Canavan disease, which results when the body produces less than normal amounts of a protein called aspartoacylase, is a fatal inherited disorder characterized by progressive damage to the brain and nervous system.
Canavan disease is named after Dr. Myrtelle Canavan who described a patient with the symptoms of Canavan disease but mistakenly diagnosed this patient with Schilder's disease . It was not until 1949, that Canavan disease was recognized as a unique genetic disease by Van Bogaert and Betrand. The credit went to Dr. Canavan, however, whose initial description of the disease dominated the medical literature.
Canavan disease, which is also called aspartoacylase deficiency, spongy degeneration of the brain, and infantile spongy degeneration, results from a deficiency of the enzyme aspartoacylase. This deficiency ultimately results in progressive damage to the brain and nervous system and causes mental retardation, seizures, tremors , muscle weakness, blindness and an increase in head size. Although most people with Canavan disease die in their teens, some die in childhood and some live into their twenties and thirties.
Canavan disease is sometimes called spongy degeneration of the brain since it is characterized by a sponginess or swelling of the brain cells and a destruction of the white matter of the brain. Canavan disease is an autosomal recessive genetic condition that is found in all ethnic groups, but is most common in people of Ashkenazi (Eastern European) Jewish descent and people of Saudi Arabian descent.
Although Canavan disease is found in people of all ethnicities, it is most common in Ashkenazi Jewish individuals. Approximately one in 40 Ashkenazi Jewish individuals are carriers for Canavan disease and approximately one in 6,400 Ashkenazi Jewish people are born with Canavan disease. People of Saudi Arabian descent also have a relatively high risk of Canavan disease.
Causes and symptoms
Canavan disease is an autosomal recessive genetic disease. A person with Canavan disease has changes (mutations) in both of the genes responsible for producing the enzyme aspartoacylase and has inherited one changed gene from his or her mother and one changed gene from his or her father.
Reduced production of aspartoacylase results in lower than normal amounts of this enzyme in the brain and nervous system. Aspartoacylase is responsible for breaking down a substance called N-acetylaspartic acid (NAA). When the body produces decreased levels of aspartoacylase, a build-up of NAA results. This results in the destruction of the white matter of the brain and nervous system and causes the symptoms of Canavan disease.
Parents who have a child with Canavan disease are called carriers, since they each possess one changed ASPA gene and one unchanged ASPA gene. Carriers usually do not have any symptoms since they have one unchanged gene that can produce enough aspartoacylase to prevent the build-up of NAA. Each child born to parents who are both carriers for Canavan disease, has a 25% chance of having Canavan disease, a 50% chance of being a carrier and a 25% chance of being neither a carrier nor affected with Canavan disease.
Most infants with Canavan disease appear normal for the first month of life. The onset of symptoms, such as a lack of head control and poor muscle tone, usually begins by two to three months of age, although some may have an onset of the disease in later childhood. Children with Canavan disease usually experience sleep disturbances, irritability, and swallowing and feeding difficulties after the first or second year of life. In many cases, irritability resolves by the third year. As the child with Canavan disease grows older there is a deterioration of mental and physical functioning. The speed at which this deterioration occurs will vary for each affected person. Children with Canavan disease are mentally retarded and most will never be able to sit, stand, walk or talk, although they may learn to laugh and smile and reach for objects. People with Canavan disease have increasing difficulties in controlling their muscles. Initially they have poor muscle tone but eventually their muscles become stiff and difficult to move and may exhibit spasms. Canavan disease can cause vision problems and some people with Canavan disease may eventually become blind. People with Canavan disease typically have disproportionately large heads and may experience seizures.
Canavan disease should be suspected in a person with a large head who has poor muscle control, a lack of head control and a destruction of the white matter of the brain, which can be detected through a computed tomography (CT ) scan or magnetic resonance imaging (MRI) . A diagnosis of Canavan disease can usually be confirmed by measuring the amount of NAA in a urine sample since a person with Canavan disease typically has greater than five to ten times the normal amount of NAA in their urine. Canavan disease can be less accurately diagnosed by measuring the amount of aspartocylase enzyme present in a sample of skin cells.
