Glycogen storage disease (GSD) is a rare genetic disorder that affects about one in 20,000 people in the U.S.[*]. People with GSD have trouble synthesizing and breaking down glucose, which can cause a laundry list of health issues, including chronic low blood sugar, enlarged liver, weak muscles, and more.
And although glycogen storage disease is inherited, it’s not necessarily a hopeless diagnosis. Gene therapies show early promise, and enzyme replacement drugs appear to help some of the GSD population with enzyme deficiency. Nutrition changes may also offer some relief. Read on to find out.
What Is Glycogen Storage Disease?
Glycogen storage disease is a metabolic disease that affects your ability to synthesize or break down and use glycogen — the storage form of glucose (more on this in the next section).
With a few exceptions, most forms of GSD inhibit glycogen breakdown. This causes excess glycogen to accumulate in muscles, liver, kidney, and other organ tissue — which is toxic.
In most cases, glycogen storage disease starts early in life. Depending on the type of GSD, the symptoms range from mild to severe — with muscle pain, enlarged organs, stunted growth, low blood sugar, and muscle weakness being a few of the most common side effects[*].
How Your Body Stores Glucose
When you eat a meal — especially a carb-rich meal — much of that meal ends up in your bloodstream as glucose, a simple sugar that provides your cells with energy[*].
This rise in blood glucose, or blood sugar, then signals your pancreas to release insulin — your blood sugar regulation hormone.
Insulin’s job is critical — it ushers glucose out of your blood and into your cells for energy or stores it away for later. This not only provides you with the fuel you need to function, it also maintains healthy blood sugar levels.
After insulin sends its message to get glucose out of your blood, your cells store glucose in one of two forms: glycogen or fat. When insulin is working correctly — when you’re insulin sensitive — most of your excess blood glucose gets stored as the first form (glycogen) in muscle and liver cells.
Glycogen storage requires certain enzymes, including:
- Glycogen synthase
- Glycogen debranching enzyme
Healthy glycogen storage enzymes promote healthy amounts of glycogen in your cells.
How Glycogen Storage Works
Here’s an oversimplification of glycogen storage from start to finish[*]:
- Your blood sugar rises after eating
- Insulin commands your cells to store any excess glucose as glycogen
- Glucose gets converted to glucose-6-phosphate
- Glucose-6-phosphate gets converted to glucose-1-phosphate
- Glucose-1-phosphate gets converted to UDP-glucose
- UDP-glucose becomes glycogen thanks to the enzyme glycogen synthase
Once stored, glycogen sits in your muscle and liver cells until you have low blood sugar — during a fast or intense exercise session, for instance.
Then, to raise your low blood sugar, glycogen converts into glucose so your body can use it for energy — a process called glycogenolysis.
How Glycogenolysis Works
Here’s what glycogenolysis looks like under normal conditions[*]:
- Your blood sugar drops because you haven’t eaten for a while, are intentionally fasting, or an intense workout
- Low blood sugar signals glycogen stores to convert into glucose-1-phosphate
- Glucose-1-phosphate converts into glucose-6-phosphate
- Your body uses glucose-6-phosphate for energy (glycolysis) or turns it into glucose and releases it into the blood via an enzyme called glucose-6-phosphatase
At least that’s how glycogen storage and breakdown normally work. But when someone has glycogen storage disease, one or more of these steps is disrupted — and this leads to problems with muscle, liver, heart, and other organ tissue.
Types of Glycogen Storage Disease
Believe it or not, there are at least 16 types of GSD (type 0 through 15). This article, however, will only cover the first eight, not counting the subtypes within each type.
Type 0 (GSD 0)
Overview[*]: Type 0 is the oddball of the GSDs. That’s because people with GSD 0 don’t have issues storing glycogen, but rather issues synthesizing glycogen.
This is a problem because glycogen is crucial for powering muscle tissue, especially during exercise. And so glycogen insufficiency often leads to impaired muscle function in those affected with Type 0 GSD.
- Type 0a — problems synthesizing muscle glycogen
- Type 0b — problems synthesizing liver glycogen
Physical Cause: mutations in the GYS1 and GYS2 genes impair the function of glycogen synthase — an enzyme that adds glucose to glycogen stores
Typical Symptoms: muscle cramping, heart pumping issues, hypoglycemia (low blood sugar)
Frequency: Unknown (under 40 cases reported, probably underdiagnosed)
Type I (GSD1, Von Gierke Disease)
Overview[*]: Type I GSD patients can’t break down glucose-6-phosphate, and end up with too much glycogen in their liver, kidney, and small intestinal cells. Because of this, those with Von Gierke disease present with low blood sugar, enlarged organs, and a host of other symptoms.
