Laboratory Studies

Blood biochemistry analysis - Elevations of creatine kinase (CK), transaminases (alanine transaminase, aspartate transaminase), and lactate dehydrogenase (LDH) are sensitive but nonspecific indicators.

A study found that after being screened by dried blood spot, presymptomatic hyperCKemia was shown in 35% of 17 confirmed cases of late-onset Pompe disease and 59% showed hyperCKemia and limb-girdle muscle weakness.^[11]

Urine analysis - Elevation of urinary glucose tetrasaccharide (Glc₄) supports the diagnosis if a clinical correlation exists. It may also be elevated in other glycogen storage disorders (GSDs).

Fasting glucose measurement - Because hypoglycemia may be found in some types of GSD, a fasting glucose level is indicated. Because the liver phosphorylase is not involved (only muscle phosphorylase), hypoglycemia is not an expected finding.

Measurement of α-glucosidase activity in dried blood spots is essential for the diagnosis of Pompe disease.

Confirmatory tests

Enzyme studies - Enzyme assay of α-glucosidase in lymphocytes and other tissue samples

Genetic testing - Analysis of mutations in the acid α-glucosidase gene

Imaging Studies

Muscle MRI - Correlates with muscle function in adult-onset Pompe disease. In addition, quantitative MRI studies have shown a progressive increase in fat in skeletal muscles of late-onset Pompe disease over time and are increasingly considered a good tool to monitor progression of the disease. The studies performed in infantile-onset Pompe disease patients have shown less consistent changes.

Chest radiography - Shows massive cardiomegaly. A chest radiograph and an echocardiogram are valuable screening tests in the diagnostic algorithm for infantile Pompe disease.

Echocardiography - Typically reveals a hypertrophic cardiomyopathy with or without left ventricular outflow tract obstruction in the early stages of the disease. In the late stages of infantile disease, patients may have impaired cardiac function and a dilated cardiomyopathy

Angiography or magnetic resonance angiography - Aneurysms, which represent glycogen storage within the intracranial vasculature, may be found.

Tests

Electrocardiography - ECG demonstrates a short PR interval and elevated QRS complexes in the infantile form. A case of Wolff-Parkinson-White syndrome has been reported in association with Pompe disease.

Spirometry - Useful for detecting signs of respiratory impairment, common in late-onset Pompe disease, even in the pre-symptomatic stage. Measurement of forced vital capacity (FVC) is done in the sitting and lying supine positions.

Electromyelography - In 1998, Aminoff reported electromyelographic findings suggestive of a myopathy, although abnormal spontaneous activity may be present.^[12] Characteristic findings are as follows:

Electrical myotonia without clinical myotonia may be present.
Myotonic discharges may be found in the paraspinal muscles.
Fibrillation potentials, positive sharp waves, and complex repetitive discharges may be found.
Myopathic findings of polyphasic responses, decreased duration of potentials, and decreased amplitude are usually present.

Polysomnography and nocturnal oximetry - Sleep-disordered breathing (SDB) appears as the first sign of respiratory muscle dysfunction, with hypoventilation that worsens during REM sleep. Sleep apnea has been reported in late-onset Pompe disease.

Sleep pathology hasn't been well categorized in infantile-onset Pompe disease. However obstructive sleep apnea and hypoventilation have been reported in these patients.^[13]

Ischemic forearm test - The ischemic forearm test is an important tool for diagnosis of muscle disorders. The basic premise is an analysis of the normal chemical reactions and products of muscle activity. Obtain consent before the test. The steps in the test are as follows:

Instruct the patient to rest. Position a loosened blood pressure cuff on the arm, and place a venous line for blood samples in the antecubital vein.
Obtain blood samples for the following tests: creatine kinase, ammonia, and lactate. Repeat in 5-10 minutes.
Obtain a urine sample for myoglobin analysis.
Immediately inflate the blood pressure cuff above systolic blood pressure and have the patient repetitively grasp an object, such as a dynamometer. Instruct the patient to grasp the object firmly, once or twice per second. Encourage the patient for 2-3 minutes, at which time the patient may no longer be able to participate. Immediately release and remove the blood pressure cuff.
Obtain blood samples for creatine kinase, ammonia, and lactate immediately and at 5, 10, and 20 minutes.
Collect a final urine sample for myoglobin analysis.

