Gaucher disease

Raphael Schiffmann MD (Dr. Schiffmann, Director of the Institute of Metabolic Disease at Baylor Research Institute, received research grants from Amicus Therapeutics, Protalix Biotherapeutics, and Shire.)
Originally released December 28, 1993; last updated November 28, 2016; expires November 28, 2019

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 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 Parkinson disease and other synucleinopathies. Glucocerebrosidase activity in brain and peripheral blood is low in Parkinson patients compared to controls.

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.


• Mutations of the GBA1 gene are the most frequent genetic risk factor for Parkinson disease and other synucleinopathies.

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 (Gaucher 1882). The disorder was diagnosed as an epithelioma of the spleen. The characteristic appearance of storage in reticuloendothelial cells was noted as early as 1907 (Marchand 1907). 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 (Epstein 1924). In 1924, Lieb characterized this material as a cerebroside akin to the compounds described earlier by Thudichum (Thudichum 1901; Lieb 1924). 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 (Aghion 1934).

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 (Hers 1963). 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 (Hers 1965; De Duve 1983). 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 (Brady et al 1965; Patrick 1965). 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 (Snyder and Brady 1969; Wenger and Olson 1981), 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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