- Type Ia — more common, standard presentation
- Type Ib — 20% of cases, shortage of white blood cells
Physical Cause: an inability to break down glucose-6-phosphate — an intermediate form of glucose — leads to excess glycogen storage. G6PC and SLC37A4 gene mutations appear to be to blame.
Typical Symptoms: hypoglycemia, overproduction of lactic acid, too many lipids in the blood (hyperlipidemia), enlarged liver, stunted growth
Frequency: 1 in 100,000 (type Ia accounts for 80% of cases)
Type II (GSD2, Pompe Disease)
Overview[*]: Pompe disease is caused by a dysfunction of acid alpha-glucosidase — an enzyme for dissolving glycogen within cells. This results in muscle weakness, especially in the heart. Most
- Classic — affects infants early in life, more severe symptoms
- Delayed onset — delayed to adulthood, milder symptoms
Physical Cause: mutations in the GAA gene causes dysfunction of acid alpha-glucosidase — an enzyme needed to break down glycogen
Typical Symptoms: muscle weakness, weak heart (cardiomyopathy), respiratory issues
Frequency: 1 in 40,000-60,000[*]
Type III (GSD3, Cori Disease)
Overview[*]: Cori disease is caused by a deficiency of the glycogen debranching enzyme, which results in toxic levels of glycogen in the liver and muscle tissue. Cori disease starts early, and children with this condition typically have an enlarged liver, stunted growth, and low blood sugar.
- IIIa — affects liver and muscles, more common
- IIIb — affects liver only, more common
- IIIc — affects liver and muscles, less common
- IIId — affects liver only, less common
Physical Cause: AGL gene mutations impair the function of glycogen debranching enzyme — which helps break down glycogen
Typical Symptoms: enlarged liver, hyperglycemia, stunted growth, hyperlipidemia
Frequency: 1 in 100,000
Type IV (Andersen disease, GSD IV)
Overview[*]: Andersen disease stems from a deficiency in glycogen branching enzyme, which leads to abnormal glycogen storage. Depending on its severity and subtype, GSD IV ranges from muscle and heart weakness to a fatal childhood condition.
- Fatal perinatal neuromuscular — most severe, low muscle tone, often fatal to newborns
- Congenital muscular — problems breathing, weak heart, often fatal in the first few months
- Progressive hepatic — most common, liver failure, often fatal in early childhood
- Non-progressive hepatic — similar to progressive hepatic, but less severe
- Childhood neuromuscular — late childhood onset, muscle weakness, heart weakness
Physical Cause: GBE1 gene mutations cause problems with glycogen branching enzyme production, which directs proper glycogen storage
Typical Symptoms: enlarged liver, muscle weakness, liver disease, poor muscle tone
Frequency: 1 in 600,000 – 800,000
Type V (GSDV, McArdle Disease)
Overview[*]: People with McArdle disease can’t break up muscle glycogen, which leads to muscle cramping, muscle pain, and fatigue during exercise. GSDV doesn’t usually present until the teens or early 20s.
Physical Cause: PYGM gene mutations disable myophosphorylase — an enzyme that dissolves muscle glycogen into glucose-1-phosphate
Typical Symptoms: exercise intolerance, muscle weakness, muscle cramps, muscle pain
Frequency: Unknown (found to affect 1 in 100,000 around Dallas, TX)
Type VI (GS DVI, Hers Disease)
Overview[*]: Hers disease affects glycogen storage liver, as opposed to muscle tissue. Hers disease often starts in infancy, and children with Hers present with an enlarged liver and hypoglycemia. Fortunately, symptoms usually improve with time.
Physical Cause: PYGL gene mutations hamper the function of liver glycogen phosphorylase — an enzyme that dissolves liver glycogen into glucose-1-phosphate
Typical Symptoms: enlarged liver, hypoglycemia, liver dysfunction
Frequency: Unknown (only about a dozen cases reported)
Type VII (GSDVII)
Overview[*]: GSDVII is another muscle glycogen disorder. Except in one subtype, those with GSDVII experience muscle pain and muscle weakness. GSDVII usually starts in childhood.
