Pompe disease is a rare inherited disorder, associated with progressive muscle damage and weakness. There are three main types of Pompe disease, classified according to age at onset and severity of symptoms. They are classic infantile-onset Pompe disease, non-classic infantile-onset Pompe disease, and late-onset Pompe disease.
Non-classic infantile-onset Pompe disease tends to begin within the first year of life, but later than the classic form that usually appears within a few months of birth.
Causes of non-classic infantile-onset Pompe
Pompe is a type of glycogen storage disease, a group of conditions associated with abnormalities in the way the body handles glycogen, a large complex sugar that is stored in muscles. Glycogen is normally broken down into smaller sugars, like glucose, to be used as an energy source by cells.
Individuals with Pompe disease cannot break down glycogen efficiently, due to defects in an enzyme called acid alpha-glucosidase, which is involved in this process. This is caused by mutations, or abnormalities, in the GAA gene that encodes for acid alpha-glucosidase.
When glycogen cannot be broken down properly, it accumulates to toxic levels and causes damage to the surrounding tissues.
The disease is inherited in an autosomal recessive manner. This means that for the symptoms to appear, the patient must inherit two mutated copies of GAA — one from the mother and one from the father. So far, over 200 different mutations have been characterized in patients with Pompe disease. Some mutations can cause only slight changes to the enzyme, meaning that it does not work as effectively as it should, while others can cause no enzyme to be made at all.
In non-classic infantile-onset Pompe disease, a person has inherited GAA copies that produce very little or no working acid alpha-glucosidase. In general, the lower the enzyme’s activity, the earlier the age of disease onset as the buildup of glycogen occurs more quickly and symptoms will become evident sooner in life.
A study, published in the Orphanet Journal of Rare Diseases, examined types of GAA mutations associated with non-classic infantile-onset Pompe disease in 31 patients. Most were from Europe, with one patient from the U.S. Results showed that in this subset of patients, around two-thirds of their mutations were of a type termed c.-32-13T>G, which results in a severely reduced amount of functional acid alpha-glucosidase.
Non-classic infantile-onset Pompe disease differs in symptoms from the classic infantile-onset form, and is usually less severe. Children show progressive muscle weakness, or myopathy, and delayed development of motor skills, such as rolling over and sitting up.
The heart is also less likely to be affected in non-classic infantile-onset Pompe disease. Some patients may experience cardiomegaly, or an enlarged heart, which can lead to heart failure if untreated, but progression is generally slower. Progressive muscle weakness can also lead to severe breathing problems and lung failure if untreated.
Initial diagnosis consists of identifying the symptoms of the disease. In some U.S. states, Pompe disease is part of newborn screening.
If Pompe disease is suspected based on symptoms, a blood or skin sample may be taken to assess the activity of the acid alpha-glucosidase enzyme. In patients who have the non-classic infantile-onset form, enzyme activity is generally very low or non-existent.
A DNA analysis can further confirm the diagnosis if a mutation is detected in the GAA gene.
Other indicators include abnormally high levels of some substances, including a type of sugar called tetrasaccharide in the urine, or the enzyme creatine kinase in the blood, which leaks from damaged muscles.
There is currently no cure for Pompe disease, but treatments are available to manage symptoms and improve survival.
In general, patients with Pompe disease will be offered enzyme replacement therapy (ERT). The U.S. Food and Drug Administration (FDA) approved Genzyme’s Lumizyme (marketed as Myozyme outside of the U.S.) in 2006. Lumizyme’s active ingredient is purified alglucosidase alfa, or a copy of the human alpha-glucosidase enzyme produced in a laboratory. This transiently provides the enzyme to the patient, breaking down glycogen while it is active. But the treatment must be taken regularly.
Children may also receive care and support to manage specific symptoms. This may include:
- Respiratory support such a mechanical ventilator to help the child inhale and exhale enough air.
- Physical therapy to help the child develop motor skills and strengthen key muscles.
- Dietary treatments, which may include specific diets or a feeding tube, to ensure the child is getting enough nutrition for proper growth and development.
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