Glycogen Storage Disease, Type II (Pompe Disease)

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.

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

The following list contains a quick reference for 8 of the GSD types: 0 - Glycogen synthase deficiency Ia - Glucose-6-phosphatase deficiency (von Gierke disease) II - Acid maltase deficiency (Pompe disease) III - Debranching enzyme deficiency (Forbes-Cori disease) IV - Transglucosidase deficiency (Andersen disease, amylopectinosis) V - Myophosphorylase deficiency (McArdle disease) VI - Phosphorylase deficiency (Hers disease) VII - Phosphofructokinase deficiency (Tarui disease) 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 specific treatment or cure exists, although diet 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.

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. In 1999, Bijvoet, Van Hirtum, and Vermey reported glycogen accumulation in murine blood vessel smooth muscle and in the respiratory, urogenital, and gastrointestinal tracts. [2] 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.[3] 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.[4] 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.

Glycogen storage disease type II

GSD type II, also known as acid maltase deficiency or Pompe disease, is a prototypic lysosomal disease. Its clinical presentation clearly differs from other forms of GSD. Deficiency of a lysosomal enzyme, alpha-1,4-glucosidase, causes GSD type II. Pompe initially described the disease in 1932. An essential pathologic finding is the accumulation of normally structured glycogen in most tissues. Three forms of the disease exist: infantile, juvenile, and adult. In the classic infantile form, the main clinical signs are cardiomyopathy and muscular hypotonia. In the juvenile and adult forms, the involvement of skeletal muscles dominates the clinical presentation. The images below illustrate histologic findings of GSD type II.

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).

Glycogen Storage Disease, Type II (Pompe Disease) Clinical Presentation

History
In the infantile form, the caregiver may report feeding difficulties and difficulty breathing. [5] 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 Several findings are characteristic, although many findings are not specific for this condition. Cardiomegaly is less likely in other diseases and helps confirm diagnosis. Hypotonia is generalized and affects bulbar musculature. Muscle atrophy is absent. Congestive heart failure or cardiomegaly is an important finding and suggests the diagnosis. This may be accompanied by a systolic murmur. Macroglossia may be present. Hepatomegaly may be present. Reflexes may be depressed or absent because of glycogen accumulation in spinal motor neurons. Alertness may be impaired. Diagnosis may be difficult because of calf hypertrophy, a rare finding that is characteristic of Duchenne muscular dystrophy. Adult form Findings may be less likely to suggest this diagnosis. Particular muscle groups may be affected, such as the upper arms and pectoral muscles. Asymmetry of affected muscle groups may be present. Limb-girdle weakness is a prominent finding. Respiratory muscle involvement is a hallmark of Pompe disease.

Glycogen Storage Disease, Type II (Pompe Disease) Workup

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 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. 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 510 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. Electromyelography In 1998, Aminoff reported electromyelographic findings suggestive of a myopathy, although abnormal spontaneous activity may be present.[6] 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. 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 acidSchiff stain is positive for inclusions.

Glycogen Storage Disease, Type II (Pompe Disease) Treatment & Management

Medical Care
In general, no specific treatment exists for GSDs. 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. In 2000, Zingone and colleagues demonstrated the abolition of the murine clinical manifestations of Von Gierke disease with a recombinant adenoviral vector.[7]These findings suggest that corrective gene therapy for GSDs may be possible in humans. An encouraging study in 1999 by Bijvoet, Van Hirtum, and Kroos provides evidence of successful enzyme replacement for the mouse model of Pompe disease, which may lead to therapies for other enzyme deficiencies.[8] For the infantile form, a recombinant enzyme replacement was approved by the FDA. A high-protein diet may be beneficial in the noninfantile form. Respiratory toilet is important in noninfantile cases.

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. A genetic counselor can determine risk to future offspring. 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.

Glycogen Storage Disease, Type II (Pompe Disease) Medication

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

Enzyme, Replacement Therapy

Class Summary
Recombinant human enzyme alpha-glucosidase has been designated an orphan drug for use in Pompe disease.[9] 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.[10] 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 creatine 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.

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Alglucosidase alfa (Lumizyme, Myozyme)

Recombinant human enzyme alpha-glucosidase (rhGAA) indicated as an orphan drug for treatment of Pompe disease (GAA deficiency). Replaces rhGAA, which is deficient or lacking in persons with Pompe disease. Alpha-glucosidase is essential for normal muscle development and function. Binds to mannose-6-phosphate receptors and then is 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. Myozyme indicated for Pompe disease. Improves ventilator-free survival in patients with infantileonset Pompe disease as compared to an untreated historical control. Lumizyme indicated for patients 8 y and older with late (noninfantile) onset Pompe disease) who do not have evidence of cardiac hypertrophy.

Glycogen Storage Disease, Type II (Pompe Disease) Follow-up

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.[11]

Complications
In the infantile form, cardiomegaly and congestive heart failure lead to death. In the infantile form of glycogen storage disease (GSD), cardiomegaly andcongestive 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. [12] 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.