Introduction

Most people start their day with breakfast, while others might opt for brunch instead. Regardless of whether it is breakfast or brunch, the food serves as a form of energy for us to perform our task. Do you know that glucose found in food is a main source of energy for us? Glucose is a form of carbohydrate and has an important role in metabolism. Now, you will start wondering what human metabolism is. Do not fret. Metabolism simply refers to the breakdown of food and its subsequent transformation into energy to meet a person's energy demands at the cellular level.

Let us begin the story of glucose, using cereal as our example. Firstly, the cereals that you consumed during breakfast will be broken down by enzymes into simple sugars and other products. Simple sugars like glucose are rapidly absorbed into the bloodstream, and this raises your blood sugar. The higher your blood sugar rises after meals and the longer the blood sugar remains high, the more likely you are to develop diabetic complications. Thus, to prevent this from happening, our body will store this excess glucose in the bloodstream as glycogen in the liver and muscles. When the blood glucose level in the body drops below a normal range, the glycogen will be converted back to glucose by enzymes.

Now imagine if one enzyme involved so far, was defective. It would result in either improperly formed glycogen, or glycogen would not get broken down into glucose. This person will suffer from a type of Glycogen Storage Disease (GSD). So what are GSDs? It is a group of inherited genetic disorders that causes glycogen to be incorrectly formed or released in the body. Glycogen is mainly stored in the liver or muscle tissues. As a result, GSDs usually have an effect on the liver, muscles, or both. 

How do people inherit Glycogen storage disease?

As mentioned in the introduction, excess glucose is converted to glycogen, and vice versa. These two processes require many different enzymes. Thus, if one of these enzymes is defective, the conversion process stops. This becomes a glycogen storage disorder. Most, but not all glycogen storage disorders are inherited in a pattern called autosomal recessive inheritance-in which a child inherits a defective allele from each parent.

Glycogen storage disorders are rare. It is estimated to occur once in every 20,000 to 40,000 babies born. They are passed on in families through their genes.

If both parents carry the defective gene, there is:

1) 25% chance that their child will develop the disease.

2) 50% chance that the child will receive one defective gene from one of the parents. (Carrier of the disease only- child will not suffer from this disease)

3) 25% chance that child will receive both normal genes, one from each parent.

Types of Glycogen Storage Diseases (GSDs)

There are many types of Glycogen Storage Diseases. This is because there are different enzymes involved in various stages of glycogen breakdown and production. Indeed, there are over 9 types. Each disorder has a different enzyme malfunction.

• Type Ia (von Gierke's disease), type Ib.
• Type II (Pompe's disease).
• Type III (Forbes-Cori disease).
• Type IV (Andersen's disease).
• Type V (McArdle's disease).
• Type VI (Hers' disease).
• Type VII (Tarui's disease).
• Type IX (liver glycogen phosphorylase kinase deficiency).
• Type 0 (Lewis' disease).

We will be focusing only on Type I. Type I GSD accounts for 90% of all GSD cases. 1 in 100,000 live births suffer from Type I. Researchers have identified two types of Type I GSD. These two types differ in their signs and symptoms and also their genetic causes.

Type Ia, or von Gierke's disease, is caused by the glucose-6-phosphatase deficiency in the liver, kidney, and small intestine. Glucose-6-phosphatase is a type of enzyme. Without glucose-6-phosphatase, glycogen cannot be broken down into glucose and the synthesis of glucose is disrupted. As a result, the liver is clogged with excess glycogen.

Type Ib is caused by glucose-6-phosphatase translocase T1 deficiency. Glucose-6-phosphate translocase is also a type of enzyme. Without glucose-6-phosphate translocase, glucose-6-phosphate cannot be transported back to the cell, to meet glucose-6-phosphatase, and no glucose will be formed. Thus glycogen cannot be broken down into glucose. 

Later, other translocases were discovered, adding 2 more subtypes of Type I GSD: Type Ic and Type Id. They are caused by defects in the translocase system.

