Pompe Disease.

Pompe disease, also known as glycogen storage disease type II (GSD-II) or acid maltase deficiency, is one of 49 known lysosomal storage disorders. Pompe disease is caused by a deficiency or complete lack of an enzyme called acid alpha-1,4-glucosidase (also called acid maltase). If this enzyme doesn’t work properly, glycogen builds up in the body’s cells and causes damage, mainly to muscles. This can be life-threatening when the breathing and heart muscles are affected.


The name Pompe disease comes from the Dutch pathologist J.C. Pompe, who first described an infant with the disease in 1932.

Cause of Acid Maltase Deficiency or Pompe disease

Pompe disease is caused by a complete or partial deficiency of the lysosomal enzyme, alpha-glucosidase. This enzyme is necessary to break down glycogen and to convert it into glucose. Without this enzyme, glycogen, a thick sticky substance, accumulates in the lysosomes (sacs within the muscle cells) and leads to severe muscle degradation. It predominately affects the heart, skeletal, and respiratory muscles of the patient.

Pompe disease was first described by Dr. Joannes Pompe (of the Netherlands) in 1936. Pompe patient Joseph Walter created the following presentation on Dr. Pompe:

Progression of Pompe disease

Patients with the infantile form of the disease are the most severely affected. These babies appear normal at birth, but exhibit symptoms by 2-3 months of age (or earlier). Progression is rapid. These patients are so severely affected that they become “limp” unable to feed or move. Their hearts become massively enlarged, and they typically die of cardio-respiratory failure before reaching 12 months of age.

In the delayed onset form progression of the disease is less rapid. Symptoms can manifest at any age of life and can greatly affect the quality of life as well as the life span of the afflicted person. Delayed onset patients that develop symptoms in childhood are more severely affected and typically die by the second or third decade of life. As the disease progresses, patients lose mobility, become wheelchair bound or bedridden. Respiratory functions greatly diminish and mechanical ventilation becomes necessary. Death results from cardio-respiratory complications.

Clinical forms of Pompe disease

Clinical forms of the disease vary according to the age of onset and percent of enzyme activity.

The Infantile Form - appears in the first few months after birth and is characterized by a rapid build-up of glycogen in muscle tissue causing severe muscle weakness and enlargement of the heart and liver. Respiratory and heart complications lead to death by the age of 12 months. The infantile form is characterized by a total lack of the alpha-glucosidase enzyme or by total inactivity of the enzyme.

The Delayed Onset Form - can present at any age. Delayed onset patients produce a minimal amount of enzyme. Progression and severity of the disease is probably attributable to the amount of enzyme produced and to the age of onset of symptoms. Glycogen build up is not as rapid as in the infantile form but the disease is progressive and can greatly decrease the life span of the afflicted person. In the delayed onset form deterioration of muscle is mainly confined to the skeletal muscles, the diaphragm, the limb-girdle, and the trunk. Respiratory complications are the main cause of death. Delayed onset patients that present symptoms early in life are usually more severely affected and rarely survive past the second or third decade of life. Patients that experience onset later in life generally progress at a slower pace.

Causes

The underlying cause of Pompe disease is always the same in all patients: the absence or marked deficiency of a specific enzyme, acid alpha-glucosidase (pronounced “AL-fa glue-CO-sih-days” and often abbreviated GAA). As explained below, this absence leads to excessive buildup of a substance called glycogen within muscle cells.  This accumulated glycogen affects muscle structure and function and results in muscle weakness. Exactly which areas of the body are affected, and how severely, may vary from patient to patient.

Why Does Glycogen Build Up?

An Enzyme Deficiency

The human body produces various enzymes that help break down substances that play a role in the function of cells throughout the body. This breakdown process occurs in small compartments within the cells called lysosomes. One particular enzyme, acid alpha-glucosidase, is responsible for breaking down glycogen in the lysosome.  Glycogen is a form of sugar that is used used for energy storage and is often found in muscle cells.

In patients with Pompe disease, this enzyme is either missing, deficient or not functioning properly. As a result, glycogen is not adequately broken down and accumulates within cell lysosomes, causing damage that leads to muscle weakness.

A Genetic Basis

The GAA gene is responsible for the production of the enzyme acid alpha-glucosidase. When there is a mutation, or defect, in this gene, the enzyme is not be produced in sufficient amounts or does not function properly. Pompe disease occurs when a person inherits this gene defect from both parents.

