AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Glycogen-storage disease type II (GSDII), also referred to as Pompe disease, is an autosomal recessive disorder that results from the deficiency of acid alpha-glucosidase, a lysosomal hydrolase. Pompe first described the disease in 1932 when he was presented with a 7-month-old girl who died after developing idiopathic hypertrophic cardiomyopathy. Pompe observed the abnormal accumulation of glycogen in all tissues examined and described the cardinal pathologic features.

Three major forms of the disorder are recognized: infantile, juvenile, and adult-onset. The infantile form usually presents by age 6 months and is marked by a progressive and rapidly fatal course. In this form, the cardiac, skeletal, and respiratory muscles are involved. Respiratory and cardiac failure are the usual proximate causes of death. The adult form is a slowly progressive disease in which the heart is not affected. Patients with adult-onset GSDII typically present with proximal muscle weakness between the second and sixth decades of life. Similar to the infantile form, patients with the adult form ultimately succumb to respiratory failure. The juvenile (intermediate) form includes infants and children older than 6 months who present with weakness but generally have no cardiac disease, and the clinical features overlap those of the other forms. In general, the older the age of onset, the less the likelihood of cardiac involvement.

Pathophysiology

Acid alpha-glucosidase is a lysosomal hydrolase that is required for the degradation of a small percentage (1-3%) of cellular glycogen. Because the main pathway for glycogen degradation is not deficient in GSDII disease, energy production is not impaired, and hypoglycemia does not occur. However, the deficiency of this enzymatic activity results in the accumulation of structurally normal glycogen in lysosomes and cytoplasm in affected individuals. Excessive glycogen storage within lysosomes may interrupt normal functioning of other organelles and leads to cellular injury. In turn, this leads to enlargement and dysfunction of the entire organ involved (eg, cardiomyopathy).

In the infantile form, clinically significant storage occurs in the heart, resulting in progressive cardiomegaly with left ventricular (LV) thickening that eventually leads to outflow tract obstruction. Storage in skeletal muscle leads to hypotonia and weakness. The respiratory muscles are also affected, resulting in hypoventilation and progressive respiratory compromise. CNS involvement primarily is limited to the anterior horn cells of the spinal cord and brain stem nuclei, although intellectual performance remains normal. Although skeletal and respiratory involvement is frequently present in the juvenile form, cardiac involvement varies. Cardiac involvement is not observed in the adult form.

Frequency

United States

Frequency is estimated at 1 case per 40,000 population for all 3 variants of GSDII. This calculation is from estimated gene frequencies in healthy individuals from various ethnic groups. The highest frequency has been observed in the African American population, in which the frequency of the infantile onset type may be as high as 1 per 14,000.

International

The frequency in Taiwan and southern China is estimated at 1 case per 50,000 individuals. The frequency in the Dutch population is estimated at 1 case per 40,000 individuals (1:138,000 for the infantile category).¹ In this affected population, 63% carry at least one of the 3 common mutations.

Mortality/Morbidity

• The infantile form is usually fatal during the first year of life. As the weakness progresses, patients develop feeding difficulties and respiratory insufficiency. Enlargement of the LV leads to outflow tract obstruction and ventricular failure. Death results from cardiopulmonary failure.
• The juvenile (intermediate) form progresses more slowly and is uniformly fatal. Patients generally do not survive beyond the second or third decade of life. All patients have involvement of respiratory muscles, and most die of respiratory failure. Several patients are reported to have died due to a basilar artery aneurysm.² All were found to have abnormal storage within the lysosomes of arterial smooth muscle fibers. Age of onset does not predict age of death.
• Patients with the adult form may survive for decades following diagnosis. Muscle weakness may interfere with normal daily activities, and respiratory insufficiency is often associated with sleep apnea. Death usually results from respiratory failure.

Race

• Common mutations associated with the infantile-onset form have been found in the Taiwanese, Dutch and African-American populations. A common mutation associated with the adult onset form has been found in Caucasians.

Sex

• This is an autosomal recessive disease; therefore, it equally affects males and females.

