Glycogen Storage Disease Type II

Inborn error of metabolism that results from the deficiency of acid alpha-glucosidase, a lysosomal hydrolase. The three variants are infantile, juvenile, and adult onset. In the classic infantile form (Pompe disease), cardiomyopathy and muscular hypotonia are the cardinal features. In the juvenile and adult forms, involvement of skeletal muscles dominates the clinical presentation.

Acid Maltase Deficiency; Pompe Syndrome; Pompe Disease; Cardiomegalia Glycogenica Diffusa; Cardiac form of Generalized Glycogenosis; GAA Deficiency; Alpha-1, 4-Glucosidase Deficiency; Glycogenosis type II.

First described by the Dutch pathologist Joannes Cassianus Pompe (1901-1945) in 1932, when he reported a 7-month-old girl who died after developing idiopathic hypertrophic cardiomyopathy.

In the United States, the frequency is estimated at 1:40,000 live births for all three variants of GSD II. Internationally, the frequency in Taiwan and southern China is estimated at 1:50,000 individuals. In the Dutch population, the frequency is 1:40,000 (1:138,000 for the infantile category). In this population, 63% carry at least one of the three common mutations.

Autosomal recessive. The gene for the affected enzyme has been mapped to 17q25.2-q25.3.

Absent acid alpha-1,4-glucosidase (acid maltase), a lysosomal enzyme, in muscle and liver. The enzyme degrades alpha-1,4 and alpha-1,6 linkages in glycogen, maltose, and isomaltose. Deficiency of the enzyme results in accumulation of glycogen within lysosomes and in the cytoplasm, eventually leading to tissue destruction.

Neonates appear normal at birth but develop hypotonia and poor feeding within a few weeks. Specific enzyme assay in muscle cells, leukocytes, or amniocytes confirms the diagnosis. Creatine kinase elevation, muscle biopsy, demonstration of massive glycogen deposits in lymphocytes in peripheral blood, measurement of acid alpha-1,4-glucosidase activity in leukocytes.

There are three major forms of the disorder.

• Infantile Form: Infants may appear normal at birth but after a few weeks they begin to develop cardiomyopathy and generalized hypotonia and muscle weakness, which are the cardinal features of the disease. Biventricular hypertrophy and either congestive or obstructive cardiomyopathy result from the accumulation of glycogen, which leads to progressive cardiac failure. Poor swallowing reflexes and decreased muscle tone contribute to feeding difficulties and aspiration. An enlarged tongue (macroglossia) and diminished airway reflexes may cause upper airway obstruction. Characteristic facial appearance with open mouth and protruding tongue. The ECG classically shows signs of biventricular hypertrophy with a short PR interval. The chest radiograph confirms the presence of cardiomegaly and may show evidence of atelectasis and aspiration. The liver is not affected, although it may be enlarged as a result of cardiac failure. Normal mental development. Normal blood glucose concentration. No effective treatment. Death usually results from respiratory failure, which is often complicated by aspiration pneumonia and/or congestive cardiac failure. The disease is rapidly progressive, and few children survive beyond the age of 1 year. Death usually results from respiratory failure and/or end-stage cardiomyopathy. Two different recombinant human α-glucosidase enzymes are now available, which showed an improved outcome for the infantile form of GSD II.
• Juvenile Form: These infants and children (onset after 6 months of age) present with delayed motor milestones, weakness, and hypotonia, but no cardiac involvement. Intelligence is normal. Other features include respiratory distress, hypotonia, macroglossia, and hepatomegaly (typically present), but no cardiomegaly or cardiomyopathy.
• Adult-Onset Form: Slowly progressive disease in which the heart is not affected. Usually the presentation is by complaints related to proximal muscle weakness, such as difficulty climbing stairs. Respiratory problems are significant in 33% of cases. Other features include exercise intolerance, orthopnea, somnolence, nighttime headache, and diminished deep tendon reflexes.

Ensure baseline ECG to establish rhythm and evidence of biventricular hypertrophy. Evaluate cardiac function; echocardiography to assess ventricular function, degree of myocardial hypertrophy and whether any cardiomyopathy is congestive or obstructive. Perform chest radiography and evaluate respiratory function. Blood examination: sodium, potassium, and creatine kinase levels, and arterial blood gas analysis. Full assessment of airway. Macroglossia may be present. Treat intercurrent respiratory infections.

Indications for surgery should be reviewed. Cardiac arrest during induction of anesthesia with halothane, but also with sevoflurane/propofol, has been reported. Monitoring and intravenous access should be established before induction of anesthesia. Direct measurement of arterial blood pressure may be useful. Hypotonic infants with macroglossia may require awake fiberoptic intubation. Maintenance of airway patency may be difficult because of macroglossia. Anesthetic agents should be selected to avoid myocardial depression; high concentrations of inhaled agents should be avoided. Muscle relaxants may not be required in hypotonic infants and may complicate postoperative recovery. Postoperative mechanical ventilation may be necessary, and weaning may be difficult with profound muscle weakness and cardiopulmonary insufficiency. Pulmonary aspiration may increase oxygen requirements. Intermittent positive pressure ventilation is mandatory in the presence of severe hypotonia. With congestive cardiomyopathy, care should be taken to maintain adequate filling pressures, increase myocardial contractility, and reduce afterload. Obstructive cardiomyopathy requires maintenance of appropriate (high normal) cardiac filling pressures and avoidance of inotropes, chronotropes, and peripheral vasodilatation which may worsen obstruction. Invasive monitoring is indicated. Watch for signs of myocardial ischemia. Spinal and epidural anesthesia may be contraindicated.

Extreme caution with myocardial depressant drugs. Conversely, myocardial hypertrophy may relatively contraindicate drugs with positive inotropic actions, such as ketamine. If muscle relaxants are required, rocuronium or cis-atracurium are the agents of choice. Select agents that allow rapid recovery postoperatively. Myocardial depressant drugs, such as barbiturates, propofol, halothane, enflurane, and nitrous oxide, should be used with extreme care. Ketamine is contraindicated in obstructive cardiomyopathy because of its inotropic and chronotropic effects, but has been successfully used in congestive (non-obstructive) cardiomyopathy. Its effect of increasing secretions may also be undesirable. Nondepolarizing muscle relaxants should be used with extreme care and only once the airway has been secured. Suxamethonium is contraindicated because of risk of hyperkalemia and rhabdomyolysis. Opioids should be used with caution because of their effects on respiratory function.

Other glycogen storage diseases.