Pompe disease is a rare, inherited and often fatal disorder that causes progressive muscle weakness and loss of muscle tissue. It is caused by the deficiency of acid alpha-glucosidase (GAA), an enzyme needed to break down glycogen (sugar that is stored for energy) in specialized structures in our body, called lysosomes. Patients with Pompe disease have little or no GAA enzyme activity and cannot break down glycogen. The excess glycogen accumulates and is stored in the heart, skeletal muscle and other tissues, causing the progressive symptoms of Pompe disease. Researchers have identified up to 70 different mutations in the GAA gene that cause the symptoms of Pompe disease, which can vary widely in terms of age of onset and severity. The severity of the disease and the age of onset are related to the degree of enzyme deficiency.
There are a variety of different names and disease categories that are used for Pompe disease. Pompe can be categorized in many ways:
- neuromuscular disorder – since it is characterized by progressive degeneration of limb and respiratory skeletal muscles, and, in infants, cardiac muscle, causing muscle degeneration and weakness and problems with neuromuscular function and movement.
- genetic disease – it is caused by a defect in a gene that is inherited from both parents
- glycogen storage disease – a substance called glycogen cannot be broken down by the body and is “stored” in cells.
- lysosomal storage disorder – the part of the cell in which the glycogen is stored are small compartments called lysosomes Learn more about lysosomal storage disorders.
- metabolic muscle disease – it involves a problem with the metabolism, or breakdown of substances, within muscle cells.
- cardiac disorder because of the heart problems that affect most infants with the disease.
Pompe disease was named after the Dutch doctor Johannes C. Pompe, who first described the disease in 1932. The disease is also known by several other names:
- Acid maltase deficiency (AMD)
- Glycogen storage disease (GSD) type II
- Glycogenosis type II
- Acid alpha-glucosidase deficiency
- Lysosomal alpha-glucosidase deficiency
Pompe disease is a disease continuum. Generally, the disorder is broken down into an infantile form and a late (or delayed) onset form.
- Classic infantile-onset Pompe disease – has a reported incidence of 1 in 100,000 and will usually present in the first two to six months of life with hypotonia and muscle weakness, feeding difficulties and failure to thrive, respiratory distress or infections and cardiac problems. Clinical examination and investigation will frequently reveal hypotonia and motor developmental delay, macroglossia, cardiomegaly, generalised hypertrophy, a murmur, cardiomyopathy, conduction disturbances (short PR interval with a broad QRS complex), respiratory distress and hepatomegaly (usually as a consequence of heart failure). Without treatment, these symptoms will progress rapidly.These cardiac features together with significant weakness of the diaphragmatic and respiratory muscles will lead to death from cardiorespiratory failure within the first year of life.
- Non-classic infantile-onset Pompe disease – This variant will usually present within the first year of life with motor developmental delay and weakness. Cardiomegaly is less a feature, and cardiac involvement is not present in some definitions of non-classic infantile-onset Pompe disease. The rate of clinical progression is slower in these children and without treatment, death will usually occur in childhood as a result of respiratory insufficiency.
- Late or adult onset Pompe disease – This variant can present at any age, although typically an earlier presentation is associated with more severe symptoms. Clinical features include proximal muscle weakness that progresses slowly, and the involvement of the respiratory muscles and diaphragm. A lower limb weakness, poor exercise tolerance and fatigue are usually present, and affected patients may become wheelchair bound in later life. Orthopnoea, sleep apnoea, and respiratory failure may also be present. Unlike the infantile-onset forms of Pompe disease cardiac involvement is not a feature, although some adults have been reported to have arteriopathy which may be associated with raised blood pressure and occasionally aortic dilatation. Without treatment, morbidity and mortality occur mainly as a result of respiratory insufficiency and failure, with death occurring anytime from the third decade onwards.
Pompe disease occurs in various populations and ethnic groups around the world. Estimates of vary, but its incidence is generally placed at approximately 1 in 40,000 births in the United States. Many late onset cases go misdiagnosed or undiagnosed, making it difficult to determine the true frequency of Pompe disease in the general population. Males and females are affected in equal numbers and the disorder has been reported in individuals of every race and ethnic group around the world.
A diagnosis is based upon 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. GAA activity assay for the diagnosis of Pompe disease can be performed in various tissues. Glycogen content can be measured in muscle biopsy samples to support the diagnosis. Prenatal testing is available on CVS samples and cultured amniocytes. Enzyme testing is not appropriate for carrier testing. Carrier testing and prenatal testing are available if the familial mutations have been previously identified.The following tests are currently available:
- Enzyme assays for acid alpha-glucosidase (GAA) in blood, cultured skin fibroblasts, muscle, and cultured amniocytes, and chorionic villi
- GAA gene sequencing
- Urinary hexose tetrasaccharide (Hex4), a marker of disease burden in Pompe disease that can be used to monitor patients with Pompe disease and as a second tier diagnostic test
- Analysis of Cross Reactive Immunological Material (CRIM status)
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.
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. The discovery of the GAA gene has led to rapid progress in understanding the biological mechanisms and properties of the GAA enzyme. As a result, an enzyme replacement therapy has been developed that has shown, in clinical trials with infantile-onset patients, to decrease heart size, maintain normal heart function, improve muscle function, tone, and strength, and reduce glycogen accumulation. A drug called alglucosidase alfa (Myozyme©), has received FDA approval for the treatment of infants and children with Pompe disease. Another algluosidase alfa drug, Lumizyme©, has been approved for late-onset (non-infantile) Pompe disease.
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