Welcome to the NORD Physician Guide to Gaucher Disease. The NORD Online Physician Guides are written for physicians by physicians with expertise on specific rare disorders. This guide was written by Roscoe O. Brady, MD, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH) (see acknowledgements for additional information).
NORD is a nonprofit organization representing all patients and families affected by rare diseases. The information NORD provides to medical professionals is intended to facilitate timely diagnosis and treatment for patients.
Gaucher disease is a lipid storage disease caused by an enzyme deficiency that results in excess glycolipid glucocerebroside throughout the body especially in the spleen, liver and bone marrow, and is characterized by a wide range of severity.
There are three distinct forms of Gaucher disease classified by the absence (type 1) or presence and extent (type 2 or type 3) of neurological complications.
Gaucher disease should be considered in persons with enlargement of the spleen and liver. Additional major signs include anemia, easy bruising, episodes of bone pain and fractures of the femur and pelvis.
Enzyme replacement therapy (ERT) has proven highly effective for individuals with Gaucher disease type 1.
What Is Gaucher Disease?
Gaucher disease is a rare, inherited metabolic disorder in which deficiency of the enzyme glucocerebrosidase results in the accumulation of harmful quantities of certain lipids, specifically the glycolipid glucocerebroside, throughout the body especially within the spleen, liver, and bone marrow. The symptoms and physical findings associated with Gaucher disease vary greatly from case to case. Some individuals develop few or no symptoms and others may have serious complications. Common manifestations of Gaucher disease include hepatosplenomegaly, anemia, thrombocytopenia, and skeletal abnormalities. Three clinical presentations of Gaucher disease have been identified that are distinguished by the absence of, or the presence and extent of, neurological involvement. All three forms of Gaucher disease are inherited as autosomal recessive traits.
Gaucher disease is categorized as a lysosomal storage disorder. Lysosomes are the major digestive units in cells containing enzymes that breakdown carbohydrates, lipids (fatty materials) and proteins that arise from membranes and other components of cells undergoing turnover. In Gaucher disease, glycolipids accumulate in the body because of the lack of the enzyme, glucocerebrosidase, leading to the various symptoms and physical findings associated with a lysosomal storage disease. Gaucher disease is the most common type of lysosomal storage disorder.
There are three distinct forms of Gaucher disease classified by the absence (type 1) or presence and extent (type 2 or type 3) of neurological complications. The majority of affected individuals have Gaucher disease type 1. Approximately 5% of patients have type 2 and type 3 Gaucher disease. Type 2 patients have severe brain damage and die early in life. Type 3 patients live longer and have involuntary horizontal eye movement and often muscle contractions.
One of the earliest manifestations of Gaucher disease is enlargement of the spleen. It may be small and detectable just below the rib cage or huge extending down the left side of the abdomen and palpable from left to right across the lower pelvis. The liver also becomes enlarged but not to the magnitude exhibited by the spleen. The skeleton may also be involved. The long bones, pelvis and vertebrae become under-mineralized resulting in severe deformation and easy fracturing. A considerable percentage of patients experience painful bone crises. Major manifestations occur in the circulation including severe thrombocytopenia with easy bruising and hemorrhage and moderate to severe anemia. The lungs can become involved, and pronounced dyspnea occurs in a small number of patients. Respiratory gas exchange is compromised, and diffuse pulmonary infiltration is evident radiographically. The lymph nodes may be enlarged, and infiltration of pharyngeal tonsils and Peyer’s patches in the intestine are common in children. Pericardial involvement has occasionally been noted. The kidneys are involved in some patients with Gaucher disease, but frank renal failure is uncommon. There is a well-recognized increase in certain hematological malignancies including B-cell or plasma cell malignancies, multiple myeloma, chronic lymphocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, large B-cell lymphoma, Hodgkin lymphoma, as well as non-hematologic malignancies 1. Patients that survive to adulthood have a significantly increased chance of Parkinsonism 2.
Gaucher disease type 2, also known as acute neuronopathic Gaucher disease, occurs in newborns and infants and is characterized by neurological complications due to the abnormal accumulation of glucocerebroside in the brain. Splenomegaly is often the first sign and may become apparent before six months of age. Hepatomegaly is not always present. Affected infants may lose previously acquired motor skills and exhibit hypotonia, spasticity, strabismus, rapid head thrusting and seizures. In addition, affected infants may experience dysphagia, resulting in feeding difficulties, retroflexion of the head, failure to thrive, and stridor due to laryngeal spasm. Anemia and thrombocytopenia may also occur. Gaucher disease type 2 often progresses to life-threatening complications such as respiratory distress or aspiration pneumonia. Severely affected newborns may show collodion skin or ichthyosiform changes and hydrops, with death in the first few weeks of life. Other children with type 2 Gaucher disease have greatly reduced lifespans, with death usually occurring between 1 and 3 years of life. It has been estimated that about 10 such infants are born in the U.S. each year.