Age

• As noted above, age of onset usually distinguishes the 3 types. Age of onset in the juvenile form may overlap both the adult and infantile forms.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Infantile form
• • These patients typically present with weakness and hypotonia in the first 6 months of life, which may manifest as respiratory and feeding difficulties.
  • Early cardiac failure due to LV enlargement and outflow obstruction may lead to respiratory and feeding difficulties as well.
  • In 1 infant described, the presenting sign was Wolff-Parkinson-White syndrome.³
  • The birth and family history usually are noncontributory, although some families may be consanguineous. Rare familial cases are reported.
• Juvenile form
• • These children present with delayed motor milestones, weakness, and hypotonia.
  • Their intelligence is normal.
• Adult form
• • These patients present with symptoms related to proximal muscle weakness, such as difficulty climbing stairs.
  • Respiratory symptoms present in approximately one third of adult-onset cases.
  • Symptoms may include exercise intolerance, orthopnea, somnolence, and headache at night or upon waking.

Physical

• Infantile form
• • Readily observed evidence of storage (eg, macroglossia, hepatomegaly, normal or increased muscle bulk)
  • Involvement of respiratory muscles manifest as respiratory distress (eg, tachypnea)
  • Cardiomegaly or cardiomyopathy leading to murmur and signs of cardiac failure
  • Profound diffuse hypotonia
• Juvenile form
• • Respiratory distress
  • Hypotonia (typically more proximal than distal)
  • Macroglossia and hepatomegaly (typically absent)
  • No associated cardiomegaly or cardiomyopathy
• Adult form
• • Proximal muscle weakness
  • Decreased bulk of involved muscles
  • Diminished deep tendon reflexes

Causes

Glycogen-storage disease type II (GSDII) is an autosomal recessive disease caused by the inheritance of 2 defective copies of the gene that encodes acid alpha-glucosidase (GAA), which has been localized to band 17q23. Carriers (ie, individuals with one normal copy and one defective copy of the gene) have no clinical manifestations. Several types of deleterious mutations are identified, including missense, nonsense, deletion, and splice site mutations. These mutations can result in the following:

• No detectable messenger RNA (mRNA) and complete absence of enzymatic protein
• A normal amount of enzyme with reduced activity (eg, reduced affinity for glycogen)
• A reduced amount of enzyme with normal activity
• No detectable enzyme activity in infantile form; varying amounts of residual enzyme activity in juvenile and adult forms

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Organic acidurias
Mitochondrial disorders

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Serum creatine kinase (CK)
• • General reflection of muscle disease
  • Greatest elevation among infants with glycogen-storage disease type II (GSDII)
  • Up to 10 times normal level
• Serum aspartate aminotransferase
• • Highest among infants with GSDII
  • Reflects liver involvement
• Enzyme activity
• • Definitive diagnosis requires the measurement of acid alpha-glucosidase activity in cultured skin fibroblasts or peripheral blood lymphocytes. Testing in lymphocytes usually requires 10 mL of whole blood in heparinized tubes, from which a white cell pellet is generated. This may not be practical in an infant. A mixed leukocyte analysis may lead to errors because granulocytes also contain a renal isomer of acid maltase, which is active in an acidic pH.
  • Reliable diagnosis can be made from a dried blood spot, such as collected for state newborn screening tests.
  • A muscle biopsy can help establish a diagnosis, but it is unnecessarily invasive.
  • Clinical analysis of GAA is available. However, the assay may fail to reveal both mutations in an affected individual. Therefore, DNA testing cannot be used in place of enzyme assay to establish the diagnosis. DNA analysis can be helpful in the identification of carriers in a family with an affected individual.

Imaging Studies

• Echocardiography establishes the degree of cardiac involvement and may also allow one to distinguish between the infantile and juvenile forms of GSDII. It may show overall enlargement of the heart, isolated LV thickening, biventricular thickening, or outflow obstruction in advanced disease.

Other Tests

• ECG
• • This test also establishes the presence and degree of cardiac involvement.
  • The characteristic finding is shortening of the PR interval.
  • Enlargement of the QRS complex also may occur.
• Electromyography
• • The electromyography (EMG) of all patients reveals a myopathic pattern.
  • Many patients exhibit pseudomyotonic discharges (ie, myotonic discharges in the absence of clinical myotonia), fibrillation potentials, and positive waves due to the anterior horn cell involvement.

Procedures

• Skin biopsy findings reveal acid alpha-glucosidase activity in cultured fibroblasts.

