Gaucher's disease

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Gaucher disease
Acid beta-glucosidase
SpecialtyEndocrinology, neurology Edit this on Wikidata

Gaucher's disease or Gaucher disease (

lungs, brain, and bone marrow
.

Manifestations may include enlarged spleen and liver, liver malfunction,

skeletal disorders or bone lesions that may be painful, severe neurological complications, swelling of lymph nodes and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin, anemia, low blood platelet count, and yellow fatty deposits on the white of the eye (sclera
). Persons seriously affected 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

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

sphingolipids.[3]

The disease is named after the French physician Philippe Gaucher, who originally described it in 1882.[4]

Signs and symptoms

  • Painless hepatomegaly and splenomegaly: the size of the spleen can be 1500–3000 g, as opposed to the normal size of 50–200 g. Splenomegaly may decrease the affected individual's capacity for eating by exerting pressure on the stomach. While painless, enlargement of spleen increases the risk of splenic rupture.
  • Hypersplenism and pancytopenia, the rapid and premature destruction of blood cells, leads to anemia, neutropenia, leukopenia, and thrombocytopenia (with an increased risk of infection and bleeding
    ).
  • Cirrhosis of the liver is rare.
  • Severe pain associated with joints and bones occurs, frequently presenting in hips and knees.
  • Neurological symptoms occur only in some types of Gaucher's (see below):
  • Type I: impaired olfaction and cognition
  • Type II: serious convulsions, hypertonia, intellectual disability, and apnea
  • Type III: muscle twitches known as myoclonus, convulsions, dementia, and ocular muscle apraxia
  • Parkinson's disease is recognized as being more common in Gaucher's disease patients and their heterozygous carrier relatives.[5]
  • Osteoporosis: 75% of patients 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.
  • Yellowish-brown skin
    pigmentation

Genetics

The three types of Gaucher's disease are

autosomal recessive
. Both parents must be carriers for a child to be affected. If both parents are carriers, the chance of the disease is one in four, or 25%, with each pregnancy for an affected child.

Each type has been linked to particular mutations. In all, about 80 known GBA gene mutations are grouped into three main types:[6]

  • 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,[7] and life expectancy is mildly decreased.[8]
  • Type II (one or two alleles L444P) is characterized by neurological problems in small children. The enzyme is hardly released into the lysosomes. Prognosis is poor: most die before the age of three.
  • Type III (also one or two copies of L444P, possibly delayed by protective polymorphisms) occurs in Swedish patients from the Norrbotten region.[9] This group develops the disease somewhat later, but most die before their 30th birthday.

The Gaucher-causing mutations may have entered the Ashkenazi Jewish gene pool in the early Middle Ages (48–55 generations ago).[10]

Pathophysiology

The disease is caused by a defect in the

light microscopy to resemble crumpled-up paper.[3]

The exact mechanism of neurotoxicity is not understood, but it is thought to involve a reaction to glucosylsphingosine.[3]

Different mutations in the GBA (beta-glucosidase) gene determine the remaining activity of the enzyme. In type I, there is some residual activity of the enzyme, accounting for the lack of neuropathology in this type.[3] Although there is some correlation between genotype and phenotype, neither the amount of stored lipids, nor the residual enzyme activity correlates well with disease symptoms.[11] This circumstance has called for alternative explanations accounting for disease symptoms including

  • jamming of the endo/lysosomal system[12]
  • ER stress[13]
  • altered lipid composition of membranes throughout the cell, including the plasma membrane,[14] and consequent changes in the dynamic and signaling properties of the cell membrane[15]
  • inflammation caused by cytokine secretion as a result of sphingolipid accumulation, and neurodegeneration caused by the accumulation of glucosylsphingosine, a neurotoxin[16]

Heterozygotes for particular acid beta-glucosidase mutations carry about a five-fold risk of developing Parkinson's disease, making this the most common known genetic risk factor for Parkinson's.[17][18]

