Glycogen Storage Disease Type II

Glycogen storage disease type II is a rare inherited condition that prevents the body from breaking down glycogen properly, leading to its buildup in cells and causing progressive muscle weakness, heart problems, and breathing difficulties that can be life-threatening without early treatment.

Table of contents

• What is Glycogen Storage Disease Type II?
• Other Names for This Condition
• Types of the Disease
• What Causes This Disease
• How Common Is This Disease
• Signs and Symptoms
• How the Disease Is Diagnosed
• Treatment Options
• Outlook and Life Expectancy

What is Glycogen Storage Disease Type II?

Glycogen storage disease type II is a rare inherited disorder in which the body cannot properly break down a complex sugar called glycogen^[1]. Glycogen is stored in cells and normally serves as an important source of energy for the body. When this stored glycogen cannot be broken down correctly, it accumulates inside structures called lysosomes, which are small compartments within cells that help break down and recycle substances^[3].

The disease occurs because people with this condition lack enough of an enzyme called acid alpha-glucosidase (also known as acid maltase or GAA)^[1]. This enzyme normally breaks down glycogen into a simpler sugar called glucose, which cells use for energy. Without sufficient amounts of this enzyme, glycogen builds up to harmful levels, particularly in muscle cells^[7].

The accumulation of glycogen damages organs and tissues throughout the body, especially muscles. This buildup impairs the ability of affected tissues to function normally^[2]. The disease particularly affects the heart and skeletal muscles, causing them to break down over time^[3].

Other Names for This Condition

Pompe disease, acid maltase deficiency, GSD-II, GSD2, GSDII, glycogenosis type II

Types of the Disease

Researchers have described two main types of glycogen storage disease type II. The types differ based on when symptoms first appear and how severe they are^[1].

Infantile-Onset Pompe Disease (IOPD)

This is the more severe form of the disease. Symptoms typically appear within the first few months of life, usually around four to eight months of age^[5]. Babies with this form have little or no acid alpha-glucosidase enzyme activity^[3].

Infants with infantile-onset disease usually present with severe muscle weakness and a floppy appearance, often described as “floppy baby syndrome” or hypotonia^[1]. They are unable to hold up their heads and cannot perform other motor tasks that are common for their age, such as rolling over^[5].

A major feature of the infantile form is an enlarged heart caused by hypertrophic cardiomyopathy, where the heart muscle becomes abnormally thick^[1]. The heart progressively fails in its blood-pumping function. Breathing muscles are also weak, leading to respiratory difficulties^[5].

Other symptoms include feeding difficulties, failure to gain weight and grow at the expected rate (called failure to thrive), an enlarged liver, an enlarged tongue, and hearing problems^[2]. Without treatment, infants with this form usually die before 12 to 18 months of age due to heart failure and respiratory weakness^[2].

Late-Onset Pompe Disease (LOPD)

This form can appear at any age after infancy—in childhood, adolescence, or adulthood^[1]. People with late-onset disease have a reduced but not completely absent amount of acid alpha-glucosidase enzyme. This type is usually milder and progresses more slowly than the infantile form, though the rate of progression can vary^[3].

The disease presents more gradually, with muscle weakness as one of the first symptoms observed. The large muscles of the legs, trunk, and later the arms slowly become weaker^[5]. This muscle weakness is particularly noticeable in muscles close to the center of the body, such as those in the hips, shoulders, and trunk^[1].

Due to this muscle weakness, walking and climbing stairs become increasingly difficult. Over time, some adults with this disease may need a wheelchair or other assistance with mobility^[5].

The muscles required for breathing, including the diaphragm and other respiratory muscles, are also affected^[5]. Over a period of time, breathing becomes difficult. An early sign is difficulty with nighttime breathing^[5]. Some patients may need to use a breathing assistance machine called a BiPap or ventilator. Respiratory failure is the most common cause of death in individuals with late-onset disease^[5].

Unlike the infantile form, heart muscle involvement does not appear to be a significant feature in late-onset disease, although it is seen in some individuals^[1].

What Causes This Disease

Glycogen storage disease type II is caused by mutations in the GAA gene^[7]. This gene provides instructions for producing the acid alpha-glucosidase enzyme. Mutations in this gene prevent the enzyme from breaking down glycogen properly, allowing it to build up in the body’s cells^[7].

Over time, this buildup damages cells throughout the body, particularly muscle cells^[7]. The disease is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations^[1]. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene but typically do not show signs and symptoms of the condition^[7].

• Skeletal muscles
• Heart
• Liver
• Tongue
• Diaphragm and respiratory muscles
• Nervous system

How Common Is This Disease

Glycogen storage disease type II is a rare condition. In the United States, it affects about 1 in every 40,000 people^[3]. The incidence of this disorder varies among different ethnic groups^[7].

Signs and Symptoms

The symptoms of glycogen storage disease type II vary depending on whether a person has the infantile-onset or late-onset form of the disease.

Most patients experience muscle symptoms, such as weakness and cramps. The disease causes progressive muscle weakness, especially in the skeletal muscles of the hips, legs, shoulders, arms, and diaphragm^[3].

