of glycosylation
- Congenital lactic acidosis
- Deficiencies of phosphofructokinase
- Disorders of uric acid metabolism
- DNA depletion syndrome
- Duchenne muscular dystrophy
- Duchenne-Becker muscular dystrophy
- Endocardial fibroelastosis
- Fatty acid oxidation disorders
- Fructose-1-phosphate aldolase deficiency
- Fructose-1,6-biphosphatase deficiency
- Galactosemia
- Hyperlipoproteinemia
- Limb-girdle muscular dystrophy
- Lysosome-associated membrane protein 2 deficiency
- Mitochondrial DNA depletion syndromes
- Mitochondrial myopathies
- Neurovisceral sphingolipidosis
- Niemann-Pick disease
- Organic acidurias
- Polymyositis
- Sphingomyelinase deficiency
- Spinal muscular atrophy
- Werdnig-Hoffman disease
- Zellweger syndrome
What to expect with Glycogen Storage Disease
If Glycogen Storage Diseases (GSDs) are detected early and managed correctly, most patients have a good chance of recovery. Proper management of diet can reduce complications related to low blood sugar, and has been shown to improve kidney dysfunction in patients with GSD type I.
In rare cases, patients with GSD type Ib can suffer from end-stage kidney disease, which might require a kidney transplantation. For patients with GLUT2 deficiency – a condition that affects the body’s ability to transport glucose, which is a form of sugar – liver size and the amount of stored sugar (glycogen) can significantly reduce after following a diet that limits the body’s production of substances called ketones (antiketogenic diet).
Possible Complications When Diagnosed with Glycogen Storage Disease
In early childhood, low blood sugar can lead to seizures and cardiac arrest. People with glycogen storage disease (GSD) type Ia can experience delayed growth, kidney problems, high levels of fat in the blood, and a type of liver cancer called hepatocellular carcinoma. On the other hand, GSD type Ib often leads to repeated bacterial infections due to a decrease in white blood cells.
If a person has GSD type IV, they can progressively lose liver function and develop cirrhosis, a liver disease. Heart disease involving weakened muscles (cardiomyopathy) and muscle weakness around the hips and shoulders (limb-girdle dystrophy) often occur in patients with GSD type II. Enlarged heart muscles is a common complication of GSD type III.
Growth delay and short stature are also seen in GSD type IX (a, b, c, d) and GSD type XII, but the latter also involves developmental and cognitive delays. For individuals with GSD types V and XIII, exercise intolerance, muscle breakdown (rhabdomyolysis), and kidney injury associated with muscle breakdown can occur.
- Low blood sugar leading to seizures and cardiac arrest in early childhood
- Delayed growth, kidney problems, high levels of fat in the blood, and hepatocellular carcinoma in GSD type Ia
- Repeated bacterial infections due to decreased white blood cells in GSD type Ib
- Progressive loss of liver function and cirrhosis in GSD type IV
- Cardiomyopathy and limb-girdle dystrophy in GSD type II
- Enlarged heart muscles in GSD type III
- Growth delay and short stature in GSD type IX (a, b, c, d) and XII
- Developmental and cognitive delays in GSD type XII
- Exercise intolerance, muscle breakdown and kidney injury associated with muscle breakdown in GSD types V and XIII
Preventing Glycogen Storage Disease
Teaching the patient and their family about changes to their diet and how often they should eat is crucial in improving the health of patients suffering from these conditions. Depending on the specific type of GSD (Glycogen Storage Disease – a group of inherited metabolic disorders) that affects the patient, unique guidance will be provided. Patients and their families will receive essential education on how to recognize low blood sugar symptoms (hypoglycemia) and the need for more sugar or carbohydrates when the patient is sick, such as having an infection.
For patients with a condition called GLUT2 deficiency, it’s important that they receive additional training on how to replace the salts and minerals (known as electrolytes) that are lost through their kidneys. These patients will also need guidance on their diet, which should avoid a sugar type called galactose, and involve regular, small meals that have enough calories to ensure normal growth.
