What is Canavan disease?

Risk Factors

Parents who carry the Canavan gene may transmit it to their offspring in an autosomal recessive genetic pattern. For the disease to occur, both parents must carry the gene. Each child has a 25-percent chance of inheriting both abnormal genes and suffering from this tragic disease. The genetic mutation is more common in Jews of Eastern and Central European background (Ashkenazi) than in the population at large, though it has been found in all ethnic groups. It is estimated that 1 in 40 Ashkenazi Jews are carriers of the Canavan gene, resulting in a disease risk of about 1 in 6,400 births in this group.

Etiology and Genetics

Canavan disease is caused by a deficiency of the enzyme aspartoacylase, which is necessary for the breakdown of a substance in the brain called N-acetylaspartic acid. The lack of the enzyme leads to the accumulation of N-acetylaspartic acid, which in turn destroys myelin, a substance that acts as essential insulation in the brain. This destruction causes brain tissue to degenerate, resulting in a spongelike appearance and progressive disability and death.

The gene for aspartoacylase has been located on chromosome 17, and recent work in molecular genetics has identified three common alterations in DNA that are responsible for the disease. The first is a mutation in codon 285 (a section or location of DNA in the gene); the second is in codon 231; and the third is in codon 305. These three mutations are the cause of greater than 99 percent of cases of Canavan disease in Ashkenazi Jews and over 55 percent in other ethnic groups.

The disease is inherited as an autosomal recessive trait and must be carried by both parents for children to be affected. The inheritance of two altered genes leads to the deficiency of aspartoacylase. If only one parent carries the Canavan gene, then children will have a 50 percent chance of inheriting the altered gene and being carriers but will not have the disease. A single gene is sufficient for the production of the enzyme that prevents buildup of N-acetylaspartic acid. If both parents carry the Canavan gene mutation, then each pregnancy carries a 25-percent risk of disease and a 50-percent risk of carrier status.

Symptoms

Newborns with Canavan disease appear normal. Symptoms of the disease begin to appear in infancy, most often by age six months. The hallmark is developmental delay, which is most often noted when infants fail to achieve early developmental milestones such as head control. The size of the head begins to increase (macrocephaly) and muscle tone and strength decrease. Motor skills are most severely affected. As damage to critical brain tissue continues, severe feeding problems, seizures, and blindness follow. Brain degeneration is progressive, and most children with the disease become severely disabled and die by age ten.

Screening and Diagnosis

Because of the increased prevalence of the Canavan gene in the Ashkenazi population, prepregnancy screening is recommended for couples in this group. Molecular diagnostic testing of blood samples is required to identify the three common gene mutations described above. If both parents are carriers of the gene, then prenatal diagnosis is available. Chorionic villus sampling may be performed in the first trimester of pregnancy, while amniocentesis is available in the second trimester.

Diagnosis of Canavan disease in at-risk infants is based on the presence of elevated amounts of N-acetylaspartic acid in the urine.

Treatment and Therapy

There is no cure or specific treatment for Canavan disease. Therapy is directed at modification of symptoms. Supportive measures such as the placement of feeding tubes, anticonvulsant medication, communication assistance, and physical therapy are often used. Antibiotics are used to treat common infections such as pneumonia.

Experimental studies for the treatment of Canavan disease are focused on gene therapy, including the introduction of functional aspartoacylase genes into an affected child’s brain to attempt to increase the missing enzyme. Medications to reduce the amount of destructive N-acetylaspartic acid in the brain are also being studied.

Prevention and Outcomes

Screening and genetic counseling are suggested for couples of Ashkenazi Jewish background and for those with a family history of Canavan disease. DNA testing is reliable and can identify whether one or both parents carry the Canavan gene in more than 99 percent of those screened. Parent screening and prenatal diagnosis are currently the only effective prevention for the disease.

Canavan disease is invariably fatal, with death often occurring by eighteen months of age, though there have been rare cases of children living into the teen years.

Bibliography

American College of Medical Genetics Board of Directors. Position Statement on Carrier Testing for Canavan Disease. Bethesda: Author, 1998. Print.

National Tay-Sachs & Allied Diseases Association. A Genetics Primer for Understanding Tay-Sachs and the Allied Diseases. Brookline: Author, 1995. Print.

Rezvani, I. “Defects in Metabolism of Amino Acids.” Kliegman: Nelson Textbook of Pediatrics. Ed. R. M. Kliegman et al. 19th ed. Philadelphia: Saunders Elsevier, 2011. Print.

Sommer, Anke, and Jörn Oliver Sass. "Expression of Aspartoacylase (ASPA) and Canavan Disease." Gene 505.2 (2012): 206–10. Print.

Surendran, Sankar. Neurochemistry of Metabolic Diseases: Lysomal Storage Diseases, Phenylketonuria, and Canavan Disease. New York: Nova Science, 2012. Print.