Glycogen Storage Disorder

Glycogen storage disorders are a group of rare inherited conditions that disrupt how the body stores or uses glycogen, a stored form of sugar that serves as the body’s main energy reserve. These disorders can lead to frequent episodes of dangerously low blood sugar, muscle weakness, and liver damage, but most types can be managed effectively with proper treatment.

Table of contents

• What is Glycogen Storage Disorder?
• Types of Glycogen Storage Disorder
• Signs and Symptoms
• Causes and Inheritance
• Diagnosis
• Treatment and Management
• Outlook and Prognosis

What is Glycogen Storage Disorder?

Glycogen storage disorders (GSDs) are a group of rare conditions in which the body cannot properly store or break down glycogen, which is a form of sugar or glucose.^[1] Glycogen is the stored form of glucose, which is the body’s main source of energy. When you eat food containing carbohydrates, your body breaks them down into glucose. Any glucose that is not needed immediately for energy is stored primarily in the skeletal muscles and liver as glycogen for later use.^[1]

The body creates glycogen from glucose through a process called glycogenesis. When the body needs extra fuel, it breaks down glycogen through a process called glycogenolysis. Several enzymes are responsible for these two processes.^[1] Children with glycogen storage disorder are missing one of the several enzymes that break down glycogen, and glycogen can build up in the liver, causing problems in the liver, muscles, or other parts of the body.^[3]

These disorders are types of inherited metabolic disorders, also known as glycogenoses or inborn errors of carbohydrate metabolism.^[2] The inability to mobilize glucose from glycogen results in low blood sugar and exercise-induced weakness in affected patients and can lead to long-term complications.^[2]

• Liver
• Skeletal muscles
• Kidneys
• Heart

GSD, glycogenosis, dextrinosis

Types of Glycogen Storage Disorder

There are at least 19 different types of glycogen storage disease based on which enzyme is affected.^[1] Your body uses many different enzymes to process glycogen, which explains why there are so many types. Healthcare providers may refer to each type based on the specific enzyme that is missing or the scientist who discovered that particular type of GSD.^[1]

Researchers know more about some types than others. GSD mostly affects the liver or muscles, while some types cause problems in other areas of the body as well.^[1] For each type of GSD, there is a lack (deficiency) of a certain enzyme involved in glycogen storage or breakdown.^[1]

The most common types of GSD include:

• Glycogen storage disease type I (GSD I), also known as von Gierke disease, is the most common type and accounts for about 25 percent of all children with GSD. It occurs in approximately 1 in 100,000 births.^[1] Symptoms typically appear when an infant is 3 to 4 months of age and may include low blood sugar, which can cause fatigue, constant hunger, and crankiness. The liver and sometimes the kidneys swell due to built-up glycogen.^[5]
• Glycogen storage disease type III (GSD III), also known as Cori disease or Forbes disease, causes glycogen to build up in the liver and muscles. Symptoms typically appear within the first year of life. Children with this type of GSD may have a swollen belly, delayed growth, and weak muscles.^[5]
• Glycogen storage disease type IV (GSD IV), also known as Andersen disease, is one of the most serious types of GSD. Symptoms typically appear in a child’s first month of life and include failure to gain weight or grow at an expected rate. This type of GSD often leads to cirrhosis of the liver and can affect the heart and other organs as well.^[5]

In most cases, GSD is diagnosed within the first year of life, but in some cases the diagnosis may not be made until later in childhood.^[3]

Signs and Symptoms

The symptoms of glycogen storage disease can vary based on the type and even from person to person with the same type.^[1] Symptoms of GSD type 1 (the most common type) usually begin at three to four months of age, but symptoms of other types can develop later in life.^[1] The onset can range from neonatal life to adulthood, and clinical manifestations result either from a failure to convert glycogen into energy or the toxic accumulation of glycogen.^[2]

The two most common symptoms are low blood sugar (hypoglycemia) and getting tired easily from physical activity, known as exercise intolerance.^[1]

Low blood sugar happens when blood glucose is below 70 mg/dL. Symptoms include:^[1]

• Shaking or trembling
• Sweating and chills
• Dizziness or lightheadedness
• Weakness
• Faster heart rate
• Intense hunger (hyperphagia)
• Difficulty thinking and concentrating
• Anxiousness or irritability
• Pale skin (pallor)
• Seizures (this can happen with severe low blood sugar)

Other symptoms of GSD may include:^[1]

• Muscle cramps or muscle weakness
• Slowed growth and poor weight gain in children
• Enlarged liver (hepatomegaly)
• Low muscle tone
• High cholesterol (hyperlipidemia)

Some of these diseases cause few symptoms while others are fatal. The specific symptoms, age at which symptoms start, and their severity vary considerably between these diseases.^[7] For some types, the main symptom is usually weakness. For other types, symptoms are low levels of sugar in the blood and protrusion of the abdomen because excess or abnormal glycogen may enlarge the liver.^[7]

Glycogen storage diseases tend to cause uric acid (a waste product) to accumulate in the joints, which can cause gout, and in the kidneys, which can cause kidney stones. In type I glycogen storage disease, kidney failure is common.^[7]

Causes and Inheritance

Inherited genetic mutations (changes) that affect the function of enzymes necessary for glycogen storage and use cause GSD. A child inherits the mutations from their biological parents.^[1] Glycogen storage disease is hereditary, meaning it is passed down from parents to children.^[3]

