Canavan disease: Difference between revisions
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'''Canavan disease''', also called '''Canavan-Van Bogaert-Bertrand disease''', '''aspartoacylase deficiency''' or '''aminoacylase 2 deficiency''',<ref>{{OMIM|271900}}</ref> is an [[autosome|autosomal]] [[dominance (genetics)|recessive]]<ref>{{cite journal |pmid=16647192 |year=2006 |month=June |author=Namboodiri, Am; Peethambaran, A; Mathew, R; Sambhu, Pa; Hershfield, J; Moffett, Jr; Madhavarao, Cn |title=Canavan disease and the role of N-acetylaspartate in myelin synthesis |volume=252 |issue=1-2 |pages=216–23 |doi=10.1016/j.mce.2006.03.016 |journal=Molecular and cellular endocrinology}}</ref> degenerative disorder that causes progressive damage to [[nerve cell]]s in the [[brain]]. This disease is one of a group of genetic disorders called [[leukodystrophies]]. |
'''Canavan disease''', also called '''Canavan-Van Bogaert-Bertrand disease''', '''aspartoacylase deficiency''' or '''aminoacylase 2 deficiency''',<ref>{{OMIM|271900}}</ref> is an [[autosome|autosomal]] [[dominance (genetics)|recessive]]<ref>{{cite journal |pmid=16647192 |year=2006 |month=June |author=Namboodiri, Am; Peethambaran, A; Mathew, R; Sambhu, Pa; Hershfield, J; Moffett, Jr; Madhavarao, Cn |title=Canavan disease and the role of N-acetylaspartate in myelin synthesis |volume=252 |issue=1-2 |pages=216–23 |doi=10.1016/j.mce.2006.03.016 |journal=Molecular and cellular endocrinology}}</ref> degenerative disorder that causes progressive damage to [[nerve cell]]s in the [[brain]].Canavan disease is also one of the most common degenerative cerebreal diseases of infancy. This disease is one of a group of genetic disorders called [[leukodystrophies]]. |
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Leukodystrophies are characterized by degeneration of [[myelin]] in the [[phospholipid]] layer insulating the [[axon]] of a [[neuron]]. The gene associated with the disorder is located on human [[chromosome 17]]. |
Leukodystrophies are characterized by degeneration of [[myelin]] in the [[phospholipid]] layer insulating the [[axon]] of a [[neuron]]. The gene associated with the disorder is located on human [[chromosome 17]]. |
Revision as of 20:46, 13 December 2010
Canavan disease | |
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Specialty | Endocrinology, neurology ![]() |
Canavan disease, also called Canavan-Van Bogaert-Bertrand disease, aspartoacylase deficiency or aminoacylase 2 deficiency,[1] is an autosomal recessive[2] degenerative disorder that causes progressive damage to nerve cells in the brain.Canavan disease is also one of the most common degenerative cerebreal diseases of infancy. This disease is one of a group of genetic disorders called leukodystrophies.
Leukodystrophies are characterized by degeneration of myelin in the phospholipid layer insulating the axon of a neuron. The gene associated with the disorder is located on human chromosome 17.
History
Canavan disease was first described in 1931 by Myrtelle Canavan.[3]
The discovery of the gene for Canavan disease, and subsequent events, generated considerable controversy. In 1987 the Greenbergs, a family with two children affected by Canavan disease, donated tissue samples to Dr Reuben Matalon, a researcher looking for the Canavan gene. He successfully identified the gene in 1993, and developed a test for it that would enable antenatal counselling of couples at risk of having a child with Canavan disease.[4] For a while the Canavan Foundation offered free genetic testing with the test. However, in 1997, Dr Matalon's employer, the Miami Children's Hospital, patented the gene and started claiming royalties on the genetic test, forcing the Canavan Foundation to withdraw their testing. A subsequent lawsuit brought by the Canavan Foundation against the Miami Children's Hospital was resolved with a sealed out-of-court settlement. [5] The case is sometimes cited in arguments about the appropriateness of patenting genes.
Prevalence
Although Canavan disease may occur in any ethnic group, it affects persons of Eastern European Jewish ancestry more frequently. About 1/40 individuals of Eastern European (Ashkenazi) Jewish ancestry are carriers.
Pathophysiology
![](http://upload.wikimedia.org/wikipedia/commons/thumb/3/3e/Autorecessive.svg/220px-Autorecessive.svg.png)
Canavan disease is inherited in an autosomal recessive fashion. When both parents are carriers, there is a 25% chance of having an affected child. Genetic counseling and genetic testing is recommended for families with two parental carriers.
