Canavan Disease: A Neurometabolic Disease Caused By Aspartoacylase Deficiency

Abstract

Canavan disease is a genetic neurodegenerative disorder caused by mutations in the ASPA gene encoding aspartoacylase, also known as aminoacylase 2. Important clinical features comprise progressive psychomotor delay, macrocephaly, muscular hypotonia as well as spasticity and visual impairment. Cerebral imaging usually reveals leukodystrophy. While it is often expected that patients with Canavan disease will die in childhood, there is increasing evidence for heterogeneity of the clinical phenotype. Aspartoacylase catalyzes the hydrolysis of N-acetylaspartate (NAA) to aspartate and acetate. Its deficiency leads to accumulation of NAA in the brain, blood, cerebrospinal fluid and in the urine of the patients. High levels of NAA in urine are detectable via the assessment of organic acids by gas chromatography - mass spectrometry. Confirmation is available by enzyme activity tests and mutation analyses. Up to now, treatment of patients with Canavan disease is only symptomatic. Although it is a panethnic disorder, information on affected individuals in populations of other than Ashkenazi Jewish origin is rather limited. Ongoing research aims at a better understanding of Canavan disease (and of related inborn errors of metabolism such as aminoacylase 1 deficiency). Unraveling underlying mechanisms may provide a basis for future therapeutic approaches.

Keywords

• Canavan disease, aspartoacylase, aminoacylase, leukodystrophy, neurodegeneration, organic acids, N-acetylaspartate, ASPA,ACYI, NAT8L

Kaynakça

1. Kaul R, Gao GP, Aloya M, Balamurugan K, Petrosky A, Michals K, et al. Canavan disease: mutations among Jewish and non-Jewish patients. Am J Hum Genet 1994; 55: 34– 41.
2. Shaag A, Anikster Y, Christensen E, Glustein JZ, Fois A, Michelakakis H, et al. The molecular basis of canavan (aspartoacylase deficiency) disease in European non-Jewish patients. Am J Hum Genet 1995; 57: 572–80.
3. Elpeleg ON, Shaag A. The spectrum of mutations of the aspartoacylase gene in Canavan disease in non-Jewish patients. J Inherit Metab Dis 1999; 22: 531–4.
4. Tallan HH. Studies on the distribution of N-acetyl-L- aspartic acid in brain. J Biol Chem 1957; 224: 41–5.
5. Mizuguchi K, Hoshino H, Hamaguchi H, Kubota M. Long term clinical course of Canavan disease – a rare Japanese case. No To Hattatsu 2009; 41: 353–6.
6. Matalon RM, Michals-Matalon K. Spongy degeneration of the brain, Canavan disease: biochemical and molecular findings. Pediatr Pathol Mol Med 2000; 18: 471–81.
7. Traeger EC, Rapin I. The clinical course of Canavan disease. Pediatr Neurol 1998; 18: 207–12.
8. Ungar M, Goodman RM. Spongy degeneration of the brain in Israel: a retrospective study. Clin Genet 1983; 23: 23–9.

