Pompe disease is a rare hereditary pathology, one of the forms of lysosomal accumulation diseases characterized by a violation of the processes of glycogen breakdown in nerve and muscle cells (skeletal muscles, myocardium). The symptoms of the disease are quite variable in the time of their manifestation and severity in different patients, progressive muscle weakness is traditionally observed, in some forms – cardiomegaly with dilated cardiomyopathy. Diagnosis of Pompe disease is made on the basis of data from a hereditary history, histological and histochemical examination of muscle tissues, biochemical blood analysis, as well as genetic studies. Treatment at the moment can be carried out with the help of enzyme replacement therapy, but the effectiveness of this technique varies from patient to patient.
Pompe disease (type 2 glycogenosis, insufficiency of acid alpha-glucosidase) is a hereditary disease in which damage to nerve and muscle tissues occurs due to impaired glycogen metabolism. It was first described in 1932 by the Dutch scientist I. Pompe, since then more than 50 cases of pathology have been officially registered. Pompe disease affects both men and women with an equal degree of probability, the incidence ranges from 1:60,000 (adult form) to 1:140,000 (early or infantile form). It is one of the few lysosomal accumulation diseases for which an effective specific treatment has been developed, approved in the USA in 2006. However, the cost of etiotropic therapy for Pompe disease is extremely high and amounts to several hundred thousand dollars per year. Mortality in the absence of treatment depends on the form of pathology – infantile infantile form often leads to death in the 1-2 year of a child’s life, with the type of disease with a delayed onset, the increase in symptoms is much slower.
Pompe disease is a classic glycogenosis, in which glycogen deposits form in the tissues of skeletal muscles, myocardium and partly of the nervous system due to the impossibility of its cleavage. This occurs as a result of a mutation of the GAA gene located on the 17th chromosome – it encodes the sequence of acid alpha–1,4-glucosidase or maltase. This is one of the key enzymes of lysosomes involved in the cleavage of the glycogen molecule into simpler segments, which eventually degrade to glucose, which enters the energy metabolism of the cell. Since glycogen is an important energy depot for structures such as skeletal muscles, myocardium, liver and nervous tissue, the manifestations of Pompe disease are reduced to pathological changes in these organs.
As a result of such changes, at first there is a shortage of energy in the cells – the needs of tissues for glucose are covered only by its intake from the blood. In addition, glycogen begins to accumulate in lysosomes with Pompe disease, forming large inclusions in the form of vacuoles, further leading to dystrophy and cell damage. Inheritance of defective variants of the GAA gene occurs in an autosomal recessive type. The presence of several forms of the disease is presumably explained by different types of mutations of the above gene. Perhaps, with some defects, there is not a complete disappearance, but only a decrease in the activity of acid alpha-1,4-glucosidase, which leads to a later development of Pompe disease and slow progression of the disease. Determining the form of pathology plays an important role in making its prognosis and treatment regimen.
To date, experts have identified several main forms of Pompe disease, the main difference between which is the timing of the onset of the disease and the severity of symptoms. In most cases, type 2 glycogenosis is encountered by pediatricians, but there is a type of disease detected in adults.
- Early infantile form – this type of Pompe disease is considered the most severe. It is detected even in the first months of life, the symptoms of myopathy, liver damage (hepatomegaly) and heart (cardiomyopathy) progress quite quickly. Usually, patients with an early infantile form of Pompe disease die of heart or respiratory failure before the age of one year.
- Late infantile form – the first symptoms occur at the age of 1-3 years, the rate of their progression is also much slower. With this type of Pompe disease, myocardial lesions are most pronounced, death occurs by adolescence from heart failure.
- Juvenile form of Pompe disease develops at the age of 6-10 years. Just as in the previous version, the heart becomes the main target organ of the disease, death from increasing heart failure occurs by the age of 20.
- Adult form of Pompe disease – the manifestation of symptoms occurs in 20-40 years. The leading symptom is slowly progressive myopathy, liver lesions are almost never registered, in some cases minor myocardial disorders are possible. With this type of Pompe disease, patients in many cases live to old age, only sometimes an earlier fatal outcome is possible due to respiratory or heart failure.
