Gaucher's disease

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Gaucher's disease
Classification and external resources
Acid beta glucosidase.png
Acid beta-glucosidase
ICD-10E75.2 (ILDS E75.220)
OMIM230800 230900 231000
eMedicineped/837 derm/709
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Gaucher's disease
Classification and external resources
Acid beta glucosidase.png
Acid beta-glucosidase
ICD-10E75.2 (ILDS E75.220)
OMIM230800 230900 231000
eMedicineped/837 derm/709

Gaucher's disease or Gaucher disease (/ɡˈʃ/) is a genetic disease in which a fatty substance (lipid) accumulates in cells and certain organs. The disorder is characterized by bruising, fatigue, anemia, low blood platelets, and enlargement of the liver and spleen. It is caused by a hereditary deficiency of the enzyme glucocerebrosidase. This enzyme acts on the glycolipid glucocerebroside. When the enzyme is defective, glucosylceramide accumulates, particularly in white blood cells, most often macrophages (mononuclear leukocytes). Glucosylceramide can collect in the spleen, liver, kidneys, lungs, brain and bone marrow.

Manifestations may include enlarged spleen and liver, liver malfunction, skeletal disorders and bone lesions that may be painful, severe neurologic complications, swelling of lymph nodes and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin, anemia, low blood platelets and yellow fatty deposits on the white of the eye (sclera). Persons affected most seriously may also be more susceptible to infection. Some forms of Gaucher's disease may be treated with enzyme replacement therapy.

The disease is caused by a recessive mutation in a gene located on chromosome 1 and affects both males and females. About 1 in 100 people in the United States are carriers of the most common type of Gaucher disease. The carrier rate among Ashkenazi Jews is 8.9% while the birth incidence is 1 in 450.[1]

Gaucher's disease is the most common of the lysosomal storage diseases.[2]:536 It is a form of sphingolipidosis (a subgroup of lysosomal storage diseases), as it involves dysfunctional metabolism of sphingolipids.

The disease is named after the French doctor Philippe Gaucher, who originally described it in 1882.[3]


Gaucher's disease has three common clinical subtypes.

These subtypes have come under some criticism for not taking account of the full spectrum of observable symptoms (the phenotypes.[5]) There are also compound heterozygous variations which considerably increase the complexity of predicting disease course.

Signs and symptoms[edit]


The disease is caused by a defect in housekeeping gene lysosomal glucocerebrosidase (also known as beta-glucosidase, EC, PDB 1OGS) on the first chromosome (1q22). The enzyme is a 55.6 KD, 497 amino acids long protein that catalyses the breakdown of glucosylceramide, a cell membrane constituent of red and white blood cells. The macrophages that clear these cells are unable to eliminate the waste product, which accumulates in fibrils, and turn into Gaucher cells, which appear on light microscopy to resemble crumpled-up paper.

In the brain (type II and III), glucosylceramidase accumulates due to the turnover of complex lipids during brain development and the formation of the myelin sheath of nerves.

Different mutations in the beta-glucosidase determine the remaining activity of the enzyme, and, to a large extent, the phenotype.

Heterozygotes for particular acid beta-glucosidase mutations carry about a fivefold risk of developing Parkinson's disease, making this the most common known genetic risk-factor for Parkinson's.[6][7] A study of 1525 Gaucher patients in the United States suggested that while cancer risk is not elevated, particular malignancies (non-Hodgkin lymphoma, melanoma and pancreatic cancer) occurred at a 2-3 times higher rate.[8]


The three types of Gaucher's disease are inherited in an autosomal recessive fashion. Both parents must be carriers in order for a child to be affected. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families who may be carriers of mutations.

Each type has been linked to particular mutations. In all, there are about 80 known mutations, grouped into three main types:[9]

Diaz et al. suggest that the Gaucher-causing mutations entered the Ashkenazi Jewish gene pool in the early Middle Ages (48-55 generations ago).[13]


Micrograph showing crinkled paper macrophages in the marrow space in a case of Gaucher disease. H&E stain.