9. Tacke U, Olbrich H, Sass JO, Fekete A, Horvath J, Ziyeh S, et al. Possible genotype-phenotype correlations in children with mild clinical course of Canavan disease. Neuropediatrics 2005; 36: 252–5.
10. Surendran S, Bamforth FJ, Chan A, Tyring SK, Goodman SI, Matalon R. Mild elevation of N-acetylaspartic acid and macrocephaly: diagnostic problem. J Child Neurol 2003; 18: 809–12.
11. Janson CG, McPhee SW, Francis J, Shera D, Assadi M, Freese A, et al. Natural history of Canavan disease revealed by proton magnetic resonance spectroscopy (1H-MRS) and diffusion-weighted MRI. Neuropediatrics 2006; 37: 209– 21.
12. Velinov M, Zellers N, Styles J, Wisniewski K. Homozygosity for mutation G212A of the gene for aspartoacylase is associated with atypical form of Canavan's disease. Clin Genet 2008; 73: 288–9.
13. Plecko B, Stöcker-Ipsiroglu S. Makrozephalie als Leitsymptom Fallbeispiele und thematischer Überblick. Monatsschr Kinderheilkd 2001; 149: 137–46. Erkrankungen
14. Bührer C, Bassir C, von Moers A, Sperner J, Michael T, Scheffner D, et al. Cranial ultrasound findings in aspartoacylase deficiency (Canavan disease). Pediatr Radiol 1993; 23: 395–7.
15. Toft PB, Geiss-Holtorff R, Rolland MO, Pryds O, Müller- Forell W, Christensen E, et al. Magnetic resonance imaging in juvenile Canavan disease. Eur J Pediatr 1993; 152: 750– 3.
16. Grodd W, Krageloh-Mann I, Petersen D, Trefz FK, Harzer K. In vivo assessment of N-acetylaspartate in brain in spongy degeneration (Canavan's disease) by proton spectroscopy. Lancet 1990; 336: 437–8.
17. Brismar J, Brismar G, Gascon G, Ozand P. Canavan disease: CT and MR imaging of the brain. AJNR Am J Neuroradiol 1990; 11: 805–10.
18. Grodd W, Krageloh-Mann I, Klose U, Sauter R. Metabolic and destructive brain disorders in children: findings with localized proton MR spectroscopy. Radiology 1991; 181: 173–81.
19. Matalon R, Michals K, Sebesta D, Deanching M, Gashkoff P, Casanova J. Aspartoacylase deficiency and N- acetylaspartic aciduria in patients with Canavan disease. Am J Med Genet 1988; 29: 463–71.
20. Divry P, Vianey-Liaud C, Gay C, Macabeo V, Rapin F, Echenne B. N-acetylaspartic aciduria: report of three new cases in children with a neurological syndrome associating macrocephaly and leukodystrophy. J Inherit Metab Dis 1988; 11: 307–8.
21. Divry P, Mathieu M. Aspartoacylase deficiency and N- acetylaspartic aciduria in patients with Canavan disease. Am J Med Genet 1989; 32: 550–1. 31. Sass JO, Sewell AC. Gas chromatography-mass
22. spectrometry for selective screening for inborn errors of
23. metabolism. In: Giessen WMA (ed), Current practice of gas
24. chromatography-mass spectrometry. Marcel Dekker, New
25. York, Basel, 2001, 341-354.
26. Bal D, Gryff-Keller A, Gradowska W. Absolute configuration of N-acetylaspartate in urine from patients with Canavan disease. J Inherit Metab Dis 2005; 28: 607–9.
27. Jakobs C, ten Brink HJ, Langelaar SA, Zee T, Stellaard F, Macek M, et al. Stable isotope dilution analysis of N- acetylaspartic acid in CSF, blood, urine and amniotic fluid: accurate postnatal diagnosis and the potential for prenatal diagnosis of Canavan disease. J Inherit Metab Dis 1991; 14: 653–60.
28. Wevers RA, Engelke U, Wendel U, de Jong JG, Gabreels FJ, Heerschap A. Standardized method for high-resolution 1H-NMR of cerebrospinal fluid. Clin Chem 1995; 41: 744– 51.
29. Barash V, Flhor D, Morag B, Boneh A, Elpeleg ON, Gilon C. A radiometric assay for aspartoacylase activity in human fibroblasts: application for the diagnosis of Canavan's disease. Clin Chim Acta 1991; 201: 175–81.