The methods of modern genetics have not yet determined the relationship between individual types of GAA gene mutations and forms of Pompe disease. Perhaps the reason for such variability of manifestations lies in something else entirely – family cases of the disease are described in the literature, when various forms of pathology were registered in relatives. The study of the patterns leading to the development of a certain type of Pompe disease is greatly complicated by the relative rarity of this syndrome.
Pompe Disease symptoms
The manifestations of Pompe disease are quite different in different forms of the disease. The early infantile type is characterized by pronounced muscle weakness of the infant, a decrease in its motor activity, tearfulness. In pediatrics, when examining such a patient, a delay in psychomotor development is often detected, a different degree of liver enlargement, palpation sometimes reveals hypertrophy of muscles, which, however, are quite weak. With the further development of Pompe disease, problems arise with feeding due to the weakness of the sucking muscles, dysphagia is detected and, as a result of all this, hypotrophy. Increasing cardiomyopathy and weakness of the respiratory muscles eventually lead to the death of the child.
Late infantile and juvenile forms of Pompe disease proceed almost the same, only the time of the appearance of symptoms of pathology differs. As a rule, muscle weakness, signs of cardiomyopathy are detected. Over time, pronounced dystrophy of skeletal muscles, cardiomegaly begins to form, against this background, the liver and spleen begin to increase. The duration of these forms of Pompe disease is about 10-12 years, after which, in the absence of treatment, a fatal outcome occurs due to decompensated heart failure. An indirect symptom will be a high frequency of colds with pulmonary complications, night apnea, headaches in the morning.
The adult form of Pompe disease is characterized by a late onset (the first manifestations occur in 20-40 years). Clinically, distal myopathy is detected first of all, manifested by weakness of the muscles of the extremities. Over time, curvature of the spine develops (scoliosis, lordosis), due to the weakness of the muscle sheath surrounding the spinal column. In some cases, slowly increasing signs of heart failure are recorded, but with this type of Pump disease, heart damage does not always occur. The course of the adult form of pathology takes several decades, so in some cases patients live to old age with an acceptable quality of life and without specific treatment.
Detection of Pompe disease can be performed by numerous clinical methods – biochemical blood analysis, study of muscle biopsy, fibroblast cultures or leukocytes of the patient, traditional studies (examination, ECG, EchoCG). During examination, weakness and dystrophy of muscles are often detected, when internal organs are involved in the pathological process, hepatomegaly and splenomegaly are detected. The electrocardiogram shows a shortening of the PQ interval, an expansion of the QRS complex due to an increase in the size of the myocardium. For the same reason, the duration of the ventricular repolarization phase increases, which is manifested by the inversion of the T wave. Echographic examination of the heart shows a sharp increase in its size due to a significant thickening of the ventricular walls. In the adult form of Pompe disease, the above myocardial changes may not be detected.
A biochemical blood test can detect both specific and indirect signs of the disease. A specific study will determine the activity of acid alpha-1,4-glucosidase in blood plasma, which will be sharply reduced in case of Pump disease. An indirect indication of the presence of pathology is a sharp increase in the activity of creatine phosphokinase due to damage to muscle tissue. Histological examination of a muscle biopsy reveals numerous glycogen inclusions in myocytes, often giving them the appearance of “foam cells”. Histochemical examination of Pompe disease reveals a sharp decrease in the activity of acid alpha-1,4-glucosidase in muscle tissue, fibroblasts and leukocytes.
A genetic determination of Pompe disease can be carried out by a geneticist – it is performed by direct sequencing of the GAA gene sequence in order to identify defective areas. In addition, it can help in the diagnosis of the disease and the compilation of a hereditary history. The genetic diagnosis of Pompe disease includes sequencing of GAA and in phenotypically healthy relatives of the patient in order to identify the carrier of the pathological gene.
Treatment and prognosis
To date, the only method of specific treatment of Pompe disease is enzyme replacement therapy in order to compensate for the deficiency of acid alpha-1,4-glucosidase. To do this, the drug alpha alglucosidase produced in the USA is used. The cost of this treatment is extremely high (the annual course costs 100-400 thousand dollars), but its effectiveness varies from patient to patient. There are currently no other ways to treat Pompe disease. Without treatment in infantile and juvenile forms of the disease, the prognosis is unfavorable, in the adult type – uncertain. Prevention is possible only by timely detection of the carrier of Pompe disease (in case of pathology in blood relatives) and subsequent genetic prenatal diagnosis.