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Canavan disease

Analysis of the nature of the metabolic lesions responsible for development of the observed clinical symptoms

Journal of Molecular Neuroscience volume 9, pages 109–125 (1997)Cite this article

Abstract

Canavan disease (CD), a rare recessive autosomal genetic disorder, is characterized by early onset and a progressive spongy degeneration of the brain involving loss of the axon’s myelin sheath. After a relatively normal birth, homozygous individuals generally develop clinical symptoms within months, and usually die within several years of the onset of the disease. A biochemical defect associated with this disease results in reduced activity of the enzymeN-acetyl-l-aspartate amidohydrolase (aspartoacylase) and affected individuals have less ability to hydrolyzeN-acetyl-l-aspartate (NAA) in brain and other tissues. As a result of aspartoacylase deficiency, NAA builds up in extracellular fluids (ECF) and is excreted in urine. From an analysis of the NAA biochemical cycle in various tissues of many vertebrate species, evidence is presented that there may be two distinct NAA circulation patterns related to aspartoacylase activity. These include near-field circulations in the brain and the eye, and a far-field systemic circulation involving the liver and kidney, the purpose of which in each case is apparently to regenerate aspartate (Asp) in order for it to be recycled into NAA as part of the still unknown function of the NAA cycle. Based on the authors’ analysis, they have also identified several metabolic outcomes of the genetic biochemical aspartoacylase lesion. First, there is a daily induced Asp deficit in the central nervous system (CNS) that is at least six times the static level of available free Asp. Second, there is up to a 50-fold drop in the intercompartmental NAA gradient, and third, the ability of the brain to perform its normal intercompartmental cycling of NAA to Asp is terminated, and as a result, the only remaining long-term source of Asp for NAA synthesis is via nutritional supplementation of Asp or its metabolic precursors. Finally, the authors identify a potential maternal-fetal interaction that may be responsible for observed normal fetal development in utero, and that provides a rationale for, and suggests how, CD might respond to far-field nutritional, transplantation, or genetic engineering techniques to alter the course of the disease.

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References

  • Adachi M. and Volk B. W. (1968) Protracted form of spongy degeneration of the central nervous system (van Bogaert and Bertrand type).Neurology 18, 1084–1092.

    PubMed  CAS  Google Scholar 

  • Afanas’ev I., Suslova T. B., Cheremisina Z. P., Abramova N. E., and Korkina L. G. (1995) Study of antioxidant properties of metal aspartates.Analyst 120, 859–862.

    PubMed  Article  CAS  Google Scholar 

  • Baslow M. H. (1997) A review of phylogenetic and metabolic relationships between the acylamino acids, N-acetyl-L-aspartic acid and N-acetyl-L-histidine in the vertebrate nervous system.J. Neurochem. 68, 1335–1344.

    PubMed  CAS  Article  Google Scholar 

  • Baslow M. H. and Lenney J. F. (1967) a-N-Acetylhistidine amido-hydrolase activity from tuna fish brain: inhibition by phenothiazines.Seventh Int. Cong. Biochem. 5, 1014.

    Google Scholar 

  • Baslow M. H. and Nigrelli R. F. (1961) Muscle acetylcholinesterase as an index of general activity in fishes.Copeia 1, 8–11.

    Article  Google Scholar 

  • Baslow M. H. and Nigrelli R. F. (1964) The effect of thermal acclimation on brain cholinesterase activity of the killifish, Fundulus heteroclitus.Zoologica 49(1), 41–51.

    CAS  Google Scholar 

  • Baslow M. H. and Yamada S. (1997a) Identification of N-acetylaspartate in the lens of the vertebrate eye: a new model for the investigation of the function of N-acetylated amino acids in vertebrates.Exp. Eye Res. 64(2), 283–286.

    PubMed  Article  CAS  Google Scholar 

  • Baslow M. H. and Yamada S. (1997b) Distribution of N-acetyl-L-histidine and N-acetyl-L-aspartate in the vertebrate eye.J. Neurochem. 69 (Suppl.), 5175D.

    Google Scholar 

  • Bennett M. J., Gibson K. M., Sherwood W. G., Divry P., Rolland M. O., Elpeleg O. N., Rinaldo P., and Jakobs C. (1993) Reliable prenatal diagnosis of Canavan disease (aspartoacylase deficiency): comparison and enzymatic and metabolite analysis.J. Inher. Met. Dis. 16, 831–836.

