Canavan Disease

Canavan disease, one of the most common cerebral degenerative diseases of infancy, is a gene-linked, neurological birth disorder in which the white matter of the brain degenerates into spongy tissue riddled with microscopic fluid-filled spaces. The disorder was named for Myrtelle Canavan, the researcher who first described the disease in 1931.

Canavan disease (CD) belongs to a group of conditions known as leukodystrophies, which result from defects in myelin. Myelin, a substance made up of proteins and lipids, is an integral component of the nervous system. It is commonly known as the "white matter" in the brain; its function is to protect nerves and allow messages to be sent to and from the brain.

In Canavan disease, the white matter deteriorates because patients have a deficiency in the enzyme aspartoacylase, which leads to the accumulation of another chemical, called N-acetyl-aspartic acid (NAA). It is not known exactly how these chemical imbalances cause the destruction of myelin.

Canavan disease causes progressive brain atrophy. There is no cure, nor is there a standard course of treatment. Treatment is symptomatic and supportive. The prognosis for those with CD is poor. Death often occurs before age 4, although some children may survive into their teens and twenties.

Although Canavan disease may occur in any ethnic group, it is more frequent among Ashkenazi Jews from eastern Poland, Lithuania, and western Russia, and among Saudi Arabians.

Screening and Diagnosis
Both parents must be carriers of the defective gene in order to have an affected child. When both parents are found to carry the Canavan gene mutation, there is a one in four (25%) chance with each pregnancy that the child will be affected with CD.

Recent developments in the understanding of the genetic defect involved in Canavan disease have increased not only the ability to diagnose CD accurately, but also the accuracy of carrier screening and prenatal detection for at-risk families.

Canavan disease can be identified by a simple prenatal blood test that screens for the missing enzyme or for mutations in the gene that controls aspartoacylase.

Another method of prenatal diagnosis that may provide information to families with unidentified mutations is linkage analysis, a form of DNA testing that compares the DNA of the fetus to that of affected and unaffected relatives to determine whether the fetus is likely to be affected.

A third method relies on the measurement of NAA levels in amniotic fluid; accurate determination of NAA levels in amniotic fluid is difficult and is only performed at one or two laboratories in the US.

Signs and Symptoms
It is not possible to describe all children with CD in the same way, since the presentation and progression of illness varies from child to child.

Symptoms of Canavan disease appear in early infancy and progress rapidly, but generally include rapidly increasing head circumference, lack of head control, reduced visual responsiveness and abnormal muscle tone such as stiffness or floppiness.

Affected children may also have mental retardation, feeding difficulties and loss of previously acquired motor skills. Paralysis, blindness, or hearing loss may also occur. Children with CD are characteristically quiet and apathetic.

As the child grows, motor skills and mental functioning deteriorate, although many affected children continue to recognize and respond to the voices of their primary caregivers.

Although many children with CD die in infancy, some survive into adolescence and even occasionally into adulthood.

Research
To date, there is no cure or effective treatment for Canavan disease, but several approaches are currently being explored.

The first is gene therapy, in which functional aspartoacylase (ASPA) genes are introduced into an affected child's brain to increase the levels of aspartoacylase. The second is the introduction of functional neuronal stem cells into an affected child's brain to increase the number of neurons that make aspartoacylase. The third is the use of medications to reduce the amount of fluid and/or decrease the amount of NAA in a child's brain.

The gene for Canavan disease has been located. Research includes studies to understand how the brain and nervous system normally develop and function and how they are affected by genetic mutations. These studies contribute to a greater understanding of gene-linked disorders such as Canavan disease, and have the potential to open promising new avenues of treatment.

This article includes information from the National Tay-Sachs & Allied Diseases Association, the Canavan Foundation, and the National Institutes of Health.

Each year, Medical College of Wisconsin physicians care for more than 180,000 patients, representing nearly 500,000 patient visits. Medical College physicians practice at Children's Hospital of Wisconsin, Froedtert Memorial Lutheran Hospital, the Milwaukee VA Medical Center, and many other hospitals and clinics in Milwaukee and southeastern Wisconsin.