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Glycogen Storage Disease (GSD)

Sugar, Brown Sugar, Sweet, Brown, Food

GSD is a genetic disorder in which an enzyme problem is present and does not allow the body to keep or process the complex carbohydrate glycogen correctly. GSD has a negative impact on the liver, muscles, and other parts of the body. Several types of GSD can occur.

How Body Stores Glucose

When you consume food – in particular, a carbohydrate abundant diet – most of that food is converted into glucose, a type of sugar, and goes into your bloodstream for your cells to use for energy.

An increase in the amount of glucose in the blood triggers the pancreas to secrete insulin, the hormone that controls blood sugar.

Insulin is vitally important- it transports glucose from the bloodstream into your cells for either energy or preservation for later. This not only gives you the energy you require to operate, but also keeps your blood sugar steady.

Having balanced blood sugar levels and cells that are sensitive to insulin is essential as it is associated with numerous chronic diseases and metabolic issues.

Insulin commands cells to remove glucose from the bloodstream, where it can be either stored as glycogen or fat. When the body is responding properly to the insulin it produces, extra glucose in the bloodstream is normally stored in the form of glycogen inside the muscles and liver cells.

Glycogen storage requires certain enzymes, including:

  • Glycogen synthase
  • Glycogen debranching enzyme
  • Acid-alpha-glucosidase

Enzymes that help store glycogen in a balanced way result in the right amount of glycogen in your cells.

How Glycogen Storage Works

Here’s an oversimplification of glycogen storage from start to finish:

  1. Your blood sugar rises after eating
  2. Insulin commands your cells to store any excess glucose as glycogen
  3. Glucose gets converted to glucose-6-phosphate
  4. Glucose-6-phosphate gets converted to glucose-1-phosphate
  5. Glucose-1-phosphate gets converted to UDP-glucose
  6. UDP-glucose becomes glycogen thanks to the enzyme glycogen synthase

Once it is kept, glycogen stays in your muscles and liver until your blood sugar drops; this could be during periods of fasting or when doing a strenuous exercise. Then, to improve your diminished blood sugar levels, glycogen transforms into glucose so that your body can use it as fuel – a process known as glycogenolysis.

How Glycogenolysis Works

Here’s what glycogenolysis looks like under normal conditions:

  1. Your blood sugar drops because you haven’t eaten for a while, are intentionally fasting, or an intense workout
  2. Low blood sugar signals glycogen stores to convert into glucose-1-phosphate
  3. Glucose-1-phosphate converts into glucose-6-phosphate
  4. 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

That is the usual way that glycogen is saved and deteriorated. However, when someone has glycogen storage disease, some of the parts of the process are not working properly, which can cause issues with the muscles, liver, heart, and other organs.

Glycogen and Glycogen Storage Disease (GSD)

A continual stream of energy is essential for the cells of the body to work correctly. This fuel is a simple sugar called glucose. Glucose comes from breaking down the food we eat. The body consumes the requisite quantity of glucose needed to run and preserves the excess to utilize later.

Prior to its preservation, the organism has to amalgamate the basic glucose components into a more complicated sugar known as glycogen. Glycogen is kept in the liver and muscle cells.

If the body requires additional energy, it will convert the glycogen stored in the liver into glucose that can be used by cells. Enzymes, a kind of specific protein, enable the production and degradation of glycogen in what is referred to as glycogen metabolism.

Sometimes a person is brought into the world without the necessary enzyme to facilitate the process, or the enzyme may not function correctly. The body is unable to process or convert glycogen efficiently.

This can cause the blood sugar levels to become extremely low when one is not eating. The body’s tissues and organs must have an adequate amount of glucose circulating in the bloodstream for them to function correctly.

A deficiency or malfunction of an enzyme can cause an abnormality known as glycogen storage disease (GSD). This is when the body does not metabolize glycogen in the correct manner. The body makes use of an array of enzymes to break down glycogen. Consequently, there are a variety of GSDs.

