Fabry disease is a hereditary disease in which a defect in the structure of genes causes insufficient activity or absence of the enzyme α–galactosidase A, accumulation of intermediate products of lipid metabolism in organs. Symptoms include pain in the extremities, decreased sweating, depression, fatigue, kidney and heart failure, acute disorders of cerebral circulation. For diagnosis, the study of enzyme activity and the amount of glycosphingolipids in blood and tissues, sequencing of genetic material is used. The treatment is based on enzyme replacement therapy.
E75.2 Other sphingolipidoses
Fabry disease got its name from the name of the German dermatologist John Fabry, who in 1898 described in detail the symptoms of pathology in a 13-year-old boy. At the same time, a similar clinical case was identified by a dermatologist from the UK, William Andersen, so the disease has another common name – Anderson-Fabry disease. Less well–known synonyms are ceramide trihexosidosis, diffuse universal angiokeratoma, hereditary dystonic lipidosis. Epidemiology depends on race and ethnicity, is 1 case per 40-120 thousand newborns. The highest prevalence is determined in the USA.
The disease is caused by a mutation of the GLA gene, which encodes the structure of the alpha-galactosidase A enzyme involved in the cleavage of glycosphingolipids. The gene is localized on the long arm of the Xq 22.1 chromosome. The polypeptide structure of the enzyme consists of 429 amino acid residues, the presence and order of which are determined by 1290 base pairs of the gene. As a result of scientific research, 599 variants of mutations and polymorphisms of the gene have been identified that alter the stability and activity of galactosidase. The most common causal mutations are missense and nonsense, they account for up to 93% of cases of the disease.
The mechanism of inheritance of pathology is defined as recessive X-linked, but continues to be studied. Hemizygous males have a single mutant X chromosome. Such a set represents the classic phenotype of the disease. Sick men are able to pass the mutation only to their daughters, sons remain healthy. Daughters who have received altered genes from a parent are heterozygous and, according to the law of recessive inheritance, must remain clinically healthy carriers. The probability of transmission of the pathological allele from the mother to children of both sexes is 50%.
In the course of clinical studies, it was found that in most women with a recessive mutant gene, the disease manifests symptoms of moderate severity, has a late onset and slow progression. Some patients have severe manifestations of pathology that require urgent medical care. The causes of the development of severe forms of the disease in heterozygous women remain unknown. There may be a phenomenon of inactivation of the normal X chromosome.
The pathogenetic basis of the disease is a deficiency of alpha–galactose A. Normally, this enzyme cleaves terminal glycolipids of a-galactosyl. In case of enzyme deficiency, intermediate metabolic products – trihexosylceramide and digalactosylceramide accumulate in cellular lysosomes. The content of ceramide-trigecoside increases significantly in endothelial and smooth muscle cells of vessels, in epithelial and perithelial cells of many organs. Digalactosyl-ceramide molecules are concentrated in the kidneys, chambers of the heart, and the central nervous system.
Thus, the basis of pathogenesis is a violation of the metabolism of membrane glycosphingolipids. Their deposition increases with an increased level of circulating lipids entering the membranes by active absorption and diffusion. The main symptoms of the disease are caused by the accumulation of metabolic products of sphingolipids in small and large vessels, include pain in the arms and legs, fever attacks, purple skin rashes. Pathological processes develop gradually, a polymorphic clinical picture is often observed in adolescents and children, in adults one organ is more affected.
Since the pathology is genetic, it begins in the prenatal period. Due to the relatively slow progression, the symptoms appear much later – by the age of 6-12 or even by the age of 30. Taking into account the time of the onset of the disease and the nature of the lesion of internal organs, two forms of the disease are distinguished:
- Classical. It begins in childhood and early adolescence. It is manifested by a multiple organ lesion.
- Atypical. Symptoms make their debut in adulthood. Isolated damage to one organ is often observed: kidneys, heart, brain. Male representatives have more pronounced signs.
- Female. This form stands out in the English-language literature. It is characterized by a slowly progressive course with mild symptoms, the absence of a leading affected organ.
Fabry disease symptoms
The most common initial symptom, which is detected in 70-80% of patients with the classic variant of pathology – acroparesthesia (neuropathic pain). They are localized in the distal parts of the feet and palms, are characterized by high intensity and duration, by nature – burning, stabbing, exhausting. There are chronic and crisis. Chronic pain is constant, but has an average intensity. Fabry crises last for several hours or days, are rapidly increasing pain attacks accompanied by hyperthermia.
In a significant part of patients, hypohidrosis and anhidrosis are observed – a decrease or complete absence of sweating. Patients do not tolerate heat well, they often overheat (for example, with crisis pains). Performance deteriorates, physical activity tolerance decreases. Sports and physical labor provoke increased pain and overheating of the body. A characteristic external sign of the disease is angioceratomas, small painless papules of reddish–purple color, which are located in clusters on the skin. Most often, the area of the lips, fingers and toes, genitals are affected.
