Fabry's disease: causes, symptoms, treatment

Fabry's disease (ceramide trihexocosidosis, Anderson's disease, diffuse universal angiokeratoma, hereditary dystonic lipidosis) - this is a hereditary metabolic disease associated with the accumulation of glycosphingolipids (a kind of fats) in some cells of the body rights. Most often the disease manifests itself as a visual impairment, specific skin changes in the form of angiokera, renal insufficiency, heart problems, damage to the nervous system. The disease is progressive and shortens life expectancy. However, to date, significant progress has been made in the treatment of the disease with the help of substitution therapy. From this article you can learn about the causes, signs and methods of treatment of Fabry's disease.

Fabry's disease has been known since 1898, when it was first described by the doctors Fabry and Anderson, whose name they carry. This is a very rare disease, its prevalence ranges from 1: 117 000 to 1: 476 000 population.

The disease refers to lysosomal accumulation diseases. In Fabry's disease, there is a deficiency or a decrease in the activity of the enzyme lysosome α-galactosidase A. Because of this, glycosphingolipids are not completely cleaved. Intermediate products of fat metabolism (globotriaosylceramide and galabiosylceramide) are deposited in various organs and tissues, causing a disturbance in their function. First of all, the accumulation occurs in endothelial and smooth muscle cells of blood vessels, kidney cells, heart muscle, central nervous system, corneal cells.

Causes

At the heart of the disease is a genetic defect of the sex X chromosome. In one of the sections of this chromosome, information on the enzyme α-galactosidase A is encoded. If a mutation occurs, this leads to a decrease in the amount of this enzyme or a decrease in its activity.

A defect has a recessive nature of inheritance. What does this mean? Since the male sex only has one X-chromosome (and the second - Y), in boys with a pathological X-chromosome, the classical picture of the disease always develops. A sick man will necessarily pass the mutant X chromosome to all his daughters without exception (that is, in 100% of cases), but his sons will be healthy.

Women have two X-chromosomes. If one of them is mutant, then these women develop clinical manifestations, but they are less pronounced, later develop and slower progress, almost always atypical forms of the disease. If the woman has the same mutant X chromosomes, one from the father, the other from the mother (the likelihood of is practically zero, given the prevalence of the disease), then the classical picture also develops Fabry's disease. A woman can transmit a mutant X chromosome to both her sons and her daughters (in the presence of one mutant X chromosome, the probability is 50%).

Symptoms

One of the manifestations of Fabry's disease can be ischemic or hemorrhagic stroke.

Two forms of the disease are known:

• classical: with onset in childhood and adolescence, with multiple organ dysfunction;
• atypical: with late onset and isolated lesion of one organ (eg, kidney or heart).

Although the disease is inherited, but its manifestations even among members of the same family are different. That is, it is not necessary that one patient simultaneously observed all the symptoms of the disease. In most cases, with the classic form of Fabry disease, symptoms from various organs and systems appear gradually, as the disease progresses.

With the classical form of the disease for the first time makes itself felt in childhood (usually up to 10 years).

What are the clinical signs of damage to organs and systems in the case of Fabry's disease? It can be:

• cutaneous manifestations: the so-called angiokeratomes. These spots on the skin a few millimeters in diameter of different colors, from red to bluish. The spots may be flat or slightly protrude above the skin level. They are usually located on the buttocks, hips, in the groin, in the navel, on the fingers, on the knees and elbows, less often - on the face in the form of a "butterfly". When pressing, the spots do not disappear. In themselves, their presence does not cause trouble for the patient, except for a cosmetic defect. Appear in childhood and gradually increase in size as they grow older. Perhaps the appearance of such spots on the mucous membrane of the mouth and conjunctiva. In their structure, angiokeratomas are dilated blood vessels covered with several layers of skin;
• Polyneuropathy: a very characteristic sign of Fabry's disease. They manifest themselves as follows: patients are concerned with burning and severe pain in the extremities. Pain occurs with a slight pain irritation, with a slight change in ambient temperature (especially in response to warm and hot water). Together with pains in the hands and feet, there are sensations of burning, tingling, crawling crawling (paresthesia), which for a long time do not pass, torturing patients. In addition to the constant pains of a neuropathic nature, painful crises may arise: these painful pains in the limbs that give to other parts of the body, lasting from a few minutes to several days, accompanied by an increase in body temperature and ESR, not removed even by narcotic drugs. Crises occur in response to weather changes, physical stress, increased body temperature, stress, alcohol intake. Another sign of polyneuropathy in Fabry's disease is a decrease or absence of sweating (hypo- or anhidrosis);
• lesions of the central nervous system: the main cause of the "suffering" of the central nervous system in Fabry's disease is the deposition of ceramides in the walls of vessels of small caliber. As a result, there are ischemic and hemorrhagic strokes. Sometimes the disease makes its debut with the development of a stroke. All cases of strokes in young people are suspicious of Fabry's disease. Strokes cause paralysis, impaired intelligibility and understanding of speech, impaired coordination, convulsive syndrome. If the lack of blood supply to brain tissue develops gradually, then the patient gradually deteriorates memory, mental processes are slowed down, there may be a violation of behavior and the emergence of mental disorders;
• defeat of the kidneys: it starts with a slight loss of protein in the urine (normal protein with urine is not excreted). This phenomenon is called proteinuria. Gradually, proteinuria increases, a significant amount of protein is lost in the urine, which leads to swelling. The content of protein fractions in the blood decreases. Gradually, the renal tubules become clogged, and chronic renal failure develops. And then the body is not able to get rid of the "slag intoxication increases. In addition, kidney damage leads to the onset of hypertension, that is, increased blood pressure, which can exacerbate the manifestations of the disease from the central nervous system and hearts. The only way to treat terminal renal failure is a kidney transplant, or a permanent hemodialysis is shown to such patients. Quite often, kidney failure causes death of patients;
• heart damage: may also cause a reduction in the life expectancy of people with Fabry's disease. Most patients develop thickening (hypertrophy) of the left ventricular wall at a young age. This condition is called hypertrophic cardiomyopathy. Blood vessels of the heart can not provide such a thick wall of the myocardium with the necessary amount of glucose. In such patients, there are symptoms of angina pectoris, even myocardial infarction is possible. Along with hypertrophy, fibrosis develops, the pumping function of the heart suffers, and heart failure develops. Dysfunction of the walls of the heart leads to the occurrence of violations of the heart rhythm. This may be syndrome of weakness of the sinus node, atrioventricular block, atrial fibrillation. Heart rhythm disturbances can cause sudden death of such patients. Sometimes, with Fabry disease, damage to the valves of the heart and large vessels develops - more often it is mitral insufficiency and aortic stenosis;
• Ophthalmic disorders: 70-90% of patients are diagnosed. There is a clouding of the cornea in the form of curls. Perhaps the gradual formation of cataracts, which, along with the damage to the vessels of the retina, causes severe vision loss;
• lesions of the gastrointestinal tract: not a very frequent symptom in the illness of Fabry. There may be nausea, vomiting (it should be borne in mind that they can be associated with intoxication due to chronic kidney failure), loosening of the stool until diarrhea;
• osteoarticular manifestations: intermittent joint pain, fever and ESR simulate joint diseases. Over time, the development of deformation of the interphalangeal joints of the hands and feet, aseptic necrosis of the head of the femur, is possible. As a result of metabolic disturbances, calcium is gradually "washed away" from the vertebrae, and osteoporosis develops;
• disorders in the blood clotting system: they are the development of peripheral vein thrombosis. Possible spontaneous thromboembolism (for example, pulmonary embolism), from which the patient may die;
• hearing and coordination disorders: with Fabry's disease, patients often complain of tinnitus, their hearing gradually decreases. Vestibular disorders are characterized by frequent dizziness and, as a result, instability in walking.

