What is Pompe disease?
Pompe disease is a rare, inherited disorder characterized by progressive muscle weakness and respiratory impairment. It is caused by mutations in a gene that encodes an enzyme called acid alpha-glucosidase (GAA). This enzyme breaks down a complex sugar called glycogen, into the simpler sugar, glucose, which is the main energy source for most cells. The GAA enzyme is active in lysosomes, which are structures that serve as recycling centres within cells. Mutations in the GAA gene mean that the enzyme does not function properly to break down glycogen, so that it builds up in the cells throughout the body, causing blockages that weaken the muscles. This build up damages organs and tissues, particularly the muscles. This leads to the progressive signs and symptoms of Pompe disease.
Pompe disease affects approximately 1 in 40,000 people worldwide. There are thought to be 10 people diagnosed with Pompe in New Zealand, but without a rare disorder registry it is hard to be exact. Pompe can occur in males and females of all ethnicities and can be diagnosed from infancy to adulthood.
Pompe disease is an autosomal recessive disease. This means someone must carry two defective copies of the GAA gene in order to have Pompe disease. This typically means that both parents contributed a defective copy and are either “carriers” with one normal copy and one defective copy, or had two defective copies and are affected by Pompe disease themselves.
Types of Pompe disease
There are three types of Pompe disease, which differ in severity and the age at which they appear. These types are known as classic infantile-onset, non-classic infantile-onset, and late-onset.
- Classic infantile-onset Pompe disease begins within a few months of birth. Infants with this disorder typically experience muscle weakness (myopathy), poor muscle tone (hypotonia), an enlarged liver (hepatomegaly), and heart defects. Affected infants may also fail to gain weight and grow at the expected rate and have breathing problems. If untreated, this form of Pompe disease leads to death from heart failure in the first year of life.
- Non-classic infantile-onset Pompe disease usually appears by age 1. Characterized by delayed motor skills (such as rolling over and sitting) and progressive muscle weakness, may have an abnormally large heart (cardiomegaly), and muscle weakness leads to serious breathing problems. Most children with non-classic infantile-onset Pompe disease live only into early childhood.
- Late-onset Pompe disease may not become apparent until later in childhood, adolescence, or adulthood. It is usually milder than the infantile forms and is less likely to involve the heart. Most individuals with late-onset Pompe disease experience progressive muscle weakness, especially in the legs and the trunk, including the muscles that control breathing. As the disorder progresses, breathing problems can lead to respiratory failure.
Infants (diagnosed <1 year)
- Weak sucking and swallowing
- Failure to gain weight
- Frequent infections
- Respiratory failure requiring ventilation
- Enlarged heart my progress to heart failure
- Slow development
- Muscle weakness
- Difficulty holding head up
Juveniles and adults
- Weak jaw and swallowing muscles, making eating difficult
- Difficulty breathing when lying down
- Shortness of breath
- Frequent infections
- May need respiratory support
- Altered gait – “Pompe waddle”
- Difficulty climbing stairs or lifting arms overhead
Individuals with the infantile form are the most severely affected. Although these infants usually appear normal at birth, the disease presents within the first two or three months of life with rapidly progressive muscle weakness, diminished muscle tone (hypotonia), and a type of heart disease known as hypertrophic cardiomyopathy, a condition characterized by abnormal thickening of the walls of the heart resulting in obstruction of blood flow in and out of the heart. In most cases, the left ventricle is affected. Symptoms of hypertrophic cardiomyopathy vary widely among affected individuals. Affected infants and children may experience shortness of breath upon exertion, fatigue, excessive sweating, and poor appetite and weight gain resulting in growth failure. As affected children age, they may experience chest pain or discomfort, irregular heartbeats, dizziness or fainting episodes (syncope) usually upon heavy exertion, and, eventually, congestive heart failure and fluid accumulation within the lungs. In some cases, affected individuals may experience sudden cardiac arrest and, potentially, sudden death.
Many infants have a large, protruding tongue and a moderate enlargement of the liver. Infants may appear floppy and may be unable to move their arms and legs properly. The legs often rest in a frog position and feel firm on palpation (pseudo-hypertrophy).
Feeding and swallowing problems, and respiratory difficulties, (often combined with respiratory tract infections), are common. Major developmental milestones such as rolling over, sitting up, and standing are delayed or not achieved. Mental development is usually normal. Some infants may experience hearing loss. The infantile form of Pompe disease is characterized by a total lack of alpha glucosidase activity and by a rapid build up of glycogen in skeletal muscle and in the heart.
