Pompe disease is a glycogen storage disease of unpredictable course. Symptomatology is characterized by progressive muscle weakness. Success has now been observed in therapy by artificial administration of the causative enzyme.
What is Pompe disease?
Storage diseases are a heterogeneous group of diseases in which various substances are deposited in organs or cells of the organism. The tissues or organs usually lose their function as a result of the deposits. The deposited substances can be of different types. Depending on the substance, a distinction is made between glycogenoses, mucopolysaccharidoses, lipidoses, sphingolipidoses, hemosideroses and amyloidoses. In glycogenoses, glycogen is stored around body tissues. In the disease, the stored carbohydrates can no longer be broken down or transformed into glucose, or only incompletely. The cause is usually an enzyme defect in the enzymes that are involved in the transformation of glucose in the body. One glycogen storage disease is Pompe’s disease, also called Pomp’s disease or acid maltase deficiency. The disease affects the lysosomal α-glucosidase or acid maltase on gene GAA. In the healthy body, the enzyme degrades the long-chain polysaccharides of lysosomes to glucose. In humans, the enzyme is present in all tissues. Nevertheless, the metabolic disease is mainly noticeable in the muscles and is therefore also classified as a myopathy. The rare disease is named after the Dutch pathologist Pompe, who first described the phenomenon in 1932. In 1954, G.T. Cori documented the disease as glycogen storage disease type II.
Causes
In the 1960s, H.G. Hers discovered deficiency of lysosomal α-glucosidase as the causative link of Pompe disease. This deficiency arises on the basis of a primary causative gene defect affecting the enzyme α-1,4-glucosidase. This enzyme is also known as acid maltase and is either completely absent or shows reduced activity. Thus, the breakdown of the sugar storage form glycogen fails to occur at the muscles. Glycogen is therefore stored in the muscle cells of the lysosomes, where it destroys the muscle cells. The residual activity of the enzyme correlates with the severity of the disease. The infantile type of Pompe disease records activities of less than one percent. The juvenile type retains residual activity of up to ten percent and the adult type retains residual activity of up to 40 percent. The disease is subject to autosomal recessive inheritance. Boys are affected just as often as girls. The causative gene defect has been localized to the q25.2-q25.3 region of chromosome 17 and is 28 kbp long. Genetically, the disease is heterogeneous and is associated with 150 different mutations to date. Patients are compound heterozygous. The infantile form is often characterized by two severe mutations. There is high concordance between genotype and disease progression in this form. This is not the case in the adult form. The prevalence is reported to be between 1:40,000 and 1:150,000. Approximately 200 people have been diagnosed in Germany.
Symptoms, complaints, and signs
The main symptoms of Pompe disease are cardiomegaly and heart failure. Neurologic and muscular deficits are also present. Pompe disease is not limited in onset to a particular age, but can affect all ages. The infantile form occurs in infants and is usually fatal in the first year of life. In most cases, the death that occurs is death from heart failure, which is due to hypertrophic cardiomegaly. The first symptoms appear in the infantile form after two months. Adolescents develop juvenile Pompe disease. In adults, medicine refers to adult Pompe disease. Symptomatically, these forms manifest themselves in progressive muscle weakness in the respiratory muscles and the skeletal muscles of the trunk. The upper arms may be affected as well as the pelvis and thighs. The course is unpredictable in the adult and juvenile forms. Severe courses are characterized by loss of the ability to breathe. Loss of locomotion is also often present. States of exhaustion set in. In some cases, substances are deposited in the arteries and may form an aneurysm, the rupture of which may be fatal.On average, the first symptoms become noticeable shortly before the age of 30 and correspond to difficulties in walking or sports. The diagnosis is usually made in the mid-30s. Around ten years later, those affected are usually dependent on a wheelchair.
Diagnosis and course of the disease
The diagnosis of Pompe disease is usually confirmed by muscle biopsy based on the patient’s history. Histologically, PAS staining can demonstrate massive glycogen deposition in the muscle. Equally well, the diagnosis can be anchored in an enzyme activity measurement of acid maltase, as can be detected in leukocytes with the dry blood test. Molecular genetic testing can also be used to confirm the diagnosis. In the blood, CK, CKMB, LDH, GOT and GPT are elevated. In the urine, elevated Glc4 is usually present. Numerous differential diagnoses must be excluded. In the infantile form, the suspected diagnosis can often be confirmed by the rapid progression due to the pronounced symptoms, which are accompanied by increasing respiratory problems and motor developmental delay. Cardiomegaly can be confirmed by radiographic findings. Theoretically, prenatal diagnosis based on amniocentesis or tissue sampling is also conceivable. The course of Pompe disease is usually more severe the earlier the onset of the disease. Nevertheless, Pompe disease is characterized by an individual and therefore actually unpredictable course of the disease. Mild forms are also observed.
Complications
As a result of Pompe disease, affected individuals suffer from significant limitations and discomfort in everyday life. Primarily, breathing difficulties occur, which lead to a greatly reduced ability to work under pressure and to fatigue in the patient. Furthermore, the lack of oxygen can also lead to a loss of consciousness, during which the affected person may possibly injure himself by falling. Breathing difficulties also have a negative effect on the heart and other internal organs, so that irreversible consequential damage can occur to the organs. Life expectancy is significantly reduced and limited by Pompe’s disease. In the worst case, the affected person can die of cardiac death. Strenuous activities or sporting activities are also still not possible for the affected person due to this disease. The treatment of Pompe disease is usually based on the symptoms and aims to increase life expectancy. Various medications are used, which usually do not lead to any particular complications. The symptoms can also be reduced with the help of physiotherapy. If psychological limitations occur, psychological treatment is still necessary.
