What is Gaucher disease?

Gaucher disease (named after Phillippe Gaucher, who reported the disease in 18821) is a sphingolipidosis, a type of lysosomal storage disease.2 The sphingolipidoses represent a group of inherited disorders caused by genetic defects in the system of lysosomal sphingolipid catabolism, which lead to a build-up of non-degraded compounds in one or more organs.3,4 Along with glycerophospholipids and cholesterol, sphingolipids form the building blocks of eukaryotic membranes.3 The addition of a carbohydrate group to ceramide (N-acylsphingosine) forms a glycosphingolipid.5 Glycosphingolipids are pivotal for the development and survival of multicellular organisms, and are also involved in cell adhesion and protein regulation.3,6,7

Gaucher disease is recognised as the most common form of the sphingolipidoses, and describes a multisystemic chronic disease involving the liver, spleen, bone marrow and lymph nodes with familial aggregation. Based on age at onset, clinical signs, and the presence, rate of progression or absence of neurological disease, different forms of Gaucher disease have been identified8:

What causes Gaucher disease?

Gaucher disease is caused by mutations in the GBA1 gene located on chromosome 1 (see genetic inheritance of Gaucher disease). Mutations in this gene lead to a marked reduction in the activity of the lysosomal enzyme glucocerebrosidase , which hydrolyses glucosylceramide into ceramide and glucose2 (Figure 1). Glucosylceramide is a ubiquitous glycosphingolipid that forms the basic building block for globoside and ganglioside complexes, which are important components of cell membranes, embedded receptors and lipid rafts.9,10

Figure 1.
Hydrolysis of glucosylceramide by glucocerebrosidase in the lysosome2

In Gaucher disease, a deficiency in glucocerebrosidase leads to an accumulation of glucosylceramide in lysosomes (Figure 2). Glucosylceramide then forms fibrillary aggregates that accumulate in macrophages, leading to the cell cytoplasm presenting a characteristic ‘crumpled tissue paper’ appearance. These cells are known as Gaucher cells and infiltrate many organs, including the bone marrow, spleen and liver, leading to the clinical manifestations of Gaucher disease.2 For instance, an abundance of Gaucher cells in bone marrow causes displacement of normal haematopoietic cells, and may lead to fibrosis, infarction, necrosis and scarring in other tissues. However, the presence of Gaucher cells does not fully explain the entire pathophysiology of Gaucher disease. Despite their large, swollen appearance, Gaucher cells are not inert storage containers but are metabolically active cells that can produce and secrete proteins to drive other pathophysiological processes.11 Indicators of macrophage activation (e.g., CC chemokine ligand 18 [CCL18], cluster of differentiation [CD]163, chitotriosidase, macrophage colony-stimulating factor and soluble CD14) have been observed in patients with Gaucher disease.12-14 Moreover, there is evidence to suggest that pro-inflammatory macrophages surround Gaucher cells and are recruited to storage lesions.11 Additionally, glucosylsphingosine (lyso-Gb1), a metabolic precursor of glucosylceramide synthesis, is elevated in patients with Gaucher disease and can act as disease biomarker.15,16 Following long-term subcutaneous infusion of glucosylsphingosine (lyso-Gb1) into mice, levels of glucosylsphingosine (lyso-Gb1) are elevated to concentrations similar to those observed in patients with moderate-to-severe Gaucher disease.17,18 Moreover, mice infused with glucosylsphingosine (lyso-Gb1) develop blood and splenic phenotypes similar to mouse models of Gaucher disease Type 1, suggesting a role for glucosylsphingosine (lyso-Gb1) in Gaucher disease pathophysiology.17

Figure 2.
In Gaucher disease, a deficiency in glucocerebrosidase functioning leads to accumulation of glucosylceramide in lysosomes and engorged macrophages19

C-ANPROM/INT//7566; Date of preparation: September 2020

 
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WORLDSymposiumTM 2022 congress reports

 

The WORLDSymposium™ was held as a hybrid meeting this year (7–11 February 2022) and brought together key opinion leaders from the field of lysosomal disorders and rare diseases.

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Diagnosing Gaucher disease


Early diagnosis is essential in implementing the appropriate patient assessment and management plans as soon as possible.

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Diagnosing Gaucher disease in siblings


Early diagnosis can reduce the likelihood of irreversible organ damage and serious complications, as well as chronic pain and disabling symptoms. Genetic counselling and carrier testing can help to achieve this.

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Gene therapy


New treatment modalities are currently being researched for Gaucher disease. The feasibility of gene therapy for Gaucher disease is currently under investigation.

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BURDEN OF DISEASE

Gaucher disease Type 1

What is Gaucher disease
Type 1?

Gaucher disease Type 1 is the most common form of the disease and may present at any stage throughout the lifespan. The clinical manifestations of Gaucher disease Type 1 include hepatomegaly, splenomegaly, thrombocytopaenia, anaemia and skeletal pathology.

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BURDEN OF DISEASE

Gaucher disease Type 2

What is Gaucher disease
Type 2?

Gaucher disease Type 2 typically affects children who present with severe neurological abnormalities before age 6 months. The primary non-neurological signs of Gaucher disease Type 2 include splenomegaly, thrombocytopaenia and lung disease. The average age of death of children with Gaucher disease Type 2 is less than 12 months; patients may die either from pneumopathy or from apnoea.

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BURDEN OF DISEASE

Gaucher disease Type 3

What is Gaucher disease
Type 3?

Gaucher disease Type 3 manifests in childhood and progresses slowly throughout the lifespan. In addition to visceral, haematological and skeletal disease manifestations, patients with Gaucher disease Type 3 develop neurological abnormalities. Neurological involvement is variable in patients with Gaucher disease Type 3; horizontal ophthalmoplegia may be the first neurological presenting symptom.

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