30. Madhavarao CN, Hammer JA, Quarles RH, Namboodiri MA. A radiometric assay for aspartoacylase activity in cultured oligodendrocytes. Anal Biochem 2002; 308: 314– 9.
31. Matalon R, Kaul R, Michals K. Canavan disease: biochemical and molecular studies. J Inherit Metab Dis 1993; 16: 744–52.
32. Kaul R, Balamurugan K, Gao GP, Matalon R. Canavan disease: genomic organization and localization of human ASPA to 17p13-ter and conservation of the ASPA gene during evolution. Genomics 1994; 21: 364–70.
33. Matalon R, Michals K, Kaul R. Canavan disease: from spongy degeneration to molecular analysis. J Pediatr 1995; 127: 511–7.
34. Kronn D, Oddoux C, Phillips J, Ostrer H. Prevalence of Canavan disease heterozygotes in the New York metropolitan Ashkenazi Jewish population. Am J Hum Genet 1995; 57: 1250–2.
35. Feigenbaum A, Moore R, Clarke J, Hewson S, Chitayat D, Ray PN, et al. Canavan disease: carrier-frequency determination in the Ashkenazi Jewish population and development of a novel molecular diagnostic assay. Am J Med Genet A 2004; 124A: 142–7.
36. Yaron Y, Schwartz T, Mey-Raz N, Amit A, Lessing JB, Malcov M. Preimplantation genetic diagnosis of Canavan disease. Fetal Diagn Ther 2005; 20: 465–8.
37. Zeng BJ, Wang ZH, Ribeiro LA, Leone P, De Gasperi R, Kim SJ, et al. Identification and characterization of novel mutations of the aspartoacylase gene in non-Jewish patients with Canavan disease. J Inherit Metab Dis 2002; 25: 557– 70.
38. Matalon R, Michals K, Gashkoff P, Kaul R. Prenatal diagnosis of Canavan disease. J Inherit Metab Dis 1992; 15: 392–4.
39. Matalon R, Michals-Matalon K. Prenatal diagnosis of Canavan disease. Prenat Diagn 1999; 19: 669–70.
40. Bennett MJ, Gibson KM, Sherwood WG, Divry P, Rolland MO, Elpeleg ON, et al. Reliable prenatal diagnosis of Canavan disease (aspartoacylase deficiency): comparison of enzymatic and metabolite analysis. J Inherit Metab Dis 1993; 16: 831–6.
41. Kelley RI. Prenatal detection of Canavan disease by measurement of N-acetyl-L-aspartate in amniotic fluid. J Inherit Metab Dis 1993; 16: 918–9.
42. Al-Dirbashi OY, Kurdi W, Imtiaz F, Ahmad AM, Al-Sayed M, Tulbah M, et al. Reliable prenatal diagnosis of Canavan disease by measuring N-acetylaspartate in amniotic fluid using liquid chromatography tandem mass spectrometry. Prenat Diagn 2009; 29: 477–80.
43. Besley GT, Elpeleg ON, Shaag A, Manning NJ, Jakobs C, Walter JH. Prenatal diagnosis of Canavan disease-- problems and dilemmas. J Inherit Metab Dis 1999; 22: 263–6.
44. Janson CG, Kolodny EH, Zeng BJ, Raghavan S, Pastores G, Torres P, et al. Mild-onset presentation of Canavan's disease associated with novel G212A point mutation in aspartoacylase gene. Ann Neurol 2006; 59: 428–31.
45. Yalcinkaya C, Benbir G, Salomons GS, Karaarslan E, Rolland, MO, Jakobs C, et al. Atypical MRI findings in Canavan disease: a patient with a mild course. Neuropediatrics 2005; 36: 336–9.
46. Leone P, Janson CG, Bilaniuk L, Wang Z, Sorgi F, Huang L, et al. Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease. Ann Neurol 2000; 48: 27–38.
47. Burlina AP, Ferrari V, Divry P, Gradowska W, Jakobs C, Bennett MJ, et al. N-acetylaspartylglutamate in Canavan disease: an adverse effector? Eur J Pediatr 1999; 158: 406– 9.
48. Truckenmiller ME, Namboodiri MA, Brownstein MJ, Neale JH. N-Acetylation of L-aspartate in the nervous system: differential distribution of a specific enzyme. J Neurochem 1985;45:1658–62.
