Type II Glycogen Storage Disease (Pompe Disease)

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Practice Essentials

Pompe disease is an inherited enzyme defect that usually manifests in childhood. The enzymes affected normally catalyze reactions that ultimately convert glycogen compounds to monosaccharides, of which glucose is the predominant component. This results in glycogen accumulation in tissues, especially muscles, and impairs their ability to function normally.

Signs and symptoms

Most patients experience muscle symptoms, such as weakness and cramps, although certain glycogen storage diseases manifest as specific syndromes, such as hypoglycemic seizures or cardiomegaly.

See Clinical Presentation for more detail.

Diagnosis

Diagnosis depends on muscle biopsy, electromyelography, the ischemic forearm test, creatine kinase levels, patient history, and physical examination findings. Biochemical assay for enzyme activity is the method of definitive diagnosis.[1]

See Workup for more detail.

Management

Unfortunately, no cure exists, although diet therapy and enzyme replacement therapy may be highly effective at reducing clinical manifestations. In some patients, liver transplantation may abolish biochemical abnormalities.

See Treatment and Medication for more detail.

Background

A glycogen storage disease (GSD) is the result of an enzyme defect. These enzymes normally catalyze reactions that ultimately convert glycogen compounds to monosaccharides, of which glucose is the predominant component. Enzyme deficiency results in glycogen accumulation in tissues. In many cases, the defect has systemic consequences; however, in some cases, the defect is limited to specific tissues. Most patients experience muscle symptoms, such as weakness and cramps, although certain GSDs manifest as specific syndromes, such as hypoglycemic seizures or cardiomegaly.

Although at least 14 unique GSDs are discussed in the literature, the 4 that cause clinically significant muscle weakness are Pompe disease (GSD type II, acid maltase deficiency), Cori disease (GSD type III, debranching enzyme deficiency), McArdle disease (GSD type V, myophosphorylase deficiency), and Tarui disease (GSD type VII, phosphofructokinase deficiency). One form, Von Gierke disease (GSD type Ia, glucose-6-phosphatase deficiency), causes clinically significant end-organ disease with significant morbidity. The remaining GSDs are not benign but are less clinically significant; therefore, the physician should consider the aforementioned GSDs when initially entertaining the diagnosis of a GSD. Interestingly, a GSD type 0 also exists and is due to defective glycogen synthase.

The chart below demonstrates where various forms of GSD affect the metabolic carbohydrate pathways.



View Image

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

The following list contains a quick reference for 8 of the GSD types:

These inherited enzyme defects usually manifest in childhood, although some, such as McArdle disease and Pompe disease, have separate adult-onset forms. In general, GSDs are inherited as autosomal recessive conditions. Several different mutations have been reported for each disorder.

Unfortunately, no cure exists, although diet therapy and enzyme replacement therapy may be highly effective at reducing clinical manifestations. In some patients, liver transplantation may abolish biochemical abnormalities. Active research continues.

Diagnosis depends on muscle biopsy, electromyelography, the ischemic forearm test, creatine kinase levels, patient history, and physical examination findings. Biochemical assay for enzyme activity is the method of definitive diagnosis.[1]

Acid maltase catalyzes the hydrogenation reaction of maltose to glucose. Acid maltase deficiency is a unique glycogenosis in that the glycogen accumulation is lysosomal rather than in the cytoplasm. It also has a unique clinical presentation depending on age at onset, ranging from fatal hypotonia and cardiomegaly in the neonate to muscular dystrophy in adults.

Pompe disease represents about 15% of all GSDs based on combined European and American data.[2]

Pathophysiology

With an enzyme defect, carbohydrate metabolic pathways are blocked, and excess glycogen accumulates in affected tissues. Each GSD represents a specific enzyme defect, and each enzyme is either in specific sites or is in most body tissues.

Acid maltase is a lysosomal enzyme that catalyzes the hydrogenation of branched glycogen compounds, notably maltose, to glucose. The conversion generally is a one-way reaction from glycogen to glucose-6-phosphate. When acid maltase is deficient, glycogen accumulates within tissues. Acid maltase is found in all tissues, including skeletal and cardiac muscle. Accumulation of glycogen in cardiac muscle leads to cardiac failure in the infantile form.[3]

In 1999, Bijvoet, Van Hirtum, and Vermey reported glycogen accumulation in murine blood vessel smooth muscle and in the respiratory, urogenital, and gastrointestinal tracts.[4] Glycogen accumulation is mostly within the lysosomes, although cytoplasmic accumulation may occur.