Histologic Findings

Light microscopy reveals large glycogen-containing vacuoles in nearly all muscle fibers. These vacuoles can be further characterized histochemically as secondary lysosomes. In general, type I and type II muscle fibers are equally affected. Electron microscopy is used to classify subtypes of the vacuoles in which glycogen accumulates. Histopathological examination of muscle is not necessary to establish diagnosis.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Enzyme replacement therapy is now available.
• Symptomatic treatment of cardiac and respiratory failure is available but does not significantly alter the clinical course.
• Anecdotal evidence suggests that a high-protein diet can provide temporary improvement; however, such a diet does not alter the disease course.
• Preclinical investigation of gene therapy is ongoing.
• The use of pharmacological chaperones (oral therapy) is currently under investigation.

Consultations

• A clinical geneticist is advised to counsel families regarding risk to future pregnancies.
• Because all patients require an EMG, consult with a neurologist.
• A pediatric cardiologist can provide assessment of all infants, children, and adolescents suspected of having glycogen-storage disease type II (GSDII) disease. Experienced interpretation of echocardiography findings is necessary.

Diet

• As noted above, alterations in diet do not provide lasting improvement. Weakness can contribute to feeding difficulty in all patients. Infants ultimately may require tube feeding to provide adequate caloric intake; however, nutritional support does not change the disease course, and some families may choose not to pursue tube feeding when facing such a fatal illness.

Activity

• Weakness may interfere with the normal daily activities of adult patients. Physical and occupational therapy may prove beneficial.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug Category: Enzyme replacement

Recombinant human enzyme alpha-glucosidase has recently been designated an orphan drug.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Counsel the parents regarding the 25% recurrence risk for each subsequent pregnancy, and provide options for prenatal diagnosis. Chorionic villus sampling and amniocentesis both can be used to determine enzyme activity in a fetus. Prenatal diagnoses as early as 10 weeks' gestation are reported. Emphasize the genetic basis to family members, and encourage communication within the family in order to identify additional carriers.

Complications

• The major complication among infant patients is aspiration pneumonia.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to counsel parents in regard to the 25% recurrence risk with each subsequent pregnancy

Special Concerns

• Successful pregnancy in a woman with the adult form of glycogen-storage disease type II (GSDII) has been reported.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Ausems MG, Verbiest J, Hermans MP, et al. Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. Eur J Hum Genet. Sep 1999;7(6):713-6. [Medline].
2. Miyamoto Y, Etoh Y, Joh R, et al. Adult-onset acid maltase deficiency in siblings. Acta Pathol Jpn. Nov 1985;35(6):1533-42. [Medline].
3. Bulkley BH, Hutchins GM. Pompe's disease presenting as hypertrophic myocardiopathy with Wolff-Parkinson-White syndrome. Am Heart J. Aug 1978;96(2):246-52. [Medline].
4. Ausems MG, Lochman P, van Diggelen OP, et al. A diagnostic protocol for adult-onset glycogen storage disease type II. Neurology. Mar 10 1999;52(4):851-3. [Medline].
5. Clinical Trials. A Study to Evaluate the Effects of Pharmacological Chaperones in Cells From Patients With Pompe Disease. clinicaltrials.gov. Available at http://clinicaltrials.gov/ct/show/NCT00515398?order=2. Accessed 2007.
6. Engel AG, Gomez MR, Seybold ME, Lambert EH. The spectrum and diagnosis of acid maltase deficiency. Neurology. Jan 1973;23(1):95-106. [Medline].
7. Engel AG, Hirschhorn R. Acid maltase deficiency. In: Engel AG, Franzine-Armstrong C, eds. Myology: Basic and Clinical. New York, NY: McGraw-Hill; 1996:1533-53.
8. Hirschhorn R. Glycogen storage disease type II: acid alpha-glucosidase (acid maltase) deficiency. In: Scriver CR, Beaudet AL, Sly W, Valle E, eds. The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw-Hill; 1995:2443-64.
9. Hirschhorn R, Reuser AJJ. Glycogen storage disease type II: acid alpha-glucosidase (acid maltase) deficiency. In: Scriver CR, Beaudet AL,et, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. 2001;3389-3420.
10. Isaacs H, Savage N, Badenhorst M, Whistler T. Acid maltase deficiency: a case study and review of the pathophysiological changes and proposed therapeutic measures. J Neurol Neurosurg Psychiatry. Sep 1986;49(9):1011-8. [Medline].
11. Umapathysivam K, Hopwood JJ, Meikle PJ. Determination of acid alpha-glucosidase activity in blood spots as a diagnostic test for Pompe disease. Clin Chem. Aug 2001;47(8):1378-83. [Medline].

Article Last Updated: Dec 12, 2007