NORD gratefully acknowledges Arnold J. J. Reuser, PhD, Associate Professor of Cell Biology & Microscopical Anatomy, Erasmus University Medical Center, Rotterdam, the Netherlands, for assistance in the preparation of this report.
Pompe disease is a single disease continuum with variable rates of disease progression and different ages of onset. First symptoms can occur at any age from birth to late adulthood. Earlier onset compared to later onset is usually associated with more rapid progression and greater disease severity. At all ages, skeletal muscle weakness and wasting causing mobility problems, but also affecting respiratory function, characterizes the disease. The most severely affected infants usually present within the first 3 months after birth. They have characteristic cardiac problems (dysfunction due to cardiac enlargement) in addition to generalized skeletal muscle weakness and a life expectancy of less than 2 years, if untreated (classic infantile Pompe disease). Less severe forms of Pompe disease with onset during childhood, adolescence, or adulthood, rarely manifest cardiac problems, but gradually lead to walking disability and reduced respiratory function. In essence, Pompe disease is a rare multisystem disorder caused by pathogenic variations in the GAA gene containing the information for production and function of a protein called acid alpha-glucosidase (GAA). Because of the shortage of this protein (an enzyme) a complex sugar named ‘glycogen’ cannot be degraded to a simple sugar like glucose. This causes the glycogen to accumulate in all kinds of tissues, but primarily in skeletal muscle, smooth muscle and cardiac muscle, where it causes damage to tissue structure and function. Pompe disease is inherited as an autosomal recessive genetic trait.
The human body can be seen as an assembly of interconnecting organs. Organs are composed of organ specific tissues, and tissues are composed of specialized cells like muscle cells, nerve cells, etc. Pompe disease belongs to a group of diseases known as the ‘lysosomal storage disorders’ (LSDs). Lysosomes are small compartments inside the cells wherein all kind of substances are re-cycled. The substances are degraded by the action of digestive enzymes and more than 50 different LSDs are presently known. Acid alpha-glucosidase (GAA) is one of these enzymes and solely responsible for the shortage or dysfunction of the GAA enzyme causes glycogen to accumulate within the lysosomes leading sequentially to cellular malfunction, cellular damage, tissue damage, and ultimately organ dysfunction. In Pompe, that is manifested as muscle weakness and wasting. Pompe disease may also be classified as a glycogen storage disease, a group of metabolic disorders characterized by abnormalities involving the use and/or storage of glycogen. There are more than 10 other glycogen storage diseases, but other than Pompe disease (glycogen storage disease type II; GSDII), they all involve defects in glycogen synthesis and degradation processes that occur outside the lysosomes, and the clinical features are different.
Infantile-onset or ‘classic infantile’ refers to the originally described form of Pompe disease characterized by onset of symptoms shortly after birth, generalized muscle weakness, and cardiac hypertrophy, in association with glycogen storage in all organs. Terms like childhood, juvenile, and adult glycogenosis type II (Pompe disease, or acid maltase deficiency) were historically introduced as names for the less severe forms of Pompe disease characterized by delayed onset and usually slower progression. Adult-onset was alternatively called ‘late-onset’. During the development of enzyme replacement therapy, the meaning of ‘late-onset’ has gradually shifted from onset late in life to Pompe disease without cardiomyopathy (disease of the heart muscle), irrespective of the age at first symptoms. Attempts are currently being made by experts in the Pompe field to reach a consensus about terminology.
Patients with the classic infantile form of Pompe disease are the most severely affected. Although hardly any symptoms may be apparent at birth, the disease usually presents within the first three months of life with rapidly progressive muscle weakness (floppy infants), diminished muscle tone (hypotonia), respiratory insufficiency, and a type of heart disease known as hypertrophic cardiomyopathy, a condition characterized by abnormal thickening of the walls of the heart (mainly the left chamber and the wall between the left and right chamber) resulting in diminished cardiac function. These problems together culminate in cardio-respiratory failure within the first 2 years of life.
Many infants have a large, protruding tongue and a moderate enlargement of the liver. The legs often rest in a frog position and feel firm on palpation (pseudo-hypertrophy).
Feeding and swallowing problems as well as respiratory difficulties, which are 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. Virtually all infants experience hearing loss. The classic infantile form of Pompe disease is characterized by a total lack of acid alpha-glucosidase (GAA) activity and by a rapid buildup of glycogen in skeletal muscle and heart.
