Gaucher's disease

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Definition

Gaucher disease is a rare genetic disorder that results in accumulation of fatty molecules called cerebrosides. It can have serious effects on numerous body organs including the liver, spleen, bones and central nervous system. Treatments based on molecular biology are becoming available, but are very expensive.

Description

Gaucher disease was first described by the French physician Philippe Gaucher in 1882. It is the most common of a class of diseases called lysosomal storage diseases, each of which is characterized by the accumulation of a specific chemical substance (a different substance depending on the exact disease). Gaucher disease is characterized by a wide array of different symptoms and the severity of the disease ranges from undetectable to lethal.

Three forms of the disease are recognized: Types I, II and III. Type I is by far the most common and shows the mildest symptoms. It is non-neuronopathic, meaning that the nervous system is not attacked. The onset of Type I can occur at any age in childhood or adult life with the average age of onset at about 21 years. Some affected individuals are have no symptoms throughout adult life. Type II, the infantile form, accounts for less than 1% of patients with Gaucher disease. It is neuronopathic (attacks the nervous system); nervous system effects are severe, and victims often die within the first year of life. Type III most often has its onset during childhood and has some of the features of both the adult and infantile forms. This affects less than 5% of persons with Gaucher disease.

Gaucher disease is caused by the absence, or near absence, of activity of an enzyme called glucocerebrosidase (GC). The normal action of GC is to break down a common molecule called glucocerebroside. If not broken down, glucocerebroside accumulates in certain cells to levels that can cause damage, especially in the spleen, liver, and bone. The common link among these organs is that they house a cell type called a macrophage. A macrophage is a large cell that surrounds and consumes a foreign substance (such as bacteria) in the body. The cellular structures in which glucocerebroside accumulates are called lysosomes.

The three forms of Gaucher disease also differ in their population genetics. Type I is most common in persons of eastern European (Ashkenazi) Jewish descent. Among this population, the disease occurs at a rate of one in 450 live births and about one in 10 to 15 persons are carriers, making it the most common genetic disease affecting Jewish people. The other two types are equally frequent in all ethnic groups. Type II occurs at a rate of one in 100,000 live births, while Type III is estimated to occur in one in 50,000 live births.

— Amy Vance

(medicine) A rare chronic, probably hereditary disease in which cells loaded with cerebrosides become localized in reticuloendothelial tissue and eventually cause tissue destruction; manifestations include enlargement of the spleen, bronzing of the skin, and anemia. Also known as cerebroside lipoidosis; familial splenic anemia.

Definition

Gaucher disease is a rare, inherited disorder in which a deficient or missing enzyme causes an abnormal buildup of a fatty substance called glucosylceramide throughout the body. Abnormal accumulations of this substance are toxic to organs and tissues, resulting in progressive, permanent damage.

Description

Gaucher disease belongs to a group of conditions called lipid storage diseases. Lipids are fatty substances used throughout the body. In lipid storage diseases, enzymes that would ordinarily break down lipids so that they can be appropriately used are absent. This results in the progressive accumulation of large quantities of these lipids.

In Gaucher disease, the specific type of lipid that accumulates is called a glucosylceramide. Deficient activity of an enzyme called beta-glucosidase results in glucosylceramide accumulation throughout the body and damage to normal tissues and organs.

There are three types of Gaucher disease. Type 1 is the most common. Each type has a characteristic age of onset and constellation of symptoms.

Demographics

In the general population, one in 50,000–100,000 develop Gaucher disease. However, Gaucher type 1 disease is considerably more common among Jewish people from eastern and central Europe (Ashkenazi Jews), affecting one in 500–1,000 individuals.

Causes and symptoms

Gaucher disease is an inherited disease, caused by a defective GBA gene. The disease is recessive, meaning that a child has to inherit a defective gene from both the mother and the father in order to have the actual condition.

Type 1 affects both children and adults. Its major manifestations include easy bruising, anemia, fatigue, liver and/or spleen enlargement, bone and joint pain, joint problems, and increased risk of bone fractures.

Type 2 usually begins to show symptoms during infancy. This type causes many of the same symptoms seen in type 1 (easy bruising, anemia, liver and/or spleen enlargement), but it also results in severe and progressive neurological problems. Damage to the central nervous system results in seizures, difficulty walking, paralyzed eye muscles, and progressive dementia. Most patients with type 2 disease die by about age two.

Type 3 causes the same kinds of symptoms seen in type 2, but the neurological involvement is more mild and the progression is more gradual.

