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Pompe Disease Overview

Pompe disease, also called glycogen storage disease type II (GSD2) or acid maltase deficiency, is a genetic disorder. It belongs to a group of rare diseases called glycogen storage diseases or glycogenosis. 

People with Pompe disease have a deficiency of a digestive enzyme called acid alpha-glucosidase (GAA). This enzyme breaks down a complex sugar called glycogen in the body. Because of the lack of the GAA enzyme in Pompe disease, glycogen builds up in the body’s cells and organs. 

This buildup of glycogen occurs throughout the body, but especially in the heart and skeletal muscles, resulting in generalized muscle weakness and enlargement of the heart, tongue, and liver,  among other symptoms.  

Pompe’s disease is a progressive condition, meaning the symptoms gradually get worse over time. However, treatments are available to slow the progression of the condition. Early treatment can prolong life expectancy in Pompe disease patients. Notably, late-onset Pompe disease progresses more slowly and can be milder. 

Other Names

Pompe disease is named after a Dutch pathologist, Johannes Cassianus Pompe, who first discovered it in 1932. About 1 in 40,000 people in the United States have this rare disease. Other names for Pompe disease are:

• Acid maltase deficiency

• Acid alpha-glucosidase deficiency (GAA deficiency)

• Lysosomal storage disease

• Glycogen storage disease type II (GSD2)

The Significance of Glycogen Buildup

Glycogen, a type of complex sugar, is the main energy source in the body. It is stored in compartments called lysosomes within the cells that store and recycle various substances. When the body needs energy, enzymes break down glycogen into glucose and send it out to the body. 

Glycogen storage disease (GSD) is a rare condition that affects how the body stores and uses glycogen because the enzymes that break down glycogen are missing. This leads to a buildup of glycogen in the body’s cells, causing problems such as progressive weakness of skeletal muscles, heart failure, and respiratory complications. 

Glycogen storage disease (GSD) is a genetic or inherited disorder that is passed down from parents to their children. It is seen in infants and young children but can also appear in adolescents and adults.

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Types of Pompe Disease

There are two main types of Pompe disease based on the age at onset and severity of symptoms.

Infantile-Onset Pompe Disease

The classic form of infantile-onset Pompe disease is a severe form of the condition that develops in infants who have little to no acid alpha-glucosidase (GAA) enzyme. The baby may appear normal at birth, but symptoms usually begin within the first year of life, typically at around 4 months. They can include progressive muscle weakness, poor muscle tone, enlargement of the cardiac muscle, and respiratory insufficiency.

In infants with non-classic Pompe’s disease, there is progressive muscle weakness and a delay in motor milestones (such as sitting up and rolling over), as well as cardiomegaly (an enlarged heart), but typically no heart failure. 

Without proper diagnosis and treatment, the infantile form of the condition progresses rapidly. Babies with classic infantile Pompe disease are severely affected and usually die in early childhood from heart failure or respiratory difficulties.

Late-Onset Pompe Disease

People with late-onset Pompe disease have a reduced amount (but not complete absence) of acid alpha-glucosidase (GAA) enzyme. Therefore, late-onset Pompe disease is a milder form of the condition. It can develop at any age, even before age 1 year, but cardiomyopathy (enlargement of the heart) does not occur until the person is an adolescent or adult. As a result, such individuals can maintain normal heart function for longer. The progression of the condition is generally slower but depends on the age of onset. 

Without proper diagnosis and treatment, people with late-onset Pompe disease can die of respiratory failure due to severe muscle weakness as the disease progresses.