Childhood Pompe disease typically presents during childhood and adult Pompe disease during adulthood. Both these forms of Pompe disease are often grouped together as late-onset Pompe disease (abbreviated as LOPD) despite the fact that the time of presentation can vary from the first year to the eighth decade. Patients who develop symptoms early in life tend to be the more severely affected and to have a faster rate of disease progression than those who develop symptoms later in life. Both children and adults usually have more GAA activity present than those who show symptoms as infants, and the glycogen buildup is not usually as rapid. However, symptoms do progress, can greatly affect the quality of life, and diminish the lifespan of affected individuals.
Childhood and adult Pompe disease are associated with progressive weakness of mainly the proximal muscles (limb girdle, upper arms and upper legs), and varying degrees of respiratory weakness due to dysfunction of the diaphragm and intercostal muscles (muscle between ribs). The lower limbs are more affected than the upper limbs. The extent of muscle involvement is highly variable. The muscles adjacent to the spinal column (para-spinal muscles) and neck are usually also involved. Weakness of the para-spinal muscles around puberty can cause abnormal curvature of the spine (scoliosis). As a result of the combination of these serious symptoms, affected individuals may become wheelchair and/or ventilator dependent.
Other symptoms can include chewing and swallowing difficulties and drooping of the upper eyelids (ptosis). Additionally, blood vessel abnormalities due to smooth muscle weakness and problems of the urinary and digestive systems have been reported.
Pompe disease is caused by pathogenic variations in the acid alpha-glucosidase (GAA) gene. Close to 500 different GAA gene variations have been identified in families with this disorder.
Pompe disease is inherited as an autosomal recessive trait. Recessive genetic disorders occur when an individual inherits two copies of an altered gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
The first symptoms of Pompe disease can occur at any age from birth to late adulthood. The timing of symptom onset is largely associated with the severity of the pathogenic variations in each of the 2 GAA gene copies in the affected person. Some pathogenic variations lead to partial loss of functional GAA enzyme, whereas other variations lead to a total loss of functional GAA enzyme. Therefore, it is very rare to find classic-infantile, childhood and adult Pompe disease in the same family. However, there have been families reported in which the father or mother is not a carrier of Pompe disease, but rather an adult patient (in some cases undiagnosed). The clinical presentation of Pompe disease is not solely dictated by the nature of the inherited pathogenic variations in the GAA gene copies. It is influenced by a number of still unknown genetic, epigenetic, and ‘environmental’ factors.
Pompe disease occurs in various populations and ethnic groups around the world. Estimates vary, but its incidence is generally placed at approximately 1 in 40,000 births in the United States. Males and females are affected in equal numbers. Not all people with Pompe disease are readily diagnosed. In the past few years, several people with Pompe disease have been identified with screening programs among patients with undiagnosed limb-girdle dystrophies and/or hyper CK-emia of unknown cause (high level of creatine kinase in the blood is often indicative of muscle damage).
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.
Clinical Testing and Work Up
In individuals suspected of having Pompe disease, blood can be drawn and the function/activity of the GAA enzyme can be measured in white blood cells (leukocytes), but only if the proper assay conditions are being used and acarbose is added to the reaction mixture to inhibit the activity of glucoamylase. The isolation of lymphocytes to prevent the interference of glucoamylase is not advised, as the successful isolation of lymphocytes is not only time consuming, but also error prone when the blood sample is not sufficiently fresh.
Alternatively, the GAA enzyme activity/functional assay can also be performed on a dried blood spot, but the assay is not any quicker or more sensitive than the leukocyte assay and also requires the use of acarbose to inhibit the glucoamylase activity. The advantage of the bloodspot test is that it allows convenient shipment of samples if a certified diagnostic laboratory test is not locally available. Additionally, dried blood spot testing allows for mass screening. The blood spot test is without any argument the most convenient methodology for the screening of large populations of newborns and, for instance, large numbers of patients with undiagnosed limb-girdle muscular dystrophies and CK-emias.
When a diagnosis of Pompe disease is based on a leukocyte or blood spot assay, it must be confirmed through molecular genetic testing (DNA analysis) or by another enzyme assay, preferably using cultured skin fibroblasts obtained by a skin biopsy. More invasive muscle biopsies are not needed and not optimal for obtaining material for GAA enzyme activity/function assays. The advantage of DNA analysis over a GAA enzyme activity assay is that the DNA test discriminates unequivocally between carriers and affected children/adults, whereas the enzyme assay does not in all cases.