Diagnosis

Diagnosis of Gaucher disease can be made by performing a bone marrow examination, and identifying specific "Gaucher cells" within the specimen. Other cells can be examined to demonstrate decreased activity of the enzyme beta-glucosidase. DNA testing can also reveal the specific mutation responsible for the disease, particularly within Ashkenazi Jewish populations.

Treatment team

The treatment team may vary, depending on the patient's specific symptoms. Early in the diagnostic phase, a geneticist may be helpful. If neurological problems predominate, a neurologist will be necessary. A hematologist may be consulted to handle the blood-related complications such as anemia. Other specialists may include an ophthalmologist, orthopedic surgeon, physical and occupational therapists, and speech and language therapist.

Treatment

Symptomatic treatment may include blood transfusions to treat anemia, removal of the enlarged spleen, and joint replacement. Some patients have been cured via bone marrow transplant, but this procedure carries a very high risk of complications and death, and requires a carefully matched donor, which can be difficult to find.

Newer treatments include enzyme replacement therapy. While not curative, intravenous enzyme replacement can decrease the severity of, or reverse, many of the complications of type 1 disease, including liver/spleen enlargement, anemia, neurologic problems, and bone abnormalities. Severe brain damage cannot be reversed, however.

Clinical trials

A variety of clinical trials on Gaucher disease are being conducted, including testing of a medicine called OGT918 that may slow or decrease the accumulation of lipids, hopefully with improved neurological outcomes. Other clinical trials are evaluating the outcome of treatment with enzyme replacement therapy in Gaucher disease types 2 and 3, the effect of alendronate sodium on bone disease in Gaucher disease, and the short- and longer-term outcome of bone marrow or umbilical cord blood transplantation in children with Gaucher disease.

Prognosis

The prognosis of Gaucher disease depends on the specific type. Because type 1 has no neurologic manifestations, it has the best prognosis. Lifespan depends on the severity of the complications, but some patients live into the 70s or 80s. Type 2 is universally fatal, generally by about age two. Patients with type 3 generally survive until about age 20 or 30.

Special concerns

Carriers of the defective gene may be identified during genetic counseling, and prenatal diagnosis is also possible.

Resources

BOOKS

"Nutritional Disorders of the Neuromuscular Transmission and of Motor Neurons." In Nelson Textbook of Pediatrics, edited by Richard E. Behrman, et al. Philadelphia: W. B. Saunders Company, 2004.

Maertens, Paul, and Paul Richard Dyken. "Storage Diseases: Neuronal Ceroid-Lipofuscinoses, Lipidoses, Glycogenoses, and Leukodystrophies." In Textbook of Clinical Neurology, edited by Christopher G. Goetz. Philadelphia: W. B. Saunders Company, 2003.

McGovern, Margaret M., and Robert J. Desnick. "Lysosomal Storage Diseases." In Textbook of Clinical Neurology, edited by Christopher G. Goetz. Philadelphia: W. B. Saunders Company, 2003.

WEBSITES

Genetics Home Reference. National Library of Medicine, National Institutes of Health. (April 27, 2004). http://ghr.nlm.nih.gov/ghr/page/Home;jsessionid=52A6DA98F1237CEFE8E49B215F316502.

National Institute of Neurological Disorders and Stroke (NINDS). (April 27, 2004). Gaucher Disease Fact Sheet.http://www.ninds.nih.gov.

ORGANIZATIONS

Center for Jewish Diseases, Department of Human Genetics, Mount Sinai Medical Center. Fifth Avenue at 100th Street, New York, NY 10029. (212) 659-6774 or (212) 241-6947. http://www.mssm.edu/jewish_genetics/overview.shtml.

Children's Gaucher Research Fund. PO Box 2123, Granite Bay, CA 95746. (916) 797-3700; Fax: (916) 797-3707. research@childrensgaucher.org. http://www.childrensgaucher.org.

National Gaucher Foundation. 5410 Edson Lane, Suite 260, Rockville, MD 20852-3130. (301) 816-1515 or 800-GAUCHER (428-2437); Fax: (301) 816-1516. ngf@gaucherdisease.org. http://www.gaucherdisease.org.

Rosalyn Carson-Dewitt, MD

A constitutional defect in the metabolism of the cerebroside kerasin. This glycoprotein accumulates in the reticuloendothelial system and leads to splenomegaly, hepatomegaly, lymph node enlargement, and bone defects.

