Gaucher Disease

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Continuing Education Activity

Gaucher disease is an autosomal recessive inborn error of metabolism due to the toxic accumulation of glucocerebroside lipids in various organs. It results from mutations in the GBA1 gene resulting in a lysosomal deficiency of glucocerebrosidase activity. This activity reviews the evaluation and management of the Gaucher disease and highlights the role of interprofessional team members in collaborating to provide well-coordinated care and enhance patient outcomes.


  • Describe the common physical findings associated with Gaucher disease.
  • Summarize the epidemiology of Gaucher disease.
  • Outline the treatment options for Gaucher disease.
  • Review the importance of coordination amongst interprofessional team members to maintain the health of the patient affected by Gaucher disease.


Gaucher disease (pronounced as GO-SHEY) is an autosomal recessive inborn error of metabolism caused by mutations in the glucocerebrosidase (GBA1) gene [1]. GBA1 is an enzyme that cleaves beta-glucosidic linkage of glucocerebroside lipids. Inborn errors of metabolism are particularly relevant in pediatrics since their presentation is very often (but not always) in the neonatal period of infancy. There are five known types of Gaucher disease: type 1, type 2, type 3, perinatal lethal and cardiovascular. The perinatal lethal form is the most severe and its complications can begin before birth or in early infancy.

Knowing the major manifestations of any inborn error of metabolism is the key to making a diagnosis. Inborn errors of metabolism primarily result from the lack (or insufficient levels) of specific enzymes needed: (1) convert fat or carbohydrates to energy or to; (2) breakdown amino acids or other metabolites, allowing them to accumulate and become toxic if not treated. Gaucher disease is a “toxic accumulation” inborn error of metabolism due to the accumulation of glucocerebroside lipids. It is the most common cause of lysosomal storage diseases. Lysosomes are subcellular organelles responsible for the physiological turnover of cell constituents. Toxic accumulation inborn errors of metabolism fall into three major categories, localized toxicity, circulating toxicity or a combination of both. Gaucher disease is an example of localized toxicity.


The underlying cause of all forms of Gaucher disease is mutations in the GBA1 gene resulting in a lysosomal deficiency of glucocerebrosidase activity. All forms of Gaucher disease lead to the toxic accumulation of glucocerebroside lipids, primarily in the liver, spleen, and bone marrow. A glucocerebroside is composed of a glucose molecule linked to the oxygen atom on carbon atom 1 of the sphingosine moiety of ceramide. All forms of Gaucher disease are also classified as lysosomal storage disorders. There are at least 40 other lysosomal storage disorders including mucopolysaccharidosis, Tay-Sachs disease, and Fabry disease [2]. All lysosomal storage disorders tend to get worse over time, in other words, they are progressive. Lysosomes are spherical intracellular organelles where many lipids and macromolecules are delivered for degradation by hydrolytic enzymes. Lysosomes are abundant in macrophages. The lysosomes in the macrophages of patients with Gaucher disease become progressively enlarged and filled with undigested glucocerebroside. The lysosomes can eventually be filled with undigested lipids that resemble “crumpled tissue paper” when visualized by electron microscopy. In the absence of appropriate treatment, the liver can expand two-fold to three-fold its normal size and the spleen by 15-fold.

Despite knowing the precise genetic causes of most forms of Gaucher disease, the exact cause remains unknown. It is possible for patients with the same mutation to have very different signs and symptoms. It is also possible for patients with similar signs and symptoms to have very different genetic mutations. Environmental factors, as well as an individual's particular genetic makeup, most likely influence the phenotypic expression of Gaucher disease.


Gaucher disease is the most common autosomal recessive disease in the Ashkenazi (Eastern European) Jewish population with a carrier frequency of 6% compared to 0.7% to 0.8% of the non-Jewish population. Cystic fibrosis (4% carrier frequency) and Tay-Sachs Disease (3.7% carrier frequency) are also common in the Ashkenazi population.

The most common form of Gaucher disease is type 1 which has a very variable phenotype ranging from early childhood symptoms to no symptoms throughout life but typically does not have a neurological component. In contrast to type 1, both type 2 and 3 are rare and do affect the central nervous system. Both type 2 and the perinatal lethal typically result in neonatal death whereas type 3 results in mid to early adulthood death.