When should one go to the doctor?
Those who suffer from Pompe disease are either affected by the hereditary disease as a child or do not experience severe symptoms in the muscles until they are adults. People with type II glycogenosis suffer from increasing wasting of the muscles. The respiratory muscles may also be affected. If the genetic defect is not discovered early during a routine examination, visits to the doctor are the order of the day as the symptoms increase. However, it can take a long time before the diagnosis is made. First, there are many diseases with a similar course. Second, genetic testing is not commonplace in medicine. Third, glycogen storage disease type II is also a metabolic disease. Many physicians are not familiar with the symptomatology of Pompe disease. In addition, late-onset Pompe disease does not have a uniform set of symptoms. In children, the disease is much easier to diagnose. Most adult patients go to the doctor with different complaints of the musculature. The symptoms described can affect the extremities, but also the respiratory muscles or the heart. Organs such as the liver may also be affected. The deterioration progresses rapidly. Therefore, visits to the doctor accumulate over time without the correct diagnosis being made. An odyssey through medical practices is not uncommon with Pompe disease.
Treatment and therapy
Pompe disease has no cure to date. There is no causative treatment available for the symptoms. Therefore, patients are treated mainly symptomatically and supportively. Palliative forms of therapy are recommended. This therapy includes dietary recommendations and respiratory as well as physiotherapy to strengthen the musculature.In the course of time, artificial respiration and nutrition become necessary. The timely decision for these measures is imperative to prolong life. Nutritionally, a high-protein diet in combination with endurance training has proven successful. Since 2006, artificial delivery of the recombinant protein is possible, which consists of CHO cells and is known as alglucosidase alfa or Myozyme. The drug is administered intravenously every 14 days. In infants, breakthrough success has been observed after early administration of the drug, which has been able to ensure survival. On older children, there is conflicting experience, and on the adult form, there is no convincing evidence of efficacy. Drug costs can be as high as 50,000 euros per year for an infant and 500,000 euros per year for an adult. Lifelong care is necessary. The response of skeletal muscles to therapy is variable. On the other hand, cardiac muscle weakness improves. Because of the blood–brain barrier, the drug does not affect disease processes in the brain. Therapeutic approaches such as gene therapy are in animal experimental stages. Gene transfer has already been successful in mice. Treatment with pharmacological chaperones can increase the residual activity of acid maltase, but is not yet practical. Supportive psychotherapeutic care to process the situation is recommended for affected families.
Outlook and prognosis
Pompe disease is an incurable hereditary disease that usually results in a shortened life expectancy. The exact prognosis depends on the specific form of the disease and the age of the affected person at onset. The prognosis is most unfavorable for the early form of Pompe disease, which, if left untreated, usually leads to death within two years. Affected individuals usually die of pneumonia or heart failure. Treatment of the disease with enzyme replacement therapy significantly improves the prognosis. The life expectancy of those affected increases significantly to an age of over ten years. However, since this form of therapy is novel, long-term prognoses are not yet available. Without treatment, the juvenile form of Pompe disease usually leads to the death of the patient before reaching adulthood. The adult form of Pompe disease has the most favorable prognosis. In either case, life expectancy increases significantly with treatment. However, affected individuals usually develop some limitations such as cognitive difficulties and hearing loss and even deafness. New treatments, such as gene therapies for Pompe disease, are currently being developed and tested and are expected to result in a much more favorable prognosis.
Prevention
To date, Pompe disease can only be prevented through genetic counseling during the family planning phase. For the parents of an affected child, the risk of recurrence is 25 percent. After a positive prenatal diagnosis, expectant parents are also given the option of terminating the pregnancy.
Follow-up
As a rule, very few and also very limited aftercare measures and options are available to those affected by Pompe disease, so they should ideally see a doctor at an early stage to prevent the occurrence of other complaints and complications. There can be no independent recovery, so a doctor should be consulted at the first signs and symptoms of the disease. The recovery process is based primarily on exercises from physiotherapy or physical therapy. Here, many of the exercises can also be repeated in the patient’s own home, which significantly promotes treatment. The help and care of one’s own family is also very important, which can also prevent depression and other psychological upsets. In the case of an existing desire to have children, those affected should take advantage of genetic testing and counseling in order to prevent a recurrence of the disease. Regular checks and examinations by a doctor are also necessary throughout life. The disease itself does not usually reduce the patient’s life expectancy. Further measures of aftercare are usually not available to the affected person.
What you can do yourself
For those affected, Pompe disease is a very stressful diagnosis, especially when the disease manifests itself at an older age.The course of the disease can be quite individual, which is why patients wish to do as much as possible on their own to ensure a mild course of the disease. The main thing is to prevent additional illnesses. For example, patients should make sure they have the best possible supply of oxygen so that they do not fall or have an accident due to dizziness. Moreover, a lack of oxygen would cause additional damage to the heart – and possibly other organs as well. Infectious diseases such as the flu or flu-like infections should also be avoided if possible, because they also affect breathing and greatly weaken the body and its immune system. Patients with Pompe disease would therefore do well to pay special attention to their immune system. They should pay attention to a fresh, high-protein diet within the dietary recommendations of their specialist. Regular exercise is also important to maintain muscle strength, especially in the legs. Endurance training in particular has proven effective in the treatment of Pompe disease. The treating physiotherapists provide the necessary assistance in this regard. For many patients and their relatives, psychological support is helpful. They also receive support and information from Pompe Deutschland e.V. (www.morbus-pompe.de).
