eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Glycogen-Storage Disease Type II (Pompe Disease)

Author: Jennifer Ibrahim, MD, Chief, Genetics Division, St Joseph's Children's Hospital
Coauthor(s): Margaret M McGovern, MD, PhD, Professor and Chair of Pediatrics, Stony Brook University, New York
Contributor Information and Disclosures

Updated: Oct 7, 2009

Introduction

Background

Glycogen-storage disease type II (GSDII), also referred to as Pompe disease, is an autosomal recessive disorder that results from the deficiency of acid alpha-glucosidase, a lysosomal hydrolase. Pompe first described the disease in 1932 when he was presented with a 7-month-old girl who died after developing idiopathic hypertrophic cardiomyopathy. Pompe observed the abnormal accumulation of glycogen in all tissues examined and described the cardinal pathologic features.

Three major forms of the disorder are recognized: infantile, juvenile, and adult-onset. The infantile form usually presents by age 6 months and is marked by a progressive and rapidly fatal course. In this form, the cardiac, skeletal, and respiratory muscles are involved. Respiratory and cardiac failure are the usual proximate causes of death. The adult form is a slowly progressive disease in which the heart is not affected. Patients with adult-onset glycogen-storage disease type II typically present with proximal muscle weakness between the second and sixth decades of life. Similar to the infantile form, patients with the adult form ultimately succumb to respiratory failure. The juvenile (intermediate) form includes infants and children older than 6 months who present with weakness but generally have no cardiac disease, and the clinical features overlap those of the other forms. In general, the older the age of onset, the less the likelihood of cardiac involvement.

Pathophysiology

Acid alpha-glucosidase is a lysosomal hydrolase that is required for the degradation of a small percentage (1-3%) of cellular glycogen. Because the main pathway for glycogen degradation is not deficient in glycogen-storage disease type II disease, energy production is not impaired, and hypoglycemia does not occur. However, the deficiency of this enzymatic activity results in the accumulation of structurally normal glycogen in lysosomes and cytoplasm in affected individuals. Excessive glycogen storage within lysosomes may interrupt normal functioning of other organelles and leads to cellular injury. In turn, this leads to enlargement and dysfunction of the entire organ involved (eg, cardiomyopathy).

In the infantile form, clinically significant storage occurs in the heart, resulting in progressive cardiomegaly with left ventricular (LV) thickening that eventually leads to outflow tract obstruction. Storage in skeletal muscle leads to hypotonia and weakness. The respiratory muscles are also affected, resulting in hypoventilation and progressive respiratory compromise. CNS involvement is primarily limited to the anterior horn cells of the spinal cord and brain stem nuclei, although intellectual performance remains normal. Although skeletal and respiratory involvement is frequently present in the juvenile form, cardiac involvement varies. Cardiac involvement is not observed in the adult form.

Frequency

United States

Frequency is estimated at 1 case per 40,000 population for all 3 variants of glycogen-storage disease type II. This calculation is from estimated gene frequencies in healthy individuals from various ethnic groups. The highest frequency has been observed in the black population, in which the frequency of the infantile onset type may be as high as 1 per 14,000.

International

The frequency in Taiwan and southern China is estimated at 1 case per 50,000 individuals. The frequency in the Dutch population is estimated at 1 case per 40,000 individuals (1:138,000 for the infantile category).¹ In this affected population, 63% carry at least one of the 3 common mutations.

Mortality/Morbidity

The infantile form is usually fatal during the first year of life. As the weakness progresses, patients develop feeding difficulties and respiratory insufficiency. Enlargement of the LV leads to outflow tract obstruction and ventricular failure. Death results from cardiopulmonary failure.

The juvenile (intermediate) form progresses more slowly and is uniformly fatal. Patients generally do not survive beyond the second or third decade of life. All patients have involvement of respiratory muscles, and most die of respiratory failure. Several patients are reported to have died due to a basilar artery aneurysm.² All were found to have abnormal storage within the lysosomes of arterial smooth muscle fibers. Age of onset does not predict age of death.

Patients with the adult form may survive for decades following diagnosis. Muscle weakness may interfere with normal daily activities, and respiratory insufficiency is often associated with sleep apnea. Death usually results from respiratory failure.

Race

Common mutations associated with the infantile-onset form have been found in the Taiwanese, Dutch, and black populations. A common mutation associated with the adult-onset form has been found in whites.

Sex

This is an autosomal recessive disease; therefore, it equally affects males and females.

Age

As noted above, age of onset usually distinguishes the 3 types. Age of onset in the juvenile form may overlap both the adult and infantile forms.

Clinical

History

• Infantile form of glycogen-storage disease type II (GSDII)
  • These patients typically present with weakness and hypotonia in the first 6 months of life, which may manifest as respiratory and feeding difficulties.
  • Early cardiac failure due to left ventricle (LV) enlargement and outflow obstruction may lead to respiratory and feeding difficulties as well.
  • In 1 infant described, the presenting sign was Wolff-Parkinson-White syndrome.³
  • The birth and family history are usually noncontributory, although some families may be consanguineous. Rare familial cases are reported.
• Juvenile form
  • These children present with delayed motor milestones, weakness, and hypotonia.
  • Their intelligence is normal.
• Adult form
  • These patients present with symptoms related to proximal muscle weakness, such as difficulty climbing stairs.
  • Respiratory symptoms present in approximately one third of adult-onset cases.
  • Symptoms may include exercise intolerance, orthopnea, somnolence, and headache at night or upon waking.

Physical

• Infantile form
  • Readily observed evidence of storage (eg, macroglossia, hepatomegaly, normal or increased muscle bulk)
  • Involvement of respiratory muscles manifest as respiratory distress (eg, tachypnea)
  • Cardiomegaly or cardiomyopathy leading to murmur and signs of cardiac failure
  • Profound diffuse hypotonia
• Juvenile form
  • Respiratory distress
  • Hypotonia (typically more proximal than distal)
  • Macroglossia and hepatomegaly (typically absent)
  • No associated cardiomegaly or cardiomyopathy
• Adult form
  • Proximal muscle weakness
  • Decreased bulk of involved muscles
  • Diminished deep tendon reflexes

Causes

Glycogen-storage disease type II is an autosomal recessive disease caused by the inheritance of 2 defective copies of the gene that encodes acid alpha-glucosidase (GAA), which has been localized to band 17q23. Carriers (ie, individuals with one normal copy and one defective copy of the gene) have no clinical manifestations. Several types of deleterious mutations are identified, including missense, nonsense, deletion, and splice site mutations. These mutations can result in the following:

• No detectable messenger RNA (mRNA) and complete absence of enzymatic protein
• A normal amount of enzyme with reduced activity (eg, reduced affinity for glycogen)
• A reduced amount of enzyme with normal activity
• No detectable enzyme activity in infantile form; varying amounts of residual enzyme activity in juvenile and adult forms
• The c.-32-13T → G mutation is the most common among adults with this disorder.⁴ No individuals with this mutation have the classic infantile form, and cardiac involvement is rare among patients with this genotype.⁵

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