    Article  CAS  Google Scholar 

  • Berlinguet L. and Laliberte M. (1966) Metabolism of N-acetyl-L-aspartic acid in mice.Can. J. Biochem. 44, 783–789.

    PubMed  CAS  Article  Google Scholar 

  • Birken D. L. and Oldendorf W. H. (1989) N-Acetyl-L-aspartic acid: a literature review of a compound prominent in H-NMR spectroscopic studies of brain.Neurosci. Biobehav. Rev. 13, 23–31.

    PubMed  Article  CAS  Google Scholar 

  • Boehme D. H. and Marks N. (1981) Protracted form of Canavan’s disease: casehistory and protein kinase activity of membrane fractions.Acta Neuropathol. 55, 221–225.

    PubMed  Article  CAS  Google Scholar 

  • Bremer H. J., Duran M., Kamerling J. P., Przyrembel H., and Wadman S. K. (1981) Disturbances of amino acid metabolism: clinical chemistry and diagnosis. Urban and Schwarzenberg, Baltimore, MD, p. 536.

    Google Scholar 

  • Buniatian H. C. H., Hovhannissian V. S., and Aprikian G. V. (1965) The participation of N-acetyl-L-aspartic acid in brain metabolism.J. Neurochem. 12, 695–703.

    PubMed  Article  CAS  Google Scholar 

  • Burns S. P., Chalmers R. A., West R. J., and Iles R. A. (1992) Measurement of human brain aspartate N-acetyl transferase flux in vivo.Biochem. Soc. Trans. 20, 107S.

    Google Scholar 

  • Canavan M. M. (1931) Schilders encephalitis periaxialis diffusa. Report of a case in a child aged sixteen and one-half months.Arch. Neurol. Psychiat. 25, 299–308.

    Google Scholar 

  • Christensen H. N. (1990) Role of amino acid transport and countertransport in nutrition and metabolism.Physiol. Rev. 70, 43–77.

    PubMed  CAS  Google Scholar 

  • D’Adamo A. F. Jr., Smith J. C., and Woiler C. (1973) The occurrence of N-acetylaspartate amidohydrolase (aminoacylase II) in the developing rat.J. Neurochem. 20, 1275–1278.

    PubMed  Article  CAS  Google Scholar 

  • During M. (1996) Gene therapy in New Zealand (letter).Science 272, 467.

    PubMed  Article  CAS  Google Scholar 

  • Elpeleg O. N., Shaag A., Anikster Y., and Jakobs C. (1994) Prenatal detection of Canavan disease (aspartoacylase deficiency) by DNA analysis.J. Inher. Met. Dis. 17, 664–666.

    Article  CAS  Google Scholar 

  • Ferrari M. D., Odink J., Bos K. D., Malessy M. J. A., and Bruyn G. W. (1990) Neuroexcitatory plasma amino acids are elevated in migraine.Neurology 40, 1582–1586.

    PubMed  CAS  Google Scholar 

  • Ford F. R. (1960)Diseases of the Nervous System in Infancy, Childhood and Adolescence. Charles C. Thomas, Pub., Springfield, IL, p. 1548.

    Google Scholar 

  • Goldstein F. B. (1976) Amidohydrolases of brain; enzymatic hydrolysis of N-acetyl-L-aspartate and other N-acyl-L-amino acids.J. Neurochem. 26, 45–49.

    PubMed  Article  CAS  Google Scholar 

  • Kaul R., Casanova J., Johnson A. B., Tang P., and Matalon R. (1991) Purification, characterization, and localization of aspartoacylase from bovine brain.J. Neurochem. 56, 129–135.

    PubMed  Article  CAS  Google Scholar 

  • Kaul R., Gao G. P., Balamurugan K., and Matalon R. (1993) Cloning of the human aspartoacylase cDNA and a common missense mutation in Canavan disease.Nature Gen. 5, 118–123.

    Article  CAS  Google Scholar 

  • Kaul R., Gao G. P., Aloya M., Balamurugan K., Petrosky A., Michals K., and Matalon R. (1994a) Canavan disease: mutations among Jewish and non-Jewish patients.Am. J. Hum. Gen. 55, 34–41.

