Glycogen storage disease type 2

Other Names: Pompe disease; Acid maltase deficiency disease; Aglucosidase alfa; Alpha-1,4-glucosidase deficiency; Cardiomegalia glycogenica diffusa; Deficiency of alpha-glucosidase; GSD II; Deficiency of lysosomal alpha-glucosidase

Glycogen storage disease type 2, also known as Pompe disease or acid maltase deficiency disease, is an inherited metabolic disorder.

Classification

While glycogen storage disease type 2 is a single disease, it may be classified in 2 forms according to the rates of disease progression, its severity and the age at which symptoms start. The classic infantile-onset starts before 12 month of age and involves the heart muscle (myocardiopathy). The later-onset form may start before 12 months of age (non-classic infantile-onset), or after 12 months of age, but does not affect the heart.

Muscle weakness is a main symptom in all forms. The infantile-onset is the most severe form and, if untreated, it may lead to death from heart failure in the first year of life. The late-onset form is usually milder, but if untreated may lead to severe breathing problems.

Cause

Mutations in the GAA gene cause glycogen storage disease type 2. The GAA gene provides instructions for producing an enzyme called acid alpha-glucosidase (commonly called acid maltase). This enzyme is active in lysosomes, which are structures that serve as the cell's recycling center. The enzyme normally breaks down glycogen into a simpler sugar called glucose, which is the main energy source for most cells. Mutations in the GAA gene prevent acid alpha-glucosidase from breaking down glycogen, allowing it to build up in the body's cells. Over time, this buildup damages cells throughout the body, particularly muscle cells.

Inheritance

Autosomal recessive inheritance, a 25% chance

Glycogen storage disease type 2 is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Symptoms

The classic infantile form of glycogen storage disease type 2 is characterized by severe muscle weakness (myopathy) and abnormally diminished muscle tone (hypotonia) without muscle wasting, and usually manifests within the first few months of life. Additional abnormalities may include enlargement of the heart (cardiomegaly), the liver (hepatomegaly), and/or the tongue (macroglossia).

The non-classic infantile form of glycogen storage disease type 2 usually presents within the first year of life. Initial symptoms may include delayed motor skills (crawling, sitting) and myopathy. Cardiomegaly may be present, but unlike the classic infantile form, cardiac failure does not typically occur. Muscle weakness may lead to serious, life-compromising breathing problems by early childhood. In the late onset form of glycogen storage disease type 2, symptoms may not be evident until childhood, adolescence, or adulthood. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abdominal wall muscle weakness
• Cardiomegaly(Enlarged heart)
• Cognitive impairment(Abnormality of cognition)
• Dysphagia(Poor swallowing)
• Dysphasia
• EEG abnormality
• Elevated serum creatine kinase(Elevated blood creatine phosphokinase)
• EMG abnormality
• Emphysema
• Gait disturbance(Abnormal gait)
• Generalized muscle weakness
• Hypertrophic cardiomyopathy(Enlarged and thickened heart muscle)
• Seizure
• Type II diabetes mellitus(Noninsulin-dependent diabetes)

30%-79% of people have these symptoms

• Arrhythmia(Abnormal heart rate)
• Atrioventricular block(Interruption of electrical communication between upper and lower chambers of heart)
• Dyspnea(Trouble breathing)
• Muscular hypotonia(Low or weak muscle tone)
• Respiratory insufficiency due to muscle weakness(Decreased lung function due to weak breathing muscles)

5%-29% of people have these symptoms

• Hepatomegaly(Enlarged liver)
• Macroglossia(Abnormally large tongue)
• Myopathy(Muscle tissue disease)
• Recurrent respiratory infections(Frequent respiratory infections)

Diagnosis

The usual initial investigations include chest X ray, electrocardiogram and echocardiography. Typical findings are those of an enlarged heart with non specific conduction defects. Biochemical investigations include serum creatine kinase (typically increased 10 fold) with lesser elevations of the serum aldolase, aspartate transaminase, alanine transaminase and lactic dehydrogenase. Diagnosis is made by estimating the acid alpha glucosidase activity in either skin biopsy (fibroblasts), muscle biopsy (muscle cells) or in white blood cells. The choice of sample depends on the facilities available at the diagnostic laboratory. Electromyography may be used initially to distinguish Pompe from other causes of limb weakness. The findings on biochemical tests are similar to those of the infantile form, with the caveat that the creatinine kinase may be normal in some cases. The diagnosis is by estimation of the enzyme activity in a suitable sample.

Treatment

Individuals with glycogen storage disease type 2 are best treated by a team of specialists (such as cardiologist, neurologist, and respiratory therapist) knowledgeable about the disease, who can offer supportive and symptomatic care. The discovery of the GAA gene has led to rapid progress in understanding the biological mechanisms and properties of the GAA enzyme. As a result, an enzyme replacement therapy has been developed that has shown, in clinical trials with infantile-onset patients, to decrease heart size, maintain normal heart function, improve muscle function, tone, and strength, and reduce glycogen accumulation.

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition. A drug called alglucosidase alfa (Myozyme©) has received FDA approval for the treatment of glycogen storage disease type 2. Myozyme is a form of GAA—the enzyme that is absent or reduced in this condition.

• Recombinant human acid alpha-glucosidase (Brand name: Myozyme®) Myozyme has been remarkably successful in reversing cardiac muscle damage and in improving life expectancy in those with the infantile form of the disease.
• Recombinant human acid alpha-glucosidase; alglucosidase alfa (Brand name: Lumizyme)Lumizyme for patients 8 years and older with late (non-infantile) onset Pompe disease (GAA deficiency) who do not have evidence of cardiac hypertrophy. The safety and efficacy of Lumizyme (alglucosidase alfa) have not been evaluated in controlled clinical trials in infantile-onset patients, or in late (non-infantile) onset patients less than 8 years of age.

Prognosis

The prognosis for individuals with Pompe disease varies according to the onset and severity of symptoms, along with lifestyle factors. Without treatment the infantile form (which can typically be predicted by mutation analysis) of the disease is particularly lethal - in these cases time to get on treatment is critical, with evidence that days (not weeks or months) matter.

Epidemiology

The disease affects approximately 1 in 13,000.