Glycogen Storage Disease Type I

Von Gierke disease, GSD I, GSDI

Glycogen storage disease type I is a rare inherited disorder that prevents the body from properly breaking down stored sugar, causing severe low blood sugar and serious health complications if left untreated.

Table of contents

• What is Glycogen Storage Disease Type I?
• Types of GSD I
• How Common is GSD I?
• What Causes GSD I?
• Organs and Tissues Affected
• Signs and Symptoms
• Complications Across the Lifespan
• Diagnosis
• Treatment and Management
• Outlook

What is Glycogen Storage Disease Type I?

Glycogen storage disease type I, also known as Von Gierke disease, is a rare inherited disorder that affects how the body processes and stores sugar. The condition was first described by Dr. Edgar Von Gierke in 1929.^[1]

In a healthy body, sugar from food is either used immediately for energy or stored as glycogen, which is a complex form of sugar. When the body needs energy between meals or during the night, special enzymes (proteins that help chemical reactions happen) break down this stored glycogen back into simple sugar called glucose. This glucose is then released into the bloodstream to fuel the body’s cells.^[2]

People with GSD I are missing a crucial enzyme needed to release glucose from glycogen. Without this enzyme, glycogen builds up in certain organs, especially the liver and kidneys. More importantly, the body cannot maintain normal blood sugar levels during periods without food, leading to dangerously low blood sugar.^[1]

Types of GSD I

There are two main types of glycogen storage disease type I, which differ in their genetic cause and some of their symptoms.^[1]

GSD Ia is the most common form, accounting for about 80 percent of all GSD I cases. It is caused by a deficiency of an enzyme called glucose-6-phosphatase (G6Pase), which is responsible for converting a substance called glucose-6-phosphate into glucose. This type results from mutations in the G6PC gene.^[2]

GSD Ib accounts for the remaining 20 percent of cases. In this type, the G6Pase enzyme itself works normally, but there is a defect in a transporter protein called glucose-6-phosphate translocase (G6PT). This transporter is responsible for moving glucose-6-phosphate into the proper location within cells where it can be converted to glucose. GSD Ib is caused by mutations in the SLC37A4 gene.^[1]

While both types share the main metabolic problems related to glucose production, people with GSD Ib have additional complications. They typically experience a shortage of white blood cells called neutropenia, which makes them prone to frequent bacterial infections. They may also have inflammation of the intestinal walls and various oral health problems including cavities, gum disease, and mouth sores. These immune and inflammatory problems are specific to GSD Ib and are not seen in people with GSD Ia.^[2]

How Common is GSD I?

Glycogen storage disease type I is a rare condition. The overall incidence is approximately 1 in 100,000 births.^[2]

What Causes GSD I?

GSD I is an inherited genetic disorder caused by mutations in specific genes. These genetic changes are passed down from parents to their children through an autosomal recessive pattern of inheritance. This means that both parents must carry and pass on a mutated copy of the gene for their child to develop the condition.^[2]

In GSD Ia, mutations occur in the G6PC1 gene, which provides instructions for making the glucose-6-phosphatase enzyme. In GSD Ib, mutations occur in the SLC37A4 gene, which provides instructions for making the glucose-6-phosphate transporter protein. Both of these proteins work together in the final step of releasing glucose from stored glycogen.^[2]

When these mutations prevent the effective breakdown of glucose-6-phosphate into glucose, the body converts this substance into glycogen and fat instead. Too much glycogen and fat stored within cells becomes toxic, damaging organs and tissues throughout the body, particularly the liver and kidneys.^[2]

• Liver
• Kidneys
• Small intestines
• Skeletal muscles
• Bone marrow (in GSD Ib)

Organs and Tissues Affected

The accumulation of glycogen in GSD I primarily affects the liver, kidneys, and small intestines. These organs lose their ability to function normally as glycogen builds up within their cells.^[2]

The liver is usually the most visibly affected organ. Excessive glycogen storage causes the liver to become greatly enlarged, a condition called hepatomegaly. This enlarged liver can give children with GSD I the appearance of having a protruding abdomen. The kidneys may also become enlarged.^[2]

In people with GSD Ib, the bone marrow is also affected, leading to problems with white blood cell production and immune function.^[2]

Signs and Symptoms

Symptoms of glycogen storage disease type I typically appear around 3 to 4 months of age. This timing corresponds with when babies begin to sleep through the night and do not eat as frequently as newborns, making the body’s inability to maintain blood sugar levels more apparent.^[1][2]

The primary symptom is hypoglycemia, or low blood sugar, which occurs during fasting periods such as between meals or overnight. Symptoms of low blood sugar include shaking or trembling, sweating and chills, dizziness, weakness, faster heart rate, intense hunger, difficulty thinking and concentrating, anxiousness or irritability, and pale skin. In severe cases, hypoglycemia can cause seizures.^[2]

