What is Gaucher Disease?

An excess accumulation of a fatty substance damages organs and tissues

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Gaucher disease is a lipid storage disease caused by the accumulation of a fatty substance (sphingolipids) in organs and tissues, leading to tissue damage. This tissue damage causes bruising, fatigue, anemia, low blood platelets, and enlargement of the liver and spleen.

What are the Symptoms of Gaucher Disease?

Gaucher disease can be separated into three major clinical subtypes (1, 2 and 3) and two other subtypes (perinatal-lethal and cardiovascular) based on the symptoms of the disease. Type 1 is the most common form and occurs significantly more frequently in people of Ashkenazi Jewish heritage compared to the general population. The other subtypes are very uncommon in both Ashkenazi Jews and the general population.

Type 1 Gaucher disease is known as a non-neuronopathic form as it does not affect the brain and spinal cord but does affect other tissues and organs. Symptoms vary from mild to severe and appear anytime between childhood and adulthood. The symptoms include hepatosplenomegaly (enlargement of the liver and spleen), anemia (decreased red blood cell count), lung diseases, and excessive bruising due to low platelet numbers (thrombocytopenia). Bone diseases occur in more than 70% of affected people and can include reduced bone mass (osteopenia), eroded or thickened areas of bone (focal lytic or sclerotic lesions), breaking down of the bone (osteonecrosis) and arthritis. These bone problems can also cause episodes of deep bone pain (bone crises).

Types 2 and 3 Gaucher disease are neuronopathic forms because they involve the central nervous system. Bone disease is not present in type 2, but does occur in type 3. Type 2 disease is also known as acute or infantile form, as it causes life-threatening medical problems early in infancy and death usually occurs by 2 – 4 years old. Type 3 Gaucher disease has a later age of onset and the disease progresses much slower, with a lifespan extending into the 30s or 40s. Individuals with type 2 and 3 Gaucher disease often experience abnormal eye movement, seizures, and brain damage, along with the typical symptoms of type 1 Gaucher disease.

The most severe type of Gaucher disease (the perinatal-lethal form) causes life-threatening complications before and immediately after birth, including extensive swelling caused by fluid accumulation (hydrops fetalis), dry, scaly skin (ichthyosis) or other skin abnormalities, hepatosplenomegaly, distinctive facial features and serious neurological problems. Most infants with this form survive for only a few days after birth.

The cardiovascular type of Gaucher disease (type IIIC) causes calcification of the heart valves leading to heart problems along with other typical Gaucher disease symptoms (eye abnormalities, bone disease and mild hepatosplenomegaly). Individuals with two copies of the D409H mutation are at increased risk for the cardiovascular form of Gaucher disease.

What Causes Gaucher Disease?

Gaucher disease is a lipid storage disease caused by mutations in the GBA gene, encoding the beta-glucocerebrosidase enzyme. Beta-glucocerebrosidase normally breaks down a fatty substance called glucocerebroside into a sugar (glucose) and a simpler fat molecule (ceramide). Mutations in the GBA gene reduce or eliminate the activity of this enzyme, leading to a toxic accumulation of glucocerebroside and other related substances, causing tissue and organ damage.

This Gaucher disease panel tests for eight mutations in GBA that have been linked to Gaucher disease: L444P, N370S, 84insG, IVS2+1G>A, V394L, D409H, Delta55bp and R496H. Four of these variants, L44P, N370S, 84insG and IVS2+1G>A, occur in 90% of the Ashkenazi Jewish individuals with Gaucher disease. All of these mutations either eliminate or significantly reduce the activity of beta-glucocerebrosidase.

The mutation names used above are the commonly used names. However, sometimes the mutations may be referred to by the nucleotide change or protein amino acid change as per HGVS nomenclature, as shown in the table below.

Common Name DNA Nucleotide Change Protein Amino Acid Change (HGVS Nomenclature)


c.1448T>C p.Leu483Pro




c.1226A>G p.Asn409Ser




c.84dupG p.Leu29AlafsTer18








c.1297G>T p.Val433Leu




c.1342G>C p.Asp448His


Delta 55bp






c.1604G>A p.Arg535His



How is Gaucher Disease Diagnosed?