Biochemistry of Glycogen storage disease Type Ia

Type Ia (Von Gierke's disease) is caused by a deficiency in glucose 6-phosphatase. Glucose-6-phosphatase is the enzyme that removes the phosphoryl group from glucose-6-phosphate (the intermediate of glycogen and glucose) to form glucose which is released from the cell. 

Phosphorylated sugar (sugar having a phosphate group) cannot pass through the cell membrane, only the de-phosphorylated form (sugar without phosphate group) can pass through. During exercise, when energy demands are raised, glycogen stores fail to be mobilized as glucose into the bloodstream to provide the needed energy. The result is severe hypoglycaemia (low blood sugar) and body fatigue. Furthermore, since the glycogen in the liver is not being broken down, it tends to accumulate and will interfere with the proper functioning of the liver cells in which it is stored. Thus, resulting in an enlarged liver.

Signs and Symptoms

How do you know whether you are suffering from Type Ia Glycogen Storage Disease? There are various signs and symptoms that can indicate to you that you are suffering from this disease. The symptoms of Type Ia are as follows:

·        Enlarged and fatty liver
·         Low blood sugar
·         Elevated levels of lactate, lipids, and uric acid in the blood
·         Growth is impaired
·         Blood platelets affected
·         Frequent nosebleeds
·         Easy bruising
·         Liver tumors, liver cancer, chronic renal disease and gout may appear after age 20-30

Type Ib has the same symptoms as Type Ia as shown above. However, type Ib has additional symptoms such as immune system weakening and victims are more susceptible to bacterial infections like pneumonia, mouth and gum infections, and inflammatory bowel disease.

Long-term complications include renal calcification in 67% who had Type Ia, and severe cases of anaemia.

Diagnosis

Diagnosis of Glycogen Storage Disease Type 1a can be carried out by several test methods. 

1) Ultrasound Scans

An abdominal ultrasound scan is used to assess and monitor the size of the liver and kidneys and to detect possible hepatic adenomas (uncommon benign epithelial liver tumors). This is a painless test which involves the use of gel on the abdomen and a scanning probe over the surface of your abdomen. The high frequency sound wave produces an image of the internal abdomen. This is similar to the ultrasound scan that a pregnant woman does during her pregnancy check-up. 

2) Liver Biopsy

A sample of tissue is taken either from the muscles or from liver and sent to the laboratory for testing and examination under the microscope.  The levels of glycogen and fat in the tissue can be measured as well as the levels of glucose-6-phosphatase activity present. This can help to confirm the type of glycogen storage disorder. However liver biopsy is only rarely required because of improved gene testing.

 3)  Blood glucose tests

Blood test is used to measure the blood glucose levels as the blood glucose is generally low with elevated lactate, uric acid, triglyceride and cholesterol in patients suffering from glycogen storage disease type 1.

Treatment

Glycogen storage diseases can be treated but cannot be cured. Yet. For Type I glycogen storage disease, it focuses on correcting the metabolic changes in the body by providing small, frequent feedings of uncooked cornstarch mixed in water, or soy milk. Since cornstarch is digested slowly, it provides a steady release of glucose. Maintenance of the blood glucose level could reverse all of the physical and chemical signs of this disease.

In addition, most doctors would restrict patients to consume certain sugars like sucrose (table sugar), fructose (sugar from fruits), lactose and galactose (sugars found in milk), but the degree of restriction is still being debated on. 

Patients diagnosed with GSD type Ib are required to take medication to increase the number of neutrophils, a type of white blood cell that fights infection. This is to reduce the risk that arises due to the weakening of the immune system.

Liver transplantation has also become a new option for some patients suffering from anemia as a result of their GSD, although the viability of this option for children is still debated upon.

In 2011, Dr David Weinstein and Dr Cathryn Mah, of the University of Florida, began testing the possibility of gene therapy for treating GSD Type Ia. Using canines as their model for comparison; they administered two doses of gene therapy to a dog that had the disease. Six weeks after therapy, the dog no longer relied on glucose supplements. This discovery indeed offers much hope to patients out there who see this as a final cure to their glycogen storage disorder. 

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