Fabry's disease

Fabry's disease (synonyms: Fabry disease, Anderson disease, diffuse angiokeratoma) is sphingolipidosis caused by deficiency of alpha-galactosidase A, which develops angiokeratomas, acroparesthesia, corneal opacity, recurrent episodes of fever to febrile digits , as well as renal or heart failure.

Deficiency of a-galactosidase A (ceramidase) leads to a violation of the cleavage of a-galactosyl from the ceramide molecule. The disease is transmitted recessively, linked to the X-chromosome, with localization of the defect Xq22. There were no ethnic peculiarities of the disease. The result of the enzymatic defect is the accumulation of uncleaved tri-and dihexosylceramide, mainly the heart muscle and kidneys, as well as in the vascular endothelium, pituitary gland, brain stem neurons, diencephalic region, nerve plexuses of the gastrointestinal tract, in skeletal muscles.

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Symptoms of Farby's Disease

The disease manifests itself usually in children from one year to 10 years, possibly in adults and rarely at an early age. The first symptoms of the disease are usually soreness and burning sensation in the hands and feet (paresthesia) arising in the pre- or pubertal period, which can be intensified by contact with hot (for example, hot water) and provoked by physical exertion, weakness, fatigue in the limbs, decreased sweating , unexplained proteinuria, fever and small purple elements on the skin. Maculopapular eruptions (angiokeratomes) are localized on the buttocks, in the navel, groin area, in the region of the lips and fingers. In children, vegetative disorders with vasomotor disturbances up to a pronounced orthostatic hypotension are not uncommon. Approximately one-third of children with Fabry's disease have articular syndrome resembling rheumatic fever. As the disease progresses, muscle pains, fatigue, vision decrease (retinal vascular injury, cataracts) appear or grow, cardiovascular system, kidney damage appears, blood pressure rises, and by the age of 30-40 years, cardiac and / or renal failure.

The defeat of the cardiovascular system in the case of Fabry disease is characterized by a variety of manifestations and often determines the prognosis of the disease: hypertrophic cardiomyopathy, valvular dysfunction, heart rhythm and conduction disorders, thromboembolic manifestations, renovascular hypertension can be observed.

Pain in Fabry's disease can be characterized as "crises", in the form of attacks of intense painful burning pains in the hands and feet and irradiating to other parts of the body, lasting from several minutes to several days, fever, causalgia, and acceleration of ESR.

Angiokeratomes have the form of a point, as if keratinized, rash of a vascular nature, not exceeding a few millimeters in diameter, which is localized in the navel, on the knees, elbows, ie. Where the skin is subjected to the greatest stretching. In skin biopsies in Fabry's disease, edema and mucoid swelling of the walls of the skin vessels are revealed, expressed by telangiectasia, degeneration and death of endotheliocytes, compensatory proliferation of recurrences and hyperplasia of mast cells. At the ultrastructural level, the transformation of endotheliocytes and pericytes into depotsity is observed in connection with the accumulation in the cytoplasm of large specific polymorphic granules of varying electron density with fine regular striation, pathognomonic for Fabry's disease. The complex of 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 can also be a characteristic corneal symptom in the form of an asterisk, identified by a slit lamp, and not affecting visual acuity.

Hypertrophic cardiomyopathy in Fabry's disease is most often non-obstructive symmetrical, less often - obstructive or apical. In some cases, hypertrophic cardiomyopathy in adolescents can occur in isolation without the effects of angiokeratosis and proteinuria. Fabry's disease can be suspected in cases of vague cardiomegaly with a combination of a shortened PR interval (less than or equal to 0.12 s), a high voltage of the ventricular complex in the left thoracic leads and giant negative T wave. In 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.

When echocardiographic study, the myocardial compaction with "granular" inclusion, hypertrophy of the interventricular septum and the posterior wall of the left ventricle are sealed. In myocardial scintigraphy with TL-201, an increase in the isotope intake in the myocardium is observed mainly in the region of the apex of the heart, caused by the deposition of glycosphingolipids and recorded before the development of obvious cardiac hypertrophy. Light microscopy of the endomyocardial biopsy specimen of the right ventricle reveals the vacuolization of the cytoplasm, and electron microscopy is electronically dense myelin-like deposits.

Valvular dysfunction is most often manifested by aortic insufficiency associated with the deposition of phospholipid deposits in the stroma of the valve, or, more rarely, in connection with dilatation of the root of the aorta.

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

Heart rhythm and conduction disorders are manifested by various variants of heterotopic arrhythmias and blockades and are associated with damage to the sinus and atrioventricular nodes. Possible weakness of the sinus node, manifested pathological bradycardia, flickering / fluttering of the atria, transverse atrioventricular blockade and their combination. The weakness of the sinus and atrioventricular nodes underlies the syndrome of sudden death of patients with Fabry disease.

Thromboembolic disorders are associated with increased platelet aggregation and a high level of beta-thromboglobulin in the blood plasma. Thrombosis of deep peripheral veins and portal system of thromboembolism are more common in the pulmonary artery system.

Abnormalities in kidney function, primarily associated with the deposition of glycolipids in the endothelium of the vessels of the renal glomeruli, are manifested by arterial hypertension, proteinuria and the subsequent development of chronic renal failure.

Often, with Fabry's disease, there are abdominal pains that occur after eating, nausea, diarrhea.

Fabry disease diagnosis

Diagnosis in male patients is clinical, based on the presence of typical skin lesions (angiokera) in the lower part of the trunk, as well as the characteristic signs of peripheral neuropathy (causing stinging pain in the extremities), corneal opacities and recurrent episodes of fever to febrile figures. Death occurs due to kidney failure or cardiac or cerebral complications of hypertension or other vascular lesions. In heterozygous women, as a rule, there are no clinical manifestations, but they may have a mild form of the disease, often characterized by opacity of the cornea.

The diagnosis is based on a study of the activity of galactosidase - prenatally in the amniotic or chorionic villus or postnatally in serum or leukocytes.

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

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Treating Fabry's Disease

The most promising for today is substitution therapy with the use of recombinant human alpha-galactosidase A, which is administered intravenously once every two weeks. A significant efficacy in the use of the drug is shown, which is expressed both in the reduction (up to complete disappearance) of the deposition of glycolipids in the vascular endothelium, and in the reduction in the severity of the clinical manifestations of the disease. Treatment with Fabrazin is supplemented by the appointment of symptomatic drugs, but when it is not possible to use this drug, symptomatic therapy becomes the main and is determined by the nature of the clinical manifestations in a particular patient. Kidney transplantation is effective in treating renal failure.