Gaucher disease type 3, also known as chronic neuronopathic Gaucher disease, occurs during the first decade of life. Type 3 patients have a varying degree of early hepatosplenomegaly that may initially be moderate and in some may become extensive. In addition to the blood and bone abnormalities discussed above, affected individuals develop neurological complications that develop and progress slower than in Gaucher disease type 2. Associated neurological complications include mental deterioration, ataxia, and myoclonic seizures. Some individuals with type 3 Gaucher disease may have horizontal gaze palsy. Patients with Type 3 Gaucher disease can also have a vertical gaze palsy that usually occurs later than the horizontal gaze paresis. A significant proportion of patients also develop interstitial lung disease. There can be wide variability in presentation and clinical course among patients with type 3 Gaucher disease. Some affected patients may live into their teens and early 20′s, while others have lived for much longer (30′s and 40′s). It is anticipated that the life span may be further extended by effective treatment such as enzyme replacement therapy (vide infra).
Gaucher disease is a autosomal recessive genetic disorder caused by mutations in a gene on human chromosome 1 that codes for an enzyme that is important for lipid metabolism. Both parents must carry a mutation of the gene in order to produce a child that is affected with the disorder. Such parents are called carriers (heterozygotes). When two heterozygotes marry, there is a 1 in 4 chance with each pregnancy that the child will have the disorder. There is 50-50 chance that the child will be a heterozygote carrying a mutation from one of its parents. Gaucher heterozygotes are generally asymptomatic. There is a 25% chance with each pregnancy that the offspring will be affected (have two mutations) or be completely unaffected (no mutations).
The cause of all three forms of Gaucher disease is the accumulation of a fatty material called glucocerebroside (also known as glucosylceramide) throughout the body and blood stream of patients. Glucocerebroside is a lipid consisting of three components. The first of these is a long chain alcohol called sphingosine (Fig 1). A long chain fatty acid is linked to the nitrogen atom (N) on carbon atom 2 of sphingosine creating a structure known as ceramide (Fig. 2). A molecule of glucose is linked to the oxygen atom on carbon 1 of the sphingosine moiety of ceramide forming glucocerebroside (Fig. 3). Organs and cells in the body contain an enzyme called glucocerebrosidase that catalyzes the hydrolytic cleavage of glucose from glucocerebroside 3 (Fig. 4). The activity of this enzyme is reduced in patients with Gaucher disease and is the metabolic defect in this disorder 4,5. The reduction of glucocerebrosidase activity causes the accumulation of toxic amounts of glucocerebroside in organs, tissues and the blood of patients with Gaucher disease. The principal source of accumulating glucocerebroside in the spleen, liver and bone marrow are rapidly turning over cells such as white blood cells (Fig. 5). Glucocerebroside also arises from the biodegradation of ganglioside GM3 in platelets (Fig. 6) and from globoside, the principal sphingolipid in red blood cells (Fig. 7). The accumulation of glucosylsphingosine (Fig. 8) in the brain is a major cause of the pathological changes that occur in the central nervous system of patients with types 2 and 3 Gaucher disease 6.
Figure 1. Sphingosine
Figure 2. Ceramide. A long chain fatty acid is linked to the nitrogen atom on carbon atom 2 of sphingosine.
Figure 3. Glucocerebroside. A molecule of glucose is linked to the oxygen atom on carbon atom 1 of the sphingosine moiety of ceramide.
Figure 4. Site of action of glucocerebrosidase, the enzyme that catalyzes the hydrolytic cleavage of glucose from glucocerebroside.
Figure 5. Structure of the principal sphingolipid of white blood cells.
Figure 6. Major sphingolipid of blood platelets.
Figure 7. Major sphingolipid of red blood cells.
Figure 8. Glucosylsphingosine. A highly cytotoxic substance that also accumulates in organs and tissues of patients with Gaucher disease but to a much lesser extent than glucocerebroside.
