Canavan disease, a rare early-onset human spongiform leukodystrophy: insights into its genesis and possible clinical...

The brain contains high concentrations of the amino acid N-acetyl-l-aspartate (NAA) and its' glutamate adduct N-acetyl-l-aspartylglutamate (NAAG), both synthesized primarily by and stored in neurons. Upon depolarization both are exported to extracellular fluid (ECF) with NAA targeted to oligodendrocytes and NAAG targeted to astrocytes where they are hydrolyzed by specific enzymes. While the functions of these substances are incompletely known, their unique tri-cellular metabolism is apparently vital to normal brain function. Canavan disease (CD) is a globally occurring but rare early-onset human spongiform leukodystrophy associated with inborn genetic errors affecting the activity of aspartoacylase (ASPA), the enzyme highly expressed in oligodendrocytes that hydrolyzes NAA. Several hypotheses attempt to explain how the lack of ASPA activity results in the inability of oligodendrocytes to build or maintain axon-enveloping myelin sheaths, a failure reflected in the CD syndrome by profound neurological disturbances. Based on evidence provided by recent studies, as well as on descriptions of several atypical mild cases of CD and of a singular human case of an inborn error where NAA cannot be synthesized, we provide insights into the possible genesis of the CD syndrome and many of its phenotypic expressions. In this article we also evaluate current hypotheses, and discuss possible clinical interventions that may be of value in treatment of CD.