Final Comments

It should be stressed that the question of which mechanisms are primarily involved in the pathogenesis of CD, and which are less critical, remains unclear at the present time. It seems clear now that an acetate deficiency caused by dysfunction in a specific enzyme in oligodendrocytes has an etiological role in CD. It is also possible that osmotic dysregulation in the CNS is mediated by excessive extracellular NAA concentrations, and that high NAA concentrations lead to seizures, which further contribute to the pathogenesis. However, we should not neglect the fact that ASPA is extensively expressed in the kidney, and therefore it is possible that renal pathologies could also contribute to disease progression by as yet undetermined mechanisms. It is also not clear whether or not the primary substrate for ASPA in the kidney is NAA, because NAA levels are very low there. If the function of ASPA in the kidney and other peripheral tissues is unrelated to NAA, which seems likely, then other approaches may need to be developed to deal with the pathological consequences of the loss of ASPA activity in those tissues.

One approach to testing if an acetate deficiency is a primary etiological mechanism of CD would be to determine whether myelin synthesis can be promoted in newborn CD infants by increasing brain acetate levels through dietary supplementation. CD pathogenesis develops predominantly after birth, and therefore this approach should be feasible. An orally administered form of acetate in a supplemented infant formula could directly provide the required substrate for the rapid myelination that takes place during early, postnatal neural development. Early diagnosis of CD using urinalysis to detect high NAA levels could be followed by immediate acetate supplementation of the diet, which may provide an extremely safe, simple and low cost treatment for CD.

In conclusion, the findings presented above provide direct support for the proposed etiology of CD as a deficiency of NAA/ASPA-derived acetate, resulting in reduced lipid synthesis, and a failure of proper myelination during CNS development. Based upon these and other findings, early postnatal acetate supplementation trials appear warranted in confirmed cases of CD.

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