Pompe disease, also known as Glycogen Storage Disease Type II, is a rare inherited disorder that progressively damages muscle and nerve cells throughout the body. It is classified as a lysosomal storage disorder, caused by a deficiency or absence of the enzyme acid alpha-glucosidase (GAA). The lack of this enzyme leads to a toxic accumulation of glycogen, a complex sugar molecule, particularly in the heart and skeletal muscles. This accumulation sets the stage for the disease’s severe manifestations.
The Genetic Basis of Pompe Disease
Pompe disease is an autosomal recessive disorder, meaning an individual must inherit a mutated copy of the GAA gene from both parents to develop the condition. This gene, located on chromosome 17, provides the instructions for making the acid alpha-glucosidase enzyme. Inheriting only one mutated copy results in an asymptomatic carrier.
The defective GAA enzyme fails to properly break down glycogen within the lysosomes. Glycogen, the stored form of sugar, accumulates to damaging levels inside these organelles. This buildup causes the lysosomes to swell, disrupting muscle cell function and leading to progressive muscle weakness. The specific mutations in the GAA gene determine the amount of residual enzyme activity, which directly correlates with the age of onset and disease severity.
Recognizing the Clinical Forms
The clinical presentation of Pompe disease is highly variable, but it is broadly classified into two main forms based on the age of symptom onset. The severity of the disease is directly related to the amount of functional GAA enzyme present.
Infantile-Onset Pompe Disease
Infantile-Onset Pompe Disease (IOPD) is the most severe form, typically presenting within the first few months of life, sometimes even at birth. Infants with IOPD have an absent or near-complete lack of GAA enzyme activity, leading to rapid disease progression. A hallmark symptom is profound generalized muscle weakness, resulting in poor muscle tone (hypotonia) and delayed motor development.
The heart is severely affected, with most infants developing hypertrophic cardiomyopathy (enlargement and thickening of the heart muscle). This cardiac involvement, along with respiratory muscle weakness, causes feeding difficulties, failure to thrive, and breathing problems. Without treatment, the classic infantile form often leads to death from cardiorespiratory failure within the first two years of life.
Late-Onset Pompe Disease
Late-Onset Pompe Disease (LOPD) is caused by a partial deficiency of the GAA enzyme, allowing patients to retain some residual activity. Symptoms can begin from late childhood through adulthood, and the disease progresses much slower than the infantile form. The clinical picture is dominated by progressive weakness of the skeletal muscles, particularly those in the trunk and proximal limbs, such as the hips and shoulders.
This muscle weakness leads to increasing difficulty walking, exercise intolerance, and chronic pain. A major concern in LOPD is the weakness of the respiratory muscles, especially the diaphragm, which can result in breathing difficulties, morning headaches, and sleep apnea. While the heart may be involved, significant cardiomegaly is less common than in the infantile form.
Diagnostic Procedures
A diagnosis of Pompe disease is confirmed through a combination of biochemical and genetic tests, often initiated following clinical suspicion. In many regions, the process begins with newborn screening, which utilizes a dried blood spot to measure GAA enzyme activity. Low GAA activity in this initial screen indicates a presumptive positive result.
The primary diagnostic confirmation method is an enzyme activity assay, which precisely measures the level of GAA activity in various cell types, such as leukocytes or cultured skin fibroblasts. A low or absent level of enzyme activity is highly suggestive of the disease. Genetic testing, involving sequencing the GAA gene, is also performed to identify the specific mutations present. This analysis is crucial for confirming the diagnosis and is helpful for genetic counseling.
Additional supporting tests may include measuring creatine kinase (CK) levels in the blood, which are often elevated due to muscle damage. Analyzing urine for elevated levels of glucose tetrasaccharide also helps distinguish Pompe disease from other neuromuscular disorders and determine muscle involvement severity.
Management and Therapeutic Approaches
The primary therapeutic intervention for Pompe disease is Enzyme Replacement Therapy (ERT), which directly addresses the underlying enzyme deficiency. ERT involves the intravenous infusion of a lab-made, functional version of the GAA enzyme, such as alglucosidase alfa or avalglucosidase alfa. This recombinant human GAA travels to the muscle cell lysosomes to break down the accumulated glycogen.
ERT is typically administered every two weeks and is a lifelong treatment intended to slow disease progression and improve motor and respiratory function. For infants with IOPD, starting ERT as early as possible is paramount, as it significantly improves survival, reverses cardiomyopathy, and allows for better motor skill acquisition. In LOPD, ERT aims to stabilize ventilatory function and motor abilities. Some patients may require combination therapies, such as an enzyme stabilizer, to enhance the replacement enzyme’s effectiveness.
Supportive care measures help manage symptoms and improve quality of life. These include:
- Physical and occupational therapy to maintain muscle strength, flexibility, and mobility. Sub-maximal aerobic exercise is preferred over strenuous resistance training.
- Respiratory support, often required for LOPD patients experiencing diaphragm weakness, which may involve non-invasive ventilation at night.
- Nutritional management, focusing on adequate protein intake.
- Reduced total energy intake to prevent obesity.