About Pompe Disease^1,2

Pompe disease is a rare, progressive, and often fatal neuromuscular disease that presents in infants, children, and adults. It is caused by a deficiency of acid alpha-glucosidase (GAA), the lysosomal enzyme that hydrolyzes lysosomal glycogen to glucose.

Clinical Presentation of Pompe Disease^1,3

Pompe disease is a heterogeneous disorder that varies with respect to age at onset, rate of disease progression, and extent of organ involvement. Disease symptoms may first present during the first months of life, during childhood or adulthood. In some cases, symptoms first appear in individuals in their 40s or 50s. Muscle weakness is a prominent feature in the presentation of Pompe disease.

Historically, Pompe disease was described by physicians as either early-onset or late-onset, depending on when the patient’s signs and symptoms first appear. However, Pompe disease may be best understood as a single disease continuum with variable rates of progression, ranging from a rapidly progressive course often fatal by 1 year of age to a relentlessly progressive course that leads to significant morbidity and premature death.

Most infants with Pompe disease have undetectable GAA enzyme activity (less than 1% of average normal GAA enzyme activity in skin fibroblasts). In patients that have symptoms in the first few months of life, Pompe disease progresses very rapidly. These patients have massive deposition of glycogen in the heart, liver, and skeletal muscles, which results in severe cardiac muscle involvement and profound muscle weakness characterized by hypotonia. Infants may experience hepatomegaly, feeding difficulties, and delays in motor milestones. Most infants die from cardiac and/or respiratory failure before the end of the first year of life.

Pompe disease tends to progress more variably in children and adults. Onset of symptoms in this population may occur anytime after infancy through adulthood. These patients have detectable, residual GAA enzyme activity (less than 40% of average normal GAA enzyme activity in skin fibroblasts). Children and adults experience variable rates of disease progression; nevertheless the course is often debilitating and life threatening. Typically, the most common signs and symptoms are progressive muscle weakness that leads to loss of mobility and impaired respiratory function. Other common clinical features include: gait abnormalities, muscle pain, difficulty climbing stairs, respiratory infections, and sleep disordered breathing. Respiratory failure is a major cause of death.

Many of these clinical features are not specific to Pompe disease and are shared with other neuromuscular disorders making the suspicion and diagnosis of Pompe disease challenging, often leading to missed or delayed diagnosis.

Major Signs and Symptoms

In Infants with Pompe Disease

• Marked cardiomegaly/cardiomyopathy
• Hypotonia (floppy baby, head lag, frog-leg posture)
• Frequent respiratory infections
• Profound and rapidly progressive muscle weakness
• Failure to achieve motor milestones
• Difficulty feeding/failure to thrive
• Progressive respiratory involvement
• Progression to cardiac failure

In Children or Adults with Pompe Disease

• Progressive muscle weakness
• Muscle pain
• Gait abnormalities/frequent falls
• Difficulty walking or climbing stairs
• Difficutly rising from chair or floor
• Scapular winging/curvature of spine
• Diaphragm weakness/exertional dyspnea
• Respiratory insufficiency/failure
• Sleep disordered breathing (nocturnal hypoventilation/orthopnea)
• Daytime somnolence/morning headaches
• Frequent respiratory infections
• Difficulty maintaining normal weight

Diagnosis^1,4-7

A number of methods are available to confirm a diagnosis of Pompe disease by measuring GAA enzyme activity using the substrate 4-MUG in dried blood on filter paper, purified lymphocytes, muscle tissue, and skin fibroblasts, or using the substrate glycogen in mixed leukocytes. The addition of acarbose to blood-derived samples inhibits the activity of maltase gluco-amylase, an alpha-glucosidase found in neutrophils whose activity masks the deficiency of GAA and causes false-negative test results. However, the procedure for obtaining a muscle biopsy is invasive and the resultant biopsy sample is frequently not suitable for determining GAA enzyme activity. The use of skin fibroblasts requires a skin biopsy and up to 6-8 weeks of cell culture. The use of blood samples is relatively less invasive. Residual GAA enzyme activity is not predictive of the age of onset or severity of disease; although GAA enzyme activity is usually not detectable in severe patients, some milder patients also lack measureable GAA enzyme activity.

Genotyping can be used to confirm the diagnosis of Pompe disease, although it is not necessary. Genotyping can also be used for family screening, determining carrier status, and prenatal diagnosis with chorionic villi or amniocytes.

Muscle biopsies can also be used for the histologic evaluation of glycogen accumulation. Using PAS staining, the abnormal glycogen appears purple and contrasts sharply with the light blue of the surrounding myofibrils. Seemingly normal biopsies, however, do not rule out Pompe disease because of variable fiber deposition of glycogen.

A Pompe disease newborn screening pilot study was performed in Taiwan to test the hypothesis that early diagnosis and treatment of Pompe disease would lead to improved patient outcomes. Preliminary results indicate that newborn screening for Pompe disease by measuring GAA enzyme activity is feasible; longterm follow up on the impact of screening is ongoing.

To learn more about Pompe disease visit www.pompe.com

1. Hirschhorn R, Reuser A. Glycogen storage disease type II: acid alpha-glucosidase (acid maltase) deficiency. In: Scriver C, Beaudet A, Sly W, Valle D, editors. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, New York: McGraw-Hill; 2001. p. 3389-420

2. Raben N, Plotz P, Byrne BJ. Acid alpha-glucosidase deficiency (glycogenosis type II, Pompe disease). Curr Mol Med. 2002; 2:145-166.

3. Chen YT, Amalfitano A. Towards a molecular therapy for glycogen storage disease type II (Pompe disease). Mol Med Today 2000; 6:245-51.

4. Winchester B, Bali D, Bodamer O, Caillaud C, Christensen E, Cooper A, et al. Methods for a prompt and reliable laboratory diagnosis of Pompe disease: report from an international consensus meeting. Mol Genet Metab 2008; 93:275-81.

5. Chamoles NA, Niizawa G, Blanco M, Gaggiolo D, Casentiini C. Glycogen storage disease type II: enzymatic screening in dried blood spots on filter paper. Clin Chimica Acta. 2004; 347: 97-102.

6. Chien YH, Chiang SC, Zhang XK et al. Early detection of pompe disease by newborn screening is feasible: results from the Taiwan screening program. Pediatrics. 2008; 122:e39-e45. Epub 2008 Jun 2.

7. Gelb MH, Turecek F, Scott CR, Chamoles NA. Direct multiplex assay of enzymes in dried blood spots by tandem mass spectrometry for the newborn screening of lysosomal storage disorders. J Inherit Metab Dis. 2006; 29:397-404.