Infantile and adult forms are inherited as autosomal recessive conditions, traced to chromosome 17. Gort and colleagues have described nine novel mutations.[5]

Glycogen accumulation within the muscle, peripheral nerves, and the anterior horn cells results in significant weakness. In the infantile form, accumulation may also occur in the liver, which results in hepatomegaly and elevation of hepatic enzymes.

Epidemiology

Frequency

United States

In a 1998 report on a random selection of healthy individuals to determine carrier frequency in New York, Martiniuk and colleagues extrapolated data for African Americans, revealing a frequency of 1 in 14,000-40,000 individuals.[6]

International

Herling and colleagues studied the incidence and frequency of inherited metabolic conditions in British Columbia. GSDs are found in 2.3 children per 100,000 births per year. In southern China and Taiwan, infantile Pompe disease is the most common GSD with a frequency of 1 in 50,000 live births. Data from screening 3000 Dutch newborns with the previously described mutations revealed a calculated frequency of 1 in 40,000 for adult-onset disease.

Mortality/Morbidity

The infantile form usually is fatal, with most deaths occurring within 1 year of birth. Cardiomegaly with progressive obstruction to left ventricular outflow is a major cause of mortality. Weakness of ventilatory muscles increases risk of pneumonia. Later clinical onset usually corresponds with more benign symptoms and disease course. Newer research holds promise for gene therapy (see Prognosis below).

The adult form manifests with dystrophy and respiratory muscle weakness. Respiratory insufficiency is a significant morbidity.

Glycogen deposition within blood vessels may result in intracranial aneurysm. Significant morbidity or mortality depends on location and clinical nature.

Sex

Males and females are affected with equal frequency because of autosomal recessive inheritance.

Age

In general, GSDs manifest in childhood. Later onset correlates with a less severe form. Some authors make a distinction between infant and childhood disease, although most investigators recognize a disease continuum because of overlap of clinical manifestations.

Because both infantile and adult forms of Pompe disease occur, it should be considered if the onset is in infancy. The infantile form manifests with hypotonia hours to weeks after birth, with typical presentation between 4-8 weeks.

Between infancy and adulthood, a youth form may manifest. It is less severe in later presentations.

The adult form emerges as skeletal and respiratory muscle weakness in patients aged 20-40 years.

History

In the infantile form, the caregiver may report feeding difficulties and difficulty breathing.[7] The child may also have an enlarged tongue and poor muscle tone.

An intermediate form manifests with muscle weakness in childhood.

In the adult form, the patient may have limb-girdle weakness. An important feature of the adult form is the respiratory muscle weakness.

Physical

Infantile form

Adult form

Laboratory Studies

Obtain a creatine kinase in all cases of suspected GSD. Creatine kinase is elevated in Pompe disease.

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

Urine studies are indicated because myoglobinuria may occur in some GSDs.

Hepatic failure occurs in some GSDs. Liver function studies are indicated.

Biochemical assay is required for definitive diagnosis. Assay reveals deficient acid maltase in fibroblasts.

 

Imaging Studies

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

Consider echocardiography to assess heart size and amount of left ventricular hypertrophy.

Other Tests

Ischemic forearm test

Interpretation of ischemic forearm test results

Electromyelography

Electrocardiography: ECG demonstrates a pan-lead 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.

Procedures

Muscle biopsy assists with the evaluation of muscle weakness.

Histologic Findings

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.

Medical Care

Unfortunately, no cure exists. However, Pompe disease has recently benefited from the introduction of enzyme replacement therapy (ERT), which, although expensive, is a major therapeutic advance. ERT with alglucosidase alfa is approved in the United States for all age groups (eg, infantile [early onset] or late onset [juvenile/adult]) affected by Pompe disease.

ERT benefits are attenuated by antibody formation, which has led to interest in combining ERT with immune modulation.