With the exception of patients with Type 2 Gaucher disease with severe central nervous system involvement and death in infancy, the rapidity and extent of the severity of the signs and symptoms in patients with Gaucher disease is remarkably variable. The life span of patients with Type 3 Gaucher disease has been mentioned previously in the section on Symptoms and Signs. The prognosis in patients with Type 1 Gaucher disease is quite variable. Many patients develop hepatosplenomegaly as early as four years of age while in others, this manifestation may not become apparent until the mid or late thirties. Generally, the earlier the onset of prominent signs that often include anemia and thrombocytopenia, the more rapidly the pathological manifestations of the disorder proceed.
All forms of Gaucher disease affect males and females in equal numbers. Gaucher disease type 1 is the most common type, accounting for more than 90 percent of cases. Individuals with Gaucher disease type 1 usually exhibit symptoms during adolescence, but the age of onset ranges from childhood to adulthood. The age of onset for Gaucher disease type 2 is during early infancy. The age of onset of Gaucher disease type 3 varies, but the disorder generally begins during childhood or adolescence.
There are approximately 6,000 individuals with Gaucher disease in the U.S. Gaucher disease is the most common genetic disorder of persons of Ashkenazic Jewish ancestry, where the incidence may be as high as 1 in 600 births. There is no ethnic prevalence associated with Gaucher disease types 2 or 3. However, there is a subtype of Gaucher disease type 3 that occurs with greater frequency in the Norrbotten region of Sweden (Norrbottnian Gaucher disease). The estimated prevalence in the Swedish Norrbotten population is 1 in 50,000.
Gaucher disease should be considered in persons with enlargement of the spleen and liver. Additional major signs include anemia, easy bruising, episodes of bone pain and fractures of the femur and pelvis. The diagnosis can be readily confirmed by measuring the activity of glucocerebrosidase in white blood cells 7 or cultures of skin fibroblasts .8 A fluorogenic mimic of glucocerebroside was employed as substrate in the investigation with skin fibroblasts. This substrate is widely used for the diagnosis of Gaucher disease at the present time. The diagnosis may be confirmed by DNA analysis for mutations in the causal genes. The identification of heterozygous carriers of Gaucher disease 9 and the prenatal diagnosis of Gaucher disease by genetic analysis are established procedures .10
Enzyme replacement therapy (ERT) has proven highly effective for patients with type 1 Gaucher disease. Anemia and low platelet counts have improved with ERT, enlargement of the liver and spleen have been greatly reduced, and skeletal findings have improved 11-15. These systemic manifestations also improve in individuals with type 3 Gaucher disease who receive ERT 16,17. However, ERT has not been effective in reducing or reversing neurological signs associated with types 2 and 3 Gaucher disease.
ERT is the standard of care for patients with Gaucher disease. Many patients have been successfully treated with purified human placental glucocerebrosidase 11. The sugar side chains of the enzyme were shortened so that it is primarily taken up by macrophages. The use of this product has been superseded by the administration of recombinant glucocerebrosidase. The first preparation was produced in Chinese hamster ovary cells 12. This preparation is called Cerezyme (imiglucerase). It is marketed by Genzyme, a Sanofi Company. Cerezyme was approved by the Food and Drug Administration for the treatment of Gaucher disease type 1 in 1994.
At the present time there are two additional sources of glucocerebrosidase. One of them called VPRIV (velaglucerase alfa) is produced from a fibrosarcoma cell line by Shire Pharmaceuticals. The other called taliglucerase alfa is from carrot root cells produced by Protalix Biotherapeutics, an Israeli company and distributed by Pfizer, Inc. under the trade name ELELYSO (which is branded as UPLYSO™ in Latin America). America). VPRIV and ELELYSO are both FDA-approved for the treatment of Gaucher disease type 1.
In 2014, the FDA approved Cerdelga (eliglustat) for the long-term treatment of adults with Gaucher disease type 1. This drug is taken orally and slows down the production of fatty materials. Cerdelga is manufactured by Genzyme Corporation, a Sanofi company.
Administration of the enzyme causes reduction in the size of the spleen and liver and improvement of the skeleton, anemia and thrombocytopenia. Severely ill patients with type 1 Gaucher disease are generally started with a dose of 60 Units (U) of enzyme per kg of body weight every other week. As patients improve, the dose may be reduced to 30 U per kg of body weight, and in many cases to 20 U per kg of body weight every other week. The frequency of administration of enzyme has been extended to every 3 weeks in a number of patients who have been maintained in good condition with this regimen. Long term benefit of ERT in patients with type 1 Gaucher has been clearly documented 13-15. Hepatosplenomegaly and hematological manifestations can be improved by ERT in patients with type 3 Gaucher disease but neurological and other complications of the condition have not responded to this therapy 16,17.