Interpretation of ischemic forearm test results

With exercise, carbohydrate metabolic pathways yield lactate from pyruvate. Lack of lactate production during exercise is evidence of pathway disturbance, and an enzyme deficiency is suggested. In such cases, muscle biopsy with biochemical assay is indicated.
Healthy patients demonstrate an increase in lactate of at least 5-10 mg/dL and ammonia of at least 100 mcg/dL. Levels return to baseline.
If neither level increases, the exercise was not strenuous enough and the test result is not valid.
Increased lactate at rest (before exercise) is evidence of mitochondrial myopathy.
Failure of lactate to increase with ammonia is evidence of a GSD resulting in a block in carbohydrate metabolic pathways. Not all GSDs have a positive ischemic test result.
Failure of ammonia to increase with lactate is evidence of myoadenylate deaminase deficiency.
Findings on the ischemic forearm test are normal in Pompe disease.

Procedures

Muscle biopsy - Assists with the evaluation of muscle weakness. Muscle biopsy shows vacuolar myopathy. Type I fibers are most often involved. Lysosomal glycogen accumulates are predominant, although the cytoplasm may be involved. Periodic acid-Schiff stain is positive for inclusions.

Numerous lipofuscin inclusions have also been reported, which is a result of inefficient lysosomal degradation. It is thought to exacerbate lysosomal and autophagic abnormalities and is resistant to enzyme replacement therapy.^[14]

Treatment & Management

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Glycogen storage disease, type II. Metabolic pathways of carbohydrates.

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Author

Ricardo R Correa Marquez, MD, EsD, FACP, FACE, FAPCR, CMQ, ABDA, FACHT Associate Professor of Medicine, Program Director, Endocrinology, Diabetes and Metabolism Fellowship Program, Director for Diversity in Graduate Medical Education, University of Arizona College of Medicine-Phoenix; Assistant Professor of Medicine, Mayo College of Medicine, Mayo Clinic Arizona; Staff Endocrinologist, Phoenix Veterans Hospital (VAMC)

Ricardo R Correa Marquez, MD, EsD, FACP, FACE, FAPCR, CMQ, ABDA, FACHT is a member of the following medical societies: Academy of Physicians in Clinical Research, American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Healthcare Trustees, American College of Physicians, American Medical Association, American Thyroid Association, Association of Program Directors in Endocrinology, Endocrine Society, National Hispanic Medical Association, World Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

Mythili Menon Pathiyil, MBBS

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

George T Griffing, MD Professor Emeritus of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for Physician Leadership, American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society, International Society for Clinical Densitometry, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

Wayne E Anderson, DO, FAHS, FAAN Assistant Professor of Internal Medicine/Neurology, College of Osteopathic Medicine of the Pacific Western University of Health Sciences; Clinical Faculty in Family Medicine, Touro University College of Osteopathic Medicine; Clinical Instructor, Departments of Neurology and Pain Management, California Pacific Medical Center

Wayne E Anderson, DO, FAHS, FAAN is a member of the following medical societies: American Academy of Neurology, American Headache Society, California Medical Association, California Neurology Society, International Headache Society, San Francisco Medical Society, San Francisco Neurological Society

Disclosure: Nothing to disclose.

Acknowledgements

Barry J Goldstein, MD, PhD Director, Division of Endocrinology, Diabetes and Metabolic Diseases, Professor, Department of Internal Medicine, Thomas Jefferson University

Barry J Goldstein, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Clinical Endocrinologists, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, and The Endocrine Society

Disclosure: Nothing to disclose.