Cancer risk may be increased, particularly

myeloma.[19][20][21] This is thought to be due to accumulation of glucosylceramide and complex glycosphingolipids.[22]

The role of

tumor necrosis factor alpha in splenic Gaucher cells (engorged macrophages).[3]

Diagnosis

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. As a result, lower than 15% of mean normal activity is considered to be diagnostic.[23] Decreased enzyme levels will often be confirmed by genetic testing. Numerous different mutations occur; sequencing of the beta-glucosidase gene is sometimes necessary to confirm the diagnosis. Prenatal diagnosis is available and is useful when a known genetic risk factor is present.[citation needed]

A diagnosis can also be implied by biochemical abnormalities such as high

immunoglobulin levels, or by cell analysis showing "crinkled paper" cytoplasm and glycolipid-laden macrophages.[citation needed
]

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[24]

Classification

Gaucher's disease (GD) has three common clinical subtypes.

phenotypes[27]
). Also, compound heterozygous variations occur which considerably increase the complexity of predicting disease course.

GD type I (non-neuropathic) is the most common and least severe form of the disease. Symptoms may begin early in life or in adulthood and mainly affect the liver, spleen, and bone. Enlarged liver and grossly enlarged spleen (together hepatosplenomegaly) are common;[3] the spleen can rupture and cause additional complications. Skeletal weakness and bone disease may be extensive.[3] Spleen enlargement and bone marrow replacement cause anemia, thrombocytopenia, and leukopenia. The brain and nervous system are not affected pathologically,[3] but lung and, rarely, kidney impairment may occur. 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 I patients may live well into adulthood. The range and severity of symptoms can vary dramatically between patients.[citation needed]

GD type II (acute infantile neuropathic) typically begins within six months of birth and has an incidence rate around 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 two.

GD type III (chronic neuropathic) can begin at any time in childhood or even in adulthood, and occurs in about 1 in 100,000 live births. It is characterized by slowly progressive, but milder neurologic symptoms compared to the acute or type II 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.[28]

Treatment

For those with type-I and most type-III,

intravenous recombinant glucocerebrosidase can decrease liver and spleen size, reduce skeletal abnormalities, and reverse other manifestations.[16][29] This treatment costs about US$200,000 annually for a single person and should be continued for life. The rarity of the disease means dose-finding studies have been difficult to conduct, so controversy remains over the optimal dose and dosing frequency.[7] Due to the low incidence, this has become an orphan drug in many countries, meaning a government recognizes and accommodates the financial constraints that limit research into drugs that address a small population.[citation needed
]

The first drug for Gaucher's was

tissue and then modified with enzymes.[30] It was approved by the FDA in 1991[31] and has been withdrawn from the market[32][33] due to the approval of similar drugs made with recombinant DNA technology instead of being harvested from tissue; drugs made recombinantly are preferable, since there is no concern about diseases being transmitted from the tissue used in harvesting, there are fewer risks of variations in enzyme structure from batch to batch, and they are less expensive to manufacture.[30]

Available recombinant glucocerebrosidases are:[16]

Miglustat is a small molecule, orally available drug that was first approved for Gaucher's disease in Europe in 2002.[36] It works by preventing the formation of glucocerebroside, the substance that builds up and causes harm in Gaucher's. This approach is called substrate reduction therapy.[37]

glucosylceramide synthase
.

Epidemiology

The National Gaucher Foundation (United States) states the incidence of Gaucher's disease is about one in 20,000 live births.[39] Around one in 100 people in the general US population is a carrier for type I Gaucher's disease, giving a prevalence of one in 40,000.[40] Among Ashkenazi Jews, the rate of carriers is considerably higher, at roughly one in 15.[40]

Type II Gaucher's disease shows no particular preference for any ethnic group.[citation needed]

Type III Gaucher's disease is especially common in the population of the northern Swedish region of Norrbotten, where the incidence of the disease is one in 50,000.[41]

