Type II Glycogen Storage Disease (Pompe Disease)

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 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]

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.

United States statistics

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 statistics

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.

Sex- and age-related demographics

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

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 the 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 classic infantile form manifests with hypotonia hours to weeks after birth, with typical presentation between 4 and 8 weeks.

In non-classic infantile-onset Pompe disease, a person has inherited GAA copies that produce very little or no working acid alpha-glucosidase. It usually is less severe compared with the classic infantile-onset Pompe disease. It typically appears within the first year of the child's life but later than the classic subtype, which manifests within the first few months.

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

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.[7, 8]  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.[9]

Morbidity/mortality

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.

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.

Complications

Without treatment, infants with Pompe disease can die usually owing to cardiorespiratory failure due to cardiomegaly or congestive cardiac failure within the first 2 years of life.

As Pompe disease is associated with progressive weakness of mainly the proximal muscles, and varying degrees of respiratory weakness due to dysfunction of the diaphragm and the intercostal muscles, affected individuals may become wheelchair dependent, and some may require support by mechanical ventilation.

The para-spinal muscles and neck are usually affected, which can cause scoliosis.

The following recommendations can be made to the patient to improve outcomes: 

• Contracture and deformity can be prevented with the use of gentle forces to counteract deforming forces. These include correction of positioning; daily stretching; provision of adequate support, especially sitting and supported standing as appropriate; and use of splinting. Orthotic intervention can help change the position and relieve pressure in those individuals who cannot do so independently. To guide successful prevention, careful consideration must be given to the number of hours per day that a muscle is in the shortened position. Surgery can be done when needed.
• Augmentative communication, including signing and the use of assistive technology, such as voice output systems, can be used to function. It allows for conservation of energy and can also compensate for weakness and reduced endurance.
• Advise patients to seek medical attention even for common symptoms such as fever and cough, as they can indicate a more serious underlying condition. Patients must also be advised to use over-the-counter medications carefully to treat upper respiratory tract symptoms, as they often contain sympathomimetic agents, which can be detrimental to the heart.
• Recommend to patients that they follow strict hygiene methods at all times.
• Encourage social interaction and encourage family education about the disease as well as methods to improve outcomes.

In the infantile classic subtype form, the caregiver may report feeding difficulties and difficulty breathing.[10] The child may also have an enlarged tongue and poor muscle tone.

In the infantile non-classic subtype form, delayed motor skills such as rolling over and sitting up may be reported.

In the adult form, the patient may report progressive limb-girdle weakness, with the pelvic muscle more affected than the scapulohumeral group.The patient may also report early tiredness and fatigue, along with sleep-disordered breathing.

1. Infantile onset - Classic subtype: This type presents within a few months after birth and is characterized by the following:

Neuromuscular manifestations

• Hypotonia since birth
• Hyporeflexia/areflexia 
• Muscle weakness
• Contractures and joint deformities, such as lordosis and scoliosis, can occur because of compensatory movement patterns due to extensive weakness and limited mobility

Respiratory system

• Respiratory muscle weakness can cause repeated episodes of pneumonia and upper respiratory tract infection
• Respiratory insufficiency leads to early morbidity and mortality

Cardiovascular system

• Hypertrophic cardiomyopathy
• Congestive heart failure
• Conduction disorders

Gastrointestinal and nutritional manifestations

• Macroglossia
• Difficulty in sucking due to facial hypotonia, oral motor weakness, and macroglossia; this can affect growth and weight gain
• Hepatomegaly
• Splenomegaly

2. Infantile onset - Non-classic subtype: This type usually presents within the first year of life and is less severe compared with the classic subtype; it is characterized by the following:

• Delayed motor skills, such as sitting up and rolling over
• Progressive muscle weakness
• Cardiomegaly - Less likely compared with the classic subtype
• Respiratory insufficiency

3. Adult onset: This type is characterized by the following:

    Musculoskeletal system

• Progressive limb-girdle weakness followed by diaphragm and accessory respiratory muscles
• Hyporeflexia
• Gait disturbances
• Myalgia and cramps
• Amyotrophy
• Fatigue and tiredness - Exercise intolerance

   Respiratory system

• ​Dsypnea on exertion
• Orthopnea
• Sleep-disordered breathing
• Sleep apnea
• Weak cough
• Frequent respiratory tract infections

   Additional features

• Dysphagia
• Difficulty in chewing
• Weight loss
• Subarachnoid hemorrhage - Especially in the basilar artery

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

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]

Unfortunately, no cure exists. However, Pompe disease has benefited from the introduction of enzyme replacement therapy (ERT), which, although expensive, is a major therapeutic advance. ERT benefits are attenuated by antibody formation, which has led to interest in combining ERT with immune modulation.

