Canavan Disease: Studies on the Knockout Mouse

  • Reuben Matalon
  • Kimberlee Michals-Matalon
  • Sankar Surendran
  • Stephen K. Tyring
Part of the Advances in Experimental Medicine and Biology book series (volume 576)

1. Abstract

Canavan disease (CD) is an autosomal recessive disorder, characterized by spongy degeneration of the brain. Patients with CD have aspartoacylase (ASPA) deficiency, which results accumulation of N-acetylaspartic acid (NAA) in the brain and elevated excretion of urinary NAA. Clinically, patients with CD have macrocephaly, mental retardation and hypotonia. A knockout mouse for CD which was engineered, also has ASPA deficiency and elevated NAA. Molecular studies of the mouse brain showed abnormal expression of multiple genes in addition to ASPA deficiency. Adenoassociated virus mediated gene transfer and stem cell therapy in the knockout mouse are the latest attempts to alter pathophysiology in the CD mouse.


Neural Stem Cell Stem Cell Therapy Canavan Disease Ashkenazi Jewish Population ASPA Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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9. References

  1. 1.
    Canavan, M.M., 1931, Schilder’s encephalitis periaxialis diffusa. Arch. Neurol. Psychiatry 25, 299–308.Google Scholar
  2. 2.
    van Bogaert, L., and Bertrand, I., 1949, Su une idiotie familiale avec degenerescence spongieuse de neuraxe (note preliminaire), Acta. Neurol. Belg. 49, 572–587.Google Scholar
  3. 3.
    Matalon, R., Michals, K., Sebesta, D., Deanching, M., Gashkoff, P., and Casanova, J., 1988, Aspartoacylase deficiency and N-acetyl-aspartic aciduria in patients with Canavan disease, Am. J. Med. Genet. 29, 463–471.PubMedCrossRefGoogle Scholar
  4. 4.
    Birnbaum, S.M., Levinton, L., Kingsley, R.B., and Greenstei, J.P., 1952, Specificity of aminoacid acylases, J. Biol. Chem. 194, 455–462.PubMedGoogle Scholar
  5. 5.
    Matalon, R.M., Michals-Matalon-K., 2000, Spongy degeneration of the brain, Canavan disease: biochemical and molecular findings, Front Biosci, Mar 1:5:D307–11.PubMedGoogle Scholar
  6. 6.
    Globus, J.H. and Strauss, I., 1928, Progressive degenerative subcortical encephalopathy (Schilder’s disease), Arch. Neurol. Psychiatry 20, 1190–1228.Google Scholar
  7. 7.
    Adachi, M., Torii, J., Schneck, L., and Volk, B.W., 1972, Electron microscopic and enzyme histochemical studies of the cerebellum in spongy degeneration (van Bogaert and Bertrand type), Acta Neuropathol. (Berl) 20, 22–31.PubMedCrossRefGoogle Scholar
  8. 8.
    Adornato, B.T., O’Brien, J.S., Lampert, P.W., Roe, T.F., and Neustein, H.B., 1972, Cerebral spongy degeneration of infancy: a biochemical and ultrastructural study of affected twins, Neurology 22, 202–210.PubMedGoogle Scholar
  9. 9.
    Kaul, R., Balamurugan, K., Gao, G.P., and Matalon, R., 1994a, Canavan disease: genomic organization and localization of human ASPA to 17p13-ter: conservation of the ASPA gene during evolution, Genomics 21, 364–370.PubMedCrossRefGoogle Scholar
  10. 10.
    Banker, B.Q., and Victor, H., 1979, Spongy degeneration of infancy, in: Genetic diseases among Ashkenazi Jews, R.M. Goodman., and A.G. Motulsky., Eds., Raven Press, New York, pp. 201–217.Google Scholar
  11. 11.
    Matalon, R., and Michals-matalon, K., 2000, Spongy degeneration of the brain, Canavan disease: biochemical and molecular findings, Front. Biosci. D, 307–311.Google Scholar
  12. 12.