History

The disease was first recognized by the French doctor Philippe Gaucher, who originally described it in 1882 and lent his name to the condition.[4] In 1902, its mode of inheritance was discovered by Nathan Brill.[3] The neuronal damage associated with the disease was discovered in the 1920s, and the biochemical basis for the disease was elucidated in the 1960s by Roscoe Brady.[3][42] 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 is National Gaucher's Disease Awareness Month in the United States.[citation needed]

Prominent people with disease

Gallery

  • Sphingolipidoses
    Sphingolipidoses

See also

References

  1. PMID 1897529
    .
  2. OCLC 663444979
    .
  3. ^
    PMID 26588331
    .
  4. ^ a b Gaucher PCE (1882). De l'epithelioma primitif de la rate, hypertrophie idiopathique de la rate sans leucemie [Primary epithelioma of the spleen, idiopathic hypertrophy of the spleen without leukemia] (academic thesis) (in French). Paris, France.{{cite book}}: CS1 maint: location missing publisher (link)[page needed]
  5. PMID 22577228
    .
  6. ^ Online Mendelian Inheritance in Man (OMIM): Gluosidase, beta, acid; GBA - 606463
  7. ^
    S2CID 25221799
    .
  8. PMID 18980271
    .
  9. PMID 2378352
    .
  10. PMID 10777718
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  11. PMID 23114583
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  12. PMID 11050411
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  14. PMID 17881272
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  15. PMID 29317695
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  16. ^
    PMID 23233555
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  17. ^ Beals JK (November 19, 2008). "ASHG 2008: Gaucher Disease Mutation Carriers at Higher Risk for Parkinson's Disease". Medscape Medical News.
  18. PMID 15525722
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  19. PMID 23594419
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  20. PMID 24588457
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  21. PMID 23510067
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  22. PMID 23510065
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  23. ^ "Gaucher Disease". symptoma. Retrieved 2015-12-07.
  24. ^ "Chitotriosidase | Gaucher Institute". www.gaucher-institute.com. Retrieved 2022-03-13.
  25. PMID 25755533
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  26. S2CID 10092272
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  27. ^ [1] Archived September 24, 2006, at the Wayback Machine
  28. S2CID 12375149
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  29. PMID 25812601
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  30. ^
    PMID 22563238
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  31. ^ World Health Organization. Regulatory Matters WHO Drug Information 5:3 1991. p 123
  32. ^ Aetna. Last reviewed 8 August 2014 Clinical Policy Bulletin Number: 0442: Enzyme-replacement Therapy for Lysosomal Storage Disorders
  33. ^ FDA Prescription and Over-the-Counter Drug Product List. 32ND Edition Cumulative Supplement Number 3: March 2012. Additions/Deletions for Prescription Drug Product List
  34. ^ "Shire Announces FDA Approval Of VPRIV(TM) (velaglucerase Alfa For Injection) For The Treatment Of Type I Gaucher Disease". Medicalnewstoday.com. Archived from the original on June 13, 2011. Retrieved 2012-08-13.
  35. ^ Yukhananov A (1 May 2012). "U.S. FDA approves Pfizer/Protalix drug for Gaucher". Chicago Tribune. Reuters. Retrieved 2 May 2012.[permanent dead link]
  36. ^ European Medicines Agency. Human Medicines Database. Zavesca (miglustat) Page Accessed 1 September 2014.
  37. ^ European Medicines Agency 1 April 2003 Scientific discussion related to approval of Zavesca.
  38. ^ "Center Watch: Cerdelga (eliglustat)".
  39. ^ Gaucher Disease at National Gaucher Foundation. Retrieved June 2012
  40. ^ a b "Gaucher Disease Genetics | About Gaucher Disease | National Gaucher Foundation". National Gaucher Foundation. Retrieved 2016-11-16.
  41. ^ "Gaucher disease - Affected population". NORD - National Organization for Rare Disorders. Archived from the original on 25 September 2013. Retrieved 21 September 2013.
  42. PMID 14282020
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  43. ^ "Eating Fried Chicken - Cold is Gold". RNZ. 2019-08-01. Retrieved 2019-08-08.

External links

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