Defining Who Has the Disease

Every gene in the body comes as a pair: one copy is passed on by the father and one by the mother. The combination of GAA genes inherited from both parents determines whether a person will be affected by Pompe disease:

  • If both genes in the pair are normal (no defect), the person will not have the disease.
  • If both genes in the pair have the defect, the person will have the disease.
  • If one gene is normal and one has the defect, the person will be a carrier. Carriers do not have Pompe disease, but they “carry” the gene defect and may pass it on to their own children.

 Figure 1. Autosomal Recessive Inheritance


Pompe disease is inherited in an autosomal recessive manner. Thus, both parents of a child with the disease must be carriers of a mutant gene for GAA, and each child born to them has a 25% chance of having the disease, a 50% chance of being a carrier, and a 25% chance of neither having the disease nor being a carrier.

Status of Carriers

Although Pompe disease carriers have one defective GAA gene, their other normal copy of GAA gene allows for the production of enough enzyme to keep cells functioning properly. Their enzyme activity is usually somewhat lower than normal, but they do not experience any symptoms.

The Odds of Inheriting Pompe Disease

The most common inheritence scenario which results in Pompe disease is when both parents are carriers. In this case, with each pregnancy the chances are:

  • 1 in 4 (25%) that the child will receive two defective genes and thus inherit the disease
  • 2 in 4 (50%) that the child will inherit only one defective gene and become a carrier
  • 1 in 4 (25%) that the child will be completely unaffected

Far less common inheritance scenarios include:

  • If both parents have Pompe disease, then every child will inherit the disease
  • If one parent has the disease and the other is a carrier, each child has a 50% chance of inheriting the disease and a 100% chance of being a carrier

Note that if one parent has Pompe disease and the other parent does not (and is also not a carrier), all children will be carriers (because they will always inherit one defective and one normal gene), but none of them will have the disease.

How Are Muscles Affected?

As excess glycogen builds up, the cell’s lysosomes begin to swell beyond their normal size and can interfere with normal muscle function. In addition, lysosomes can rupture causing cellular damage. The following illustration provides a cross-section view of this process.

  1. In the healthy muscle cell, lysosomes are normal.
  2. With Pompe disease, accumulated glycogen causes lysosomes to expand, interfering with normal structure and function.
  3. In addition, glycogen and other contents may leak out of the lysosomes and further damage the cell and surrounding tissue

Damage to individual muscle cells eventually results in weakness of larger muscle bundles, leading to patients’ symptoms. The symptoms typically get worse over time, as more glycogen accumulates and the destructive process continues.

How Do Symptoms Vary Among Patients?

Pompe disease is a genetic disorder that is always present at birth. However, symptoms may not always be apparent at birth and can present at any age from infancy through adulthood. Regardless of the age of onset, symptoms usually worsen over time. Typically, the earlier symptoms manifest, the more serious the disease course is likely to be.

Moreover, while all people with Pompe disease have lower-than-normal amounts of the GAA enzyme activity (and sometimes none at all), the amount of residual enzyme activity also often varies with the patient’s age:

  • Affected infants under age 1 usually have less than 1% of normal enzyme levels[1]
  • In children and adult patients, enzyme levels usually range from 1% to 40% of normal[3]

In infants, the almost complete absence of the enzyme seems to consistently result in very severe signs and symptoms, including extreme muscle weakness, breathing difficulties, and serious heart problems. These symptoms generally progress, or worsen, at a very rapid rate, and are often fatal.

The variable enzyme levels seen in older patients are not necessarily associated with specific patterns of symptoms, which can vary widely and be difficult to predict. Unlike affected infants, older patients usually have little or no heart problems. Their muscle and breathing problems may start out milder and worsen gradually.

Disease progression

Pompe disease is described as a progressive disease because it gets worse over time. The progressive nature of Pompe disease is a result of its underlying cause: the ongoing buildup of a substance called glycogen inside muscle cells. As excess glycogen continues to accumulate, it interferes with normal cell function and causes continuous damage to cells, resulting in worsening muscle weakness that can affect movement, breathing, and, in infants, heart function.

Learn more about the underlying cause of Pompe disease 

Pompe disease has a single underlying cause in all patients, the absence or marked defiency of the enzyme, acid alpha-glucosidase (GAA) but it often affects patients differently.

While it is always progressive for every patient—muscle weakness always gets worse over time—there is great variability from one person to another in:

  • The age at which symptoms first appear
  • The speed, or rate, of progression
  • Exactly which muscles are affected

The presentation of Pompe disease is highly variable, always progressive, and often debilitating.

