ASPA

The ASPA gene provides instructions for making an enzyme called aspartoacylase. In the brain, this enzyme breaks down a compound called N-acetyl-L-aspartic acid (NAA) into aspartic acid (an amino acid that is a building block of many proteins) and another molecule called acetic acid.

The cycle of production and breakdown of NAA appears to be critical for maintaining the brain's white matter, which consists of nerve fibers covered by myelin. Myelin is the fatty substance that insulates and protects nerves. Although the precise function of NAA is unknown, it is probably essential for making certain fats (lipids) that are used to produce myelin. Researchers believe that NAA may also play a role in transporting molecules of water out of nerve cells.

Canavan disease - caused by mutations in the ASPA gene

More than 55 mutations in the ASPA gene are known to cause Canavan disease. Two specific mutations cause most cases of the disease in people of Ashkenazi (eastern and central European) Jewish descent. One of these mutations changes a single protein building block (amino acid) in aspartoacylase. Specifically, this mutation replaces the amino acid glutamic acid with the amino acid alanine at position 285 of the enzyme (written as Glu285Ala or E285A). The other common mutation, which is written as Tyr231Ter or Y231X, prematurely stops protein production and leads to an abnormally small, nonfunctional version of the enzyme.

A different mutation is most common in people who are not of Ashkenazi Jewish descent. This mutation substitutes the amino acid glutamic acid for the amino acid alanine at position 305 of aspartoacylase (written as Ala305Glu or A305E).

Mutations in the ASPA gene reduce or eliminate the activity of aspartoacylase, which prevents the normal breakdown of NAA in the brain. Recent studies suggest that if NAA is not broken down properly, the resulting chemical imbalance may interfere with the formation of myelin as the nervous system develops. A buildup of NAA also leads to the progressive destruction of existing myelin around nerve cells. Nerve fibers without this protective covering malfunction and die, damaging the brain and causing the serious signs and symptoms of Canavan disease.