    CAS  Google Scholar 

  • Kaul R., Balamurugan K., Gao G. P., and Matalon R. (1994b) Canavan disease: genomic organization and localization of human ASPA to 17p13-ter and conservation of the ASPA gene during evolution.Genomics 21, 364–370.

    PubMed  Article  CAS  Google Scholar 

  • Kaul R., Gao G. P., Matalon R., Aloya M., Su Q., Jin M., Johnson A. B., Schutgens R. B., and Clarke J. T. (1996) Identification and expression of eight novel mutations among non-Jewish patients with Canavan disease.Am. J. Hum. Gen. 59, 95–102.

    CAS  Google Scholar 

  • Kelley R. I. (1993) Prenatal detection of Canavan disease by measurement of N-acetyl-L-aspartate in amniotic fluid.J. Inher. Metab. Dis. 16, 918, 919.

    PubMed  Article  CAS  Google Scholar 

  • Kish S. J., Robitaille Y., el-Awar M., Gilbert J., Deck J., Chang L. J., and Schut L. (1991) Brain amino acid reductions in one family with chromosome 6p-linked dominantly inherited olivopontocerebellar atrophy.Ann. Neurol. 30, 780–784.

    PubMed  Article  CAS  Google Scholar 

  • Kvittingen E. A., Guldal G., Borsting S., Skalpe I. O., Stokke O., and Jellum E. (1986) N-acetylaspartic aciduria in a child with a progressive cerebral atrophy.Clin. Chim. Acta 158, 217–227.

    PubMed  Article  CAS  Google Scholar 

  • Levine R. J. (1996) Canavan gene therapy protocol (letter)Science 272, 1085.

    PubMed  Article  CAS  Google Scholar 

  • Matalon R., Michals K., Sebasta D., Deanching M., Gashkoff P., and Casanova J. (1988) Aspartoacylase deficiency and N-acetylaspartic aciduria in patients with Canavan disease.Am. J. Med. Genet. 29, 463–471.

    PubMed  Article  CAS  Google Scholar 

  • Matalon R., Kaul R., Casanova J., Michals K., Johnson A., Rapin I., Gashkoff P., and Deanching M. (1989) Aspartoacylase deficiency: the enzyme defect in Canavan disease.J. Inher. Metab. Dis. 12, 329–331.

    PubMed  Article  Google Scholar 

  • Matalon R., Kaul R., and Michals K. (1993) Canavan disease: biochemical and molecular studies.J. Inher. Met. Dis. 16, 744–752.

    Article  CAS  Google Scholar 

  • Matalon R., Michals K., and Kaul R. (1995) Canavan disease: from spongy degeneration to molecular analysis.J. Pediatr. 127, 511–517.

    PubMed  Article  CAS  Google Scholar 

  • Oldendorf W. H. (1971) Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection.Am. J. Physiol. 221, 1629–1639.

    PubMed  CAS  Google Scholar 

  • Pevzner L. Z. (1979)Functional Biochemistry of the Neuroglia (Tiplady B., ed.), Plenum, New York, p. 306.

    Google Scholar 

  • Reddy D. V. N. (1967) Distribution of free amino acids and related compounds in ocular fluids, lens and plasma of various mammalian species.Invest. Opthalmol. 6, 478–483.

    CAS  Google Scholar 

  • Reilmann R., Rolf L. H., and Lange H. W. (1994) Huntington’s disease: the neuroexcitatoxin aspartate is increased in platelets and decreased in plasma.J. Neurol. Sci. 127, 48–53.

    PubMed  Article  CAS  Google Scholar 

  • Riikonen R. S., Kero P. O., and Simell O. G. (1992) Excitatory amino acids in cerebrospinal fluid in neonatal asphyxia.Pediatr. Neurol. 8, 37–40.

    PubMed  Article  CAS  Google Scholar 

  • Sager T. N., Fink-Jensen A., and Hansen A. J. (1997) Transient elevation of interstitial N-acetylaspartate in reversible global brain ischemia.J. Neurochem. 68, 675–682.

