Canavan disease and the role of N-acetylaspartate in myelin synthesis

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Canavan disease and the role of N-acetylaspartate in myelin synthesis
Namboodiri AM, Peethambaran A, Mathew R, Sambhu PA, Hershfield J, Moffett JR, Madhavarao CN.

Mol Cell Endocrinol. 2006 Jun 27;252(1-2):216-23

In this article, the authors give further proof that N-acetylaspartate acts as an acetate carrier from mitochondria to the cytosol, and is thus important for lipogenesis and myelination in the central nervous system.
They recall that in the brain of Canavan disease mice (APSA -/-), there was nearly an 80% reduction in free acetate levels.
Supplementing these mice with glyceryl triacetate increases the brain acetate levels without affecting N-acetylaspartate levels and without toxicity.

For more information on Canavan disease, see chapter 229 of OMMBID.
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Philippe Campeau, MD
Resident in Medical Genetics at McGill University
OMMBID Blog Administrator

One Response to “Canavan disease and the role of N-acetylaspartate in myelin synthesis”

  1. pcampeau

    Excerpts from chapter 229 written by Arthur Beaudet

    Chapter 229: Aspartoacylase Deficiency (Canavan Disease)


    The disorder now identified as aspartoacylase deficiency is equivalent to the condition variously called spongy degeneration of the brain, spongy degeneration of the central nervous system in infancy, or spongy degeneration of infancy, and many publications have used the eponymic designation, Canavan disease. The first definition of this condition as a distinct clinical entity is properly credited to van Bogaert and Bertrand in 1949.1,2 In retrospect, the first clinical description is attributed to Globus and Strauss in 1928.3 In 1931, Canavan described an infant with prominent enlargement of the head and cerebral and cerebellar spongy degeneration under the designation “Schilder’s encephalitis periaxialis diffusa.”4 Eiselsberg is credited with the recognition of the familial nature of the disorder in 1937,5 but, like Jervis,6,7 she described the condition as Krabbe disease. The reports of von Bogaert and Bertrand1,2 were comprehensive and described the essential pathologic and clinical features as well as the predilection for the occurrence of the disorder in Ashkenazic infants. In a more detailed review of the historical literature,8 Banker et al. pointed out that the Canavan eponym is hardly justified, because her report was not the first clinical description, did not recognize the familial or ethnic aspect to the disorder, and did not recognize spongy degeneration as the unique pathologic feature; the designation aspartoacylase deficiency may be most appropriate, but the eponym is widely used.

    Unraveling of the biochemical basis of infantile spongy degeneration began with the description of urinary excretion of N-acetylaspartic acid (NAA) by Kvittingen et al.,9 but aspartoacylase was reported to be normal in cultured fibroblasts; presumably the failure to demonstrate the enzyme deficiency was due to the choice of conditions for enzyme analysis. In 1987, Hagenfeldt et al. reported N-acetylaspartic aciduria and identified aspartoacylase deficiency,10 but neither of these biochemical reports recognized the association with infantile spongy degeneration. Matalon et al.,11,12 and Divry et al.13,14 are credited with the recognition that aspartoacylase deficiency correlated with infantile spongy degeneration (Canavan disease). Kaul et al. went on to isolate a cDNA clone for human aspartoacylase and identified the common mutation in Jewish patients.15 Matalon and colleagues have contributed extensively to observations in recent years as reviewed elsewhere.16


    It should be possible to suspect the diagnosis of aspartoacylase deficiency based on clinical features and cranial imaging studies. Ashkenazic ancestry is present in a substantial fraction of cases. If the disorder is suspected, a diagnosis can be confirmed by the demonstration of increased amounts of NAA in the urine using gas chromatography/mass spectroscopy (GC/MS)89,90 and/or by enzyme analysis of cultured fibroblasts;11,91 enzyme analysis of leukocytes is not reported. The mass spectra for derivitized metabolites of NAA have been published, and accurate quantitation of levels in urine, plasma, and cerebrospinal fluid have been reported using stable isotope dilution methods.89,90 Normal ranges of NAA in urine were reported as 6.6 to 35.4 or 12.7 ± 7.8 M/mM of creatinine in two studies with affected values typically being more than twentyfold above the upper limits of normal. Activity of aspartoacylase is readily detected in cultured skin fibroblasts with values being profoundly reduced in affected patients.89,90 Enzyme activity has been measured spectrophotometrically as aspartic acid produced using absorbance at 340 nm to quantitate conversion of NADH to NAD in the presence of malate dehydrogenase and aspartate aminotransferase.10,11 A sensitive radiometric assay utilizes ion exchange chromatography to quantitate the production of [3H]acetate from [3H]NAA.91 Since the first two cases of N-acetylaspartic aciduria were reported without recognizing the association with infantile spongy degeneration, it seems likely that some infants will continue to be diagnosed on the basis of urinary organic acid analysis in patients with neurologic symptoms where the diagnosis of infantile spongy degeneration is not specifically being considered. For this reason, laboratories performing urinary organic acid analysis should be alert to the conditions necessary for extraction and detection of NAA and to the significance of this compound in the urine. Mutation analysis will also permit diagnosis in the majority of Jewish patients and in a significant fraction of non-Jewish patients, but biochemical studies should remain the primary basis for diagnosis or ruling out the condition.


    There is no known treatment for aspartoacylase deficiency. It is of interest to know whether inhibitors of the enzyme that synthesizes NAA can be developed and tested for safety and efficacy in animal models. Although there are reports of attempts at somatic gene therapy,101,102 studies are very preliminary, and success in this regard is likely to be years away.

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