Pompe disease: what is it, symptoms, treatment, prognosis

What is Pompe disease?

Pompe disease (generalized glycogenosis, glycogenosis type 2) Is an inherited disorder caused by the accumulation of a complex sugar called glycogen in the cells of the body. The accumulation of glycogen in certain organs and tissues, especially muscles, impairs their ability to function normally.

Scientists have described three types of Pompe disease, differing in severity and the age at which they appear. This is:

• classic infantile;
• non-classical infantile;
• late.

Classic form Pompe infantile disease begins within a few months after birth. Children with the disorder usually experience muscle weakness (myopathy), poor muscle tone (muscle hypotonia), enlarged liver (hepatomegaly) and heart defects. Affected children may not gain weight or grow (called a developmental failure) and may have problems with the respiratory system. If untreated, this form of the disease leads to death from heart failure in the first year of life.

Non-classical form Infantile Pompe disease usually appears at the age of 1 year. It is characterized by delayed motor skills and progressive muscle weakness. The heart can be abnormally large (cardiomegaly), but sick people usually do not experience heart failure. The muscle weakness in this disorder leads to severe breathing problems, and most children with non-classical childhood Pompe disease live only in early childhood.

Late-onset Pompe disease may appear no later than in childhood, adolescence, or adulthood. Late-onset disease is usually milder than the infantile form of the disorder and is less likely to affect the heart. Most people with late-onset illness experience progressive muscle weakness, especially in the legs and trunk, including the muscles that control breathing. As the disorder progresses, breathing problems can lead to respiratory failure.

Signs and symptoms

Patients with the classic infantile form of Pompe disease are most severely affected. Although symptoms may be mild at birth, the disease usually manifests itself within the first three months of life with rapidly progressive muscle growth. weakness, muscle hypotonia, respiratory failure, and a type of heart disease known as hypertrophic cardiomyopathy, a condition characterized by an abnormal thickening of the walls of the heart (mainly the left chamber and the wall between the left and right chambers), which leads to a decrease cardiac function. These problems together lead to heart failure during the first two years of life.

Many children have a large protruding tongue and mild liver enlargement. The legs often lie in the frog position.

Eating, swallowing, and breathing problems are common and are often associated with respiratory tract infections. Major developmental milestones such as rolling over, sitting and standing are delayed or not achieved. Mental development is usually normal. Almost all children experience hearing loss. The classic childhood form of Pompe disease is characterized by a complete lack of acid alpha-glucosidase (GAA) production and a rapid accumulation of glycogen in skeletal muscle and heart.

Other symptoms may include difficulty chewing and swallowing and drooping of the upper eyelids (ptosis). In addition, blood vessel abnormalities have been reported due to weakness of smooth muscles and problems of the urinary and digestive systems.

Causes of Pompe disease

The disease is caused by pathogenic changes in the gene acid alpha-glucosidase (GAA). About 500 different gene variations have been identified in families with this disorder. GAA.

Pompe disease is inherited as an autosomal recessive trait. Recessive genetic disorders occur when a person inherits two copies of an altered gene for the same trait, one from each parent. If a person inherits one normal gene and one defective gene, the person will become an asymptomatic carrier of the disease. The risk that carrier parents will pass both the altered gene and have a sick child is 25% with each pregnancy. The risk of having a baby, carrier like parents, is 50% with each pregnancy. The risk of inheriting normal genes from both parents is 25%. The risk is the same for both men and women.

The first symptoms of Pompe disease can occur at any age, from birth to late adulthood. The timing of the onset of symptoms is largely related to the severity of the pathogenic changes in each of the 2 copies of the gene GAA in a sick person. Some pathogenic changes lead to a partial loss of the functional GAA enzyme, while others lead to a complete loss of the functional GAA enzyme. Therefore, the classic infantile, childhood and adult Pompe disease is very rare in the same family.

The clinical picture of Pompe disease is not only dictated by the nature of hereditary pathogenic changes in the copy of the GAA gene. It is influenced by a number of still unknown genetic, epigenetic and "environmental" factors.

Affected populations

The disease occurs in various populations and ethnic groups around the world. The prevalence varies, but is approximately 1 in 140,000 (classic infantile) and 1 in 60,000 adults (late onset). Men and women suffer equally.

Diagnostics

A diagnosis of Pompe disease is first suggested for symptoms such as muscle weakness, fatigue, and breathing problems. In adults, Pompe disease can be confused or misdiagnosed as other chronic muscle diseases such as multiple sclerosis, muscular dystrophy of the extremities and polymyositis.

In infants and children, Pompe disease can be confused with other types of muscular dystrophy. Confirmation of the diagnosis can be carried out by examining the activity of acid alpha-glucosidase in cultured skin cells, muscles or blood. With a disease, the activity of the enzyme will be reduced or absent. Children with infantile onset usually have GAA enzyme levels below 1%. Late-onset individuals have GAA enzyme levels below 40%.

Testing for genetic mutations in the GAA gene also helps confirm the diagnosis. Carriers of the disease are most accurately identified using genetic mutation analysis.

Treatment

Treatment for Pompe disease is specific, symptomatic and supportive. Treatment requires the coordinated efforts of a team of specialists with experience in the treatment of neuromuscular disorders. Pediatricians or therapists, neuropathologists, orthopedists, cardiologists, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan treatment. Genetic counseling is of paramount importance to affected individuals and their families.

- Enzyme replacement therapy.

Enzyme replacement therapy is an approved therapy for all patients with Pompe disease. Therapy involves intravenous administration of recombinant human acidic α-glucosidase (Mayozyme). The drug was developed by Genzyme Corp. and successfully passed clinical trials, which involved 39 patients aged 1 month to 3.5 years. In 2006, it was approved by the FDA for the treatment of patients with infantile disease in the United States. The drug "Mayozyme" is one of the most expensive drugs in the world, and the annual course costs from 100 to 300 thousand US dollars, depending on the age and weight of the patient. Since 2013, the drug has been registered in the Russian Federation.

- Supportive therapy.

Adjunctive treatment for Pompe disease is symptomatic and supportive. Patients may require respiratory support as most patients have some degree of respiratory distress. Physical therapy is helpful to strengthen the respiratory muscles. Some patients may require respiratory support through mechanical ventilation during the night and / or during periods of the day. In addition, mechanical ventilation may be needed for additional support during respiratory tract infections. The decision about the duration of respiratory support is best made by the family with careful consultations with the patient's doctors and other members of the healthcare team, based on the specifics the patient.

Physical therapy is recommended to improve strength and physical ability. Occupational therapy may be required, including the use of a cane or walker. Some patients may require a wheelchair. Speech therapy will help to improve articulation and speech of patients.

For some patients, orthopedic devices, including braces, may be recommended. Surgery may be required for certain orthopedic symptoms, such as contractures or spinal deformities.

Because the disease can weaken the muscles used to chew and swallow, adequate measures may be required to ensure proper nutrition and weight gain. Some patients may require specialized high-calorie diets.

Some babies may need to have a feeding tube inserted through the nose, down the esophagus, and into the stomach (nasogastric tube). Some babies will need to insert a feeding tube directly into their stomach through a small surgical opening in the abdominal wall. Some people with late-onset illness may need a bland diet, but few need tube feeding.

Forecast

Without enzymatic replacement therapy, the heart of a child with an infantile form of the disease gradually thickens and enlarges. These children die before the age of one, either from cardiorespiratory failure or from a respiratory infection. For people with late-onset Pompe disease, the prognosis depends on the age of onset. In general, the later the age of onset, the slower the progression of the disease. Ultimately, the prognosis depends on the degree of damage to the respiratory muscles.