    PubMed  CAS  Article  Google Scholar 

  • Sandberg M., Butcher S. P., and Hagberg H. (1986) Extracellular overflow of neuroactive amino acids during severe insulin-induced hypoglycemia: in vivo dialysis of the rat hippocampus.J. Neurochem. 47, 178–184.

    PubMed  CAS  Article  Google Scholar 

  • Scriver C. R. and Rosenberg L. E. (1973) Amino acid metabolism and its disorders, inMajor Problems in Clinical Pediatrics, vol. X (Schaffer A. L., ed.), Saunders, Philadelphia, PA, p. 491.

    Google Scholar 

  • Shaag A., Anikster Y., Christensen E., Glustein J. Z., Fois A., Michelakakis H., Nigro F., Pronicka E., Ribes A., Zabot M. T., et al. (1995) The molecular basis of Canavan (aspartoacylase deficiency) disease in European non-Jewish patients.Am. J. Hum. Gen. 57, 572–580.

    CAS  Google Scholar 

  • Swahn C. G. (1990) Determination of N-acetylaspartic acid in human cerebrospinal fluid by gas chromatography-mass spectrometry.J. Neurochem. 54, 1584–1588.

    PubMed  Article  CAS  Google Scholar 

  • Tallan H. H. (1957) Studies on the distribution of N-acetyl-L-aspartic acid in brain.J. Biol. Chem. 224, 41–45.

    PubMed  CAS  Google Scholar 

  • Tallan H. H., Moore S., and Stein W. H. (1954) Studies on the free amino acids and related compounds in the tissues of the cat.J. Biol. Chem. 211, 927–939.

    PubMed  CAS  Google Scholar 

  • Truckenmiller M. E., Namboodiri M. A. A., Browstein M. J., and Neale J. H. (1985) N-Acetylation of L-aspartate in the nervous system: differential distribution of a specific enzyme.J. Neurochem. 45, 1658–1662.

    PubMed  Article  CAS  Google Scholar 

  • Urenjak J., Williams S. R., Gadian D. G., and Noble M. (1992) Specific expression of N-acetylaspartate in neurons, oligodendrocyte-type-2 astrocyte progenitors, and immature oligodendrocytes in vitro.J. Neurochem. 59, 55–61.

    PubMed  Article  CAS  Google Scholar 

  • Yamada S., Tanaka Y., Sameshima M., and Furuichi M. (1992) Occurrence of N-acetylhistidine in the muscle and deacetylation by several tissues of Nile tilapia (Oreochromis niloticus).Comp. Biochem. Physiol. [B]103, 579–583.

    Article  Google Scholar 

  • Yamada S., Tanaka Y., Sameshima M., and Furuichi M. (1993) Properties of N-acetylhistidine deacetylase in brain of trout Oncorhynchus mykiss.Comp. Biochem. Physiol. [B]106, 309–315.

    Article  Google Scholar 

  • Yamada S., Tanaka Y., Sameshima M., and Furiuchi M. (1994) Effects of starvation and feeding on tissue N-acetylhistidine levels in Nile tilapia Oreochromis niloticus.Comp. Biochem. Physiol. [A]109, 277–283.

    Article  Google Scholar 

  • Yamada S., Tanaka Y., and Furuichi M. (1995) Partial purification and characterization of histidine acetyltransferase in brain of Nile tilapia (Oreochromis niloticus).Biochim. Biophys. Acta 1245, 239–247.

    PubMed  Google Scholar 

  • Winick M. (1976)Malnutrition and Brain Development. Oxford University Press, New York, p. 169.

    Google Scholar 

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Affiliations

  1. Nathan S. Kline Institute for Psychiatric Research, Center for Neurochemistry, 10962, Orangeburg, NY

    Morris H. Baslow & Tracy R. Resnik

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  1. Morris H. Baslow
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  2. Tracy R. Resnik
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Baslow, M.H., Resnik, T.R. Canavan disease. J Mol Neurosci 9, 109–125 (1997). https://doi.org/10.1007/BF02736855

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  • DOI: https://doi.org/10.1007/BF02736855

Index Entries

  • N-acetylaspartate
  • N-acetylaspartic aciduria
  • N-acetylaspartic acidemia
  • N-acetylhistidine
  • Canavan disease
  • hypoaspartia