Dietary treatment proposed for Canavan's disease

Abstract

Disruption of lipid synthesis by abnormal acetate production in the brain contributes to the pathophysiology of Canavan’s disease, a hereditary disorder of the CNS. Individuals with this disease “develop spongy degeneration of the brain, and usually do not survive beyond age 10 years”, explains corresponding author M A Aryan Namboodiri (Uniformed Services University of Health Sciences, Bethesda, MD, USA). Although Canavan’s disease has been linked with mutations in the gene encoding aspartoacylase (ASPA), the underlying pathological mechanisms had been unclear. ASPA converts Nacetylaspartate (NAA) to L-aspartate and acetate in brain oligodendrocytes, and NAA has been proposed to participate in lipid synthesis via the aspartate pathway. Namboodiri and colleagues postulated that ASPA-derived acetate contributes to lipid synthesis during myelination. To test this theory, they measured acetate content and lipid synthesis in brain samples from ASPA knockout mice compared with samples from wild-type mice. The researchers report that mutant mice had reduced amounts of myelin-associated lipids and free acetate, and showed no detectable ASPA activity (Proc Natl Acad USA 2005; 102: 5221–26). The researchers also analysed samples from a patient who had died from Canavan’s disease. They found that the patient was homozygous for a common ASPA mutation and had significantly lower amounts of complex glycolipids than those from a healthy individual. The reduced acetate concentrations indicate that “the myelin lipid deficiency results from a lack of available acetate in the brain during development”, explains Namboodiri. The researchers postulate that NAA that is derived from neurons generates acetate in oligodendrocytes, where it has an important role in lipid synthesis, possibly in the myelin sheath. Namboodiri and colleagues suggest dietary supplementation with acetate as a potential treatment for Canavan’s disease. However, the success of oral supplementation will “depend on the ability of acetate to be absorbed in the intestine, transported across the blood–brain barrier, and taken up by the oligodendrocytes”, cautions Vadivel Ganapathy (Medical College of Georgia, Augusta, GA, USA). “It is [also] premature to conclude that the inability of NAA to serve as the source of acetate due to ASPA deficiency is the only possible mechanism underlying the pathogenesis of Canavan’s disease.”