Pompe disease

Definition

Pompe disease, also called acid maltase deficiency, is a non-sex linked recessive genetic disorder that is the most serious of the glycogen storage diseases affecting muscle tissue. It is one of several known congenital (present at birth) muscular diseases (myopathies), as distinct from a muscular dystrophy , which is a family of muscle disorders arising from faulty nutrition. The Dutch pathologist J. C. Pompe first described this genetic disorder in 1932.

Description

Pompe disease is also known as glycogen storage disease type II (GSD II) because it is characterized by a buildup of glycogen in the muscle cells. Glycogen is the chemical substance muscles use to store sugars and starches for later use. Some of the sugars and starches from the diet that are not immediately put to use are converted into glycogen and then stored in the muscle cells. These stores of glycogen are then broken down into sugars, as the muscles require them. Acid maltase is the chemical substance that regulates the amount of glycogen stored in muscle cells. When too much glycogen begins to accumulate in a muscle cell, acid maltase is released to break down this excess glycogen into products that will be either reabsorbed for later use in other cells or passed out of the body via the digestive system. Individuals affected with Pompe disease have either a complete inability or a severely limited ability to produce acid maltase. Since these individuals cannot produce the amounts of acid maltase required to process excess glycogen in the muscle cells, the muscle cells become overrun with glycogen. This excess glycogen in the muscle cells causes a progressive degeneration of the muscle tissues.

Acid maltase is an enzyme. An enzyme is a chemical that facilitates (catalyzes) the chemical reaction of another chemical or of other chemicals; it is neither a reactant nor a product in the chemical reaction that it catalyzes. As a result, enzymes are not used up in chemical reactions, but rather recycled. One molecule of an enzyme may be used to catalyze the same chemical reaction over and over again several hundreds of thousands of times. All the enzymes necessary for catalyzing the various reactions of human life are produced within the body by genes. Genetic enzyme deficiency disorders, such as Pompe disease, result from only one cause: the affected individual cannot produce enough of the necessary enzyme because the gene designed to make the enzyme is faulty. Enzymes are not used up in chemical reactions, but they do eventually wear out, or accidentally get expelled. Also, as an individual grows, they may require greater quantities of an enzyme. Therefore, most enzyme deficiency disorders will have a time component to them. Individuals with no ability to produce a particular enzyme may show effects of this deficiency at birth or shortly thereafter. Individuals with only a partial ability to produce a particular enzyme may not show the effects of this deficiency until their need for the enzyme, because of growth or maturation, has outpaced their ability to produce it.

The level of ability of individuals with Pompe disease to produce acid maltase, or thier ability to sustain existing levels of acid maltase, are the sole determinants of the severity of the observed symptoms in individuals and the age of onset of these symptoms.

Pompe disease is categorized into three separate types based on the age of onset of symptoms in the affected individual. Type a, or infantile, Pompe disease usually begins to produce observable symptoms in affected individuals between the ages of two and five months. Type b, or childhood, Pompe disease usually begins to produce observable symptoms in affected individuals in early childhood. This type generally progresses much more slowly than infantile Pompe disease. Type c, or adult, Pompe disease generally begins to produce observable symptoms in affected individuals in the third or fourth decades of life. This type progresses even more slowly than childhood Pompe disease.

Genetic profile

The locus of the gene responsible for Pompe disease has been localized to 17q23. The severity of the associated symptoms and the age of onset in affected individuals have been closely tied to the particular mutation at this locus. Three specific mutations and one additional mutation type have been demonstrated to occur along the gene responsible for Pompe disease. Each of these is associated with varying symptoms.

A gene is a particular segment of a particular chromosome . However, within the segment containing a particular gene there are two types of areas: introns and exons. Introns are sections of the segment that do not actively participate in the functioning of the gene. Exons are those sections that do actively participate in gene function. A typical gene consists of several areas that are exons divided by several areas of introns.

One mutation on the gene responsible for the production of acid maltase is a deletion of exon 18. A second mutation on the gene responsible for the production of acid maltase is the deletion of a single base pair of exon 2. Both these mutations are associated with a complete inability of the affected individual to produce acid maltase. Individuals with these mutations will invariably be affected with infantile (type a) Pompe disease.