A hereditary disorder of glucocerebroside metabolism, marked by the presence of Gaucher's cells in many tissues. Occurs in dogs (Australian silky terriers), sheep, pigs and mice. See also glucocerebroside, gaucher's cells.

Gaucher's disease
Classification and external resources
ICD-10	E75.2 (ILDS E75.220)
ICD-9	272.7
OMIM	230800 230900 231000
DiseasesDB	5124
MedlinePlus	000564
eMedicine	ped/837  derm/709
MeSH	D005776

Gaucher's disease (pronounced /ɡoʊˈʃeɪz dɨziːz/) is a genetic disease in which a fatty substance (lipid) accumulates in cells and certain organs.

Gaucher's disease is the most common of the lysosomal storage diseases.^[1]:536 It is caused by a hereditary deficiency of the enzyme glucocerebrosidase (also known as acid β-glucosidase). The enzyme acts on a fatty substance glucocerebroside (also known as glucosylceramide). When the enzyme is defective, the substance accumulates, particularly in cells of the mononuclear cell lineage. Fatty material can collect in the spleen, liver, kidneys, lungs, brain and bone marrow. Symptoms 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. The disease is caused by a recessive gene on chromosome 1 and affects both males and females.

Some forms of Gaucher's disease may be treated with enzyme replacement therapy. It is named after the French doctor Philippe Gaucher, who originally described it in 1882.^[2]

Contents 1 Classification 2 Signs and symptoms 3 Pathophysiology 4 Genetics 5 Diagnosis 6 Treatment 7 Epidemiology 8 History 9 Additional images 10 See also 11 References 12 External links

Classification

Gaucher's disease has three common clinical subtypes.

• Type I (or nonneuropathic type) is the most common form of the disease, occurring in approximately 1 in 50,000 live births. It occurs most often among persons of Ashkenazi Jewish heritage. Symptoms may begin early in life or in adulthood and include enlarged liver and grossly enlarged spleen (together hepatosplenomegaly); the spleen can rupture and cause additional complications. Skeletal weakness and bone disease may be extensive. Spleen enlargement and bone marrow replacement cause anemia, thrombocytopenia and leukopenia. The brain is not affected, but there may be lung and, rarely, kidney impairment. Patients in this group usually bruise easily (due to low levels of platelets) and experience fatigue due to low numbers of red blood cells. Depending on disease onset and severity, type 1 patients may live well into adulthood. Many patients have a mild form of the disease or may not show any symptoms.

• Type II (or acute infantile neuropathic Gaucher's disease) typically begins within 6 months of birth and has an incidence rate of approximately 1 in 100,000 live births. Symptoms include an enlarged liver and spleen, extensive and progressive brain damage, eye movement disorders, spasticity, seizures, limb rigidity, and a poor ability to suck and swallow. Affected children usually die by age 2.

• Type III (the chronic neuropathic form) can begin at any time in childhood or even in adulthood, and occurs in approximately 1 in 100,000 live births. It is characterized by slowly progressive but milder neurologic symptoms compared to the acute or type 2 version. Major symptoms include an enlarged spleen and/or liver, seizures, poor coordination, skeletal irregularities, eye movement disorders, blood disorders including anemia and respiratory problems. Patients often live into their early teen years and adulthood.

These subtypes have come under some criticism for not taking account of the spectrum of observable symptoms (the phenotypes.[1]) There are also compound heterozygous variations which considerably increase the complexity of predicting disease course.

Signs and symptoms

• Painless hepatomegaly and splenomegaly; the size of the spleen can be 1500-3000 ml, as opposed to the normal size of 50-200 ml.
• Hypersplenism: the rapid and premature destruction of blood cells, leading to anemia, neutropenia and thrombocytopenia (with an increased risk of infection and bleeding)
• Cirrhosis of the liver is rare
• Neurological symptoms occur only in some types of Gaucher's (see below):
  • Type II: serious convulsions, hypertonia, mental retardation, apnea.
  • Type III: muscle twitches known as myoclonus, convulsions, dementia, ocular muscle apraxia.
• Osteoporosis: 75% develop visible bony abnormalities due to the accumulated glucosylceramide. A deformity of the distal femur in the shape of an Erlenmeyer flask is commonly described (aseptic necrosis of the femur joint).
• Yellowish-brown skin pigmentation

Pathophysiology

Acid beta-glucosidase

The disease is caused by a defect in the housekeeping gene lysosomal gluco-cerebrosidase (also known as beta-glucosidase, EC 3.2.1.45, PDB 1OGS) on the first chromosome (1q21). The enzyme is a 55.6 KD, 497 amino acids long protein that catalyses the breakdown of glucocerebroside, 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.