Time of presentation varies from 10 to 70 years old. Patients who develop symptoms earlier in life tend to be the more severely affected. Late onset patients have varying amounts of acid alpha-glucosidase activity. Glycogen build up is not as rapid as in the infantile form, but the disease is progressive and can greatly affect the quality of life and decrease the lifespan of an affected person.
Late onset Pompe disease is generally associated with progressive proximal muscle weakness, varying degrees of respiratory weakness and little to no cardiac involvement. The lower limbs are affected more often than the upper limbs. The muscles adjacent to the spinal column (paraspinal muscles) and neck muscles are often involved. Overall, the extent of organ involvement is highly variable. The disease progresses more slowly than the infantile form. However, progressive muscle weakness can eventually cause serious complications including swallowing difficulties, difficulty walking and severe respiratory failure.
Children with late onset Pompe disease may also develop drooping of the upper eyelids (ptosis), abnormal enlargement of the liver, abnormal curvature of the spine (scoliosis), and tightening of certain joints resulting in restricted or stiff movements (contractures). Affected individuals may also experience difficulty chewing and/or swallowing.
When late onset Pompe disease occurs during adulthood, the pattern of muscle weakness exhibited is similar to that found in other chronic muscle disorders and tends to affect lower limbs more than upper limbs. Approximately one-third of the adult cases present with respiratory failure, and initial symptoms may include headache at night or upon awakening, sleeping difficulties including sleep apnea, nausea, fatigue, difficulty breathing except in an upright position (orthopnea), and laboured breathing upon exertion (exertional dyspnea).
A diagnosis of Pompe disease is based upon a thorough clinical evaluation, a detailed patient and family history, and a variety of tests. Prenatal diagnosis is possible when a pregnancy is believed to be at risk for Pompe disease.
A blood sample (dried blood spots) can be taken and an enzyme assay – a test that measures the activity of a specific enzyme – can be performed. An enzyme assay can also be performed on drawn blood, in which the enzyme activity of GAA is measured in certain white blood cells called lymphocytes. These exams are a reliable and convenient means of diagnosing Pompe disease.
When a diagnosis of Pompe disease is based upon a blood-based enzyme assay, it must be confirmed through molecular genetic testing or by another assay on a separate blood or tissue sample. Molecular genetic testing can detect mutations in the GAA gene that causes Pompe disease.
In the past, surgical removal and microscopic study (biopsy) of samples of skin and muscle tissue was used to help diagnosis Pompe disease. However, these exams can take weeks to process, causing a delay in the initiation of treatment. Skin and muscle biopsies are no longer necessary to obtain a diagnosis of Pompe disease.
A variety of additional tests may be performed to detect or assess symptoms potentially associated with Pompe disease such as sleep studies, breathing tests to measure lung capacity, and electromyography, a test to measure muscle function.
Specific tests may also be performed to assess the heart including chest x-rays, electrocardiogram, and echocardiogram. Chest x-rays allows physicians to assess the size of the heart, which can be enlarged in some infants with Pompe disease. An electrocardiogram measures the electrical activity of the heart and can detect abnormal heart rhythms. An echocardiogram uses reflected sound waves to create a picture of the heart and can reveal abnormal thickening of the heart muscle tissue.
In families with a known mutation of the GAA gene, prenatal diagnosis is possible through chorionic villi sampling (CVS) or amniocentesis. During CVS, foetal tissue samples are removed and enzyme assays are performed on cultured tissue cells (fibroblasts) and/or white blood cells (leukocytes). During amniocentesis, a sample of the fluid that surrounds the developing foetus is removed and studied.
In cases where a parent has a known genetic abnormality (i.e. carrier), pre-implantation genetic diagnosis (PGD) may be an option. PGD can be performed on embryos created through in vitro fertilization. PGD refers to testing an embryo to determine whether it has the same genetic abnormality as the parent.
Pompe disease has no cure. However, there are treatments and therapies. Some therapies are for speech, physical, respiratory, occupational, nutritional, dietary and psychological. The only treatment is an enzyme replacement therapy called Myozyme which replaces the defective or missing enzyme in those with Pompe. In clinical trials, with infantile-onset patients, Myozyme has been shown to decrease heart size, maintain normal heart function, improve muscle function, tone, and strength, and reduce glycogen accumulation. Myozyme must be injected directly into the vein as the enzyme would be destroyed by the digestive system if taken in the form of pills etc.
Individuals with Pompe disease are best treated by a team of specialists (such as cardiologist, neurologist, and respiratory therapist) knowledgeable about the disease, who can offer supportive and symptomatic care.
Suggested diagnostic pathway
Diagnostic Pathway on Pompe Community website