Most GSDs have autosomal recessive inheritance, meaning both parents have to pass on the mutation for the child to get the condition.^[1] For most types of GSD, both parents are unaffected carriers, meaning they carry one copy of a misspelled gene that can cause GSD paired with a normal copy of the gene. When both parents pass the misspelled gene to a child, the child has no normal copy of that gene and therefore develops GSD.^[3]

A few types, like GSD type IX, have an X-linked inheritance. This means that the X chromosome carries the mutation.^[1]

Diagnosis

Glycogen storage diseases are diagnosed through clinical evaluation, biochemical testing, and genetic identification of mutations in specific enzymes. Imaging studies may also help assess organ involvement.^[2]

Glycogen storage disease is diagnosed by examining a piece of muscle or liver tissue under a microscope (biopsy) and by doing magnetic resonance imaging (MRI) to detect glycogen in the tissues. Doctors confirm the diagnosis by analyzing the DNA.^[7] Other tests, such as liver, skin, muscle, and blood tests, are done to determine the specific type of glycogen storage disease.^[7]

Biochemical testing includes liver enzyme levels and blood glucose measurements.^[2] Glycogen storage disease type II (Pompe disease) is now part of the screening test for newborns in many states in the United States.^[7]

Genetic testing to determine whether a couple is at increased risk of having a baby with a hereditary genetic disorder is also available.^[7]

Treatment and Management

Management focuses on addressing the underlying enzyme deficiency and preventing complications.^[2] There is no specific treatment available for most types of GSD, so symptomatic therapy is the mainstay of medical care. No cure is currently available for this group of metabolic disorders.^[2]

Treatment often includes dietary modifications to maintain blood glucose levels and prevent low blood sugar. The primary goals are good control of low blood sugar and other metabolic disturbances.^[8] Maintaining nutritional support for these patients is crucial. It helps to prevent low blood sugar and support growth and development.^[8]

Diet is the cornerstone of treatment. Survival requires numerous small meals, consumption of uncooked cornstarch, and testing blood sugar levels every few hours around the clock. Vigilance is needed 24 hours a day, 7 days a week, without exception.^[15]

In addition to drinking cornstarch every few hours around the clock, people with GSD must also eat small meals every one to four hours in order to maintain blood glucose at an appropriate level. The GSD diet is very restricted as foods containing sucrose (table sugar), fructose (sugar found in fruits), and lactose and galactose (sugars found in milk products) must be avoided.^[15]

Cornstarch Therapy

Glycogen storage disease was almost always fatal until 1971, when it was discovered that continuous glucose therapy could prevent low blood sugar. In 1982, cornstarch therapy was introduced as a slow release form of glucose.^[15]

Cornstarch is a complex carbohydrate that is difficult for the body to digest; therefore, it acts as a slow release carbohydrate and maintains normal blood sugar levels for a longer period of time than most carbohydrates in food. Ingesting regular doses of uncooked cornstarch throughout the day enables people with GSD to wait three to four hours between meals.^[15]

In 2012, the FDA approved a modified cornstarch product for the dietary management of GSD. This “superstarch” can maintain blood sugar levels for 7 to 8 hours overnight, allowing GSD patients and their families to get a full night of sleep. This was the first major breakthrough in the management of GSD in over 25 years.^[15]

A novel form of physically modified cornstarch differs from classic cornstarch in regard to its structure. Evidence suggests better control of low blood sugar in persons with GSD types I and III and an extended duration of normal blood sugar and better metabolic control for patients.^[8]

Additional Medical Care

To avoid a crisis situation, many children diagnosed with GSD have a gastric or naso-gastric tube placed. In infancy, the tube is critical for frequent feeds during the day and for using a continuous feeding pump at night.^[15]

Prevention of gouty attacks is important in the event dietary modifications fail to lower uric acid levels. Medications may be used to prevent these events. Renal protection is also very important. Urinary calculi are also commonly seen, and supplementation with citrate can help prevent renal calculi from forming. Certain medications may also be utilized to treat microalbuminuria (small amounts of protein in the urine).^[8]

Frequent infections in patients with certain types of GSD require intensive intravenous antibiotic treatment to control infections. Patients may even require medications that boost the immune system if infections are recurrent.^[8]

Lipid control is also important with lipid-lowering therapy. This helps to avoid pancreatitis and atherosclerotic disease.^[8]

In some cases, enzyme replacement therapy or liver transplantation may be indicated.^[2]

Outlook and Prognosis

The prognosis varies, depending on the specific GSD type, with some forms associated with a relatively normal life expectancy, while others may lead to severe complications like organ failure and developmental delays. Early diagnosis and appropriate management may improve outcomes significantly.^[2]

Most types of glycogen storage disorder are manageable with treatment.^[1] Dietary interventions have markedly improved the outcome for these disorders, from a previously fatal condition to one where people can do well with proper care.^[14]

The child’s outcomes depend on the form of GSD they inherit.^[5] Each type of GSD carries specific risks. As children mature into adolescence, they may face additional complications depending on their specific type of GSD.^[5]

A survey showed that patients can live an independent life and they cope with daily activities very well despite the challenges of this disease.^[8]