Many of the symptoms of Gaucher disease are similar to other common disorders, and previously the diagnosis of this disease could take an extended period. However, it is now known that an enzyme assay from a simple blood test and molecular genetic analysis of the GBA gene can provide an accurate diagnosis in a short time-frame.

Patients with Gaucher disease have beta-glucocerebrosidase activity of only 0-30% that of an unaffected healthy individual. This enzyme assay is a quick and accurate way to identify people with two defective copies of the GBA gene and the resulting reduced enzyme activity. However, the enzyme assay is not suitable for the identification of carriers – unaffected people with one defective GBA gene and one normal GBA gene. Molecular analysis of the GBA gene is required for the identification of carriers and is also a useful technique for the accurate diagnosis of affected individuals. This Gaucher disease panel tests for eight mutations (L444P, N370S, 84insG, IVS2+1G>A, V394L, D409H, Delta55bp and R496H) in GBA that affect the activity of beta-glucocerebrosidase, leading to Gaucher disease.

Other tests may also be conducted to establish the severity and progression of the disease. These analyses include blood tests to identify cell abnormalities (low red blood cell or platelet counts), and X-rays and scans to identify bone abnormalities and liver, spleen, heart and lung damage.

How is Gaucher Disease Treated?

Enzyme replacement therapy (ERT) is used to treat Gaucher disease and greatly enhances the quality of life of affected patients. ERT provides affected people with artificial beta-glucocerebrosidase, intravenously at high doses every two weeks. The artificial enzymes are usually well tolerated, however some people may experience hypersensitivity or have allergic reactions. Individuals with type 1 Gaucher disease appear to benefit from ERT the most. Individuals with type 2 usually do not respond to ERT and only minimal benefits are seen in individuals with Type 3.

Another treatment option involves substrate reduction therapy (SRT) that aims to limit the production of the substrate that beta-glucocerebrosidase usually metabolizes. SRT blocks glucosylceramide synthetase, the enzyme that produces glucocerebroside (also called glucosylceramide). The idea behind SRT is that if the glucocerebroside levels are low, even the reduced levels of beta-glucocerebrosidase in affected patients will be enough to prevent toxic accumulation of glucocerebroside. However non-specificity is a concern when using SRT, because these agents can also block the formation of other necessary glycosphingolipids in the body. Two SRT agents, miglustat and eliglustat, are currently in use. Miglustat is used to treat individuals with mild to moderate disease when ERT is not an option, due to allergy, hypersensitivity or poor venous access. It is effective in deceasing liver and spleen volume, improving platelet counts and hemoglobin levels and increasing bone density. Eliglustat is effective for individuals with type 1 disease who are currently not receiving any other therapy, as well as those previously treated with ERT. Eliglustat is not transported through the blood-brain barrier thus may not be effective for neuronopathic forms of Gaucher disease.

The effective management of Gaucher disease requires physical examinations and taking a medical history every 6-12 months. This medical history should include any weight changes, fatigue, signs of depression, changes in social, domestic, school or work related activities, bleeding, abdominal pain, shortness of breath and bone pain. Neurological exams are key to detecting type 2 and 3 disease early in children. Hemoglobin concentrations and platelet counts should be taken regularly, as well as other blood tests to check liver enzymes, iron, ferritin, and vitamins B12 and D levels. Liver and spleen volumes should be monitored using MRI or CT and EKG and echocardiography with Doppler studies should be done to screen for pulmonary hypertension.

Recommended Links:
Ferreira JC, Schreiber-Agus N, Carter SM, Klugman S, Gregg AR, Gross SJ. (2014) Carrier testing for Ashkenazi Jewish disorders in the prenatal setting: navigating the genetic maze. Am J Obstet Gynecol. 211(3): 197-204.

Hruska KS, LaMarca ME, Scott C, Sidransky E. (2008) Gaucher Disease: Mutation and Polymorphism Spectrum in the Glucocerebrosidase Gene (GBA). Hum Mutat. 29(5): 567-583.

Pastores GM, Hughes DA. (2000) [Updated 2015 Feb 26]. Gaucher Disease. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.