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Glycogen storage disease type II (also called Pompe disease or acid maltase deficiency) is a neuromuscular, autosomal recessive metabolic disorder in the family of lysosomal storage diseases caused by a deficiency in the enzyme Acid alpha-glucosidase (EC 3.2.1.20), which is needed to break down glycogen—a long, branched glucose polymer and stored form of sugar used for energy. It is the only glycogen storage disease with a defect in lysosomal metabolism and was the first glycogen storage disease to be identified, in 1932.

The build-up of glycogen causes progressive muscle weakness (myopathy) throughout the body and affects various body tissues, particularly in the heart, skeletal muscles, liver and nervous system.

The disease is named after Johann Pompe, who characterized it in 1932.^[1][2]

[edit] Genetic prevalence

Glycogen storage disease type II has an autosomal recessive pattern of inheritance.

The disorder is estimated to occur in about 1 in 40,000–300,000 births.

It has an autosomal recessive inheritance pattern. This means the defective gene is located on an autosome, and two copies of the gene—one from each parent—are required to be born with the disorder. As with all cases of autosomal recessive inheritance, children have a 1 in 4 chance of inheriting the disorder when both parents carry the defective gene, and although both parents carry one copy of the defective gene, they are usually not affected by the disorder.

[edit] Variants

Pompe disease has historically been divided into three forms defined by age of onset and progression of symptoms (see below). More recently there has been a trend to divide the disease into two groups: infantile onset (involving the massive enlargement of the heart) and late onset (no heart enlargement).

Infantile, or early onset, is noticed shortly after birth. Symptoms include severe lack of muscle tone, weakness, and enlarged liver (hepatomegaly) and heart. Mental function is not affected. Development appears normal for the first weeks or months but slowly declines as the disease progresses. Swallowing may become difficult and the tongue may protrude and become enlarged. Most children die from respiratory or cardiac complications before 2 years of age.

Juvenile onset symptoms appear in early to late childhood and include progressive weakness of respiratory muscles in the trunk, diaphragm and lower limbs, as well as exercise intolerance. Intelligence is normal.

Adult onset symptoms also involve generalized muscle weakness and wasting of respiratory muscles in the trunk, lower limbs, and diaphragm. Many patients report respiratory distress, headache at night or upon waking, diminished deep tendon reflexes, and proximal muscle weakness, such as difficulty in climbing stairs. Intellect is not affected. A small number of adult patients live without major symptoms or limitations.

Pompe's disease is one of the infiltrative causes of restrictive cardiomyopathy.

[edit] Treatment

Cardiac and respiratory complications are treated symptomatically. Physical and occupational therapy may be beneficial for some patients. Alterations in diet may provide temporary improvement but will not alter the course of the disease. Genetic counseling can provide families with information regarding risk in future pregnancies.

On April 28, 2006 the US Food and Drug Administration approved a biologics license application (BLA) for Myozyme (alglucosidase alfa, rhGAA),^[3] the first treatment for patients with Pompe disease primarily developed by Dr. Yuan-Tsong Chen^[4] (陳垣崇) while he was at Duke University (Dr. Chen is currently the director of the Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan). Myozyme falls under the FDA Orphan Drug designation and was approved under a priority review. Myozyme is manufactured by Genzyme Corp. in Cambridge, Massachusetts, USA.

The FDA approved Myozyme for administration by intravenous infusion of solution into a vein. The safety and efficacy of Myozyme were assessed in two separate clinical trials in 39 infantile-onset patients with Pompe disease ranging in age from 1 month to 3.5 years at the time of the first infusion.

Myozyme costs an average of $300,000 a year, and must be taken for the patients' entire life. Some insurers have refused to pay for it.^[5]

On August 14, 2006, Health Canada approved Myozyme for the treatment of Pompe disease. On June 14, 2007 the Canadian Common Drug Review issued their recommendations regarding public funding for Myozyme therapy. Their recommendation was to provide funding to treat a very small subset of Pompe patients (Infants less one year of age with Cardiomyopathy).^[6] The vast majority of developed countries are providing access to therapy for all diagnosed Pompe patients.^[7]

In June 2007 it was reported that ZyStor Therapeutics was in the process of developing an enzyme replacement therapy for Pompe disease by leveraging their glycosylation independent lysosomal targeting technology (GILT).^[8]

[edit] Prognosis

The prognosis for individuals with Pompe disease varies according to the onset and severity of symptoms. Without treatment the disease is particularly lethal in infants and young children.

Myozyme (alglucosidase alfa), which helps break down glucose, is a combined form of the human enzyme acid alpha-glucosidase, and is also currently being used to replace the missing enzyme. In a study^[9] which included the largest cohort of patients with Pompe disease treated with enzyme replacement therapy (ERT) to date findings showed that Myozyme treatment clearly prolongs ventilator-free survival and overall survival in patients with infantile-onset Pompe disease as compared to an untreated historical control population. Furthermore, the study demonstrated that initiation of ERT prior to 6 months of age, which could be facilitated by newborn screening, shows great promise to reduce the mortality and disability associated with this devastating disorder.

On December 13, 2007, Genzyme released the initial results of its Late Onset Treatment Study (LOTS). The study was undertaken to evaluate the safety and efficacy of Myozyme in juvenile and adult patients with Pompe disease. LOTS was a randomized, double-blind, placebo-controlled study that enrolled 90 patients at eight primary sites in the United States and Europe. Participants received either Myozyme or a placebo every other week for 18 months. The average age of study participants was 44 years. The primary efficacy endpoints of the study sought to determine the effect of Myozyme on functional endurance as measured by the six-minute walk test and to determine the effect of Myozyme on pulmonary function as measured by percent predicted forced vital capacity.

The results showed that, at 18 months, patients treated with Myozyme increased their distance walked in six minutes by an average of approximately 30 meters as compared with the placebo group (P=0.0283; Wilcoxon test). The placebo group did not show any improvement from baseline. The average baseline distance walked in six minutes in both groups was approximately 325 meters. Percent predicted forced vital capacity in the group of patients treated with Myozyme increased by 1 percent at 18 months. In contrast, it declined by approximately 3 percent in the placebo group (P=0.0026; Wilcoxon test). The average baseline percent predicted forced vital capacity in both groups was approximately 55 percent.

The results for both efficacy endpoints were consistent across various prospectively defined subgroups.

[edit] References

[edit] External links

• United Pompe Foundation
• The website of the Pompe's Group of the Association for Glycogen Storage Disease (UK)
• International Pompe Association—A federation of Pompe disease patient's groups worldwide.
• Genzyme's Pompe Information site
• FDA Approval News for Myozyme
• Canadian Association of Pompe
• Hide & Seek Foundation for Lysosomal Disease Research
• GeneReview/NIH/UW entry on Glycogen Storage Disease Type II (Pompe Disease)