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  • Updated 12.28.2019
  • Released 12.28.1993
  • Expires For CME 12.28.2022

Gaucher disease


This article includes discussion of Gaucher disease, acid beta-glucocerebrosidase deficiency, familial splenic anemia, glucocerebrosidase deficiency, glucosylceramide lipidosis, histiocytosis, and Norrbottnian disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


Gaucher disease is a storage disorder caused by mutations in the GBA1 gene, which codes for lysosomal acid beta-glucocerebrosidase (glucocerebrosidase), resulting in accumulation of glucosylceramide (glucocerebroside). Type 2 (acute neuronopathic) and type 3 (chronic neuronopathic) Gaucher disease are in a phenotypic continuum of neurologic abnormalities with variable courses. Sudden unexpected death and unusual behavior may occur in Gaucher type 3, particularly in Egyptian patients. Enzyme replacement therapy has no effect on the neurologic complications of the disease. CSF glycoprotein nonmetastatic B (GPNMB) may be used to quantify neurologic involvement in Gaucher disease. Mutations in the GBA1 gene are the most common genetic risk factor for adult-onset, isolated Parkinson disease; multiple system atrophy; and dementia with Lewy bodies. Substrate reduction therapy, pharmacological chaperone therapy, and gene therapy for neuronopathic Gaucher disease are currently being tested or are in the advanced planning stages.

Key points

• Neuronopathic Gaucher disease has a very wide clinical spectrum--from congenital and early infantile Gaucher disease type 2 to very mild with horizontal supranuclear gaze palsy as the only neurologic abnormality and normal or even superior intelligence.

• Current treatment for the non-neuronopathic and for the chronic neuronopathic forms of the disease includes enzyme replacement, which targets only the non-neurologic aspects of the disease.

• Substrate synthesis reduction has shown to be effective in controlling the non-neurologic aspects of Gaucher disease, and the approach is being tried in Gaucher disease type 3 patients.

• Adult-onset, isolated Parkinson disease; multiple system atrophy; and dementia with Lewy bodies are not features of neuronopathic Gaucher disease. Rather, GBA1 mutations are a risk factor for developing these neurodegenerative diseases.

Historical note and terminology

The first example of Gaucher disease was documented in a patient with hepatosplenomegaly. The case was described in the doctoral thesis of Philippe C E Gaucher (51). The disorder was diagnosed as an epithelioma of the spleen. The characteristic appearance of storage in reticuloendothelial cells was noted as early as 1907 (83). The first step toward the description of the chemistry of the material accumulating in these cells evolved from the identification of its "lipoid" character by morphologists. Later, Epstein demonstrated that spleens from Gaucher patients yielded considerable amounts of an alcohol-soluble substance (40). In 1924, Lieb characterized this material as a cerebroside akin to the compounds described earlier by Thudichum (126; 79). The correct identification of the sugar in the sphingolipid compound was not achieved until 1934, when Aghion demonstrated that the lipid accumulating in the tissues of patients with Gaucher disease was a glucosyl, not a galactosyl, a derivative of ceramide (03).

The discovery of the lysosome as an organelle in 1955 by De Duve and colleagues changed the definition of the storage disorders. Within a short time, the first lysosomal storage disorder was described and was shown to be due to a deficiency of acid alpha-1,4-glucosidase (alpha-glucosidase) in a patient with Pompe disease (57). Other storage disorders quickly became recognized as diseases resulting from the lack of a degradative capacity—notably a lysosomal enzyme--with the expected lysosomal accumulation of substrate (58; 34). The accumulation of acid beta-glucocerebrosidase (glucocerebroside) was already well known in patients with Gaucher disease. Attention was focused on the possibility that the material accumulated because of a specific deficiency in its degradative pathway, leading to the description of the enzyme deficiency in 1965 (19; 100). It had been recognized that a variety of clinical disorders were related to glucocerebroside storage. Although these subtypes were originally thought to be distinguished by the relative amount of residual enzyme present (118; 141), experience has shown that this is incorrect.

The discovery of the enzyme deficiency led to the development of several approaches to understand the biology of the lysosomes and to the development of enzyme replacement therapy to replace the missing gene product. The development of this treatment and the steps that have been taken toward gene transfer in Gaucher disease will be reviewed later in this summary.

Note on nomenclature. This summary follows the current guidelines for gene and protein nomenclature and for mutation description. Please see Gene and mutation nomenclature for those guidelines. The enzyme, acid beta-glucocerebrosidase (GBA) is often referred to as glucocerebrosidase in the literature. The description of mutations in the older literature refers to the processed protein after excision of the 39 amino acid leader peptide. The current guidelines for mutation nomenclature stipulate that numbering begins with the leader peptide.

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