Canavan disease - AbsoluteAstronomy.com

Canavan disease, also called Canavan-Van Bogaert-Bertrand disease, aspartoacylase deficiency or aminoacylase 2 deficiency, is an autosomal

Autosome

An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...

recessive degenerative disorder that causes progressive damage to nerve cells in the brain

Human brain

The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...

. 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

Myelin

Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...

in the phospholipid

Phospholipid

Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...

layer insulating the axon

Axon

An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....

of a neuron

Neuron

A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...

. The gene associated with the disorder is located on human chromosome 17.

Greenberg v. Miami Children's Hospital Research Institute

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. 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. 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 Europe

Eastern Europe

Eastern Europe is the eastern part of Europe. The term has widely disparate geopolitical, geographical, cultural and socioeconomic readings, which makes it highly context-dependent and even volatile, and there are "almost as many definitions of Eastern Europe as there are scholars of the region"...

an Jewish ancestry more frequently. About 1/40 individuals of Eastern Europe

Eastern Europe

an (Ashkenazi) Jewish ancestry are carriers.

Pathophysiology

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

Genetic counseling

Genetic counseling or traveling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning...

and genetic testing

Genetic testing

Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...

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

Enzyme

Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

aspartoacylase

Aspartoacylase

Aspartoacylase is a hydrolase enzyme which breaks down N-acetylaspartate. A deficiency is associated with Canavan disease....

. 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

Myelin

sheath of the nerve fiber

Nerve fiber

A nerve fiber is a threadlike extension of a nerve cell and consists of an axon and myelin sheath in the nervous system. There are nerve fibers in the central nervous system and peripheral nervous system. A nerve fiber may be myelinated and/or unmyelinated. In the central nervous system , myelin...

s in the brain. The myelin sheath is the fat

Fat

Fats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water. Chemically, fats are triglycerides, triesters of glycerol and any of several fatty acids. Fats may be either solid or liquid at room temperature, depending on their structure...

ty covering that surrounds nerve

Nerve

A peripheral nerve, or simply nerve, is an enclosed, cable-like bundle of peripheral axons . A nerve provides a common pathway for the electrochemical nerve impulses that are transmitted along each of the axons. Nerves are found only in the peripheral nervous system...

cells and acts as an insulator

Electrical insulation

thumb|250px|[[Coaxial Cable]] with dielectric insulator supporting a central coreThis article refers to electrical insulation. For insulation of heat, see Thermal insulation...

, which allows for efficient transmission of nerve impulses.

Symptoms

Symptoms of Canavan disease, which appear in early infancy

Infant

A newborn or baby is the very young offspring of a human or other mammal. A newborn is an infant who is within hours, days, or up to a few weeks from birth. In medical contexts, newborn or neonate refers to an infant in the first 28 days after birth...

and progress rapidly, may include mental retardation

Mental retardation

Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...

, loss of previously acquired motor skill

Motor skill

A motor skill is a learned sequence of movements that combine to produce a smooth, efficient action in order to master a particular task. The development of motor skill occurs in the motor cortex, the region of the cerebral cortex that controls voluntary muscle groups.- Development of motor skills...

s, feeding difficulties, abnormal muscle

Muscle

Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...

tone (i.e., floppiness or stiffness), poor head control, and megalocephaly (abnormally enlarged head). Paralysis

Paralysis

Paralysis is loss of muscle function for one or more muscles. Paralysis can be accompanied by a loss of feeling in the affected area if there is sensory damage as well as motor. A study conducted by the Christopher & Dana Reeve Foundation, suggests that about 1 in 50 people have been diagnosed...

, blindness

Blindness

Blindness is the condition of lacking visual perception due to physiological or neurological factors.Various scales have been developed to describe the extent of vision loss and define blindness...

, or seizure

Seizure

An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...

s 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

Lithium citrate

Lithium citrate is a chemical compound of lithium and citrate that is used as a mood stabilizer in psychiatric treatment of manic states and bipolar disorder. For the medical aspects of lithium citrate, see lithium pharmacology....

. 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

Lithium citrate

significantly decreased the levels of N-acetyl aspartate

N-Acetyl aspartate

N-Acetylaspartic acid, or N-acetylaspartate , is a derivative of aspartic acid with a formula of C6H9NO5 and a molecular weight of 175.139....

. 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.

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.

Prognosis

Death usually occurs before age 4, bit some children with milder forms of the disease survive into their teens and twenties.

Current research

Research involving triacetin

Triacetin

The triglyceride 1,2,3-triacetoxypropane is more generally known as triacetin and glycerin triacetate. It is the triester of glycerol and acetic acid....

supplementation has shown promise in a rat model. Triacetin, which can be enzymatically cleaved to form acetate

Acetate

An acetate is a derivative of acetic acid. This term includes salts and esters, as well as the anion found in solution. Most of the approximately 5 billion kilograms of acetic acid produced annually in industry are used in the production of acetates, which usually take the form of polymers. In...

, enters the brain more readily than the negatively charged acetate. The defective enzyme in Canavan disease, aspartoacylase, converts N-acetylaspartate into aspartate and acetate. Mutations in the gene for aspartoacylase prevent the breakdown of N-acetylaspartate, and reduce brain acetate availability during brain development. Acetate supplementation using Triacetin is meant to provide the missing acetate so that brain development can continue normally.

A team of researchers headed by Paola Leone

Paola Leone

Paola Leone, Ph.D., is a leading researcher of Canavan disease.Dr. Leone was born and raised in Cagliari, Italy. She received her undergraduate and graduate training in Italy, followed by post-doctoral studies in Montreal and Yale University in New Haven, CT. She holds a doctorate degree in...

are currently at the University of Medicine and Dentistry of New Jersey

University of Medicine and Dentistry of New Jersey

The University of Medicine and Dentistry of New Jersey is the state-run health sciences institution of New Jersey, United States. It has eight distinct academic units...

, in Camden, New Jersey

Camden, New Jersey

The city of Camden is the county seat of Camden County, New Jersey. It is located across the Delaware River from Philadelphia, Pennsylvania. As of the 2010 United States Census, the city had a total population of 77,344...

. The brain gene therapy is conducted at Cooper University Hospital

Cooper University Hospital

Cooper University Hospital is a provider of health services, medical education, and clinical research in southern New Jersey and the Delaware Valley, in the United States...

. The procedure involves the insertion of six catheter

Catheter

In medicine, a catheter is a tube that can be inserted into a body cavity, duct, or vessel. Catheters thereby allow drainage, administration of fluids or gases, or access by surgical instruments. The process of inserting a catheter is catheterization...

s into the brain that deliver a solution containing 600 billion to 900 billion engineered virus

Virus

A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...

particles. The virus, a modified version of AAV

Adeno-associated virus

Adeno-associated virus is a small virus which infects humans and some other primate species. AAV is not currently known to cause disease and consequently the virus causes a very mild immune response. AAV can infect both dividing and non-dividing cells and may incorporate its genome into that of...

, is designed to replace the aspartoacylase enzyme. 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.

External links

The source of this article is wikipedia, the free encyclopedia. The text of this article is licensed under the GFDL.