Affected infants may also develop a buildup of lactic acid in the body, called lactic acidosis, high blood levels of uric acid (a waste product), and excess amounts of fats in the blood, known as hyperlipidemia.^[2]

As children with GSD I grow older, they typically have thin arms and legs and short stature. The enlarged liver may be quite noticeable. Some children may also experience diarrhea and develop deposits of cholesterol in the skin called xanthomas.^[2]

People with GSD Ib have additional symptoms related to their immune system dysfunction. They usually have neutropenia, which becomes apparent by age 1, making them prone to recurrent bacterial infections. They may also have chronic inflammation of the intestinal walls, similar to inflammatory bowel disease. Oral health problems are common, including cavities, inflammation of the gums, chronic gum disease, abnormal tooth development, and mouth ulcers.^[2]

Complications Across the Lifespan

Without proper treatment, glycogen storage disease type I leads to numerous complications that can develop at different stages of life.^[2]

People with GSD I may experience delayed puberty. Beginning in young to mid-adulthood, affected individuals can develop thinning of the bones called osteoporosis, a form of arthritis resulting from uric acid crystals in the joints known as gout, kidney disease, and high blood pressure in the blood vessels that supply the lungs, called pulmonary hypertension.^[2]

Females with this condition may also have abnormal development of the ovaries, a condition known as polycystic ovaries.^[2]

In affected teens and adults, tumors called adenomas may form in the liver. These tumors are usually noncancerous (benign), but occasionally they can become cancerous (malignant).^[2]

Diagnosis

The diagnosis of glycogen storage disease type I involves recognizing the characteristic symptoms and confirming the diagnosis through laboratory tests and genetic testing.^[1]

Doctors typically suspect GSD I when an infant or young child presents with severe hypoglycemia during fasting, an enlarged liver, and certain blood test abnormalities. Blood tests may show low glucose levels, high levels of lactic acid, elevated uric acid, and high cholesterol and triglyceride levels.^[1]

For GSD Ib specifically, blood tests will also reveal neutropenia, or low white blood cell counts.^[2]

Genetic testing can confirm the diagnosis by identifying mutations in the G6PC1 gene for GSD Ia or the SLC37A4 gene for GSD Ib. This testing helps differentiate between the two subtypes and can guide treatment decisions.^[1]

Treatment and Management

There is no cure for glycogen storage disease type I, so treatment focuses on managing symptoms and preventing complications. The cornerstone of treatment is maintaining normal blood sugar levels through careful dietary management.^[1]

The primary treatment approach involves frequent feedings of carbohydrates to prevent hypoglycemia. Affected individuals need to eat regularly throughout the day and often require nighttime feedings or continuous overnight nutrition. Many people with GSD I use uncooked cornstarch as a treatment because it provides a slow, steady release of glucose over several hours. This helps maintain blood sugar levels between meals and overnight.^[1]

Certain sugars, particularly fructose and galactose (found in fruits, table sugar, and dairy products), should be limited or avoided because they can worsen metabolic problems in people with GSD I.^[1]

Medications may be needed to manage specific complications. For example, allopurinol can help prevent gout attacks by lowering uric acid levels. Medications called ACE inhibitors may be used to treat kidney problems and high blood pressure. Lipid-lowering medications such as statins can help control high cholesterol and triglyceride levels to prevent pancreatitis and heart disease.^[8]

For people with GSD Ib, treatment also includes medications to boost white blood cell counts. A medication called filgrastim, which is a type of growth factor, can help increase neutrophil production and reduce infection risk. Despite this treatment, people with GSD Ib often still need antibiotic treatment for frequent infections.^[8]

Regular monitoring by a team of specialists is essential. This typically includes physicians who specialize in metabolism, nutritionists, and other healthcare providers who can address the various complications of the disease. With proper dietary management and medical care, many people with GSD I can lead relatively normal, independent lives.^[8]

Outlook

With early diagnosis and proper dietary management, the outlook for people with glycogen storage disease type I has improved dramatically. Maintaining good metabolic control through frequent feedings and appropriate use of cornstarch can help prevent many of the serious complications associated with this condition.^[1]

Despite the challenges of managing this disease, surveys have shown that patients can live independent lives and cope well with daily activities when they receive appropriate care and support.^[8]

Long-term complications such as liver adenomas, kidney disease, osteoporosis, and gout remain concerns, particularly for individuals whose blood sugar and metabolic parameters are not well controlled. Regular medical follow-up is essential throughout life to monitor for and manage these potential complications.^[2]

Research into potential genetic therapies for GSD I is ongoing, offering hope for future treatments that could address the underlying cause of the disease rather than just managing its symptoms.^[8]