Pompe Disease

Diagnostic Workup

The following six tests may aid in the diagnosis of Pompe disease.

Enzyme Activity Testing of Cultured Skin Fibroblasts or Muscle Tissue
Enzyme activity testing via a cultured skin fibroblast or muscle biopsy is the definitive step in the diagnostic process, as it can provide proof of low or absent acid alpha-glucosidase (GAA) activity and render a conclusive diagnosis of Pompe disease. Using cultured skin fibroblasts may be preferable to a muscle biopsy due to the less invasive approach. Cultured skin fibroblasts may also be more conclusive in testing for Pompe disease. A muscle biopsy can provide histopathological information about the level of glycogen storage within the lysosomes of muscle cells and may also return faster results.

Enzyme activity testing shows that the GAA deficiency is more pronounced in infantile-onset patients than in late-onset patients. In some infants, the test reveals a complete absence of enzyme activity while in late-onset patients, the severity of the deficiency can vary dramatically. Researchers report that most infants generally demonstrate less than 1% of normal GAA enzyme activity, while juveniles display less than 10% and adults less than 40%, as measured in skin fibroblasts.^[2]
More about Belgian Laboratories where enzyme activity can be tested

Histopathologic examination of muscle biopsies--which is not necessary for a diagnosis but may offer other helpful findings--can reveal the degree of glycogen deposition within the lysosomes of muscle cells. Vacuoles generally stain positive for glycogen and, in some cases, for the lysosomal enzyme acid phosphatase as well. The increase of acid phosphatase, which catalyzes the conversion of orthophosphoric monoester and water into alcohol and orthophosphate, may be due to a compensatory effort. In infantile-onset patients, the increase in glycogen content can be more than tenfold, while the elevation in late-onset patients generally ranges from normal to threefold.^[1]

Enzyme Levels (CK, AST, ALT)
A 1999 study found that creatine kinase (CK) elevation is a sensitive marker for Pompe disease. Of 18 patients examined, 18 (100%) demonstrated elevated CK levels, while a review of the literature revealed that 94.3% of patients displayed increased levels. The greatest elevation can be found in infantile-onset patients (as high as 2000 IU/L)^[3], while in some cases, adults may have CK levels within the normal reference range. A blood test including a CK examination may be ordered as an early step to determine whether more invasive testing is warranted.

Patients may demonstrate elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). There has been at least one report in which these laboratory findings served as the first clue in a juvenile patient. DiFiore and colleagues in 1993 described a case in which a still asymptomatic juvenile patient presented only with an isolated rise in AST.

Note that Pompe patients typically do not display any abnormalities of glucose metabolism such as hypoglycemia. In addition, Pompe patients usually have normal responses to epinephrine and glucagon administration.^[1]

Electromyography (EMG)
In some cases, a neurology consult is requested in the early stages of diagnosis as a result of clinical suspicion of a neuromuscular disorder. An EMG exam generally reveals a myopathic pattern in all Pompe patients, although some muscles may appear normal in late-onset patients. Other common findings may include pseudomyotonic discharges (myotonic discharges without clinical myotonia), fibrillation potentials, positive sharp waves, and excess electrical irritability^[6]. In addition, there are usually no abnormalities in conduction times for motor and sensory nerves.^[1]

Radiology (X-ray)
In other instances, a chest X-ray showing the presence of cardiomegaly starts the investigation while in other cases another laboratory test provides the first clue.

Echocardiography and Electrocardiography (ECG)
A cardiology consult is generally warranted in infantile-onset patients. Depending on the patient's individualized presentation, this may occur before or after clinical suspicion of a myopathic disorder is aroused.

Both echocardiography and electrocardiography can determine the degree of cardiac involvement. In infants, these imaging studies play a key role in establishing whether the patient has infantile-onset or late-onset Pompe disease. Infantile-onset patients generally show massive cardiomegaly while late-onset patients rarely ever display hypertrophy of the heart.^[1]

Certain findings are common in Pompe disease. Echocardiography may reveal left ventricular (LV) thickening and/or outflow obstruction in infantile-onset patients, while the ECG exam typically shows a shortening of the PR interval as well as very tall and broad QRS complexes.^{[3, 6]} Late-onset patients usually have normal patterns.

Ischemic Forearm Test
An ischemic forearm test, which evaluates the functioning of carbohydrate metabolic pathways, can help to narrow down the diagnostic investigation by eliminating other possible enzyme deficiencies that cause myopathy (i.e. mitochondrial myopathy or myoadenylate deaminase deficiency). These disorders would return an abnormal result on this exam. Because the production of lactate is unaffected in Pompe disease, however, the ischemic forearm test is normal.^[7]

References

1. Hirschhorn, Rochelle and Arnold J. J. Reuser. Glycogen Storage Disease Type II: Acid-Alpha Glucosidase (Acid Maltase) Deficiency. In: Wonsiewicz M, Noujaim S, Boyle P, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th Edition. New York: McGraw-Hill; 2001; 3389-3420.

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

3. King, Frank J. Acid Maltase Deficiency Myopathy. eMedicine Specialties. Available at: http://www.emedicine.com/pmr/topic2.htm . Accessed November 7, 2002.

4. Ausems MG, Lochman P, van Diggelen OP, et al. A diagnostic protocol for adult-onset glycogen storage disease type II. Neurology 1999 Mar 10; 52(4): 851-3. .

5. DiFiore MT, Manfredi R, Marri L, et al. Acid maltase deficiency in childhood. Early diagnosis and clinical follow-up of late-onset glycogen storage disease type II. Acta Neurol (Napoli) 1993 Aug;15(4): 258-67.

6. Ibrahim, Jennifer. Glycogen Storage Disease Type II. eMedicine Specialties. Available at: http://www.emedicine.com/ped/topic1866.htm Accessed November 7, 2002.

7. Anderson, Wayne E. Glycogen Storage Disease Type II. eMedicine Specialties. Available at: http://www.emedicine.com/med/topic908.htm . Accessed November 7, 2002.