The taking of a skin biopsy and the growing of a skin fibroblasts culture may not be feasible in every diagnostic setting, but should always be considered as there are important advantages to this procedure. The GAA enzyme activity test on this material is superior over others as it is the most sensitive test and discriminates best between classic-infantile, childhood and adult Pompe disease. Cultured fibroblasts can be stored forever and used as eternal source of GAA enzyme, DNA and mRNA for all kinds of present day and future sophisticated analyses.
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. Muscle MRI’s are also used to measure the degree of damage that has occurred to the muscles.
Specific tests may also 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.
If the specific GAA gene mutations in both parents are known, prenatal diagnosis is possible through chorionic villi sampling (CVS) or amniocentesis. Pre-implantation genetic diagnosis (testing an embryo to determine whether it has the same genetic abnormalities as the parents) may also be an option. PGD can be performed on embryos created through in vitro fertilization. Families interested in PGD should seek the counsel of a certified genetics professional.
The treatment of Pompe disease is disease-specific, symptomatic, and supportive. Treatment requires the coordinated efforts of a team of specialists with expertise in treating neuromuscular disorders. Pediatricians or internists, neurologists, orthopedists, cardiologists, dieticians, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling is of utmost importance for affected individuals and their families.
Enzyme Replacement Therapy
Enzyme replacement therapy is an approved treatment for all patients with Pompe disease. It involves the intravenous administration of recombinant human acid α-glucosidase. This treatment, manufactured by Genzyme, a Sanofi Corporation, is Lumizyme (marketed as Myozyme outside the United States), and was first approved by the U.S. Food and Drug Administration (FDA) in 2006. It has been approved for all patients with Pompe disease.
Additional treatment of Pompe disease is symptomatic and supportive. Respiratory support may be required, as most patients have some degree of respiratory compromise and/or respiratory failure. Physical therapy may be helpful to strengthen respiratory muscles. Some patients may need respiratory assistance through mechanical ventilation (i.e. bipap or volume ventilators) during the night and/or periods of the day. In addition, it may be necessary for additional support during respiratory tract infections. Mechanical ventilation support can be through noninvasive or invasive techniques. The decision about the duration of respiratory support is best made by the family in careful consultation with the patient’s physicians and other members of the healthcare team based upon the specifics of the patient.
Physiotherapy is recommended to improve strength and physical ability. Occupational therapy, including the use of canes or walkers, may be necessary. Eventually, some individuals may require the use of a wheelchair. Speech therapy can be beneficial to improve articulation and speech for some patients.
Orthopedic devices including braces may be recommended for some patients. Surgery may be required for certain orthopedic symptoms such as contractures or spinal deformity.
Since Pompe disease can weaken muscles used for chewing and swallowing, adequate measures may be required to ensure proper nutrition and weight gain. Some patients may need specialized, high-calorie diets and may need to learn techniques to change the size and texture of food to lower the risk of aspiration. Some infants may require the insertion of a feeding tube that is run through the nose, down the esophagus and into the stomach (nasogastric tube).
In some children, a feeding tube may need to be inserted directly into the stomach through a small surgical opening in the abdominal wall. Some individuals with late onset Pompe disease may require a soft diet, but few require feeding tubes.
Gene therapy remains an exciting option and progress continues. Gene therapy in Pompe disease is directed toward restoring the acid a-glucosidase production and activity in crucial tissues like the diaphragm in order to improve respiratory capacity. Other gene therapy efforts seek to restore the body’s ability to produce acid a-glucosidase by transducing the functional GAA gene in liver cells in vivo, or in bone marrow stem cells ex vivo followed by stem cell transplantation. At this time multiple groups are working to advance this therapy to the clinic.
Several modifications to the recombinant human acid a-glucosidase that is presently used for enzyme replacement therapy are currently being explored. For example, carbohydrate side chains are being modified to improve uptake by muscle cells. Small molecule therapies to enhance the function of patient’s residual, endogenous acid a-glucosidase, as well as to stabilize the intravenously administered form of rhGAA are also currently in development.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Some current clinical trials also are posted on the following page on the NORD website:
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