Age of Onset: When Symptoms First Appear

Although the genetic defect that causes Pompe disease is always present at birth, symptoms may first show up at any time from infancy through adulthood.

Disease Course in Infants

When symptoms first appear in infancy (during the first few months of life), Pompe disease generally progresses very rapidly and is almost always fatal by the age of 1 year, usually from heart and/or breathing failure.

Learn more about signs and symptoms in infants 

The very rapid disease progression seen in infants makes prompt diagnosis particularly important, so that disease management can begin as early as possible.

Disease Course in Children & Adults

In children and adults, Pompe disease is progressive, often causing great difficulties as muscles weaken, especially those used for breathing, walking, and other movements. Many patients eventually rely on ventilators to help them breathe and wheelchairs to get around.

An individual could have mild symptoms and slow progression over many years, or symptoms that progress rapidly. Because the course of the disease is hard to predict, careful monitoring is important to address changes in health status, as they arise.

 

How is the disease diagnosed?

Pompe disease is diagnosed by screening for the common mutations in the GAA gene, by measuring the level of the GAA enzyme in a blood sample, or by a muscle biopsy. Once a diagnosis is obtained, consultation with a geneticist and screening of other family members is recommended.

Is there any treatment?

The U.S. Food and Drug Administration has approved alglucosidase alfa (Myozyme) for use in patients with Pompe disease. A type of enzyme replacement therapy, Myozyme is a form of GAA — the enzyme that is absent or reduced in the disorder. The drug is usually administered via intravenous infusion every other week. Myozyme has been remarkably successful in reversing cardiac muscle damage and in enhancing life expectancy in those with the infantile form of the disease. The therapy, however, is less effective in skeletal muscle.

People with Pompe disease need highly specialized care from a variety of specialists, especially as the disease progresses.

What are some key areas of Pompe research at NIAMS?

For the past two decades, researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) - Dr. Paul Plotz, Chief of the NIAMS Arthritis and Rheumatism Branch, and a group of scientists in his lab led by Dr. Nina Raben - have made significant strides toward our understanding of Pompe disease. While it was originally hoped that enzyme replacement therapy could cure Pompe disease, the NIAMS group discovered that skeletal muscle is resistant to the treatment. This finding was made in mouse models of the disease that were generated in the lab; these models are now used throughout the world by scientists involved in the research and development of Pompe therapies.

The group is focusing its current efforts on using the new information to improve treatment of the resistant muscle fibers. These studies are partially funded by a cooperative research and development agreement (CRADA) with Genzyme, the company that produces Myozyme.

The NIAMS group recently uncovered new clues related to the cellular defects in Pompe disease. They identified structures in many skeletal muscle cells in Pompe patients and mice that appeared to be large collections of cellular debris that should have been delivered to, and processed in, the lysosomes, the “recycling centers” of the cell. This debris would normally have been digested in the lysosomes into the building blocks that the cell uses to keep itself in shape — amino acids to build proteins, sugars like glucose to provide energy, and fatty acids to build membranes and to provide energy. So, not only were the lysosomes filled with glycogen which could not be digested, but other materials were building up outside — unable to reach the recycling place. This buildup looked like the kind of material that is normally carried to the lysosomes by a remarkable system, called “autophagy” — literally meaning self-eating. This system picks up worn out cell parts for delivery to the lysosomes for recycling. Dr. Raben recognized that this pick-up and recycling system does not function properly in Pompe skeletal muscle, and the stressed recycling centers appear to be overwhelmed. The NIAMS group is currently testing new strategies to intervene in Pompe disease by exploring ways to modulate the autophagic machinery.

Enzyme Replacement Therapy

In 1999 the first human clinical trials for Pompe disease with enzyme replacement therapy began in the Netherlands with four infantile patients at Sophia Children’s Hospital in Rotterdam. Six months later another clinical trial was started in the Netherlands with three delayed onset patients. At the same time Duke University Medical Center in the US initiated a new infantile clinical trial with three patients.

Genzyme Corporation, the sponsor of these first clinical trials, received FDA and EMEA approval for enzyme replacement therapy for all Pompe patients in 2006.

Gene Replacement Therapy

Gene replacement therapy will eventually be the cure for Pompe disease and other rare disorders. But until this dream is realized, enzyme replacement therapy offers hope in the near future for those affected by the devastation of Pompe disease.