The US Food and Drug Administration (FDA) has approved several enzymes that provide an exogenous source of the lysosomal enzyme acid alpha-glucosidase (GGA), which is deficient in Pompe disease. Enzyme replacement available in the United States includes the following:

• Avalglucosidase alfa (Nexviazyme): Indicated for treatment of patients aged 1 year and older with late-onset Pompe disease.
• Alglucosidase alfa (Myozyme): Shown to improve ventilator-free survival in patients with infantile-onset Pompe disease compared with untreated historical controls. It has not been adequately studied for treatment of other forms of Pompe disease.  
• Alglucosidase alfa (Lumizyme): Indicated for infantile-onset Pompe disease and also for late (non-infantile) Pompe disease. 

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 non-infantile 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.[15] These findings suggest that corrective gene therapy for GSDs may be possible in humans.

Diet

A high-protein diet consisting of 20-25% protein 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.

Consultations

As Pompe disease is a multisystem disorder, a multidisciplinary approach is required. Team members should include specialists in the fields of neurology, pulmonology, general medicine (internal medicine, pediatrics, metabolism), cardiology, occupational therapists, and disease geneticists. A genetic counselor can determine risk to future offspring.[16]

Recent advances

AT-GAA (cipaglucosidase alfa and miglustat) is an investigative treatment for late-onset Pompe disease being developed by Amicus Therapeutics.

Amicus Therapeutics anticipates completing a rolling application by mid-year (2021) to seek approval of its investigational therapy AT-GAA for late-onset Pompe disease in the United States. The announcement follows a pre-filing meeting with the FDA. It was granted orphan drug status in 2017 by the FDA for late-onset Pompe disease.

AT-GAA is a two-component therapy comprising cipaglucosidase alfa, a laboratory-made version of GAA designed to enter cells more effectively, in combination with miglustat to stabilize the enzyme’s structure. Cipaglucosidase alfa is administered directly into the bloodstream, whereas miglustat is taken as oral capsules.

By providing GAA to cells, the therapy is expected to reduce glycogen accumulation, thereby preventing it from reaching toxic levels and damaging tissues. The therapy received the FDA’s breakthrough therapy designation for late-onset Pompe, which is intended to speed up its development and review.

Miglustat is sold under the brand name Zavesca as a treatment for Gaucher disease. Chaperones such as miglustat work by increasing the structural stability of proteins or enzymes, or by correcting protein misfolding.

As Pompe disease is genetically inherited in an autosomal recessive pattern, it cannot be prevented if disease-causing mutations have not been identified in family members. Genetic counselors can educate families about the disease's inheritance patterns and risks, as well as support them through testing and family-planning decisions. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are appropriate when the mutations have been already identified in the family. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy

Phupong and Shotelersuk describe prenatal electron microscopy of skin fibroblasts to exclude Pompe disease in the fetus.[17]

Some of the recommendations for monitoring are as follows[18] :

Cardiology recommendations 

• Obtain a chest radiograph at regular intervals

• Obtain an echocardiogram at regular intervals to evaluate the extent of cardiomyopathy

• Obtain a 24-hour ambulatory ECG at baseline and at regular intervals, as patients are at risk for life-threatening arrhythmias, including patients on enzyme replacement therapy

Pulmonary recommendations 

• Clinical assessment of respiratory status, both asleep and awake, should be performed at each medical visit

• Pulmonary function must be assessed annually or with changes in patients’ clinical condition

•  When clinically indicated, chest radiographs and polymnography must be obtained

• Maximizing clearance of airway secretions should routinely be performed

• Assessment of respiratory function during sleep needs to be made whenever the patient complains of daytime sleepiness or unexplained fatigue or has observed apneas during sleep, or when vital capacity falls below 40–50% predicted

• All pulmonary infections should be aggressively managed

Gastrointestinal recommendations

• Obtain videofluoroscopic swallowing assessment and evaluation for gastroesophageal reflux to guide management of feeding (oral/gavage feeding) as clinically indicated

• Provide oral stimulation and non-nutritive sucking for infants who are nonoral feeders

• Monitor growth parameters carefully

Musculoskeletal recommendations

• Screen for osteopenia/osteoporosis with dual-energy x-ray absorptiometry (DEXA) and follow up as needed

• Assess musculoskeletal impairments, functional deficits, levels of disability, and societal participation at regular intervals and as needed, including radiographs as needed for monitoring of scoliosis, hip stability, and long bone integrity

• Enhance muscle function by providing practice, movement, and gentle strengthening within limits of physiological stability by following guidelines for strengthening muscles from other progressive muscle disease

• Prevent and minimize contracture and deformity 

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

Class Summary

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

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.

Alglucosidase alfa (Lumizyme, Myozyme)

Myozyme has been shown to improve ventilator-free survival in patients with infantile-onset Pompe disease compared with untreated historical controls. It has not been adequately studied for treatment of other forms of Pompe disease. Lumizyme is indicated for infantile-onset Pompe disease and also for late (non-infantile) Pompe disease. 

Avalglucosidase alfa (Nexviazyme)

Indicated for treatment of patients aged 1 year and older with late-onset Pompe disease.