Another approach to the treatment of patients with Gaucher disease is to try to block the formation of glucocerebroside with compounds that inhibit the addition of glucose to ceramide (Fig.2). A product of this type called Miglustat (Zavesca) is marketed by Actelion. It is approved by the FDA for the treatment of patients with Gaucher disease “for whom enzyme replacement therapy is not an option”.
Oral delivery of plant Glucocerebrosidase (prGCD) ERT as a carrot cell suspension, (expressed) is under development. Additionally, a number of investigations are directed toward reducing the formation of glucocerebroside 18-20. Molecular chaperone therapy that prevents intracellular mis-folding and subsequent destruction of mutant forms of glucocerebrosidase is also under active investigation 21. Blocking the activity of histone deacetylases may be a promising strategy to restore reduced mutant glucocerebrosidase activity 22. Future investigations may include the use of viral vectors to increase the expression of the gene for glucocerebrosidase 23.
Information on current clinical trials is posted at www.clinicaltrials.gov
NORD does not endorse or recommend any particular studies.
1. Lo SM, Stein P, Mullaly S, Bar M, Jain D, Pastores GM, Mistry PK. Expanding the spectrum of the association between Type 1 Gaucher disease and cancers: A series of patients with up to 3 sequential cancers of multiple types. Correlation with genotype and phenotype. Am J Hematol 2010; 85: 340-345.
2. Sidransky E et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med 2009; 361: 1651-1661.
3. Brady RO, Kanfer J, Shapiro D. The metabolism of glucocerebrosides. I. Purification and properties of a glucocerebroside-cleaving enzyme from spleen tissue. J Biol Chem 1965; 240: 39-42.
4. Brady RO, Kanfer JN, Shapiro, D. Metabolism of glucocerebrosides. II. Evidence of an enzymatic deficiency in Gaucher’s disease. Biochem Biophys Res Commun 1965; 18: 221-225.
5. Brady RO, Kanfer JN, Bradley RM, Shapiro D. Demonstration of a deficiency of glucocerebroside-cleaving enzyme in Gaucher’s disease. J Clin Invest 1966; 45: 1112-1115.
6. Nilsson O, Svennerholm L. Accumulation of glucosylceramide and glucosylsphingosine (psychosine) in cerebrum and cerebellum in infantile and juvenile Gaucher disease. J Neurochem 1982; 39: 709-718.
7. Kampine JP, Brady RO, Kanfer JN, Feld M, Shapiro D. The diagnosis of Gaucher’s disease and Niemann-Pick disease using small samples of venous blood. Science 1967; 155(3758):86-8.
8. Beutler E, Kuhl W, Trinidad F, Teplitz R, Nadler H. Detection of Gaucher’s disease and its carrier state from fibroblast cultures. Lancet 1970; 2(7668):369.
9. Brady RO, Johnson WG, Uhlendorf BW. Identification of heterozygous carriers of lipid storage diseases. Am J Med 1971; 51: 423-431.
10. Schneider EL, Ellis WG, Brady RO, McCulloch JR, Epstein CJ. Infantile Type II) Gaucher’s disease: in utero diagnosis and fetal pathology. J Pediatr 1972; 81: 1134-1139.
11. Barton NW, Brady RO, Dambrosia JM, DiBisceglie AM, Doppelt SH, et al. Replacement therapy for inherited enzyme deficiency — macrophage-targeted glucocerebrosidase for Gaucher’s disease. N Engl J Med 1991; 324: 1464-1470.
12. Grabowski GA, Barton NW, Pastores G, Dambrosia JM, Banerjee TK, McKee MA, Parker C, Schiffmann R, Hill SC, Brady RO. Enzyme therapy in Gaucher disease Type 1: Comparative efficacy of mannose-terminated glucocerebrosidase from natural and recombinant sources. Ann Int Med 1995; 122: 33-39.
13. Weinreb NJ, Charrow J, Andersson HC, Kaplan P, Kolodny EH, Mistry P, Pastores G, Rosenbloom BE, Scott CR, Wappner RS, Zimran A. Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry. Am J Med 2002; 113: 112-119.
14. Weinreb NJ, Goldblatt J, Villalobos J, Charrow J, Cole JA, Kerstenetzky M, Vom Dahl S, Hollak C. Long-term clinical outcomes in type 1 Gaucher disease following 10 years of imiglucerase treatment. J Inherit Metab Dis 2012 doi:10.1007/s10545-012-9528-4
15. Deegan, PB, Cox TM. Imiglucerase in the treatment of Gaucher disease: a history and perspective. Drug Design, Development and Therapy 2012; 6: 81-106.
