Fabry's disease

Fabry disease (synonyms: Fabry disease (syndrome), Anderson disease, diffuse angiokeratoma) is a sphingolipidosis caused by alpha-galactosidase A deficiency, which causes angiokeratomas, acroparesthesia, corneal opacity, recurrent episodes of fever to febrile levels, and renal or cardiac failure.

Deficiency of alpha-galactosidase A (ceramidase) results in a disruption of the cleavage of alpha-galactosyl from the ceramide molecule. The disease is transmitted recessively, linked to the X chromosome, with the defect localized at Xq22. No ethnic features of the disease have been identified. The result of the enzymatic defect is the accumulation of unsplit tri- and dihexosylceramide, mainly in the cardiac muscle and kidneys, as well as in the vascular endothelium, pituitary gland, neurons of the brainstem, diencephalic region, nerve plexuses of the gastrointestinal tract, and skeletal muscles.

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Symptoms of Farbi disease

The disease usually manifests itself in children from one to 10 years old, possibly in adults and rarely in early childhood. The first symptoms of the disease are usually pain and burning in the arms and legs (paresthesia) occurring in the pre- or pubertal period, which can increase with contact with hot (for example, hot water) and are provoked by physical exertion, weakness, fatigue, pain in the limbs, decreased sweating, unexplained proteinuria, fever and small purple elements on the skin. Maculopapular rashes (angiokeratomas) are localized on the buttocks, in the navel area, inguinal area, in the area of the lips and fingers. Children often have vegetative disorders with vasomotor disorders up to pronounced orthostatic hypotension. Approximately 1/3 of children with Fabry disease have a joint syndrome resembling rheumatic. As the disease progresses, muscle pain and fatigue appear or increase, vision decreases (damage to the retinal vessels, cataracts), signs of damage to the cardiovascular system and kidneys appear, blood pressure increases, and by the age of 30-40, cardiac and/or renal failure develops.

Cardiovascular damage in Fabry disease is characterized by a variety of manifestations and often determines the prognosis of the disease: hypertrophic cardiomyopathy, valvular dysfunction, cardiac rhythm and conduction disturbances, thromboembolic manifestations, and renovascular hypertension may be observed.

Pain in Fabry disease can be in the form of “crises”, in the form of attacks of intense, excruciating, burning pain in the arms and legs and radiating to other parts of the body, lasting from several minutes to several days, fever, causalgia, and increased ESR.

Angiokeratomas have the appearance of a point-like, keratinized, vascular rash, no more than a few millimeters in diameter, which is localized in the navel area, on the knees, elbows, i.e. where the skin is subject to the greatest stretching. In skin biopsies in Fabry disease, edema and mucoid swelling of the walls of skin vessels, pronounced telangiectasias, degeneration and death of endotheliocytes, compensatory proliferation of pericytes and hyperplasia of mast cells are detected. At the ultrastructural level, transformation of endotheliocytes and pericytes into depocytes is detected due to accumulation in the cytoplasm of large specific polymorphic granules of varying electron density with fine regular striation, pathognomonic for Fabry disease. The complex of the listed structural changes can be interpreted as a manifestation of systemic vasculopathy. Most often, angiokeratomas occur in adolescence and in some cases may be the first manifestation of the disease.

One of the first symptoms may also be a characteristic corneal symptom in the form of a star, revealed with a slit lamp and not affecting visual acuity.

Hypertrophic cardiomyopathy in Fabry disease is most often non-obstructive symmetrical, less often - obstructive or apical. In some cases, hypertrophic cardiomyopathy in adolescents can occur in isolation without angiokeratosis and proteinuria. Fabry disease can be suspected in cases of unclear cardiomegaly with a combination of a shortened PR interval (less than or equal to 0.12 s), high ventricular complex voltage in the left chest leads and giant negative T waves. In the case of vasorenal hypertension, myocardial hypertrophy, along with a specific lesion (accumulation of glycolipids), is associated with persistent arterial hypertension and causes left ventricular failure. With excessive hypertrophy of the interventricular septum (usually more than 20 mm), an obstructive form of hypertrophic cardiopathy develops.

Echocardiographic examination reveals myocardial compaction with "granular" inclusions, hypertrophy of the interventricular septum and posterior wall of the left ventricle. Myocardial scintigraphy with TL-201 reveals an increase in isotope entry into the myocardium, primarily in the apex of the heart, caused by the deposition of glycosphingolipids and recorded even before the development of obvious cardiac hypertrophy. Light microscopy of endomyocardial biopsy of the right ventricle reveals vacuolization of the cytoplasm, and electron microscopy reveals electron-dense myelin-like deposits.

Valvular dysfunction most often manifests itself as aortic insufficiency associated with the deposition of phospholipid deposits in the valve stroma or, less commonly, due to dilation of the aortic root.

Approximately 50% of patients have mitral valve prolapse in combination with aortic dilation and latent cardiomyopathy.

Heart rhythm and conduction disturbances are manifested by various variants of heterotopic arrhythmias and blocks and are associated with damage to the sinus and atrioventricular nodes. Weakness of the sinus node, manifested by pathological bradycardia, atrial fibrillation/flutter, transverse atrioventricular block and their combination, are possible. Weakness of the sinus and atrioventricular nodes underlie the syndrome of sudden death in patients with Fabry disease.

Thromboembolic disorders are associated with increased platelet aggregation and high levels of beta-thromboglobulins in the blood plasma. Deep peripheral vein thrombosis and portal system thromboembolism in the pulmonary artery system are more common.

Renal dysfunction, associated primarily with the deposition of glycolipids in the endothelium of the renal glomeruli, is manifested by arterial hypertension, proteinuria and the subsequent development of chronic renal failure.

Often with Fabry disease, abdominal pain occurs after eating, nausea, and diarrhea.

Diagnosis of Fabry disease

The diagnosis in male patients is clinical, based on the presence of typical skin lesions (angiokeratomas) in the lower torso, as well as characteristic signs of peripheral neuropathy (causing burning pain in the extremities), corneal opacity, and recurrent episodes of fever to febrile levels. Death occurs due to renal failure or cardiac or cerebral complications of hypertension or other vascular lesions. Heterozygous females are usually clinically asymptomatic, but may have a mild form of the disease, often characterized by corneal opacity.

Diagnosis is based on testing for galactosidase activity, either prenatally in amnyocytes or chorionic villi or postnatally in serum or leukocytes.

The most accessible method for diagnosing Fabry disease is to determine alpha-galactosidase activity in leukocytes or cultured skin fibroblasts. The study of biopsy material, including skin and kidneys, is also of diagnostic significance. Prenatal diagnosis of the disease is possible by determining alpha-galactosidase activity in cultured cells obtained from amniotic fluid.

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Treatment of Fabry disease

The most promising therapy to date is replacement therapy using recombinant human alpha-galactosidase A, which is administered intravenously once every two weeks. Significant effectiveness has been demonstrated with the drug, which is expressed both in a decrease (up to complete disappearance) of glycolipid deposition in the vascular endothelium and in a decrease in the severity of clinical manifestations of the disease. Treatment with Fabrazyme is supplemented by the prescription of symptomatic agents, however, if it is impossible to use this drug, symptomatic therapy becomes the main one and is determined by the nature of clinical manifestations in a particular patient. Kidney transplantation is effective in the treatment of renal failure.