    Matalon, R., Michals-Matalon, K, 1998, Molecular: basis of Canavan disease, Eur J Paediatr Neurol. 2(2):69–76.PubMedCrossRefGoogle Scholar
  13. 13.
    Ozand, P.T.; Gascon, G., and Dhalla, M., 1990, Aspartoacylase deficiency and Canavan disease in Saudi Arabia, Am. J. Med. Genet. 35, 266–268.PubMedCrossRefGoogle Scholar
  14. 14.
    Matalon, R., Michals-Matalon, K., 1999, Recent advances in Canavan disease, Adv. Pediatr. 46, 493–506.PubMedGoogle Scholar
  15. 15.
    Matalon, R., Matalon, K.M., 2002, Canavan disease prenatal diagnosis and genetic counseling, Obstet. Gynecoi Clin North Am. Jun:29(2):297–304.CrossRefGoogle Scholar
  16. 16.
    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. Inherit. Metab. Dis. 12, 329–331.PubMedCrossRefGoogle Scholar
  17. 17.
    Zeng, B.J., Wang, Z.H., Ribeiro, L.A., Leone, P., De Gasperi, R., Kim, S.J., Raghavan, S., Ong, E., Pastores, G.M., Kohodny, E.H., 2002, Identification and characterization of novel mutations of the Aspartoacylase gene in non-Jewish patients with Canavan disease, J Inherit.Metab. Dis., Nov:25(7):557–570.PubMedCrossRefGoogle Scholar
  18. 18.
    Shaag, A., Anikster, Y., Christensen, E., Glustein, J.Z., Fois, A., Michelakakis, H., Nigro, F., Pronicka, E., Ribes, A., Zabot, M.T., Elpeleg, O.N., 1995, The molecular basis of Canavan (aspartoacylase deficiency) disease in European non-Jewish patients, Am. J. Hum. Genet. 57, 572–580.PubMedGoogle Scholar
  19. 19.
    Olsen, T.R., Tranebjaerg, L., Kvittingen, E.A., Hagenfeldt, L., Moller, C., and Nilssen, O., 2002, Two novel aspartoacylase (ASPA) gene missense missense mutations specific to Norweigian and Swedish patient with Canavan disease, J. Med. Genet. 39, e55.PubMedCrossRefGoogle Scholar
  20. 20.
    Bluml, S., Seymour, K., Philippart, M., Matalon, R., and Ross, B., 1998, Elevated brain water in Canavan disease: impact of a diuretic therapy, Proceeding of the 6th International Society for Magnetic Resonance in Medicine, P 171.Google Scholar
  21. 21.
    Leone, P., Janson, CG., Bilaniuk, L, Wang, Z., Sorgi, F., Huang, L., Matalon, R., Kaul, R., Seng, Z., Freese, A., McPhee, S.W., Mee, E., During, MJ., 2000, Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease. Ann: Neurol. Jul;48(1):27–38.CrossRefGoogle Scholar
  22. 22.
    Kaul, R., Gao, G.P., Balamurugan, K. and Matalon, R., 1993, Human aspartoacylase cDNA and mis-sense mutation in Canavan disease, Nat. Genet. 5, 118–123.PubMedCrossRefGoogle Scholar
  23. 23.
    Kaul, R., Gao, G.P., Aloya, M., Balamurugan, K., Petrosky, A., Michals, K., and Matalon, R., 1994b, Canavan disease: Mutations among non-Jewish patients, Am. J. Hum. Genet. 55, 34–41.PubMedGoogle Scholar
  24. 24.
    Kaul, R., Gao, G.P., Michals, K., Whelan, D.T., Levin, S. and Matalon, R., 1995, Novel (cys 125 arg) missense mutation in an Arab patient with Canavan disease, Hum. Mutat. 5, 269–271.PubMedCrossRefGoogle Scholar
  25. 25.