Symptoms Of Pompe Disease

Symptoms of Early-Onset (Infantile) Pompe’s Disease

• Hypotonia (poor muscle tone), also called floppy infant syndrome (a baby that feels limp like a ragdoll)

• Delayed motor milestones, such as rolling over and sitting up

• Cardiomegaly (enlargement of the cardiac muscle)

• Hepatomegaly (enlarged liver)

• Macroglossia (enlargement of the tongue)

• Failure to thrive (slowed growth and trouble gaining weight)

• Feeding problems due to poor sucking and swallowing

• Respiratory infections due to respiratory insufficiency

• Difficulty breathing

• Hearing problems

Symptoms in Late-Onset Pompe Disease Patients

• Progressive proximal muscle weakness in the trunk, legs, and arms (for example, trouble getting up from a chair or raising an arm)

• Difficulty walking and changes in gait

• Muscle pain

• Frequent falls

• Inability to exercise

• Dyspnea (shortness of breath) with physical activity

• Frequent respiratory infections

• Morning headaches

• Fatigue

• Unexplained weight loss

• Dysphagia (difficulty swallowing)

• Problems with hearing

• Arrhythmia (abnormal heart rhythm)

• Sleep apnea

Systemic Effects On The Body

Pompe disease affects many organ systems throughout the body, including the heart, lungs, and muscles. Almost everyone with the disorder requires oxygen support and mobility aids at some point.

Causes and Genetics

Gene Mutations Involved

Pompe disease occurs due to a mutation (alteration) in the GAA gene which codes for the enzyme acid alpha-glucosidase. The body uses this enzyme to break down glycogen to glucose and use it for energy. Without the enzyme, glycogen builds up in the lysosomes of cells, causing damage throughout tissues and organs in the body.

Inheritance Patterns

Pompe disease has an autosomal recessive pattern of inheritance. This means that both parents are carriers and carry one copy of the defective gene each. While the parents themselves don’t have any symptoms, if their offspring inherits two copies of the defective gene (one from each parent), they will have Pompe disease.

Risk Factors

If both parents are carriers of the Pompe disease gene mutation, there is a:

• 25% risk that a child will inherit one copy of the mutated gene from each parent and develop Pompe disease.

• 50% chance that a child will inherit one copy of the mutated gene from one parent and a normal gene from the other parent and be a carrier with no symptoms but can pass on the gene to their offspring.

• 25% chance that a child will inherit normal genes from both parents and not be a carrier nor have Pompe disease.

How is Pompe Disease Diagnosed?

Enzyme Assays and Other Tests

Many conditions can cause symptoms similar to Pompe disease. However, if a healthcare provider suspects glycogen storage disease, they might do a GAA enzyme analysis to make a Pompe disease diagnosis. This test can provide a reliable laboratory diagnosis of Pompe by measuring GAA enzyme levels in a blood sample or skin or muscle biopsy sample. Other tests may include:

• Blood tests such as creatine kinase (elevated levels of this enzyme indicate muscle damage). 

• Electrocardiogram (EKG) and echocardiogram to study the heart.

• Pulmonary function tests to check lung function.

• Electromyogram to check muscle function.

• Sleep study to diagnose sleep apnea.

Genetic Testing

Genetic testing is considered the gold standard for a definitive diagnosis of Pompe disease. If there is a known history of mutations in the GAA gene in a family, at-risk family members can undergo genetic testing for carrier status or a Pompe disease diagnosis. A genetic test for Pompe disease can be done with a blood test, saliva sample, or cheek swab.

In addition, prenatal genetic testing can be done for at-risk pregnancies. Preimplantation genetic testing of embryos is also possible. Newborn screening can also be done in families with a history of Pompe’s disease.

Genetic test results can be difficult to understand, so it’s important to work with a genetic counselor who can help you understand the implications.

Genetic testing can not only confirm if you have Pompe disease but the type of Pompe and the expected severity and progression of the condition. Early diagnosis is key because it can help you get the appropriate treatment to slow the progression of the disease. A confirmed diagnosis of Pompe disease also gives you the opportunity to participate in clinical trials that are looking at new and advanced treatments for the condition. 

Health Conditions With Similar Symptoms 

Other conditions that can cause similar symptoms as Pompe disease include:

• Hypothyroidism (underactive thyroid gland)

• Congenital muscular dystrophy

• Spinal muscular atrophy

• Myocarditis

• Other glycogen storage diseases

• Respiratory chain disorders

• Danon disease

• Limb-girdle muscular dystrophy

• Becker muscular dystrophy

• Myasthenia gravis

• Polymyositis

• Rheumatoid arthritis

Management Guideline: How is Pompe Disease Treated?

