Gaucher's disease

Gaucher's disease is sphingolipidosis, which is a consequence of a deficiency of glucocerebrosidase, which leads to the deposition of glucocerebroside and its associated components. Symptoms of Gauchers disease vary depending on the type, but most often include hepatosplenomegaly or changes in the CNS. The diagnosis is based on the study of leukocyte enzymes.

Gaucher's disease is a rare disease, inherited by an autosomal recessive type, first described in 1882; is found mainly in Ashkenazi Jews. It is the most frequent lysosomal accumulation disease caused by a deficiency in the lysosomes of the enzyme beta-glucocerebrosidase. This deficiency leads to the accumulation of the substrate of this enzyme in the cells of the reticuloendothelial system of the whole organism, especially in the cells of the liver, bone marrow and spleen.

There are 3 types of Gaucher disease.

• Type 1 (observed in adults, has a chronic course) is not accompanied by neuronopathy - the mildest and most frequent (among Ashkenazi Jews 1: 500-2000) type of disease. The central nervous system is not affected.
• Type 2 (children suffer, acute course with neuronal damage) is rare. In addition to visceral lesions, there is a massive fatal lesion of the nervous system. Children die in infancy.
• Type 3 (juvenile, has a subacute current with lesions of neurons) is also rare. It is characterized by a gradual and uneven involvement of the nervous system.

Polymorphism of Gaucher disease is caused by a variety of mutations in the structural gene of glucocerebrosidase on chromosome 1, although a different severity of disease can be observed within one specific genotype. A key role in the degree of damage is given to the macrophage reaction in response to the accumulation of glucocerebroside, but its mechanisms are unknown. However, a complete analysis of specific mutations of the gene allows predicting the clinical course of the disease with the revealed genotypes.

A typical Gaucher cell has a diameter of approximately 70-80 μm, an oval or polygonal shape and a pale cytoplasm. It contains two or more hyperchromic nuclei, displaced toward the periphery, between which fibrils pass parallel to each other. The Gaucher cell differs significantly from the foam cells in xanthomatosis or Niemann-Pick disease.

Electron-microscopic examination. Accumulating beta-glucocerebroside, formed from decomposing cell membranes, precipitates in lysosomes and forms long (20-40 mm) tubules that can be seen with light microscopy. Similar cells can be found in chronic myelogenous leukemia and myeloma, in which the metabolism of beta-glucocerebroside is accelerated.

[1], [2], [3], [4], [5]

Symptoms of Gaucher Disease

Normally, glucocerebrosidase hydrolyses glucocerebrosides with the formation of glucose and ceramides. Genetic defects of the enzyme lead to the accumulation of glucocerebrosides in tissue macrophages with phagocytosis, forming Gaucher cells. Accumulation of Gaucher cells in the perivascular spaces in the brain causes gliosis in neuronopathic forms. Three types are known, differing in epidemiology, enzyme activity and manifestations.

I type (not neuropathic) is the most common (90% of patients).

The residual activity of the enzyme is the highest. The Ashkenazi Jews are at the highest risk; the frequency of carriage among them is 1:12. The onset of manifestations varies from a two-year-old to an old age. Symptoms and signs include splenomegaly, bone changes (eg, osteopenia, pain crises, osteolytic changes with fractures), delay in physical development, later puberty, ecchymosis. Nasal bleeding and ecchymosis, which are a consequence of thrombocytopenia, occur frequently. On the roentgenogram, the broadening of the ends of long bones (deformation in the form of an Erlenmeyer flask) and the thinning of the cortical plate are revealed.

Type II (acute neuronopathic) is the most rare, the residual activity of the enzyme is the lowest. Clinical manifestations appear in infancy. Symptoms and signs include progressive neurological disorders (eg, stiffness, convulsions) and death by the age of two.

III type (subacute neuronopathic) occupies an intermediate position in frequency, enzyme activity and clinical severity. Symptoms appear in childhood. Clinical manifestations vary depending on the subtype and include progressive dementia and ataxia (Ilia), lesions of bones and internal organs (Nib) and supernuclear palsy with opacity of the cornea (Hs). If the patient is experiencing an adolescent period, in the future he can live a long time.

Symptoms of Gaucher Disease

Diagnosis of Gaucher's Disease

The diagnosis is based on the study of leukocyte enzymes. The carrier is identified, and the types are distinguished on the basis of mutational analysis. Although there is no need for biopsy, Gaucher cells-lipid-laden tissue macrophages in the liver, spleen, lymph nodes, or bone marrow, that have the characteristic appearance of wrinkled tissue or paper, have diagnostic significance.

Diagnosis of Gaucher's Disease

[6]

Treatment of Gaucher Disease

Substitutional enzyme therapy using placental or recombinant glucocerebrosidase is effective in types I and III; at the II type of treatment does not exist. The enzyme is modified to efficiently deliver it to the lysosomes. Patients receiving replacement enzyme therapy need routine monitoring of hemoglobin and platelet levels; routine assessment of liver and spleen sizes using CT or MRI; routine evaluation of bone lesions with the use of examination of the bone system, dual-energy x-ray absorptiometry scanning (MRI).

Miglustat (100 mg orally three times a day), an inhibitor of glucosylceramide synthetase, reduces the concentration of glucocerebroside (a substrate for glucocerebrosidase) and is an alternative for patients who can not receive replacement enzyme therapy.

Splenectomy can be effective for patients with anemia, leukopenia or thrombocytopenia or if an enlarged spleen causes discomfort. Patients with anemia may also need transfusion of blood products.

Treatment of Gaucher Disease

Transplantation of bone marrow or stem cells provides a radical cure for patients who have Gaucher disease, but it is considered the last hope, since the incidence and mortality are significant.