The signs and symptoms of Gaucher disease can be classified into visceral, hematologic, skeletal, and metabolic components. The visceral components include enlarged liver and spleen (hepatosplenomegaly).

Hematological components can include thrombocytopenia, anemia, and leukopenia. Cerebroside accumulation in the bone marrow is thought to decrease platelet production resulting in low platelet count. Similarly, cerebroside accumulation in the spleen is thought to result in an excessive break down of red blood cells resulting in anemia as well as more active removal of white blood cells (WBC) resulting in a low WBC count. The rapid and premature destruction of blood cells can lead to an increased risk of bleeding and infections.

The skeletal components can include bone crisis, the death of bone cells (called avascular necrosis or osteonecrosis), a low bone density compared to normal peak density, pathological bone fracture, and Erlenmeyer flask deformity. Much of these skeletal abnormalities are attributed to the buildup of glucocerebroside-laden macrophages in the bone-marrow where they restrict blood flow and the delivery nutrients and oxygen which can result in intense pain, bone cell necrosis, low bone density, and growth abnormalities.


Classic glycolipid-laden macrophages are found in liver biopsy and bone marrow samples.

Liver biopsy samples typically reveal glycolipid-laden Gaucher cells evident in the sinusoids, but the hepatocytes do not manifest overt glycolipid storage because of biliary excretion of glucocerebroside and because exogenous glycolipid turnover is typically handled by the mononuclear phagocytes. As hepatocytes are spared, there is a very low incidence of liver failure in individuals with Gaucher disease.

The pathologic hallmark of Gaucher disease is Gaucher cells in the macrophage-monocyte system typically found in the bone marrow. These cells have a characteristic wrinkled-paper appearance, resulting from intracytoplasmic substrate deposition, and stain positive with periodic acid–Schiff. Histologic evaluation should not be used as a primary diagnostic tool.

History and Physical

Gaucher disease can present with several signs and symptoms, depending on the underlying type. Commonly seen presenting symptoms are as follows:

  • Painless hepatomegaly and splenomegaly
  • Hypersplenism and pancytopenia
  • Severe joint pains, most frequently affecting hips and knees.
  • Impaired olfaction and cognition (Type I)
  • Serious convulsions, hypertonia, intellectual disability, and apnea (Type II)
  • Myoclonus, seizures, dementia, and ocular muscle apraxia (Type III)
  • Parkinsonism
  • Osteoporosis
  • Yellowish-brown skin pigmentation

The diagnosis of Gaucher disease depends upon finding a low GBA1 enzyme level in peripheral blood leukocytes as well as establishing the presence of mutant alleles in the GBA1 gene. Despite the fact that only a blood sample is needed to diagnosis Gaucher disease, some patients undergo unnecessary invasive bone marrow or liver biopsy before making a correct diagnosis. Physician awareness of the signs and symptoms of Gaucher disease can help avoid such mishaps. Moreover, before an accurate diagnosis is made, many patients with an enlarged liver or spleen are told they could have cancer.


Laboratory Studies

CBC Count

  • CBC and platelet count will access the degree of cytopenia.

Liver Function Enzyme Testing

  • Mild elevation of liver enzyme levels is common; the presence of jaundice or abnormal hepatocellular synthetic function merits further study.


  • Regular monitoring should be performed.

Enzyme Activity

  • Diagnosis is confirmed through measurement of glucocerebrosidase activity in peripheral blood leukocytes. Less than 15% of mean normal activity is diagnostic.

Genotype Testing

  • Molecular diagnosis is often helpful in Ashkenazi patients, in whom 6 GBA1 mutations (c.84insG, L444P, N370S,  IVS2+1g>a, V394L, and R496H) account for most disease alleles.
  • In some ethnicities, sequencing of the exons of GBA1 may be necessary in order to establish the genotype.
  • Mutation analysis has limited predictive value with respect to Gaucher disease progression. Avoid relying on PCR-based tests for individual mutations because they do not reveal the presence of recombinant alleles associated with greater severity of the disease.

