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Gaucher disease
Medical expert of the article
Last reviewed: 12.07.2025
Gaucher disease is a sphingolipidosis resulting from a deficiency of glucocerebrosidase, which results in the deposition of glucocerebroside and related components. Symptoms of Gaucher disease vary depending on the type, but most commonly include hepatosplenomegaly or CNS changes. Diagnosis is based on white blood cell enzyme testing.
Gaucher disease is a rare autosomal recessive disorder first described in 1882 and occurs primarily in Ashkenazi Jews. It is the most common lysosomal storage disorder caused by a deficiency of the enzyme beta-glucocerebrosidase in lysosomes. This deficiency results in the accumulation of the enzyme substrate in the cells of the reticuloendothelial system throughout the body, particularly 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 common (among Ashkenazi Jews 1:500-2000) type of the disease. The central nervous system is not affected.
- Type 2 (affects children, acute course with neuronal damage) is rare. In addition to visceral lesions, massive fatal damage to the nervous system is observed. Children die in infancy.
- Type 3 (juvenile, has a subacute course with neuronal damage) is also rare. It is characterized by gradual and uneven involvement of the nervous system.
The polymorphism of Gaucher disease is due to a variety of mutations in the structural glucocerebrosidase gene on chromosome 1, although disease of varying severity can also be observed within one specific genotype. The key role in the degree of damage is attributed to the macrophage reaction in response to the accumulation of glucocerebroside, but its mechanisms are unknown. However, a complete analysis of specific gene mutations allows us to predict the clinical course of the disease with the identified genotypes.
A typical Gaucher cell is approximately 70-80 µm in diameter, oval or polygonal in shape, and has pale cytoplasm. It contains two or more hyperchromatic nuclei displaced toward the periphery, with fibrils running parallel to each other between them. The Gaucher cell differs significantly from the foam cells of xanthomatosis or Niemann-Pick disease.
Electron microscopic examination. Accumulating beta-glucocerebroside, formed from disintegrating cell membranes, precipitates in lysosomes and forms long (20-40 mm) tubes that are visible under light microscopy. Similar cells can be found in chronic myeloid leukemia and myeloma, in which beta-glucocerebroside metabolism is accelerated.
Symptoms of Gaucher disease
Normally, glucocerebrosidase hydrolyzes glucocerebrosides to form glucose and ceramides. Genetic defects of the enzyme lead to accumulation of glucocerebrosides in tissue macrophages during phagocytosis, forming Gaucher cells. Accumulation of Gaucher cells in perivascular spaces in the brain causes gliosis in neuronopathic forms. Three types are known, differing in epidemiology, enzyme activity and manifestations.
Type I (non-neuropathic) is the most common (90% of patients).
Residual enzyme activity is highest. Ashkenazi Jews are at highest risk; carrier frequency is 1:12. Onset varies from age 2 to old age. Symptoms and signs include splenomegaly, bone changes (eg, osteopenia, pain crises, osteolytic changes with fractures), failure to thrive, late puberty, and ecchymosis. Epistaxis and ecchymosis secondary to thrombocytopenia are common. Radiographs show widening of the ends of the long bones (Erlenmeyer flask deformity) and thinning of the cortical plate.
Type II (acute neuronopathic) is the rarest and has the lowest residual enzyme activity. Clinical manifestations appear in infancy. Symptoms and signs include progressive neurological impairment (eg, rigidity, seizures) and death by age two.
Type III (subacute neuronopathic) is intermediate in frequency, enzyme activity, and clinical severity. Symptoms appear in childhood. Clinical manifestations vary by subtype and include progressive dementia and ataxia (Ilia), bone and visceral involvement (Nib), and supranuclear palsy with corneal opacity (Shc). If the patient survives adolescence, he or she may live a long time.
Diagnosis of Gaucher disease
Diagnosis is based on the study of white blood cell enzymes. Carrier status is identified and types are differentiated based on mutation analysis. Although a biopsy is not necessary, Gaucher cells are diagnostic - lipid-laden tissue macrophages in the liver, spleen, lymph nodes or bone marrow that have a characteristic wrinkled or papery appearance.
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Treatment of Gaucher disease
Enzyme replacement therapy with placental or recombinant glucocerebrosidase is effective in types I and III; there is no treatment for type II. The enzyme is modified to ensure efficient delivery to lysosomes. Patients receiving enzyme replacement therapy require routine monitoring of hemoglobin and platelet levels; routine assessment of liver and spleen size using CT or MRI; and routine assessment of bone lesions using bone scan, dualenergy x-ray absorptiometry scanning, or MRI.
Miglustat (100 mg orally three times daily), a glucosylceramide synthetase inhibitor, reduces glucocerebroside (a substrate for glucocerebrosidase) levels and is an alternative for patients who cannot receive enzyme replacement therapy.
Splenectomy may be effective for patients with anemia, leukopenia, or thrombocytopenia, or if the enlarged spleen causes discomfort. Patients with anemia may also require blood transfusions.
Bone marrow or stem cell transplantation provides a curative cure for patients with Gaucher disease, but is considered a last resort because morbidity and mortality are significant.