The disease proceeds in such a way that by 30-40 years the patients have a whole "bouquet" of various symptoms. Usually, at this age, with a classical form of illness, the patient suffers from severe renal failure and has a number of vascular problems from the central nervous system or heart.

It should be remembered that there are atypical variants of the course of the disease, in which one organ or system is affected. In this case, the disease manifests itself in adulthood, for example, a sudden stroke in 40 years or heart failure of an unknown genesis.

Diagnostics

In addition to a variety of clinical manifestations to confirm the diagnosis of Fabry disease, it is necessary to determine the activity of lysosomal enzyme α-galactosidase A in the culture of cells of skin fibroblasts, leukocytes, serum, plasma, any biopsy (skin, kidney and etc).

Molecular genetic methods of diagnosis can detect a mutation in a specific area of ​​the X chromosome. Such methods allow prenatal (prenatal) diagnosis to be performed to exclude a fetal disease in families where the mutation was observed.

Treatment

Since 2001, the replacement therapy with recombinant preparations of α-galactosidase A has been successfully used in the treatment of the disease. These are such medicines as Replagal and Fabrazim. Replagal is administered intravenously in a dose, mg / kg twice a month, and Fabrazyme is administered, mg / kg twice a month. Both drugs are comparable in effectiveness. Against the background of the use of these drugs, it is possible to achieve a reduction in the severity of the pain syndrome, regression of hypertrophy myocardium of the left ventricle, stabilize kidney function and prevent the development of chronic renal and cardiac insufficiency.

Prospects for treatment are behind genetic engineering. Potentially successful, perhaps, will be the introduction of a normal gene (artificially created) encoding α-galactosidase A, into cells of the human body, in particular, the bone marrow.

Along with substitution therapy, symptomatic treatment is performed. To reduce painful pains and paresthesias, anticonvulsants are used (Carbamazepine, Gabapentin, Pregabalin, Diphenin). It is recommended to refrain from physical exertion, to avoid stress and temperature changes. Also with an anesthetic goal, patches and ointments with lidocaine are used to localize the pain sensations.

Problems with the kidneys and high blood pressure of kidney genesis are leveled by the use of ACE inhibitors (Ramipril, Lisinopril, Prestarium, Enap) and angiotensin II receptor blockers (Irbesartan, Valsartan, Losartan). In cases where renal failure reaches the terminal stage, hemodialysis or kidney transplantation is indicated.

Given the tendency to thrombosis, such patients are prescribed to constantly take Aspirin, Cardiomagnum or Clopidogrel to prevent complications in the form of thrombosis and thromboembolism. These measures also serve to prevent the development of strokes.

In cases of heart rhythm disturbances, antiarrhythmic drugs are used.

Cosmetic defects (angiokeratomes) can be removed by laser therapy.

Thus, Fabry's disease is a rare hereditary disease with the defeat of many organs. Most often it manifests itself in childhood, but it is possible and later forms (especially in women). If the disease is not treated, it becomes the cause of severe renal or heart failure, stroke, thromboembolism, from which the patient may die. The use of substitution therapy can prevent formidable complications and increase the duration and quality of life of such patients.