Once a biochemical diagnosis of Canavan disease is made, DNA testing may be recommended. Detection of an ASPA gene alteration in a person with Canavan disease can confirm an uncertain diagnosis and help facilitate prenatal diagnosis and carrier testing of relatives. Although there are a number of different ASPA gene changes responsible for Canavan disease, most clinical laboratories typically test for only two to three common gene changes. Two of the ASPA gene changes are common in Ashkenazi Jews with Canavan disease and the other ASPA gene change is common in those of other ethnic backgrounds. Testing for other types of changes in the ASPA gene is only done on a research basis.
DNA testing is the only means of identifying carriers of Canavan disease. If possible, DNA testing should be first performed on the affected family member. If a change in the ASPA gene is detected, then carrier testing can be performed in relatives such as siblings, with an accuracy of greater than 99%. If the affected relative does not possess a detectable ASPA gene change, then carrier testing will be inaccurate and should not be performed. If DNA testing of the affected relative cannot be performed, carrier testing of family members can still be performed but will be less accurate. Carrier testing for the three common ASPA gene mutations identifies approximately 97–99% of Ashkenazi Jewish carriers and 40–55% of carriers from other ethnic backgrounds.
Carrier testing of individuals without a family history of Canavan disease is only recommended for people of Ashkenazi Jewish background since they have a higher risk of being carriers. As of 1998, both the American College of Obstetricians and Gynecologists and the American College of Medical Genetics recommend that DNA testing for Canavan disease be offered to all Ashkenazi Jewish couples who are planning children or who are currently pregnant. If only one member of the couple is of Ashkenazi Jewish background than testing of the Jewish partner should be performed first. If the Jewish partner is a carrier, than testing of the non-Jewish partner is recommended.
Prenatal testing through chorionic villus sampling (CVS) and amniocentesis is available to parents who are both carriers for Canavan disease. If both parents possess an ASPA gene change, which is identified through DNA testing, then DNA testing of their baby can be performed. Some parents are known to be carriers for Canavan disease since they already have a child with Canavan disease, yet they do not possess ASPA gene changes that are detectable through DNA testing. Prenatal diagnosis can be performed in these cases by measuring the amount of NAA in the amniotic fluid obtained from an amniocentesis. This type of prenatal testing is less accurate than DNA testing and can lead to misdiagnoses.
A child with Canavan disease will require treatment from a pediatric neurologist , pediatric ophthalmologist, and a pediatric surgeon for the installation of certain kinds of feeding tubes. Physical and occupational therapists can and educational specialists can provide supportive treatment.
There is no cure for Canavan disease and treatment largely involves the management of symptoms. Seizures and irritability can often be controlled through medication. Children with loss of head control will often benefit from the use of modified seats that can provide full head support. When feeding and swallowing becomes difficult, liquid diets and/or feeding tubes become necessary. Feeding tubes are either inserted through the nose (nasogastric tube) or through a permanent incision in the stomach (gastrostomy). Patients with a later onset and slower progression of the disease may benefit from special education programs and physical therapy. Research trials of gene therapy are ongoing and involve the transfer of an unchanged ASPA gene into the brain cells of a patient. The goal of gene therapy is to restore normal amounts of aspartoacylase in the brain and nervous system and prevent the build-up of NAA and the symptoms of Canavan disease. The initial results of these early clinical trials have been somewhat promising but it will take time for gene therapy to become a viable treatment for Canavan disease.
The life span and progression of Canavan disease is variable and may be partially dependent on the type of medical care provided and other genetic risk factors. Most people with Canavan disease live into their teens, although some die in infancy or survive into their 20's and 30's. There can be a high degree of variability even within families; some families report having one child die in infancy and another die in adulthood. Although different ASPA gene changes are associated with the production of different amounts of enzyme, the severity of the disease does not appear to be related to the type of ASPA gene change. It is, therefore, impossible to predict the life span of a particular individual with Canavan disease.
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Canavan Foundation. 320 Central Park West, Suite 19D, New York, NY 10025. (212) 877-3945.
Canavan Research Foundation. Fairwood Professional Building, New Fairwood, CT 06812. (203) 746-2436. [email protected] <http://www.canavan.org>.
National Foundation for Jewish Genetic Diseases, Inc. 250 Park Ave., Suite 1000, New York, NY 10017. (212) 371-1030. <http://www.nfjgd.org>.
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Lisa Maria Andres, MS, CGC
Rosalyn Carson-DeWitt, MD