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

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

Research suggests that heterozygotes for particular acid beta-glucosidase mutations are at an increased risk of Parkinson's disease.^[3] 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.^[4]

Genetics

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:^[5]

• Type I (N370S homozygote), the most common, also called the "non-neuropathic" type occurs mainly in Ashkenazi Jews, at 100 times the occurrence in the general populace. The median age at diagnosis is 28 years of age,^[6] and life expectancy is mildly decreased^[7]. There are no neurological symptoms.
• Type II (1 or 2 alleles L444P) is characterized by neurological problems in small children. The enzyme is hardly released into the lysosomes. Prognosis is dismal: most die before reaching the third birthday.
• Type III (also 1-2 copies of L444P, possibly delayed by protective polymorphisms) occurs in Swedish patients from the Norrbotten region. This group develops the disease somewhat later, but most die before their 30th birthday.

Diaz et al. suggest that the Gaucher-causing mutations entered the Ashkenazi Jewish gene pool in the early Middle Ages (48-55 generations ago).^[8]

Diagnosis

A definitive diagnosis is made with 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.

Treatment

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 up to $550,000 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.^[6] 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.

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^[update], another oral drug, isofagomine tartrate, is under development.

Epidemiology

The National Gaucher Foundation states that 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: among Ashkenazi Jews the rate of carriers is considerably higher, at roughly 1 in 15.^[9]

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.

History

The disease was first recognised by the French doctor Philippe Gaucher, who originally described it in 1882 and lent his name to the condition.^[2] The biochemical basis for the disease would be elucidated in 1965.^[10] The first effective treatment for the disease, the drug Ceredase, was approved by the FDA in June 1995. An improved drug, Cerezyme, was approved by the FDA in 2001 and has replaced the use of Ceredase.

Additional images

Sphingolipidoses

See also

• Niemann-Pick disease
• Fabry disease
• Tay-Sachs
• Krabbe disease
• Metachromatic leukodystrophy

References

1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0. 
2. ^ ^{a b} Gaucher PCE (1882). De l'epithelioma primitif de la rate, hypertrophie idiopathique de la rate sans leucemie [academic thesis]. Paris, France. 
3. ^ 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. 
4. ^ 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. 
5. ^ Online 'Mendelian Inheritance in Man' (OMIM) 606463
6. ^ ^{a b} Grabowski GA (2008). "Phenotype, diagnosis, and treatment of Gaucher's disease". Lancet 372: 1263–1271. doi:10.1016/S0140-6736(08)61522-6. 
7. ^ 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. PMID 18980271. 
8. ^ 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. PMID 10777718. 
9. ^ "National Gaucher Foundation". http://www.gaucherdisease.org/prevalence.php. Retrieved on 2007-05-30. 
10. ^ Brady RO, Kanfer JN, Shapiro D (1965). "Metabolism of glucocerebrosides. II. Evidence of an enzymatic deficiency in Gaucher's disease". Biochem. Biophys. Res. Commun. 18: 221–5. doi:10.1016/0006-291X(65)90743-6. PMID 14282020. 

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• Hide & Seek Foundation For Lysosomal Disease Research

v • d • e (LSD) Inborn error of lipid metabolism: lipid storage disorders (E75, 272.7-272.8) Sphingolipidoses (to ceramide) From ganglioside (gangliosidoses) Ganglioside: GM1 gangliosidoses · GM2 gangliosidoses (Sandhoff disease, Tay-Sachs disease, AB variant) From globoside Globotriaosylceramide: Fabry's disease From sphingomyelin Sphingomyelin: phospholipid: Niemann-Pick disease (SMPD1-associated, type C) Glucocerebroside: Gaucher's disease From sulfatide (sulfatidoses, leukodystrophy) Sulfatide: Metachromatic leukodystrophy · Multiple sulfatase deficiency Galactocerebroside: Krabbe disease To sphingosine Ceramide: Farber disease NCL Infantile · Jansky-Bielschowsky disease · Batten disease Other Cerebrotendineous xanthomatosis · Cholesteryl ester storage disease (Wolman disease) · Sea-blue histiocyte syndrome see also enzymes, sphingolipids

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