CD is a relatively rare, but always fatal, inherited degenerative brain disease. A disorder of central nervous system (CNS), it affects myelin, the brain's white matter, which protects nerves and allows messages to be sent to and from the brain.
CD has been linked to mutations in the gene for the enzyme aspartoacylase (ASPA), which leads to the buildup of N-acetylaspartic acid (NAA) in the brain. Significant accumulation of NAA in the brain is closely associated with CD, which is characterized by the destruction of myelin. This causes the white matter to degenerate into spongy tissue riddled with microscopic fluid-filled spaces. However, the relation to accumulated NAA and the cause for the destruction of myelin is not known.
In this new research, myelin lipid synthesis was studied in the mouse model of Canavan disease. The objective was to test the hypothesis that deficiency in the supply of NAA-derived acetate results in decreased synthesis of myelin-related fatty acids and lipids, and that this lipid synthesis deficiency causes CD.
Analyses of newly synthesized lipids in the brain revealed significant decreases in four or five major myelin lipids in CD mice at the time of peak myelination. Acetate levels in the brain decreased by about 80% while acetate levels in the liver and kidney remained unchanged. Analysis of the lipid content of white matter from a human Canavan patient showed decreases in a number of myelin lipids relative to normal white matter.
These results demonstrate that myelin lipid synthesis is significantly compromised in CD, and provide the first direct evidence that defective myelin synthesis, resulting from a deficiency of NAA-derived acetate, is involved in the pathogenesis of CD. Further, these results make a strong case for acetate supplementation as a potential therapy for this devastating and fatal congenital disease, warranting comprehensive clinical trials.
This research was conducted by scientists in the Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences in Bethesda, Md. Studies were conducted in collaboration with University of Texas Medical Branch, Wayne State University, Albert Einstein College of Medicine and the Henry Ford Hospital, and were supported by the Henry M. Jackson Foundation for the Advancement of Military Medicine.
Background
Canavan disease is a relatively rare, but always fatal, inherited, degenerative brain disorder. Currently, there is no cure for the disease, nor is there a standard course of treatment. The disorder was named after Myrtelle Canavan, the researcher who first described the disease in 1931.
Although Canavan disease may occur in any ethnic group, it is more frequent among Ashkenazi Jews, which comprises about 90 percent of Jewish people in America.
The Henry M. Jackson Foundation for the Advancement of Military Medicine (www.hjf.org) is a private, not-for-profit organization chartered by Congress to support military medical research and education at the Uniformed Services University of the Health Sciences (www.usuhs.mil) and throughout military medicine.
Journal
Proceedings of the National Academy of Sciences