Symptoms in Infants

Babies with infantile-onset disease may not have any signs of the condition at birth, but symptoms usually start within the first year of life, most often around 4 months of age^[3]. Common symptoms include:

• Poor muscle tone or “floppy baby” appearance
• Inability to hold up the head
• Delayed motor milestones
• Muscle weakness in the arms and legs
• An enlarged heart
• Difficulty breathing and respiratory distress
• Feeding difficulties
• Trouble gaining weight and growing at the expected rate
• Respiratory infections
• Hearing problems
• An enlarged liver
• An enlarged tongue

Symptoms in Children and Adults

Late-onset symptoms may be milder and progress more slowly, though they can still cause severe weakness and breathing problems^[3]. Common symptoms include:

• Progressive muscle weakness, especially in the legs and trunk
• Increasing difficulty walking
• Difficulty climbing stairs
• Muscle pain over a large area
• Breathing difficulties, especially during sleep
• Loss of ability to perform tasks requiring muscle strength
• Fatigue

As the disease progresses in people with late-onset disease, breathing problems can lead to respiratory failure, which is the most common cause of serious complications^[3].

How the Disease Is Diagnosed

Diagnosis of glycogen storage disease type II depends on several methods. The definitive diagnosis is made by measuring the activity of the acid alpha-glucosidase enzyme^[4].

Initial Investigations

The usual initial investigations include a chest X-ray, an electrocardiogram (a test that measures the electrical activity of the heart), and an echocardiography (an ultrasound of the heart)^[5]. Typical findings include an enlarged heart with nonspecific conduction defects.

Biochemical investigations include blood tests to measure creatine kinase, an enzyme that is typically increased about 10-fold in people with this disease^[5]. Other blood markers may also be elevated.

Enzyme Testing

The most important test for diagnosis is the measurement of acid alpha-glucosidase enzyme activity. This can be done in several types of samples, including skin cells obtained from a biopsy, muscle cells from a muscle biopsy, or white blood cells from a blood sample^[5]. People with the disease will show reduced or absent enzyme activity.

Genetic Testing

Genetic testing can identify mutations in the GAA gene^[1]. This testing can confirm the diagnosis and help identify the specific type of mutation, which may provide information about the likely severity of the disease.

Other Tests

Additional tests may include muscle biopsy, which can show characteristic changes in muscle tissue with large empty spaces (vacuoles) due to glycogen accumulation^[2]. Electromyography, a test that measures the electrical activity of muscles, may also be performed.

Newborn Screening

Some areas now include testing for glycogen storage disease type II in newborn screening programs. The newborn screen measures the level of acid alpha-glucosidase enzyme in a blood sample taken from the baby’s heel^[6]. When the enzyme level is low, it means the baby could have the disease, though further testing is needed to confirm the diagnosis.

Treatment Options

While there is no cure for glycogen storage disease type II, treatments are available that can significantly improve outcomes, especially when started early^[1].

Enzyme Replacement Therapy

The main treatment is enzyme replacement therapy (ERT), which provides an external source of the missing acid alpha-glucosidase enzyme^[13]. This therapy is given through an intravenous (IV) infusion, typically every two weeks.

Several enzyme replacement medications have been approved and are available, including alglucosidase alfa (available under the brand names Myozyme and Lumizyme), avalglucosidase alfa (Nexviazyme), and cipaglucosidase alfa given in combination with miglustat (Pombiliti with Opfolda)^[13].

Enzyme replacement therapy helps prevent glycogen from building up in tissues and muscles. It helps maintain normal heart size and function and improves muscle tone^[10]. The therapy has been shown to improve survival in patients with infantile-onset disease compared with untreated patients, and it helps slow disease progression in late-onset disease.

Early initiation of treatment is critical to improving outcomes. The effectiveness of treatment is better when it is started before significant organ damage has occurred^[1].

Supportive Therapies

In addition to enzyme replacement therapy, several supportive therapies can help manage symptoms:

Physical therapy helps build strength and maintain muscle function. Physical therapists work with patients to develop exercises that can improve motor skills and the ability to perform daily tasks^[10].

Occupational therapy helps patients maintain independence in daily activities. Occupational therapists work on strategies to compensate for muscle weakness and maintain quality of life^[10].

Speech therapy may be needed if facial and tongue muscle weakness causes speech or swallowing difficulties. Speech therapists work to maintain or improve language and speaking ability^[10].

Respiratory therapy is important for managing breathing difficulties. Some patients may need breathing assistance devices such as BiPap machines or ventilators, especially during sleep^[10].

Nutritional support may be beneficial. Some people with the disease can improve muscle strength by eating a high-protein diet, especially one containing branched-chain amino acids^[13]. When combined with exercise, this eating plan can help build strength. Some patients, particularly infants, may need feeding tubes to ensure adequate nutrition.

Monitoring

People with glycogen storage disease type II require lifelong care and regular monitoring^[10]. This involves closely monitoring glycogen levels in muscles, the heart, and other tissues such as the lungs. Regular assessment allows doctors to identify complications as they arise and begin prompt treatment to minimize or manage their severity.

Outlook and Life Expectancy

The outlook for people with glycogen storage disease type II has improved dramatically with the development of enzyme replacement therapy. Before treatment was available, the infantile form of the disease was usually fatal, with most babies dying before 12 months of age^[2].

With enzyme replacement therapy started early, many babies with infantile-onset disease are now able to live longer lives with improved growth and development^[6]. The outcome has drastically changed since enzyme replacement therapy became available, improving with early initiation of treatment^[2].

For people with late-onset disease, enzyme replacement therapy can help slow disease progression and improve quality of life. While the disease still progresses, treatment can help maintain muscle function and breathing ability for longer periods^[10].

The key to better outcomes is early detection and prompt initiation of treatment. This is why newborn screening programs that test for this disease are so important^[1]. When the disease is detected early and treatment is started before significant damage occurs, people with glycogen storage disease type II have the best chance of living longer and enjoying a better quality of life.