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Gaucher disease

Wednesday 1 October 2003

Definition: Gaucher disease refers to a cluster of autosomal recessive disorders resulting from mutations in the gene encoding glucocerebrosidase. Acid beta-glucocerebrosidase, also known as beta-glucosidase (GBA) (EC, is a lysosomal enzyme that catalyzes the breakdown of the glycolipid glucosylceramide to ceramide and glucose.

This disease is the most common lysosomal storage disorder. The affected gene encodes glucocerebrosidase, an enzyme that normally cleaves the glucose residue from ceramide.


- Gaucher cells in Gaucher disease

Digital slides

- JRC:3544 : Gaucher disease type 1.


- Gaucher disease in bone marrow


- Gaucher disease type 1 (MIM.230800)
- Gaucher disease type 2 (MIM.230900)
- Gaucher disease type 3 (MIM.231000)
- perinatal lethal Gaucher disease (608013)


- Gaucher cells
- Kupffer cells with striated or corrugated cytoplasm


- gaucher cells with membrane-bound spindled, tubular inclusions


- fetal Gaucher disease (9745785)


As a result, glucocerebroside accumulates principally in the phagocytic cells of the body but in some forms also in the central nervous system.

Glucocerebrosides are continually formed from the catabolism of glycolipids derived mainly from the cell membranes of senescent leukocytes and erythrocytes. Three clinical subtypes of Gaucher disease have been distinguished.

The most common, accounting for 99% of cases, is called type I, or the chronic non-neuronopathic form. In this type, storage of glucocerebrosides is limited to the mononuclear phagocytes throughout the body without involving the brain. Splenic and skeletal involvements dominate this pattern of the disease. It is found principally in Jews of European stock. Patients with this disorder have reduced but detectable levels of glucocerebrosidase activity. Longevity is shortened but not markedly.

Type II, or acute neuronopathic Gaucher disease, is the infantile acute cerebral pattern. This infantile form has no predilection for Jews. In these patients, there is virtually no detectable glucocerebrosidase activity in the tissues.

Hepatosplenomegaly is also seen in this form of Gaucher disease, but the clinical picture is dominated by progressive central nervous system involvement, leading to death at an early age. A third pattern, type III, is sometimes distinguished, intermediate between types I and II.

These patients are usually juveniles and have the systemic involvement characteristic of type I but have progressive central nervous system disease that usually begins in the teens or twenties.

These specific patterns run within families, resulting from different allelic mutations in the structural gene for the enzyme.


The glucocerebrosides accumulate in massive amounts within phagocytic cells throughout the body in all forms of Gaucher disease. The distended phagocytic cells, known as Gaucher cells, are found in the spleen, liver, bone marrow, lymph nodes, tonsils, thymus, and Peyer patches. Similar cells may be found in both the alveolar septa and the air spaces in the lung.

In contrast to the lipid storage diseases already discussed, Gaucher cells rarely appear vacuolated but instead have a fibrillary type of cytoplasm likened to crumpled tissue paper.

Gaucher cells are often enlarged, sometimes up to 100 μm in diameter, and have one or more dark, eccentrically placed nuclei. Periodic acid-Schiff (PAS) staining is usually intensely positive. With the electron microscope, the fibrillary cytoplasm can be resolved as elongated, distended lysosomes, containing the stored lipid in stacks of bilayers.2

The accumulation of Gaucher cells produces a variety of gross anatomic changes. The spleen is enlarged in the type I variant, sometimes up to 10 kg. It may appear uniformly pale or have a mottled surface owing to focal accumulations of Gaucher cells. The lymphadenopathy is mild to moderate and is body-wide.

The accumulations of Gaucher cells in the bone marrow may produce small focal areas of bone erosion or large, soft, gray tumorous masses that cause skeletal deformities or destroy sufficient bone to give rise to fractures. In patients with cerebral involvement, Gaucher cells are seen in the Virchow-Robin spaces, and arterioles are surrounded by swollen adventitial cells.

There is no storage of lipids in the neurons, yet neurons appear shriveled and are progressively destroyed. It is suspected that the lipids that accumulate in the phagocytic cells around blood vessels are in some manner toxic to neural tissue.

The clinical course of Gaucher disease depends on the clinical subtype. In type I, symptoms and signs first appear in adult life and are related to splenomegaly or bone involvement. Most commonly, there is pancytopenia or thrombocytopenia secondary to hypersplenism. Pathologic fractures and bone pain occur if there has been extensive expansion of the marrow space.

Although the disease is progressive in the adult, it is compatible with long life. In types II and III, central nervous system dysfunction, convulsions, and progressive mental deterioration dominate, although organs such as the liver, spleen, and lymph nodes are also affected.

The diagnosis of homozygotes can be made by measurement of glucocerebrosidase activity in peripheral blood leukocytes or in extracts of cultured skin fibroblasts.

Because there is substantial overlap between the enzyme levels in normal individuals and heterozygotes, such assays are not reliable for carrier detection. In principle, detection of specific mutations can be used for detecting heterozygotes. Because more than 150 allelic mutations can cause Gaucher disease, however, it is not possible to use a single genetic test.

Chitotriosidase, an enzyme synthesized by macrophages, is markedly elevated in patients with Gaucher disease. It is a reasonably specific biomarker for Gaucher disease because levels are only slightly elevated in other disorders affecting macrophages.


- Eblan MJ, Goker-Alpan O, Sidransky E. Perinatal lethal Gaucher disease: a distinct phenotype along the neuronopathic continuum. Fetal Pediatr Pathol. 2005 Jul-Aug;24(4):205-22. PMID: 16396828