Types of GSD

GSDs all focus on different enzymes which are used for either saving or breaking down glycogen. At the minimum, there are 13 different kinds of glycogen storage disorders.

Doctors know more about some types than others. GSD mostly affects the liver and the muscles. Certain types of ailments may lead to complications in other parts of the body as well. Types of GSD and the parts of the body they affect the most include:

  • Type 0 (Lewis’ disease) – Liver.
  • Type I (von Gierke’s disease) Type Ia – Liver, kidneys, intestines; Type Ib – Liver, kidneys, intestines, blood cells.
  • Type II (Pompe’s disease) – Muscles, heart, liver, nervous system, blood vessels.
  • Type III (Forbes-Cori disease) – Liver, heart, skeletal muscles, blood cells.
  • Type IV (Andersen’s disease) – Liver, brain, heart, muscles, skin, nervous system.
  • Type V (McArdle’s disease) – Skeletal muscles.
  • Type VI (Hers’ disease) – Liver, blood cells.
  • Type VII (Tarui’s disease) – Skeletal muscles, blood cells.
  • Type IX – Liver.
  • Type XI (Fanconi-Bickel syndrome) – Liver, kidneys, intestines.

It is estimated that approximately every 20,000 to 25,000 newborns have a glycogen storage disorder. The four most prevalent varieties of GSD are I, II, III, and IV, and type I is by far the most widespread.

It is thought that nearly 90% of those with GSD fall into categories I through IV. It is estimated that around one quarter of those with Glycogen Storage Disease have type I. Although GSDs VI and IX can have gentle signs, they could be overlooked when it comes to diagnosis.

In many cases, the most extreme types of GSD are discovered in infants and young children. It is possible that certain types of mildness may not become apparent until someone has reached adulthood.

Symptoms and Causes

Symptoms vary based on the type of GSD. Some GSDs affect mostly the liver. These encompass Type 0, Type I, Type III, Type IV, Type VI, and Type IX. At times, however, there may be similarities in the symptoms involving both muscle and heart.

Apart from GSD type 0, these varieties might result in a liver enlargement. A large liver is associated with decreased blood sugar as surplus glycogen is stored in the liver rather than distributed as glucose in the bloodstream.

The signs of reduced blood sugar level, or hypoglycemia, could include excessive sweating, shaking, fatigue, disorientation and sometimes convulsions. Certain forms of GSD, in particular Types V and VII, largely influence the muscles of the skeleton. The most frequent indications of these types are muscular atrophy and muscular spasms.

Other symptoms that may occur include:

  • Tiredness.
  • Very slow growth.
  • Obesity (being very overweight).
  • Problems with bleeding and blood clotting.
  • Kidney problems.
  • Low resistance to infections.
  • Breathing problems.
  • Heart problems.
  • Mouth sores.
  • Gout.

GSDs Causes

GSDs happen when a mutation arises in the gene which would normally code for the enzyme that is either not functioning correctly or not produced at all. The gene is passed down from parents to children.

In order to receive the GSD, a person typically has to inherit a defective gene from both of their parents. It is not always certain that both parents will transmit the gene to their offspring if they both possess it.

Diagnosis and Tests

The physician may suspect a certain kind of GSD that impacts the liver in the presence of four different warning signs. These include:

  • A low blood glucose level.
  • An enlarged liver.
  • Lagging growth.
  • Abnormal blood tests.

Medical history can be indicative of GSD, so it can potentially provide the doctor with a preliminary idea. He or she may suggest some tests that might include:

  • Blood tests – To find out your blood glucose level and to see how your liver, kidneys and muscles are working.
  • Abdominal ultrasound – To see if your liver is enlarged.
  • Tissue biopsy – Testing a sample of tissue from a muscle or your liver to measure the level of glycogen or enzymes present.
  • Gene testing – To look for problems with the genes for different enzymes. Gene testing can confirm a GSD.

Glycogen Storage Disease (GSD) Treatment

Treatment varies depending on the type of GSD. For GSDs with implications on the liver, the goal of care is to keep glucose levels in the blood in check.

