What is Pompe disease, what are its symptoms, causes and diagnosis?

Pompe disease is a disease that affects muscles throughout the body. The cause is a missing enzyme that has lost its activity due to a genetic mutation.

Therefore, large amounts of glycogen accumulate in the cells, causing damage and gradual loss of muscle mass.

The disease becomes life-threatening if the respiratory muscles and heart are affected.

In the literature, this disease may be referred to by many other names that are synonymous. You may come across names such as acid maltase deficiency (AMD), glycogenosis type II (GSD), glycogenosis type II or acid alpha-glucosidase deficiency.

A breakthrough in the diagnosis and treatment of Pompe disease came in the early 21st century with the introduction of the dry blood drop screening test and enzyme replacement therapy.

The disease manifests as muscle weakness, which - if left untreated - progresses and shortens the patient's life expectancy.

The disease was first described in 1932 by the Dutchman Johannes C. Pompe. He microscopically examined the muscles of infants who died of an unknown disease within 7 months of birth. The common feature of their disease was an enlarged heart.

He noticed that tiny nodules of polysaccharide glycogen were found in the muscles of these babies.

It was not until several years later that the cause of glycogen deposition in the muscles was discovered, which was a deficiency of a certain enzyme.

In addition to being a pathologist, Pompe was also a fighter and opponent of fascism. During World War II, he was executed as a warning to other opponents of the regime. At the time, he was only 44 years old.

The disease was named Pompe's disease in his honour.

The worldwide incidence of the disease is unusual, with approximately 1 in 40 000 people reported to suffer from it. However, the geographical spread of the disease is not uniform and there are some ethnic differences.

In the African-American population, the prevalence is slightly higher, approximately 1 in 14 000.

In fact, the numbers may well be higher. Many people have the disease but have not yet been properly diagnosed or are unaware of it.

In 2004, a global Pompe disease registry was created, with more than 1,200 patients from 29 countries registered.

Pompe disease is a genetic disorder caused by a mutation in the gene for an enzyme called alpha-glucosidase or synonym acid maltase. This enzyme interferes with carbohydrate metabolism.

Glycogen is a polysaccharide that is found as an energy store in the liver and muscles. Its microscopic shape is branched. We can think of it as a bottle-cleaning brush.

These branched fibers are made up of glucose molecules, which are the body's main source of energy. When the body needs to replenish energy quickly, it "bites" from glycogen.

To break down glycogen into glucose, the body has created the enzyme alpha-glucosidase (GAA).

If this enzyme has reduced activity or is even completely absent, glycogen cannot be used. Unused glycogen accumulates in the liver, heart and skeletal muscles. This causes muscle disease - myopathy - the main feature of Pompe disease.

Glycogen that cells cannot use is stored in specific organelles called lysosomes. The accumulation of glycogen triggers a cellular process called autophagy, in which the cell "eats" itself.

The accumulation of lysosomes in a muscle cell also damages it mechanically by disrupting the contractile apparatus of the muscle fibres.

Respiratory muscles are most affected. Why this is so, we don't know yet.

In addition to muscle wasting, nerve damage is also involved in this disease.

Glycogen accumulates in the Schwann cells, which form the protective sheath of the nerve, and in the myenteric nerve plexuses, which are responsible for parasympathetic innervation of the digestive tract, which ensures the expulsion of intestinal contents and the secretion of enzymes, acids and hormones.

In the CNS, glycogen accumulates in the spinal cord, brain stem and glial cells. However, excess glycogen accumulated in peripheral nerves and the CNS does not cause clinical symptoms.

The disease is an autosomal recessive type of inheritance. This means that the parents do not have to be ill. They may only be carriers of the genetic mutation and the disease will manifest itself in their offspring.

Each individual has a genetic make-up of 46 chromosomes, half of which are inherited from the mother and half from the father.

If both parents are carriers of the mutation (outwardly healthy), their child has a 25% risk of developing Pompe disease clinically, a 50% risk of being only a carrier of the recessive trait, and a 25% chance of being completely healthy.

Symptoms of Pompe disease vary from a very severe course, rapidly progressive and fatal in newborns and infants, to late manifestations in adulthood with slow progression.

There are three forms of Pompe disease, which are divided according to the age of onset of symptoms - infantile, juvenile and adult forms.

Whether the disease manifests immediately after birth or only in adulthood depends on the activity of the GAA enzyme.

In newborns with symptoms of Pompe disease, the activity is almost zero. In the juvenile form, the GAA activity varies between 1% and 10%. Patients with the adult form have a preserved enzyme activity of 5-30%.

Patients with the adult form of Pompe disease are the majority, approximately 70%.

Infantile form

This is the form of the disease with the most severe and most rapidly progressive clinical picture. Such a child has symptoms immediately from birth.

It is manifested by the so-called 'floppy baby' syndrome. The child is like a rag doll, with muscle hypotonia and weakness. An extremely enlarged heart (cardiomegaly) is present, causing severe arrhythmias and heart failure.

In a child, we may find an enlarged liver - hepatomegaly.

Infants die by about 1 year of age from respiratory and heart failure.

Juvenile form

This type of the disease manifests itself from the age of 1 to 18 years. Among the first symptoms may be delayed gross motor development of the toddler, e.g. late initiation of walking.

Later, the child is clumsy, hates physical exertion, and does not want to play, run, or exercise as much as his peers.