    Kaul, R., Gao, G.P., Matalon, R., Aloya, M., Su, M., Jin, M., Johnson, A.B., Shutgens, R.B. and Clarke, J.T., 1996, Identification and expression of eight novel mutations among non-Jewish patients with Canavan disease, Am. J. Hum. Genet. 59, 95–102.PubMedGoogle Scholar
  26. 26.
    Matalon, R., Kaul, R. and Michals, K, 1994, Carrier rate of Canavan disease among Ashkenazi Jewish individuals, Am. J. Hum. Genet. 55, A157.Google Scholar
  27. 27.
    Kronn, D., Oddoux, C., Phillips, J. and Ostrer, H., 1995, Prevalence of Canavan disease heterozygous in the New York metropolitan Ashkenazi Jewish individuals, Am. J. Hum. Genet. 57, 1250–1252.PubMedGoogle Scholar
  28. 28.
    Alford, R.L., DeMarchi, J.M., and Richards, C.S., 1998, Frequency of a DNA polymorphism at position Y231 in the aspartoacylase gene and its impact on DNA-based carrier testing for Canavan disease in Ashkenazi Jewish population, Hum. Mutat. (suppl. 1), S161–162.PubMedGoogle Scholar
  29. 29.
    Propheta, O., Magal, N., Shohat, M., Eyal, N., Navot, N. and Horowitz, M., 1998, A benign polymorphism in the aspartoacylase gene may cause misrepresentation of Canavan gene testing, Eur. J. Hum. Genet. 6, 635–637.PubMedCrossRefGoogle Scholar
  30. 30.
    Surendran, S., Bamforth, F.J., Chan, A., Tyring, S.K., Goodman, S.I., and Mataon, R., 2003a, Mild elevation of N-acetyl aspartic acid, macrocephaly: diagnostic problem for Canavan disease, J. Child Neurol. 18, 809–812.PubMedGoogle Scholar
  31. 31.
    Baslow, M.H., Suckow, R., Sapirstein, V., and Hungund, B.L., 1999, Expression of aspartoacylase activity in cultured rat macroglial cells is limited to oligodendrocytes, J. Mol. Neurosci. 13, 47–53.PubMedCrossRefGoogle Scholar
  32. 32.
    Surendran, S., Matalon, K.M., Szucs, S., Tyring, S.K., Matalon, R., 2003 Metabolic changes in the knockout muse for Canavan’s disease implications for patients with Canavan’s disease, J Child Neurol, Sep: 18(9):611–5.PubMedGoogle Scholar
  33. 33.
    Goldstein, F.B., 1969, The enzymatic synthesis of N-cetyl-L-aspartic acid by subcellular preparations of the rat brain, J. Biol. Chem. 244, 4257–4260.PubMedGoogle Scholar
  34. 34.
    Birken, D.L., and Olendroff, W.H., 1989, N-acetyl-Laspartic acid: a literature review of a compound prominent in 1H-NMR spectroscopic studies of brain, Neurosci. Behav. Rev. 13, 23–31.Google Scholar
  35. 35.
    Jacobson, K.B., 1957, Studies on the role of N-acetylaspartic acid in mammalian brain, J. Gene Physiol. 43, 323–333.CrossRefGoogle Scholar
  36. 36.
    Tallan, H.H., Moore, S., and Stein, W.H., 1956, N-acetyl-L-aspartic acid in brain, J. Biol. Chem. 219, 257–264.PubMedGoogle Scholar
  37. 37.
    Kato, T., Nishina, M., Matsushita, K., Hori, E., Mito, T., and Takashima, S., 1997, Neuronal maturation and N-acetyl-L-aspartic acid development in human fetal and child brains, Brain Dev. 19, 131–133.PubMedCrossRefGoogle Scholar
  38. 38.
    Frahm, J., Bruhn, H., Gyngell, M.L., Merboldt, K.-D., Hanicke, W., and Sauter, R., 1989, Localized proton NMR spectroscopy in different regions of the human brain in vivo. Relaxation times and concentrations of cerebral metabolites, Magn. Reson. Med. 11, 47–63.PubMedGoogle Scholar
  39. 39.
