eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Glycogen-Storage Disease Type II

Jennifer Ibrahim, MD, Chief, Genetics Division, St Joseph's Children's Hospital
Margaret M McGovern, MD, PhD, Professor and Chair of Pediatrics, Stony Brook University, New York

Updated: Oct 7, 2009

Introduction

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 glycogen-storage disease type II 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.

Glycogen storage disease type II. Photomicrograph of the liver. Note the intensively stained vacuoles in the hepatocytes (periodic acid-Schiff, original magnification X 27).

Glycogen storage disease type II. Photomicrograph of the liver. Note the regular reticular net and hepatocytes vacuolization (Gordon-Sweet stain, original magnification X 25).

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 glycogen-storage disease type II 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 is primarily 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 glycogen-storage disease type II. This calculation is from estimated gene frequencies in healthy individuals from various ethnic groups. The highest frequency has been observed in the black 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 black populations. A common mutation associated with the adult-onset form has been found in whites.

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

History

• Infantile form of glycogen-storage disease type II (GSDII)
  • 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 left ventricle (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 are usually 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 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
• The c.-32-13T → G mutation is the most common among adults with this disorder.⁴ No individuals with this mutation have the classic infantile form, and cardiac involvement is rare among patients with this genotype.⁵

Differential Diagnoses

Cardiomyopathy, Hypertrophic
Endocardial Fibroelastosis
Limb-Girdle Muscular Dystrophy
Metabolic Myopathies

Other Problems to Be Considered

Organic acidurias
Mitochondrial disorders

Workup

Laboratory Studies

The following studies are indicated in glycogen-storage disease type II (GSDII)

• Serum creatine kinase (CK)
  • General reflection of muscle disease
  • Greatest elevation among infants with glycogen-storage disease type II
  • As much as 10 times normal level
• Serum aspartate aminotransferase
  • Highest among infants with glycogen-storage disease type II
  • 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. Pilot programs for newborn detection of Pompe disease are anticipated in the near future.
  • A muscle biopsy can help establish a diagnosis but 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 glycogen-storage disease type II. It may show overall enlargement of the heart, isolated left ventricle (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

Medical Care

• Enzyme replacement therapy (ERT) has been available since 2006.^6,7 A 3-year follow-up revealed significant reductions in the risk of death and invasive ventilation among treated patients.⁸ Approximately half of patients on ERT develop infusion-associated reactions. However, these are readily managed with premedication using various combinations of antipyretic, anti-inflammatory, and antihistamine medications.
• 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

Enzyme replacement

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

Alglucosidase alfa (Myozyme)

Recombinant human enzyme alpha-glucosidase (rhGAA) is indicated as an orphan drug for treatment of Pompe disease. Replaces rhGAA, which is deficient or lacking in persons with GSDII. Alpha-glucosidase is essential for normal muscle development and function. Binds to mannose-6-phosphate receptors and is then transported into lysosomes; undergoes proteolytic cleavage that results in increased enzymatic activity and ability to cleave glycogen. Improves infant survival without requiring invasive ventilatory support compared with historical controls without treatment.

Dosing

Adult

Data limited; administer as in pediatrics

Pediatric

20 mg/kg IV q2wk; initial infusion rate not to exceed 1 mg/kg/h; may increase infusion rate by 2 mg/kg/h q30min to a maximum of 7 mg/kg/h if tolerated

Interactions

None reported

Contraindications

None known

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Serious adverse effects reported include heart and lung failure; infusion-related reactions are common (51%) and include life-threatening anaphylaxis, shock, or respiratory or cardiac events (eg, bronchospasm, dyspnea, arrhythmias, hypotension, hypertension); medical support measures must be readily available; discontinue or temporarily stop infusion if reaction occurs; common adverse effects include pneumonia, respiratory failure and distress, infection, and fever

Follow-up

Further Outpatient Care

• Counsel the parents of children with glycogen-storage disease type II (GSDII) regarding the 25% recurrence risk for each subsequent pregnancy, and provide options for prenatal diagnosis.⁹
• 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

Medicolegal Pitfalls

• Failure to counsel parents of children with glycogen-storage disease type II (GSDII) 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.

