An additional controversy concerning NAA is that it is toxic to neurons when the concentration is substantially elevated in the brain, as in the case of many Canavan disease patients.29 Canavan disease (CD) is a fatal, hereditary leukodystrophy that compromises myelination in the CNS. CD is caused by mutations in the gene for ASPA,30,31 an enzyme that currently is thought to function exclusively to hydrolyze NAA into L-aspartate and free acetate. However, ASPA is strongly expressed in other tissues such as kidney, even though the only known substrate, NAA, is present predominantly in the nervous system.32 Despite the established connection between mutations in the gene for ASPA in CD, and the lost capacity to deacetylate NAA, the specific connection between ASPA deficiency and the failure of proper CNS development is unclear.33 It has been proposed that lack of deacetylase activity against NAA leads to toxic increases in the concentration of NAA in the brain.34 Indeed, the level of extracellular NAA may be a critical factor in determining if it has toxic effects. For example, Pliss and colleagues reported that injection of 0.25 micromoles/ventricle of NAA into the lateral cerebral ventricles of rats did not induce any detectable neuronal death in the hippocampus,35 whereas Akimitsu et al. reported that intraventricular injection of 8 micromoles of NAA into the lateral ventricle of rats induced strong seizures.36 Seizures are one of the symptoms of CD, but it has not been conclusively demonstrated that elevated NAA levels are responsible for the seizure activity. The question of the toxicity of NAA has not been fully answered, but it is possible that exceptionally high levels of NAA in the brains of some CD patients may be involved in some of the pathogenesis, possibly by inducing seizure activity.
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