    Kreis, R., Ernst, T., and Ross, B.D., 1993, Absolute quantitation of water and metabolites in the human brain. Part II: Metabolite concentrations, J. Magn. Reson. 102, 9–19.CrossRefGoogle Scholar
  40. 40.
    Matalon, R., Rady, P.L., Platt, K.A., Skinner, H.B., Quast, M.J., Campbell, G.A., Matalon, K., Ceci, J.D., Tyring, S.K., Nehls, M., Surendran, S., Wei, J., Ezell, E.L., and Szucs, S., 2000, Knock-out mouse for canavn disease: a model for gene transfer to the central nervous system, J. Gene Med.2, 165–175.PubMedCrossRefGoogle Scholar
  41. 41.
    Slusher, B.S., Robinson, M.B., Tsai, G., Simmons, M.L., Richards, S.S., and Coyle, J.T., 1990, Rat brain N-acetylated α linke acidic dipeptidase activity: purification and immunologic characterization, J. Biol.Chem. 265, 21297–21301.PubMedGoogle Scholar
  42. 42.
    Tyson, R.L., and Sutherland, G.R., 1998, Labeling of N-acetylaspartate and N-acetylaspartylglutamate in rat neocortex, hippocampus and cerebellum from [1–13C]glucose, Neurosci. Lett. 251, 181–184.PubMedCrossRefGoogle Scholar
  43. 43.
    Burlina, A.P., Corazza, A., Ferrari, V., Erhard, P., Kunnecke, B., Seelig, J., and Burlina, A.B., 1994, Detection of increased urinary N-acetylaspartylglutamate in Canavan disease, Eur. J. Pediatr. 153, 538–539.PubMedCrossRefGoogle Scholar
  44. 44.
    Krawczyk, H., and Gradowska, W., 2003, Characterization of the 1H and 13C NMR spectra of N-acetylaspartylglutamate and its detection in urine from patients with Canavan disease, J. Pharm. Biomed. Anal. 31, 455–463.PubMedCrossRefGoogle Scholar
  45. 45.
    Surendran, S., Ezell, E., Quast, MJ, Wei, J., Tyring SK., Michals-Matalon, and Matalon, R., 2004c, Aspartoacylase deficiency does not affect N-acetylaspartylglutamate level or glutamate carboxypeptidase II activity in the knockout mouse brain, Brain Res. 1016, 268–271.PubMedCrossRefGoogle Scholar
  46. 46.
    Blakeley, R.D., Robinson, M.B., Thompson, R.C., and Coyle, J.T., 1988, Hydrolysis of the brain dipeptide N-acetyl-L-aspartyl-glutamate: subcellular and regional distribution, ontogeny and the effect of lesions on N-acetylated alpha-linked acidic dipeptidase activity, J. Neurochem. 50, 1200–1209.CrossRefGoogle Scholar
  47. 47.
    Stauch, B.L., Robinson, M.B., Forloni, G., Tsai, G., and Coyle, J.T., 1989, The effects of N-acetylated alpha-linked acidic dipeptidase (NAALADase) inhibitors on [3H]NAAG catabolism in vivo, Neurosci. Lett. 100, 295–300.PubMedCrossRefGoogle Scholar
  48. 48.
    Dehnes, Y., Chaudhry, F.A., Ullensvang, K., Lehre, K.P., Storm-Mathisen, J., and Danbolt, N.C., 1998, The glutamate transporter EAAT4 in rat cerebellar purkinje cells: a glutamate-gated chloride channel concentrated near the synapse in parts of the dendritic membrane facing astroglia, J. Neurosci. 18, 3606–3619.PubMedGoogle Scholar
  49. 49.