The third mutation on the gene responsible for the production of acid maltase is a complicated mutation within intron 1 that causes the cutting out of exon 2. This mutation is generally not complete in every copy of the gene within a given individual so it is associated with a partial ability of the affected individual to produce acid maltase. Individuals with this mutation will be affected with either childhood (type b), or, more commonly, adult (type c) Pompe disease. In fact, greater than 70% of all individuals affected with adult Pompe disease possess this particular mutation.

The final mutation class known to occur on the gene responsible for the production of acid maltase is missense at various locations along the various exons. Missense is the alteration of a single coding sequence (codon) that codes for a single amino acid that will be used to build the protein that is the precursor to the acid maltase molecule. These missense mutations generally prevent the production of acid maltase and lead to infantile (type a) Pompe disease.

The exact mutations responsible for the other 30% of the adult (type c) and the remainder of the childhood (type b) Pompe disease cases have not yet been determined.

Demographics

Pompe disease is observed in approximately one in every 100,000 live births. In 2000, it was estimated that between 5,000 and 10,000 people were living somewhere in the developed world with a diagnosed case of Pompe disease. It is observed in equal numbers of males and females and across all ethnic subpopulations.

Since Pompe disease is a recessive disorder, both parents must be carriers of the disorder for it to be passed to their children. In the case of carrier parents with one child affected by Pompe disease, there is a 25% likelihood that their next child will also be affected with the disorder. However, because type c (adult) Pompe disease generally does not show symptoms in the affected individual until that individual is past 30, it is possible for an affected individual to parent children. In this case, the probability of a second child being affected with Pompe disease is 50%. Should two affected individuals bear offspring; the probability of their child being affected with Pompe disease is 100%.

In families with more than one affected child, the symptoms of the siblings will closely correspond. That is, if one child develops infantile Pompe disease, a second child, if affected with the disorder, will also develop the infantile form.

Signs and symptoms

The symptoms of Pompe disease vary depending on the severity of the deficiency of acid maltase in the affected individual. The most acid maltase deficient individuals will develop infantile Pompe disease and will exhibit the most severe symptoms. Likewise, the least acid maltase deficient individuals will develop adult Pompe disease and have less severe symptoms.

Infantile (type a) Pompe disease is characterized by the so-called "floppy baby" syndrome. This condition is caused by extreme weakness and lack of tone of the skeletal muscles. This observed weakness in the skeletal muscles is accompanied by the much more serious problems of overall weakness of the heart muscle (cardiomyopathy) and the muscles of the respiratory system, primarily the diaphragm. Enlargement of the heart (cardiomegaly), tongue and liver are also observed. Glycogen accumulation is observed in most tissues of the body.

Childhood (type b) Pompe disease is characterized by weakness of the muscles of the trunk and large muscle mass with little muscle tone. This is due to a buildup of glycogen in the muscle cells. The heart and liver of those affected with childhood maltase deficiency are generally normal. However, there is a progressive weakening of the skeletal and respiratory muscles. The observed muscle weakness in childhood Pompe disease affected individuals gradually progresses from the muscles of the trunk to the muscles of the arms and the legs. Glycogen accumulation is observed primarily in the muscle tissues.

Adult (type c) Pompe disease is characterized by fatigue in younger affected individuals and by weakness of the muscles of the trunk in older affected individuals. The observed muscle weakness in adult Pompe disease affected individuals gradually progresses from the muscles of the trunk to the muscles of the arms and the legs. High blood pressure in the artery that delivers blood to the lungs (pulmonary hypertension) is also generally observed in affected adults. Glycogen accumulation is observed primarily in the muscle tissues.

Diagnosis

Infantile Pompe disease is generally diagnosed between the ages of two and five months when symptoms begin to appear. The first indicator of infantile Pompe disease is general weakness and lack of tone (hypotonia) of the skeletal muscles, particularly those of the trunk.