The FDA has approved the lysosomal glycogen-specific enzyme alglucosidase alfa (Lumizyme) for the treatment of infantile-onset Pompe disease, including in patients younger than age 8. This approval eliminates previous restrictions on the drug’s use to late (non-infantile) onset Pompe disease in patients 8 years of age and older.[10]  Approval was based on new data demonstrating similarities between Lumizyme and Myozyme, which is already approved for use in younger patients, and on a study of 18 patients with infantile-onset Pompe disease that showed similar improvements in ventilator-free survival as patients treated with Myozyme. The new agent will carry a boxed warning on the risk for anaphylaxis, severe allergic reactions, immune-mediated reactions, and cardiorespiratory failure.[10]

In some cases, diet therapy is helpful. Meticulous adherence to a dietary regimen may reduce liver size, prevent hypoglycemia, allow for reduction in symptoms, and allow for growth and development. A high-protein diet may be beneficial in the noninfantile form.

Respiratory toilet is important in noninfantile cases.

In some patients, liver transplantation may abolish biochemical abnormalities.

In 2000, Zingone and colleagues demonstrated the abolition of the murine clinical manifestations of Von Gierke disease with a recombinant adenoviral vector.[11] These findings suggest that corrective gene therapy for GSDs may be possible in humans.

 

Content.

 

Consultations

Consult a tertiary care center with access to a neurologist specializing in muscle disorders. This is helpful for determining differential diagnosis and the risk for other family members.

Referral to a clinical geneticist is appropriate. A genetic counselor can determine risk to future offspring.[12]

Because of the supportive nature of care for infants with this disease, an expert in pediatric cardiology may be very beneficial.

Diet

A high-protein diet may provide increased muscle function in cases of weakness or exercise intolerance. In particular, a high-protein diet containing branched chain amino acids may slow or arrest disease progression.

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Alglucosidase alfa (Lumizyme, Myozyme)

Clinical Context:  Replaces rhGAA, which is deficient or lacking in persons with Pompe disease. Alpha-glucosidase is essential for normal muscle development and function. It binds to mannose-6-phosphate receptors and then is transported into lysosomes, then undergoes proteolytic cleavage that results in increased enzymatic activity and ability to cleave glycogen. Infant survival is improved without requiring invasive ventilatory support compared with historical controls without treatment.

Class Summary

Enzyme replacement therapy is approved in the United States and may ameliorate clinical symptoms. Enzyme replacement therapy may be used for all age groups (ie, infantile [early onset] or late onset [juvenile/adult]) affected by Pompe disease.

Strothotte et al assessed the effects of alglucosidase alfa replacement therapy on various stages of late-onset Pompe disease, using a series of tests on 44 patients with the condition.[13] Replacement therapy was administered for 1 year (20 mg/kg IV q2wk), with tests performed at baseline and then every 3 months. Results from the 6-minute walk and modified Gowers' maneuver tests changed significantly, as did creatinine kinase levels. Other test outcomes (eg, from serial arm function tests, timed 10 m walk tests, 4-stair climb tests) remained the same from baseline to endpoint. The patients experienced no serious adverse events. According to the authors, the data imply that the treatment of Pompe disease with alglucosidase alfa replacement can stabilize neuromuscular deficits and produce mild functional improvement in patients.

Further Inpatient Care

Patients may require support by mechanical ventilation.

Deterrence/Prevention

Phupong and Shotelersuk describe prenatal electron microscopy of skin fibroblasts to exclude Pompe disease in the fetus.[14]

Complications

In the infantile form, cardiomegaly and congestive heart failure lead to death.

In the infantile form of glycogen storage disease (GSD), cardiomegaly and congestive heart failure lead to death.

Prognosis

The adult form is not necessarily fatal, but complications such as aneurysmal rupture or respiratory failure may cause significant morbidity or mortality.

Although the infantile form typically is fatal, newer research offers promise.[15, 16] Sun and colleagues report treatment with a muscle-targeting adeno-associated virus vector in knockout mice resulted in persistent correction of muscle glycogen content. Mah and colleagues report sustained levels of correction of both skeletal and cardiac muscle glycogen with recombinant adeno-associated virus vectors in a mouse model.[17]

Author

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

Disclosure: Nothing to disclose.

Specialty Editors

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.

Kent Wehmeier, MD, Professor, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, St Louis University School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

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

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.

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

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