- Classical (most common) — exercise leads to muscle pain and breakdown of muscle tissue, which can damage the kidneys
- Severe Infantile — poor muscle tone, enlarged heart, often fatal in the first year
- Late Onset — muscle weakness typically begins in adulthood
- Hemolytic — characterized by the breakdown of red blood cells, which leads to anemia (low red blood cells)
Physical Cause: PFKM gene mutations impair the function of phosphofructokinase — an enzyme that helps convert muscle glycogen into glucose
Typical Symptoms: muscle pain, muscle weakness, muscle cramps, enlarged heart, high uric acid, exercise intolerance
Frequency: Unknown, probably rare
How Common Is Glycogen Storage Disease?
There are at least seven other types of GSD described in the literature. And these types have similar roots to types I through VII.
The truth is: GSDs of all types are probably underdiagnosed. As genetic testing becomes more common, and as research progresses, the number of reported cases may increase.
And with more diagnoses, it’s also likely that researchers will discover more (and better) therapies.
Drugs And Gene Therapy For GSD
GSD treatment usually revolves around symptom-management, but scientists have recently developed therapies that go beyond managing symptomatology. Below are a few of these therapies.
But first, a standard disclaimer. This article does not take the place of medical advice. Please consult a healthcare professional for that.
In 2014, the FDA approved the drug Lumizyme to treat Pompe disease (GSD2). Lumizyme is an is enzyme replacement therapy that replaces the glycogen breakdown enzyme that people with Pompe disease lack[*].
Rapamycin is a drug that regulates the mammalian target of rapamycin (mTor) pathway. In brief, the mTor pathway governs cell metabolism, growth, and much more. Relevant here: the mTor pathway also affects the enzyme glycogen synthase, responsible for proper glycogen storage
Skipping to the punchline: rapamycin given to dogs with Cori disease (GSD IIIa) inhibited glycogen synthase, reduced muscle and liver glycogen, and prevented damage to both liver and muscle tissue[*].
# 3 Gene Therapy
Want to modify gene expression in your average mammal? It’s possible. Just inject that mammal with a virus.
You read that right. Injecting dogs, cats, mice, and even sheep with adeno-associated virus (AAV) has delivered promising results for multiple forms of GSD, including von Gierke disease, Pompe disease, and McArdle disease[*].
What about human trials? Well, five people with Pompe disease showed modest improvement, with few side effects, from AAV therapy[*].
Sugar And GSD
If you or a loved one suffers from glycogen storage disease, the first thing you can do is address sugar intake.
Sugary, highly processed, and high-carb foods will raise your blood sugar, aka blood glucose. High blood glucose is a huge problem if your body has a hard time breaking down, storing, or releasing glycogen.
Yes, people with GSD will store excess glucose as glycogen; but, unfortunately, that glycogen can’t convert back to glucose for energy later on. Which means glycogen builds to toxic levels.
Less glycogen is usually a good thing for people with GSD, so it’s logical that minimizing the blood sugar response (called hypoglycemia treatment) can help[*]. With less sugar in the blood, less glycogen gets stored.
The obvious way to reduce sugar in the blood? Eat fewer carbs.
The Keto Diet For GSD
Your body tends to run on glucose. But in a low-sugar, hypoglycemic state, your body doesn’t just call it quits. Instead, it starts producing ketones from dietary and stored fat — your backup energy source.
Ketones, like glucose, are eventually converted to ATP (aka cellular energy) through a process called the Krebs cycle. But unlike glucose, ketones don’t spike your blood sugar, and don’t need to be stored as glycogen.
Because of this, the ketogenic diet — a high-fat, low-carb nutritional plan that gets you burning fat over sugar — has shown promise for treating glycogen storage disease. Here are some examples:
- A high-fat diet lessened myopathy (muscle weakness) in two boys with Cori disease (type III GSD) over the course of about 2.5 years. This benefit stopped when the high-fat diet stopped and resumed when they resumed the high-fat diet[*].
- A high-fat diet alleviated cardiomyopathy (heart muscle weakness) in two siblings with Cori disease over the course of one year. Cardiac enzymes, along with signs of congestive heart failure, both improved measurably[*].
- A ketogenic diet was used to treat a patient with GSD V, or McArdle disease — resulting in less muscle pain and weakness[*]
Glycogen Storage Disease Next Steps
If you think your child or a loved one suffers from glycogen storage disease, the first thing to do is consult your doctor. Depending on the type of GSD, there are one or more potential drug therapies on the market or in the pipeline.
You might also research nutritional options for GSD. Research on low carb keto diets is still early, but several small case studies have shown promise.
To learn more about keto, you can read our free startup guide here.
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