    Furuta, A., Rothstein, J.D., and Martin, L.J., 1997, Glutamate transporter protein subtypes are expressed differentially during rat CNS development, J. Neurosci. 17, 8363–8375.PubMedGoogle Scholar
  50. 50.
    Surendran, S., Rady, P.L., Matalon, K., Quast, M.J., Rassin, D.K., Campbell, G.A., Ezell, E.L., Wei, J., Tyring, S.K., Szucs, S., and Matalon, R., 2003b, Expression ofglutamate transporter, GABRA6, serine priteinase inhibitor 2 and low levels of glutamate and GABA in the brain of knock-out mouse for Canavan disease, Brain Res. Bull. 61, 427–435.PubMedCrossRefGoogle Scholar
  51. 51.
    Petroff, O.A., Hyder, F., Mattson, R.H., and Rothman, D.L., 1999, Topiramate increases brain GABA, homocarnosin and pyrolidone in patients with epilepsy, Neurology 52, 473–478.PubMedGoogle Scholar
  52. 52.
    Gibson, KM., Hoffman GF., Hodson, AK., Bottiglieri, T., Jacobs, C., 1988, 4-Hydroxybutyric acid and the clinical phenotype of succinic semialdehyde dehydrogenase deficiency, an inborn error of GABA metabolism, J. Inherit. Metab. Dis. 16, 704–715.Google Scholar
  53. 53.
    Surendran, S., Ezell, EL., Quast, MJ., Wei, J., Tyring, SK., Michals-Matalon, K. and Matalon, R (2004d) Mental retardation and hypotonia seen in the knockout mouse for Canavan disease is not due to succinate semialdehyde deficiency, Neurosci. Lett. 358, 29–32.PubMedCrossRefGoogle Scholar
  54. 54.
    Kang, S.J., Sanchez, I., Jing, N., Yuan, J., 2003, Dossociation between neurodegeneration and caspase-11-mediated activation of caspase-1 and caspase-3 in a mouse model for amyotrophic lateral sclerosis, J. Neurosci.23, 5455–5460.PubMedGoogle Scholar
  55. 55.
    Hisahara, S., Yuan, J., Momoi, T., Okano, H., and Miura, M., 2001, Caspase-11 mediates oligodendrocyte cell death and pathogenesis of autoimmune mediated demyelination, J.Exp.Med. 193, 111–122.PubMedCrossRefGoogle Scholar
  56. 56.
    Harrison, D.C., Davis, R.P., Bond, B.C., Campbell, C.A., Jmes, M.F., Parsons, A.A., and Philpott, K.L., 2001, Caspase mRNA expression in a rat model of focal cerebral ischemia, Brain Res. Mol. Brain Res. 89, 133–146.PubMedCrossRefGoogle Scholar
  57. 57.
    Thiemmara, V., Pays, L., Danty, E., Jourdan, F., Moyse, E., and Mehlen, P., 2002, Serine protease inhibitor 2 Spi2 mediated apoptosis of olfactory neurons, Cell Death Differ. 9, 1343–1351.PubMedCrossRefGoogle Scholar
  58. 58.
    Dinarello, C.A., 1998, Interlekin-1 receptors and interleukin-1 receptor antagonist. Int. Rev. Immunol. 16, 457–499.PubMedGoogle Scholar
  59. 59.
    Dandoy-Dron, F., Benboudjema, L., Guillo, A., Jaegly, A., Jasmin, C., Dormont, D., Tovey, M.G., and Dron, M., 2000, Enhanced levels of scrapie responsive gene mRNA in BSE-infected mouse brain, Brain Res. Mol. Brain Res. 76, 173–179.PubMedCrossRefGoogle Scholar
  60. 60.
    Surendran, S., Tyring, S.K., Michals-Matalon, K and Matalon, R., 2004a, Therapeutic options in prevention and treatment of aspartoacylase gene mutation resulting abnormalities in Canavan disease, Current pharmacogenomics 2, 13–20.CrossRefGoogle Scholar
  61. 61.