Gaucher disease is suggested based on the overall clinical picture. Initial laboratory testing may include enzyme testing. Decreased enzyme levels will often be confirmed by genetic testing. As there are numerous different mutations, sequencing of the beta-glucosidase gene is sometimes necessary to confirm the diagnosis. Prenatal diagnosis is available, and is useful when there is a known genetic risk factor.

A diagnosis can also be implied by biochemical abnormalities such as high alkaline phosphatase, angiotensin-converting enzyme (ACE) and immunoglobulin levels, or by cell analysis showing "crinkled paper" cytoplasm and glycolipid-laden macrophages.

Some lysosomal enzymes are elevated, including tartrate-resistant acid phosphatase, hexosaminidase, and a human chitinase, chitotriosidase. This latter enzyme has proved to be very useful for monitoring Gaucher's disease activity in response to treatment, and may reflect the severity of the disease


For type 1 and most type 3 patients, enzyme replacement treatment with intravenous recombinant glucocerebrosidase (imiglucerase) can dramatically decrease liver and spleen size, reduce skeletal abnormalities, and reverse other manifestations. This treatment costs approximately US$200,000 annually for a single patient and should be continued for life. The rarity of the disease means that dose-finding studies have been difficult to conduct, so there remains controversy over the optimal dose and dosing frequency.[10] Due to the low incidence, this has become an orphan drug in many countries, meaning that a government recognizes and accommodates the financial constraints that limit research into drugs that address a small population. Velaglucerase alfa was approved by the Food and Drug Administration (FDA) as an alternative treatment in February 2010.[14] In May 2012 the FDA approved an additional treatment – Taliglucerase alfa, or Elelyso.[15]

Successful bone marrow transplantation cures the non-neurological manifestations of the disease, because it introduces a monocyte population with active beta-glucosidase. However, this procedure carries significant risk and is rarely performed in Gaucher patients. Surgery to remove the spleen (splenectomy) may be required on rare occasions if the patient is anemic or when the enlarged organ affects the patient’s comfort. Blood transfusion may benefit some anemic patients. Other patients may require joint replacement surgery to improve mobility and quality of life. Other treatment options include antibiotics for infections, antiepileptics for seizures, bisphosphonates for bone lesions, and liver transplants. Substrate reduction therapy may prove to be effective in stopping Type 2, as it can cross through the blood barrier into the brain. There is currently no effective treatment for the severe brain damage that may occur in patients with types 2 and 3 Gaucher disease. Gene therapy may be a future step.

Gaucher's disease has recently become a target for more than one effort at pharmacological chaperoning, which involves the use of orally administered drugs that operate at a molecular level. Miglustat is one of these oral drugs. It was approved for the treatment of this disease in 2003. As of June 2009, another oral drug, isofagomine tartrate, is under development.


The National Gaucher Foundation (United States) states that the incidence of Gaucher's disease is about 1 in 20,000 live births.[16] Around 1 in 100 people in the general U.S. population is a carrier for type 1 Gaucher's disease, giving a prevalence of 1 in 40,000.[17] Among Ashkenazi Jews the rate of carriers is considerably higher, at roughly 1 in 15.[17]

Type 2 Gaucher's disease shows no particular preference for any ethnic group.

Type 3 Gaucher's disease is especially common in the population of the Northern Swedish region of Norrbotten where the incidence of the disease is 1 in 50,000.[18]


The disease was first recognized by the French doctor Philippe Gaucher, who originally described it in 1882 and lent his name to the condition.[3] The biochemical basis for the disease was elucidated in 1965.[19] The first effective treatment for the disease, the drug alglucerase (Ceredase), was approved by the FDA in April 1991. An improved drug, imiglucerase (Cerezyme), was approved by the FDA in May 1994 and has replaced the use of Ceredase.

October marks National Gaucher's Disease Awareness Month in the United States.