Enzyme Replacement Therapy (ERT)

The only approved treatment for Pompe disease is enzyme replacement therapy (ERT). This involves receiving medications through intravenous injection. These medications are genetically engineered enzymes that work like the natural GAA enzyme in the body, helping to correct the GAA deficiency and reduce glycogen buildup in the cells. The treatment can help to improve heart function and muscle function and slow the progression of the disease. Examples of ERT include:

• Alglucosidase alfa (Myozyme, Lumizyme)

• Avalglucosidase alfa (Nexviazyme)

ERT is a lifelong treatment, and you need regular infusions, typically every two weeks.

Supportive Therapies

Supportive treatments for Pompe disease include: 

• Cardiovascular care: Regular checks for heart problems and prescription of necessary treatments. 

• Respiratory therapy: To improve lung function, lower the risk of infections and respiratory complications, and provide respiratory support with mechanical ventilation, if needed.

• Nutritional therapy: Special diets or feeding tubes may be necessary due to weak chewing and swallowing muscles. 

• Physical therapy: To improve muscle tone, strength, and physical ability. Learn what a physical therapist does.

• Occupational therapy: For mobility training and use of devices such as canes or walkers. What’s the difference between occupational therapy and physical therapy?

• Speech therapy: To improve articulation and speech. 

• Orthopedic devices: Braces may be recommended for some patients. 

• Surgery: Certain orthopedic problems, such as contractures or spinal deformities, may require surgical treatment. 

Emerging Treatments and Research

Experimental treatments for Pompe disease that are being studied and developed include:

• Autophagy inhibition: A treatment that prevents the formation of autophagic vacuoles in cells to slow disease progression. 

• Pharmacological chaperone therapy: A treatment that aims to restore enzymatic activity through protein stabilization. 

• Gene therapy: A treatment for Pompe disease that aims to provide the body with a working copy of the dysfunctional GAA gene, allowing the body to make its own GAA enzyme.

Living With Pompe Disease

Management Strategies

People with Pompe’s disease require care from a multidisciplinary team of healthcare professionals, including cardiologists, pulmonologists, neurologists, respiratory therapists, physical therapists, occupational therapists, and psychologists. 

Resources, Support Groups, and Advocacy Networks For Patients and Caregivers

• Clinical Trials

• Pompe and You

• Pompe Disease News

• National Organization for Rare Disorders (NORD)

• National Institute of Neurological Disorders and Stroke (NINDS)

Frequently Asked Questions

What Is The Life Expectancy for Pompe Disease?

The life expectancy of a person with Pompe’s disease depends on the age at onset and the severity of the condition. This genetic disorder has a clinical spectrum ranging from severe (symptoms develop in infancy) to milder (symptoms develop in late childhood, adolescence, or adulthood). The earlier symptoms develop, the more severe the condition and the lower the life expectancy.

Babies born with severe GAA deficiency (classic infantile Pompe disease) develop serious breathing problems due to weak respiratory muscles and heart failure due to enlargement of the heart muscle, leading to death within the first year of life. Infants with non-classic Pompe’s disease may live to early childhood.

People with late-onset Pompe disease have a partial deficiency of the GAA enzyme and develop symptoms later in life, with normal heart function maintained for longer. They have a slower progression, but unfortunately, they also usually die in their 20s or 30s.

Is Pompe Disease Terminal?

Yes, Pompe disease is terminal. There is no cure for the condition. However, treatments are available to slow the progression of the condition and increase the quality of life. Without treatment, the infantile form of the condition is fatal in early childhood.

Can Pompe Be Cured?

There is currently no cure for Pompe disease. However, treatments can slow disease progression. The natural history of the condition is a buildup of glycogen in cells, which causes muscle weakness and affects heart and lung function. Enzyme replacement therapy can help people with Pompe live longer. New treatments like gene therapy are also being investigated. You can participate in a clinical trial on Pompe disease, looking at new, advanced treatments and cures. 

What Organ Is Most Affected By Pompe Disease?

The heart and skeletal muscles are most affected by Pompe disease.