Multimedia

Media file 1: Glycogen storage disease type II. Photomicrograph of the liver. Note the intensively stained vacuoles in the hepatocytes (periodic acid-Schiff, original magnification X 27).

Media file 2: Glycogen storage disease type II. Photomicrograph of the liver. Note the regular reticular net and hepatocytes vacuolization (Gordon-Sweet stain, original magnification X 25).

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. Kroos MA, Pomponio RJ, Hagemans ML, et al. Broad spectrum of Pompe disease in patients with the same c.-32-13T->G haplotype. Neurology. Jan 9 2007;68(2):110-5. [Medline].

5. van der Beek NA, Soliman OI, van Capelle CI, Geleijnse ML, Vletter WB, Kroos MA, et al. Cardiac evaluation in children and adults with Pompe disease sharing the common c.-32-13T>G genotype rarely reveals abnormalities. J Neurol Sci. Dec 15 2008;275(1-2):46-50. [Medline].

6. Kishnani PS, Corzo D, Leslie ND, et al. Early treatment with alglucosidase alpha prolongs long-term survival of infants with Pompe disease. Pediatr Res. Sep 2009;66(3):329-35. [Medline].

7. Nicolino M, Byrne B, Wraith JE, et al. Clinical outcomes after long-term treatment with alglucosidase alfa in infants and children with advanced Pompe disease. Genet Med. Mar 2009;11(3):210-9. [Medline].

8. Merk T, Wibmer T, Schumann C, Krüger S. Glycogen storage disease type II (Pompe disease)--influence of enzyme replacement therapy in adults. Eur J Neurol. Feb 2009;16(2):274-7. [Medline].

9. [Guideline] Cunniff C. Prenatal screening and diagnosis for pediatricians. Pediatrics. Sep 2004;114(3):889-94. [Medline].

10. 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].

11. 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.

12. Engel AG, Gomez MR, Seybold ME, Lambert EH. The spectrum and diagnosis of acid maltase deficiency. Neurology. Jan 1973;23(1):95-106. [Medline].

13. 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.

14. 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.

15. 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.

16. 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].

17. 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].

18. Van der Beek NA, Hagemans ML, Reuser AJ, Hop WC, Van der Ploeg AT, Van Doorn PA, et al. Rate of disease progression during long-term follow-up of patients with late-onset Pompe disease. Neuromuscul Disord. Feb 2009;19(2):113-7. [Medline].

Keywords

GSDII, Pompe disease, Pompe's disease, acid maltase deficiency, AMD, alpha-1, 4 glucosidase deficiency, glucosidase acid alpha deficiency, GAA deficiency, cardiac form of generalized glycogenosis, glycogen-storage disease type II, type 2 glycogenosis, idiopathic hypertrophic cardiomyopathy, hypoglycemia, cardiomegaly, basilar artery aneurysm, sleep apnea, hypotonia, Wolff-Parkinson-White syndrome, macroglossia, hepatomegaly, enlargement of the heart, isolated left ventricle thickening, biventricular thickening, outflow obstruction, treatment, diagnosis

Contributor Information and Disclosures

Author

Jennifer Ibrahim, MD, Chief, Genetics Division, St Joseph's Children's Hospital
Jennifer Ibrahim, MD is a member of the following medical societies: American Society of Human Genetics
Disclosure: Nothing to disclose.

Coauthor(s)

Margaret M McGovern, MD, PhD, Professor and Chair of Pediatrics, Stony Brook University, New York
Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics and American Society of Human Genetics
Disclosure: Genzyme Grant/research funds PI

Medical Editor

Edward Kaye, MD, Vice President of Clinical Research, Genzyme Corporation
Edward Kaye, MD is a member of the following medical societies: American Academy of Neurology, American Society of Gene Therapy, American Society of Human Genetics, Child Neurology Society, and Society for Inherited Metabolic Disorders
Disclosure: Genzyme Corporation Salary Management position

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Hagop Youssoufian, MD, MSc, Vice President of Clinical Research, ImClone Systems Incorporated
Hagop Youssoufian, MD, MSc is a member of the following medical societies: American Society for Clinical Investigation, American Society of Clinical Oncology, American Society of Hematology, and American Society of Human Genetics
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)