See also[edit]


  1. ^ Zimran A, Gelbart T, Westwood B, Grabowski GA, Beutler E (1991). "High frequency of the Gaucher disease mutation at nucleotide 1226 among Ashkenazi Jews". Am. J. Hum. Genet. 49 (4): 855–859. PMC 1683177. PMID 1897529. 
  2. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0. 
  3. ^ a b Gaucher PCE (1882). De l'epithelioma primitif de la rate, hypertrophie idiopathique de la rate sans leucemie [academic thesis]. Paris, France. 
  4. ^ Dreborg, Sten; Erikson, Anders; Hagberg, Bengt (29 February 1980). "Gaucher disease-norrbottnian type". European Journal of Pediatrics 133 (2): 107–118. doi:10.1007/BF00441578. PMID 7363908. 
  5. ^ [1][dead link]
  6. ^ Jacquelyn K Beals (November 19, 2008). "ASHG 2008: Gaucher Disease Mutation Carriers at Higher Risk for Parkinson's Disease". Medscape Medical News. 
  7. ^ Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R (2004). "Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews". N. Engl. J. Med. 351 (19): 1972–7. doi:10.1056/NEJMoa033277. PMID 15525722. 
  8. ^ Landgren O, Turesson I, Gridley G, Caporaso NE (2007). "Risk of Malignant Disease Among 1525 Adult Male US Veterans With Gaucher Disease". Archives of Internal Medicine 167 (11): 1189–1194. doi:10.1001/archinte.167.11.1189. PMID 17563029. 
  9. ^ Online 'Mendelian Inheritance in Man' (OMIM) 606463
  10. ^ a b Grabowski GA (2008). "Phenotype, diagnosis, and treatment of Gaucher's disease". Lancet 372 (9645): 1263–1271. doi:10.1016/S0140-6736(08)61522-6. PMID 19094956. 
  11. ^ Weinreb NJ, Deegan P, Kacena KA, et al. (December 2008). "Life expectancy in Gaucher disease type 1". Am. J. Hematol. 83 (12): 896–900. doi:10.1002/ajh.21305. PMC 3743399. PMID 18980271. 
  12. ^ Dahl, N; Lagerström, M; Erikson, A; Pettersson, U (August 1990). "Gaucher disease type III (Norrbottnian type) is caused by a single mutation in exon 10 of the glucocerebrosidase gene". American journal of human genetics 47 (2): 275–8. PMC 1683716. PMID 2378352. 
  13. ^ Diaz GA, Gelb BD, Risch N, et al. (2000). "Gaucher disease: the origins of the Ashkenazi Jewish N370S and 84GG acid beta-glucosidase mutations". Am. J. Hum. Genet. 66 (6): 1821–32. doi:10.1086/302946. PMC 1378046. PMID 10777718. 
  14. ^ "Shire Announces FDA Approval Of VPRIV(TM) (velaglucerase Alfa For Injection) For The Treatment Of Type 1 Gaucher Disease". Retrieved 2012-08-13. 
  15. ^ Yukhananov, Anna (1 May 2012). "U.S. FDA approves Pfizer/Protalix drug for Gaucher". Chicago Tribune. Reuters. Retrieved 2 May 2012. 
  16. ^ Gaucher Disease at National Gaucher Foundation. Retrieved June 2012
  17. ^ a b "National Gaucher Foundation". Retrieved 2007-05-30. 
  18. ^ "Gaucher disease - Affected population". NORD - National Organization for Rare Disorders. Retrieved 21 September 2013. 
  19. ^ Brady RO, Kanfer JN, Shapiro D (1965). "Metabolism of glucosylceramidase. II. Evidence of an enzymatic deficiency in Gaucher's disease". Biochem. Biophys. Res. Commun. 18 (2): 221–5. doi:10.1016/0006-291X(65)90743-6. PMID 14282020. 

20. McNeill A, Duran R, Proukakis C, et al. Hyposmia and cognitive impairment in Gaucher disease. Mov Disord 2012a; 27(4):526-32.;jsessionid=C01DC8815868224B03C4630874E1C50E.f02t02 21. McNeill A, Duran R, Hughes DA, et al. A clinical and family history study of Parkinson's disease in heterozygous glucocerebrosidase mutation carriers. J Neurol Neurosurg Psych 2012b; ;83(8):853-4.

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