    Rothwell, N.J., and Luheshi, G.N., 2000, Interleukin 1 in the brain: biology, pathology, and therapeutic target, Trends Neurosci. 23, 618–625.PubMedCrossRefGoogle Scholar
  62. 62.
    Matalon, R., Surendran, S., Rady, P., Quast, J.J., Campbell, G.A., Matalon, K.M., Tyring, S.K., Wei, J., Peden, C.S., Ezell, E.L., Muzyczka, N., and Mandel, R.J., 2003, Adeno-associated virus-mediated Aspartoacylase gene transfer to the brain of knockout mouse for Canavan disease, Eur.J.Pediatr. 153, 538–539.Google Scholar
  63. 63.
    Snyder, E.Y., Deitcher, D.L., Walsh, C., Arnold-Aldea, S., Hartwieg, E.A., and Cepko, C.L., 1992, Multipotent neural cell lines can engraft and participate in development of mouse cerebellum, Cell 68, 33–51.PubMedCrossRefGoogle Scholar
  64. 64.
    Brüstle, O., Maskos, U., and McKay, R.D.G., 1995, Host-guided migration allows targeted introduction of neurons into the embryonic brain, Neuron 15, 1275–1285.PubMedCrossRefGoogle Scholar
  65. 65.
    Sun, S., Guo, Z., Xiao, X., Liu, B., Liu, X., Tang, P.H., and Mao, N., 2003, Isolation of mouse marrow mesenchymal progenitors by a novel and reliable method, Stem cells 21, 527–535.PubMedCrossRefGoogle Scholar
  66. 66.
    Turnpenny, L., Brickwood, S., Spalluto, C.M., Piper, K., Cameron, I.T., Wilson, D.I., and Hanley, N.A., 2003, Derivation of human embryonic germ cells: an alternative source of pluripotent stem cells, Stem Cells 21, 598–609.PubMedCrossRefGoogle Scholar
  67. 67.
    Rosario, C.M., Yandava, B.D., Kosaras, B., Zurakowski, R., Sidman, L., and Snyder, E.Y., 1997, Differentiation of engrafted multipotent neural progenitors towards replacement of missing granule neurons in meander tail cerebellum may help determine the locus of mutant gene action, Development 124, 4213–4224.PubMedGoogle Scholar
  68. 68.
    Snyder, E.Y., Yoon, C., Flax, J.K., and Macklis, J.D., 1997, Multipotent neural precursors can differentiate toward replacement of neurons undergoing targeted apoptotic degeneration in adult mouse neocortex, Proc. Natl. Acad. Sci. USA 94, 11663–11668.PubMedCrossRefGoogle Scholar
  69. 69.
    Brundin, L., Brismar, H., Danilov, A.I., Olsson, O., and Johansson, C.B., 2003, Neural stem cells: a potential source for remyelination in neuroinflammatory disease, Brain Pathol. 13, 322–328.PubMedCrossRefGoogle Scholar
  70. 70.
    Na, R., McCarthy, M., Neyt, C., Lai, E., and Fishell, G., 1998, Telencephalic progenitors maintain anteroposterior identities cell autonomously, Curr. Biol. 8, 987–990PubMedCrossRefGoogle Scholar
  71. 71.
    Surendran, S., Shihabuddin, L.S., Clarke, J., Taksir, T.V, Stewart, G.R., Parsons, G., Yang, W., Tyring SK., Michals-Matalon K., and Matalon, R., 2004b, Mouse neural progenitor cells differentiate into oligodendrocytes in the brain of a knockout mouse model of Canavan Disease, Dev. Brain Res. 2004 Oct 15:153(1):19–27.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Reuben Matalon
    • 1
  • Kimberlee Michals-Matalon
    • 1
  • Sankar Surendran
    • 1
  • Stephen K. Tyring
    • 1
    • 2
  1. 1.Department of PediatricsUniversity of Texas Medical BranchGalveston
  2. 2.Department of DermatologyUniversity of Texas Health Science CenterHouston

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