Cardiovascular symptoms include arrhythmias, arterial hypertension, hypertrophic cardiomyopathy. Teenagers suffer from bouts of hypertension. Adult patients experience chest pain, dizziness, palpitations and shortness of breath, fainting. Kidney damage at the initial stage is asymptomatic. With a prolonged course of the disease, the filtration and concentration function of the kidneys decreases, seeking medical help often occurs already with chronic renal failure requiring hemodialysis.
Neurological symptoms are more common in adults. Headaches and dizziness are typical. Accumulation of lipid metabolism products in blood vessels causes circulatory disorders in the brain. Transient ischemic attacks and strokes occur. Ophthalmic disorders have specific features. The most common are vortex keratopathy in children and clouding of the lens (bilateral anterior and radial posterior cataracts) in older people. Possible formation of conjunctival aneurysms, retinal edema or papilloedema, optic neuritis with loss of visual fields, central scotomas. Hearing changes are represented by ringing in the ears and deterioration of sound perception. Depression and anxiety prevail in the psychoemotional sphere of patients.
Neuropathic pain in Fabry disease is hardly stopped by painkillers, therefore they cause depression, low motivation to study, professional activity and other social activity. In severe cases, acroparesthesia is provoked by minimal physical exertion or mental fatigue. As a result, children and adolescents switch to home schooling, which is accompanied by a narrowing of the circle of friends, the formation of a sense of isolation. Patients are at risk for suicide attempts. Renal, cardiovascular and cerebrovascular complications can lead to disability, death.
If Fabry disease is suspected, the patient is examined by doctors of several specialties: neurologist, cardiologist, dermatologist, geneticist. The diagnosis is established on the basis of typical clinical manifestations, burdened family history, as well as according to laboratory and instrumental diagnostics. Fabry disease is important to differentiate with collagenoses, fibromyalgia, Raynaud’s disease. Specific research methods include:
- Analysis of alpha-galactosidase activity. Blood (leukocytes), dry blood spots, kidney biopsy material, skin fibroblast culture are examined. In men, the activity of the enzyme is reduced. In women, indicators corresponding to the norm, the lower limit of the norm or slightly reduced can be determined.
- Quantitative analysis of sphingolipids. The amount of globotriazylsphingosine in blood plasma and dry blood spots is being studied. The test is widely used in screening examinations. High indicators are likely to indicate the presence of a disease. The results are used not only to confirm the diagnosis, but also to monitor the effectiveness of treatment.
- DNA sequencing. In sick men, mutations are diagnosed in the hemizygous set, in sick women or female carriers – in the heterozygous set. The GLA gene is being investigated. Detection of mutational changes in its structure is the most accurate way to diagnose Fabry disease, especially in relation to women.
- MRI of the brain. T2 images often show a high-intensity signal in the white matter of the parietal and frontal cortex. The T1-weighted image reveals a hyperintensive signal in the gray matter of deep structures. The disease is characterized by an isolated lesion of the posterior tubercle of the thalamus. In addition, vascular malformations are detected.
- ECG, Echo-KG, MRI of the heart. Hypertrophy of the left ventricle is typical, at an early stage of the disease – shortening of the P-R interval, at a late stage – atrioventricular blockade. On MRI, the contrast is visualized later on the inner surface of the left ventricle.
The only effective method of combating the disease is enzyme replacement therapy. Since the early 2000s, treatment has been carried out with recombinant alpha-galactose A preparations. Timely drug therapy can reduce the severity of neuropathic pain, reduce the severity of hypertrophy of the left heart ventricle, restore kidney functionality. Symptomatic remedies are used to improve the well-being of patients as soon as possible. Paresthesia and pain are relieved by anticonvulsants, local remedies with lidocaine.
In case of renal insufficiency and arterial hypertension, ACE inhibitors, AT1-receptor blockers, hemodialysis are prescribed. Antiplatelet agents are used to prevent thrombosis and strokes, and antiarrhythmic drugs are used for tachycardia. Treatment methods continue to be developed. Currently, the direction of genetic engineering is considered to be potentially successful. It is assumed that it will soon be possible to introduce into the cells of the human body a structurally correct gene that sets the production of the alpha subunit of galactosidase A.
Prognosis and prevention
Timely initiation of therapy ensures a favorable course of the disease: symptoms are completely stopped or remain poorly expressed, the quality of life of patients increases, women become able to conceive and bear a child. Without treatment, the average life expectancy of men is 40-60 years, women – 40-70 years. Preventive measures consist in identifying the carrier of the mutation, medical and genetic counseling of couples in which there is a partner with a confirmed diagnosis or burdened family history. At the onset of pregnancy, such couples need preimplantation and prenatal diagnostics.