16. Mengel E, Arnoff J, Reinke J, Beck M. Long term follow up of the Mainz cohort of Gaucher disease type 3 patients. Mol Genet Metabol 2013; 108: S65-S66.
17. Burrow Tk Witte D, Bailey L, Prada C, SunY, Cohen M, Wu, Grabowski G. Abnormal pathology findings in a patient with Gaucher disease type 3 treated with enzyme replacement therapy. Mol Genet Metab 2013; 108: S27.
18. Platt FM, Jeyakumar M. Substrate reduction therapy. Acta Paediatr Supp 2008; 97: 88-93.
19. Lukina E,Watman N, Arreguin EA, Dragosky M, Iastrebner M et al. Improvement in hematological, visceral, and skeletal manifestations of Gaucher disease type 1 with oral eliglustat tartrate (GENZ-112638) treatment: 2-year results of a phase 2 study. Blood 2011; 116: 4095-4098.
20. Larsen SD, Wilson WW, Abe A, Shu LM, George CH et al. Property-based design of a glucosylceramide synthase inhibitor that reduces glucosylceramide in the brain. J Lipid Res 2012; 53: 282-291.
21. Bendikov-Bar I, Mair G, Filocamo M, Horowitz M. Ambroxol as a pharmacological chaperone for mutant glucocerbrosidase. Blood Cells Mol Dis 2013; 50(2):141-5.
22. Lu J, Yang C, Chen M, Ye DY, Lonser RR, Brady RO, Zhuang Z. Histone deacetylase inhibitors prevent the degradation and restore the activity of glucocerebrosidase in Gaucher disease. Proc Natl Acad Sci USA 2011; 108: 21200-21205.
23. Sardi AP, Clarke J, Vial C , Chan M, Tamsett TJ et al. Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies. Proc Natl Acad Sci USA 2013; 110(9):3537-42.
Support for patients with Gaucher disease is provided by:
Support primarily devoted toward children including those with Type 3 Gaucher disease is provided by:
National Organization for Rare Disorders (NORD)
PO Box 1968
55 Kenosia Avenue
Danbury, CT 06813-1968
Telephone: (203) 744-0100 or (800) 999-NORD
E-mail: [email protected]
NORD is grateful to Roscoe O. Brady, MD, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), for writing this guide.
Dr. Brady’s accomplishments include the identification of the metabolic defects in hereditary lipid storage disorders including Gaucher disease, Niemann-Pick disease, Fabry disease, and Tay-Sachs disease.
A brief history of Dr. Brady’s pioneering role in promoting better understanding of Gaucher disease may be found at the following location on the website of the National Institutes of Health (NIH): http://history.nih.gov/exhibits/gaucher/docs/page_05.html
Roscoe Brady was born in Philadelphia, PA. He attended the Pennsylvania State University and obtained his M.D. degree from Harvard Medical School in 1947. He interned at the Hospital of the University of Pennsylvania. From 1948 to 1952 he was a post-doctoral fellow in the Department of Physiological Chemistry at the University of Pennsylvania School of Medicine and fellow in clinical medicine in the Department of Medicine. After two and one-half years on active duty in the U.S. Naval Medical Corps, he joined the National Institutes of Health in 1954. He was Chief of the Developmental and Metabolic Neurology Branch in the National Institute of Neurological Disorders and Stroke from 1972 to 2006. Dr. Brady received the Lasker Foundation Award in 1982; the Kovalenko Medal from the National Academy of Sciences USA in 1991; the Alpert Foundation Prize from Harvard Medical School in 1992 and the National Medal of Technology and Innovation in 2008.
He is a member of the National Academy of Sciences, USA and the Institute of Medicine of the National Academy of Sciences. Dr. Brady and his colleagues identified the enzymatic defects in Gaucher disease, Niemann-Pick disease, Fabry disease and the specific metabolic abnormality in Tay-Sachs disease. He and his associates developed diagnostic, carrier detection and prenatal tests for these conditions. He developed effective enzyme replacement therapy for patients with Gaucher disease and Fabry disease. He is currently investigating substrate depletion, molecular chaperone therapy and gene therapy for patients with metabolic storage disorders.
This guide was made possible through the Collaborations, Coalitions and Sponsorship Program of Pfizer.
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