Later, hypotrophy of the skeletal muscles, especially of the upper limbs and trunk, is noticeable.

The respiratory muscles are also affected. This causes respiratory insufficiency, which can be an early sign of the disease in some patients. The child or adolescent is already panting heavily during light physical activity, talking or even eating.

The course is fairly progressive. Children who become ill around 1 year of age die of respiratory failure by age 6. If the disease develops later, in older children or in adolescence, they survive into young adulthood, until about age 25.

The adult form

The first symptoms of the disease appear in the 3rd-4th decade. During life, mild symptoms may appear, such as poor tolerance of walking up stairs and hills and an inability to manage longer periods of walking, endurance running and other activities.

Most people with these symptoms do not seek medical attention.

Later, physical changes such as protruding shoulder blades, scoliosis, emaciated limbs due to atrophied muscles, duck-walking, hunched sacral spine, difficulty getting up from a sitting position, and more are noticeable.

Half of the patients see a doctor only when they have difficulty breathing. Patients gasp at first only during light activities, later also at rest.

In this form, there is only mild or no heart involvement.

The most common difficulties of patients with Pompe disease:

• Inability to walk up stairs and hills.
• weakness when getting up from a chair
• unsteady gait, also called duck or myopic gait
• stumbling while walking and frequent falls
• weakness in raising arms above the head, inability to hold hands when combing and washing hair
• problems when running
• muscle pain and cramps
• protruding shoulder blades
• scoliosis of the spine
• rapid shortness of breath during physical activity and exercise
• difficulty breathing during sleep, sleep apnoea
• recurrent upper respiratory tract infections
• waking up with a headache
• significant daytime fatigue
• weakness of the masticatory muscles when chewing, difficulty swallowing food
• clumsy tongue
• slurred speech
• gastroesophageal reflux

Clinical picture

In the diagnosis of Pompe disease, the characteristic clinical picture of the disease is decisive. In infants, the symptoms are immediately apparent. Generalized muscle weakness and low muscle tone are the main symptoms that draw attention to the disease.

In the juvenile and adult forms, symptoms may not be overtly expressed but may come on gradually.

It is important to think differentially diagnostically about other causes of muscle weakness, e.g. various forms of muscular dystrophies, myositis, metabolic myopathies, etc.

Biochemical analysis of blood

Extremely elevated levels of creatine kinase (CK) are found in blood samples. This is an enzyme found in the cytoplasm of cells, especially in skeletal muscle, heart and brain.

Elevated levels are found in the blood when muscle cells are damaged, when the myocardium is damaged, e.g. after a heart attack, or when the blood-brain barrier is damaged.

However, it is not a specific marker. Its values may also be elevated after extreme muscular exertion, after intramuscular injections, after trauma, in kidney disease and also in other muscular diseases such as muscular dystrophies.

Electromyographic examination

Electromyography (EMG) is an ancillary neurological examination that provides information about the electrical activity of muscles. In addition to diagnosing muscle diseases, it is also used in the investigation of many neurological diseases.

In this examination, a needle is inserted into the muscle and used as an electrode. A weak electrical impulse is sent to the part of the muscle being examined. This irritates the adjacent nerve fibre, which manifests as a muscle tic.

The result is displayed on the monitor in the form of curves.

In Pompe disease, several non-specific EMG curve pathologies are seen. The result should always be correlated with other investigations.

Muscle biopsy

Muscle biopsy, i.e. the surgical removal of a piece of muscle and its histopathological examination under a microscope, is essential for the diagnosis of Pompe disease.

However, not all muscles are equally damaged. Therefore, a false negative result is possible if the sample is taken from a muscle that is not damaged by glycogen accumulation.

Evidence of enzyme activity

A very specific test to prove the diagnosis of Pompe disease is the demonstration of reduced or absent activity of the enzyme alpha-glucosidase.

Tissues that contain lysosomes - cellular organelles in which glycogen has accumulated - are examined. Suitable material includes blood containing lymphocytes, skin or muscle fibres obtained by biopsy.

A relatively modern method is the determination of the activity of the enzyme alpha-glucosidase from a dry drop of blood. This test was invented in 2001. Its simplicity makes it suitable for screening, i.e. actively searching for patients with Pompe disease.

In case of positivity, the diagnosis should be confirmed by examination of the GAA enzyme from lymphocytes, fibroblasts, muscles or genetic testing.

Genetic testing

This is a DNA analysis that detects the presence of a mutation in the alpha-glucosidase gene. Currently, there are approximately 300 known genetic mutations that can affect this gene and cause GAA deficiency.

The course of Pompe disease depends on several factors:

• the form of the disease
• the activity of the GAA enzyme
• the age at which the first symptoms appear
• correct diagnosis and appropriate treatment

The most severe course is the infantile form, which is characterised by almost zero activity of the enzyme alpha-glucosidase.

Only 20% of children with Pompe disease live longer than 1 year. They die of respiratory failure or heart failure.

At least some GAA activity is present in the juvenile and adult forms, so the course may not be as rapidly progressive as in the infant form.

The greatest risk that shortens the life of patients with this disease is the involvement of the respiratory muscles. On average, patients need to be put on artificial pulmonary ventilation between the ages of 30 and 50.

Observational studies have shown that an average of 15 years elapses between the first symptoms and the introduction of ventilation.

The progression of the disease is therefore variable. Most patients gradually become wheelchair-bound and require the assistance of another person throughout the day.

Respiratory failure is the most common cause of death.