Pompe Disease And The Heart: Impact Of The Disease On Cardiac Function

Overview

Pompe disease, also known as Type II Glycogen Storage Disorder (GSDII) or acid maltase deficiency (AMD), is a rare and inheritable metabolic disorder. This disease is characterised by the buildup of glycogen in lysosomes, a complex sugar stored in muscle cells for energy. Lysosomes act like the digestive system of cells,¹ containing a myriad of enzymes that break down complex molecules like carbohydrates so that they can be used for energy production in cells. One such enzyme is the enzyme acid alpha-glucosidase (GAA), otherwise known as acid maltase. Pompe disease is caused by a deficiency in the GAA enzyme, which is essential for breaking down glycogen. 

Causes of pompe disease

As suggested in its alternative name, Type II Glycogen Storage Disorder (GSDII), Pompe disease is primarily characterised by a deficiency in glycogen storage. This is caused by mutations in the GAA enzyme, which is uniquely responsible for breaking down glycogen into glucose in the lysosome. Over 300 variations of the GAA gene have been reported since the discovery of the disease.⁵

In a healthy cell, glycogen is completely degraded into glucose by GAA enzymes in the lysosome and escapes into the bloodstream, where it circulates the body.² Deficiency of functional GAA enzymes causes accumulation of glycogen in the lysosomes in multiple tissues throughout the body, especially skeletal and cardiac muscles.³ Extent of damage to muscle tissue, and thus severity of disease symptoms depends largely on the levels of GAA activity and varies between patients. 

This disease is an autosomal recessive disease, meaning that an individual must inherit 2 dysfunctional copies of the GAA gene, one from each parent, to develop the disease. Carriers with only one dysfunctional GAA gene do not develop symptoms but can pass the gene on to their offspring. 

Pompe’s disease is primarily divided into two broad forms based on the severity of the symptoms: (i) Infantile-onset Pompe disease (IOPD), and (ii) Late-onset Pompe disease (LOPD). 

The level of disease severity is directly related to the levels of GAA enzyme activity in muscle tissue. <1% GAA activity is present in classic IOPD, causing a severe build-up of glycogen in both cardiac and skeletal muscle tissue.⁴ In the case of LOPD, GAA enzyme function is generally only partially lost, with activity levels ≤ 30% resulting in slower disease progression.⁶

Symptoms of pompe disease

Infantile-onset pompe disease

IOPD occurs in infants ≤12 months, and typically presents with more severe and progressive symptoms. If left untreated, patients may not survive past their first year of life.⁴  

Symptoms:⁷ 

• Hypertrophic cardiomyopathy
  • Heart muscles, particularly the left ventricle walls, thicken abnormally, impairing the heart’s ability to pump blood efficiently
• Cardiorespiratory failure
  • Weakened heart function leads to breathing difficulties, feeding problems, chest pain, etc  
  • Leads to a progressive decline in the ability to breathe independently⁹
• Generalised muscle weakness 
• Floppy infant syndrome (hypotonia)
  • Poor muscle control and strength, which makes it difficult for them to perform typical movements such as supporting their head, sitting, standing, rolling over, etc 

Non-classic IOPD also occurs in patients below the age of 1, however, cardiomyopathy is less severe. Patients have less rapid progression of disease symptoms and thus tend to survive longer.⁸ However, similarly to classic IOPD, if non-classic IOPD is left untreated, severe muscle weakness ultimately causes respiratory failure in early childhood.⁹  

Late-onset pompe disease

LOPD occurs in patients any time after 12 months of age, from juveniles to adults, and generally has milder symptoms. The partial loss of enzyme function is why symptoms of LOPD are milder and have reduced cardiac involvement.⁵

Symptoms:¹⁰

• Muscle weakness
  • Reduced ability to perform physical activities and inability to keep up
• Respiratory insufficiency
  • Mainly due to weakness of the diaphragm
• Milder signs include myalgia (muscle pain/cramps) and fatigue

It is important to note that many of the symptoms may overlap with other diseases.¹¹ and there are risks of differential diagnoses. As such, Pompe disease must be accurately diagnosed promptly so that the correct steps can be taken to manage and treat the illness. 

How is it diagnosed? 

Diagnostic steps involved include:⁶

• Clinical exam and patient history
  • Clinical and physical examinations to assess muscle weakness, respiratory difficulties and other characteristic symptoms of the disease
  • Given the inheritable nature of the disease, detailed family history to identify the risks of genetic predisposition to Pompe disease
  • Patient history is important to assess any prior developmental delays and growth patterns, especially in children
• Cardiac evaluation with ECG (echocardiography)
  • ECG reveals hypertrophic cardiomyopathies, with or without obstructed blood flow¹²
• X-ray and imaging with MRI (Magnetic Resonance Imaging) and CT (Computed Tomography) scans
  • Helps to identify abnormalities present in muscles, including the heart and skeletal muscles^13,14
• Muscle biopsies
  • Identify the extent of glycogen accumulation in muscle tissue
• Enzyme assays
  • Measurement of GAA enzyme activity in dried blood spots or white blood cells 
• Genetic testing
  • GAA genes are sequenced to identify any mutations
  • Serves as a confirmation of the diagnosis, in combination with enzyme assays
• Newborn screening
  • Many countries now include Pompe disease in their newborn screening panels¹⁵, allowing for early detection and treatment of the disease

Management and treatment of pompe disease

Damage done to the muscle tissue in Pompe disease gets worse over time, and is particularly rapid in IOPD. As such, treatment must focus on slowing the progression of the disease and improving its symptoms. 

Enzyme replacement therapy (ERT) 

The primary treatment for Pompe disease involves infusions of recombinant human GAA enzymes, known more commonly as alglucosidase alfa.¹⁶ In this way, ERT helps to reduce the accumulation of glycogen in cells, supplementing the GAA enzyme that is deficient in patients with the disease. 

This treatment, beginning in 2006, has since been shown to improve skeletal muscle function, as well as cardiac and respiratory function.¹⁷ Given that cardiorespiratory failure is the main cause of death in Pompe disease, in this way, ERT helps to extend patients’ lifespans. 

To this day, ERT remains the only FDA-approved treatment for Pompe disease. 

Respiratory and cardiac care and support

Patients should undergo routine monitoring of respiratory and pulmonary functions, as well as regular cardiac evaluations to monitor heart function. This helps with early detection of abnormalities, and treatment adjustments where necessary. 

In the event of the need for respiratory support, non-invasive ventilatory support is a common treatment option to manage respiratory insufficiencies, particularly in sleep. However, in the event of failure, invasive mechanical ventilation may be necessary in more severe cases.¹⁸

Summary

Pompe disease is a rare, inheritable metabolic disorder that involves the buildup of glycogen in muscle tissue. The disease manifests in 2 broad forms: (i) Infantile-onset Pompe disease (IOPD), whereby the disease begins before the first year of age, and (ii) Late-onset Pompe disease (LOPD), where the disease begins any time after the first year of age. LOPD presents with milder symptoms, including muscle weakness and breathing difficulties. On the other hand, IOPD is typically more severe, with a much more significant impact on the function of the heart, often leading to death by heart and lung failure before 12 months of age if left untreated. 

Timely management and treatment of the disease is important. Early diagnosis through newborn screening and genetic screening may help initiate prompt treatment. If you, or your child, have a history of breathing difficulties and an inability to keep up in physical activities, it may be time to contact a doctor. With timely and appropriate care, patients with Pompe disease can achieve  improved health and quality of life.