It is generally enough to keep the energy needs of the cells fulfilled and avoid any long-term issues connected to an inadequately controlled GSD. One should regularly consume raw cornstarch and/or dietary supplements to manage the condition.

Because cornstarch is a complex carbohydrate that is difficult to break down, it helps to keep blood sugar levels at a steady rate for a longer period than many other types of carbs in food.

By consuming several smaller portions that contain little to no sugar, it is possible to maintain blood glucose levels while also avoiding an accumulation of glycogen in the liver.

Intravenous solutions of carbohydrates may be provided throughout the evening period to avert an abatement in one’s blood glucose levels throughout the hours of slumber, though this comes with a greater risk of grave cases of hypoglycemia compared to using unpasteurized cornstarch day and night.

It may be required to think about liver transplantation for Type IV GSDs who are experiencing progressive liver disease, once a comprehensive assessment has been conducted.

1. Lumizyme

In 2014, the Food and Drug Administration sanctioned Lumizyme to be employed in treating Glycogen Storage Disease Type 2 (Pompe disease). Lumizyme is an enzyme replacement treatment that substitutes for the glycogen breakdown enzyme that individuals with Pompe condition are missing.

Lumizyme, or alglucosidase alfa, has exhibited potential benefits in trial runs for both Pompe’s disease and Cori disease.

2. Rapamycin

Rapamycin is a medication that controls the mTor pathway of mammals. To put it succinctly, the mTor pathway regulates cell metabolism, expansion, and many other things. Importance here: the mTor pathway also has an effect on the enzyme glycogen synthase, which is responsible for maintaining accurate glycogen storage.

In conclusion, the administration of rapamycin to dogs with Cori disease (GSD IIIa) suppressed glycogen synthase, decreased the amount of glycogen in both muscle and liver tissue, and consequently preserved the integrity of both organ tissues.

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. Giving shots of adeno-associated virus (AAV) to canines, felines, rodents, and even sheep has been successful in treating multiple kinds of GSD, such as von Gierke illness, Pompe illness, and McArdle ailment.

What about human trials? In a case study involving five individuals diagnosed with Pompe disease, AAV therapy yielded modest progress and little to no undesirable aftermath.

Sugar And GSD

If you or someone close to you has glycogen storage disease, the initial course of action you should take is to manage their sugar consumption.

Foods that contain a lot of sugar, which have gone through many processes and contain a lot of carbohydrates, will cause your blood glucose levels to go up. A major issue arises when your body is unable to properly breakdown, store, or disseminate glycogen when the blood glucose levels are too high.

People with GSD have the capability to save excess glucose as glycogen; however, unfortunately, it is unable to be changed back to glucose when needing energy later. Which means glycogen builds to toxic levels.

It is sensible to suppose that controlling the amount of blood sugar (known as hypoglycemia treatment) in people suffering from GSD would be beneficial as lower levels of glycogen is typically regarded as beneficial. The amount of sugar in the blood decreases, leading to less glycogen being held in reserve.

The obvious way to reduce sugar in the blood? Eat fewer carbs. Investigators are attempting to use diets that are very low in carbs and rich in fat to restrict the storage of glycogen for managing GSD.

The Keto Diet For GSD

Your body tends to run on glucose. But if your blood sugar is low and your body is hypoglycemic, your body does not stop working. Instead of relying on glucose, the body starts to generate ketones from the fat we have consumed or saved to be used as a backup source of energy.

Ketones, as is the case with glucose, go through the Krebs cycle which results in the production of ATP, also known as cellular energy. In contrast to glucose, ketones do not elevate the sugar levels in the blood and do not require to be stored as glycogen.

The ketogenic diet, which involves consuming a high fat, low-carb diet to start burning fat instead of sugar, has been proposed as a potential solution 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

Despite the limited sample size of studies conducted so far, the evidence suggests that the ketogenic or very low-carb diet could possibly be beneficial for families affected by GSD. Further research is warranted.

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