Canavan disease is caused by a defective ASPA gene which is responsible for the production of the enzyme aspartoacylase. This enzyme breaks down the concentrated brain molecule N-acetyl aspartate. Decreased aspartoacylase activity prevents the normal breakdown of N-acetyl aspartate, and the lack of breakdown somehow interferes with growth of the myelin sheath of the nerve fibers in the brain. The myelin sheath is the fatty covering that surrounds nerve cells and acts as an insulator, which allows for efficient transmission of nerve impulses.
Symptoms
Symptoms of Canavan disease, which appear in early infancy and progress rapidly, may include mental retardation, loss of previously acquired motor skills, feeding difficulties, abnormal muscle tone (i.e., floppiness or stiffness), poor head control, and megalocephaly (abnormally enlarged head). Paralysis, blindness, or seizures may also occur.
Treatment
There is no cure for Canavan disease, nor is there a standard course of treatment. Treatment is symptomatic and supportive, but there is an experimental treatment using lithium citrate. When a person has Canavan Disease, his or her levels of N-acetyl aspartate are chronically elevated. The lithium citrate has proven that, in a rat genetic model of Canavan Disease, the lithium citrate significantly decreased the levels of N-acetyl aspartate. When tested on a human, the subject reversed during a two week wash-out period after withdrawal of lithium. The investigation reported that the N-acetyl aspartate levels decreased in regions of the brain tested and magnetic resonance spectroscopic values that are more characteristic of normal development and myelination. With this evidence it is suggested that a larger controlled trial of lithium may be warranted as supportive therapy for children with Canavan disease by significantly decreasing the elevated amounts of N-acetyl aspartate.[6]
In addition, there are experimental trials of gene therapy. A healthy gene is cloned to take over for the defective one that causes Canavan disease.[7]
Prognosis
Death usually occurs before age 4 without treatment. Some children may survive into their twenties via newer gene therapy treatments which have extended their life expectancy. In some cases, this helps to temporarily stop the progression of the disease.[citation needed]
Current research
Research involving triacetin supplementation has shown promise in a mouse model.[8] Triacetin, which can be enzymatically cleaved to form acetate, enters the brain more readily than the negatively charged acetate.
A team of researchers headed by Paola Leone are currently at the University of Medicine and Dentistry of New Jersey, in Camden, New Jersey. The brain gene therapy is conducted at Cooper University Hospital. The procedure involves the insertion of six catheters into the brain that deliver a solution containing 600 billion to 900 billion engineered virus particles. The virus, a modified version of AAV, is designed to replace the aspartoacylase enzyme.[7] Children treated with this procedure to date have shown marked improvements, including the growth of myelin with decreased levels of the n-acetyl-aspartate toxin.[9]
See also
References
- ^ Online Mendelian Inheritance in Man (OMIM): 271900
- ^ Namboodiri, Am; Peethambaran, A; Mathew, R; Sambhu, Pa; Hershfield, J; Moffett, Jr; Madhavarao, Cn (2006). "Canavan disease and the role of N-acetylaspartate in myelin synthesis". Molecular and cellular endocrinology. 252 (1–2): 216–23. doi:10.1016/j.mce.2006.03.016. PMID 16647192.
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ignored (help)CS1 maint: multiple names: authors list (link) - ^ Canavan MM (1931). "Schilder's encephalitis periaxialis diffusa. Report of a case in a child aged sixteen and one-half months". Archives of Neurology and Psychiatry. 25: 299–308.
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instead. - ^ a b Janson C; et al. (2002). "Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain". Hum Gene Ther. 13 (11): 1191–412. PMID 12162821.
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ignored (help) Cite error: The named reference "pmid12162821" was defined multiple times with different content (see the help page). - ^ Mathew R, Arun P, Madhavarao CN, Moffett JR, Namboodiri MA (2005). "Progress toward acetate supplementation therapy for Canavan disease: glyceryl triacetate administration increases acetate, but not N-acetylaspartate, levels in brain" (PDF). J. Pharmacol. Exp. Ther. 315 (1): 297–303. doi:10.1124/jpet.105.087536. PMID 16002461.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ "Our Story: The Search for a Cure". Canavan Research Foundation. Retrieved Nov 22, 2010.
External links
- Information on the disorder from the National Institute of Neurological Disorder and Stroke
- Cell & Gene Therapy Center at UMDNJ
- Canavan Research Illinois - A public charity devoted to curing Canavan disease
- Canavan Research - A foundation devoted to curing Canavan disease
- GeneReview/UW/NIH entry on Canavan disease
- Jacob's Cure - A foundation dedicated to curing Canavan disease
- The Canavan Foundation - offering information, support, testing, and sponsoring research into Canavan disease