A blood test called a serum CK test is the most commonly used test to determine whether muscular degeneration is causing an observed muscular weakness. It is used to rule out other possible causes of muscle weakness, such as nerve problems. To determine the CK serum level, blood is drawn and separated into the part containing the cells and the liquid remaining (the serum). The serum is then tested for the amount of creatine kinase (CK) present. Creatine kinase is an enzyme found almost exclusively in the muscle cells and not typically in high amounts in the bloodstream. Higher than normal amounts of CK in the blood serum indicate that muscular degeneration is occurring: that the muscle cells are breaking open and spilling their contents, including the enzyme creatine kinase (CK) into the bloodstream. Individuals affected with Pompe disease have extremely high serum CK levels. Those affected with infantile Pompe disease have much higher serum CK levels than those affected with the childhood or adult forms. The actual serum CK level, once observed to be higher than normal, can also be used to differentiate between various types of muscular degeneration.

Serum CK levels cannot be used to distinguish Pompe disease from other glycogen storage diseases. Pompe disease (type II glycogen storage disease) is differentially diagnosed from type I glycogen storage disease by blood tests for abnormally low levels of glucose (hypoglycemia) and a low pH, or high acidity, (acidosis). Hypoglycemia and acidosis are both characteristic of type I glycogen storage disease, but neither is characteristic of Pompe disease.

It is sometimes possible to determine the abnormally low levels of the acid maltase enzyme in the white blood cells (leukocytes) removed during the above blood serum tests. If these levels can be determined and they are abnormally low, a definitive diagnosis of Pompe disease can be made. When the results of this leukocyte test are not clear, Pompe disease types a and b may be positively diagnosed by testing muscles cells removed from the affected individual (muscle biopsy) for the actual absence or lack of sufficient acid maltase. This test is 100% accurate for type a and type b Pompe disease, but it may give improper results for type c Pompe disease. In these hard-to-identify cases of type c Pompe disease, an identical test to that performed on the leukocytes may be performed on cultured fibroblasts grown from a sample from the affected individual. This test is 100% accurate for type c Pompe disease.

Treatment and management

As of early 2001, there is no treatment or cure for Pompe disease. The only potential treatment for this deficiency is enzyme replacement therapy. This approach was initially undertaken in the 1970s for Pompe disease with no success. A new enzyme replacement therapy is, however, currently in human clinical trials that began in 1999.

Prognosis

Pompe disease of all three types is 100% fatal. Individuals affected with infantile Pompe disease generally die from heart or respiratory failure prior to age one. Individuals affected with childhood Pompe disease generally die from respiratory failure between the ages of three and 24. Individuals affected with adult Pompe disease generally die from respiratory failure within 10 to 20 years of the onset of symptoms.

Human clinical trials involving enzyme replacement therapy, in which a synthetic form of acid maltase is administered to affected individuals, were begun in 1999 at Duke University Medical Center in North Carolina and Erasmus University Rotterdam in the Netherlands. Genzyme Corporation and Pharming Group N. V. announced the first results of these trials in a joint press release on October 5, 2000. These two companies currently own the worldwide patent rights to the synthetic enzyme being studied. As of early 2001, these clinical trials are still in phase I/II of the three-stage testing process for use in humans.

Resources

PERIODICALS

Chen, Y., and A. Amalfitano. "Towards a molecular therapy for glycogen storage disease type II (Pompe disease)." Molecular Medicine Today (June 2000): 245-51.

Poenaru, L. "Approach to gene therapy of glycogenosis type II (Pompe disease). Molecular Genetics and Metabolism (July 2000): 162-9.

ORGANIZATIONS

Acid Maltase Deficiency Association (AMDA). PO Box 700248, San Antonio, TX 78270-0248. (210) 494-6144 or (210) 490-7161. Fax: (210) 490-7161 or 210-497-3810. <http://www.amda-pompe.org>.

Association for Glycogen Storage Disease (United Kingdom). 0131 554 2791. Fax: 0131 244 8926. <http://www.agsd.org.uk>.

WEBSITES

Neuromuscular Disease Center<http://www.neuro.wustl.edu/neuromuscular/msys/glycogen.html> (February 12, 2001).

OMIM—Online Mendelian Inheritance in Man. <http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?232300> (February 12, 2001).

The Pompe's Disease Page. <http://www.cix.co.uk/~embra/pompe/Welcome.html> (February 12, 2001).

OTHER

"Genzyme General and Pharming Group Reports Results From First Two Clinical Trials for Pompe Disease." Genzyme Corporation Press Release (October 5, 2000).

"Pompe disease therapy to be tested." Duke University Medical Center Press Release (May 24, 1999).

Paul A. Johnson