Associated Marker Testing

  • Angiotensin-converting enzyme, total acid phosphatase, and ferritin levels are usually elevated. These levels may normalize with treatment.
  • Monitoring chitotriosidase enzyme is useful except in the 10% of the population that has a deficiency in this protein.
  • Monitoring glucosylsphingosine levels may be useful, as the level has been shown to correlate with response to therapy.


  • Ultrasonography - may reveal abdominal organomegaly.
  • MRI - may be useful in revealing early skeletal involvement (avascular necrosis, spinal degradation, and degree of bone marrow infiltration.
  • Radiography - may reveal skeletal manifestations and pulmonary involvement.
  • Dual-energy x-ray absorptiometry - may evaluate osteopenia and bone crises.
  • Echocardiograms are helpful in evaluating the possibility of pulmonary hypertension.
  • In neuronopathic Gaucher disease, monitoring of EEG, brainstem-evoked potential, swallowing studies, and neuro-ophthalmologic evaluation should be done at regular intervals.

Bone Marrow Aspiration

  • In the past, the diagnosis was made by finding classic glycolipid-laden macrophages in bone marrow aspirate. Today, aspiration is not typically needed due to alternative less invasive tests.
  • Bone marrow aspiration is not the initial diagnostic test because the blood enzyme test is more sensitive, specific, less invasive.

Liver Biopsy

  • Liver biopsy may be performed to evaluate unexplained hepatomegaly. However, a biopsy is rarely needed because a specific diagnostic test is available.

Treatment / Management

Treatment for Gaucher disease falls into two categories, enzyme replacement therapy, and substrate reduction therapy.[3] In general, enzyme replacement therapy provides an intravenous infusion containing the enzyme that is deficient or absent in the body. In the case of Gaucher disease, this would be the GBA1 enzyme (also called beta-glucosylceramidase or beta-glucocerebrosidase). The FDA has approved both Cerezyme (imiglucerase) and VPRIV (velaglucerase alfa) for Gaucher disease type 1 and 3 enzyme replacement therapy. Enzyme replacement therapy typically cannot replace an enzyme deficient in the brain due to the blood-brain barrier and therefore is not effective for treating the central nervous system problems associated with type 2 and 3 Gaucher disease. Enzyme replacement therapy will help with the “non-brain” signs and symptoms associated with type 3 Gaucher disease, e.g., enlarged organs and skeletal issues.

Enzyme replacement therapy does not correct the underlying genetic defect and acts only to relieve signs, symptoms, and ongoing damage caused by the accumulation of toxins. Moreover, it is possible to develop antibodies to the replacement enzyme.

Substrate reduction therapy is an orally administered small-molecule drug (not protein) that relies on a strategy distinct from that of enzyme replacement therapy. In substrate reduction therapy the goal is to reduce the levels of a substrate such that toxic accumulation of the substrate’s subsequent degradative product is diminished to a level that is clinically less toxic. In the case of Gaucher disease, the goal is to use substrate reduction therapies that can inhibit the first committed step in glycosphingolipid biosynthesis. There are two FDA-approved substrate reduction therapy drugs to treat patients with Gaucher disease, i.e., eliglustat and miglustat. Eliglustat, a glucosylceramide synthase inhibitor, does not effectively cross the blood-brain barrier is indicated only for type 1 Gaucher disease.[4] It is not yet known if eliglustat is safe or effective in children. Miglustat can cross the blood-brain barrier and could, therefore, be potentially beneficial for type 2 and 3 Gaucher disease. Nevertheless, miglustat is currently indicated only for the treatment of mild to moderate type 1 Gaucher disease only in adults.

Differential Diagnosis

  • Multiple myeloma
  • Lewy body dementia
  • Niemann-Pick disease
  • Parkinson disease
  • Sphingomyelinase deficiency

Enhancing Healthcare Team Outcomes

Evaluation and treatment of Gaucher disease is difficult and requires a coordinated team approach of physicians, nurse practitioners, and physician assistants to maintain the health of the patient. [Level V]

Article Details

Article Author

William L. Stone

Article Author

Hajira Basit

Article Editor:

Samip R. Master


6/7/2022 6:50:50 PM



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