49. Burlina AP, Skaper SD, Mazza MR, Ferrari V, Leon A, Burlina AB. N-acetylaspartylglutamate selectively inhibits neuronal responses to N-methyl-D-aspartic acid in vitro. J Neurochem 1994;63:1174–7.
50. Tieman SB, Butler K, Neale JH. N-acetylaspartylglutamate. A neuropeptide in the human visual system. JAMA 1988;259:2020.
51. Akimitsu T, Kurisu K, Hanaya R, lida K, Kiura Y, Arita K, et al. Epileptic seizures induced by N-acetyl-L-aspartate in rats: in vivo and in vitro studies. Brain Res 2000;861:143– 50.
52. Kitada K, Akimitsu T, Shigematsu Y, Kondo A, Maihara T, Yokoi N, et al. Accumulation of N-acetyl-L-aspartate in the brain of the tremor rat, a mutant exhibiting absence-like seizure and spongiform degeneration in the central nervous system. J Neurochem 2000;74:2512–9.
53. Moffett JR, Ross B, Arun P, Madhavarao CN, Namboodiri AM. N-Acetylaspartate in the CNS: from neurodiagnostics to neurobiology. Prog Neurobiol 2007;81:89–131.
54. Hession AO, Esrey EG, Croes RA, Maxwell CA. N- acetylglutamate and N-acetylaspartate in soybeans (Glycine max L.), maize (Zea maize L.), and other foodstuffs. J Agric Food Chem 2008;56:9121–6.
55. Delaney B, Amanda SZ, Powley CR, Powley CR, Gannon S, Munley SA, et al. Acute and repeated dose oral toxicity of N-acetyl-l-aspartic acid in Sprague-Dawley rats. Food Chem Toxicol 2008;46:2023–34.
56. Karaman S, Myhre A, Donner EM, Munley SM, Delaney B. Mutagenicity studies with N-acetyl-L-aspartic acid. Food Chem Toxicol 2009;47:1936–40.
57. Taylor DL, Davies SE, Obrenovitch TP, Doheny MH, Patsalos PN, Clark JB, et al. Investigation into the role of N-acetylaspartate in cerebral osmoregulation. J Neurochem 1995;65:275–81.
58. Davies SE, Gotoh M, Richards DA, Obrenovitch TP. Hypoosmolarity induces an increase of extracellular N- acetylaspartate Neurochem Res 1998;23:1021–5. in the rat striatum.
59. Baslow MH. Molecular water pumps and the aetiology of Canavan disease: a case of the sorcerer's apprentice. J Inherit Metab Dis 1999;22:99–101.
60. Baslow MH. Evidence supporting a role for N-acetyl-L- aspartate as a molecular water pump in myelinated neurons in the central nervous system. An analytical review. Neurochem Int 2002;40:295–300.
61. Baslow MH. N-acetylaspartate in the vertebrate brain: metabolism and function. Neurochem Res 2003;28:941–53.
62. Surendran S, Matalon KM, Szucs S, Tyring SK, Matalon R. Metabolic changes in the knockout mouse for Canavan's disease: implications for patients with Canavan's disease. J Child Neurol 2003;18:611–5.
63. Kumar S, Biancotti JC, Matalon R, de Vellis J. Lack of aspartoacylase activity disrupts survival and differentiation of neural progenitors and oligodendrocytes in a mouse model of Canavan disease. J Neurosci Res 2009;87:3415– 27.
64. Madhavarao CN, Moffett JR, Moore RA, Viola RE, Namboodiri MA, Jacobowitz DM. Immunohistochemical localization of aspartoacylase in the rat central nervous system. J Comp Neurol 2004;472:318–29.
65. Bhakoo KK, Craig TJ, Styles P. Developmental and regional distribution of aspartoacylase in rat brain tissue. J Neurochem 2001;79:211–20.
66. Kirmani BF, Jacobowitz DM, Kallarakal AT, Namboodiri MA. Aspartoacylase is restricted primarily to myelin synthesizing cells in the CNS: therapeutic implications for Canavan disease. Brain Res Mol Brain Res 2002;107:176– 82.
67. Hagenfeldt L, Bollgren I, Venizelos N. N-acetylaspartic aciduria due to aspartoacylase deficiency--a new aetiology of childhood leukodystrophy. J Inherit Metab Dis 1987;10:135–41.
68. Chakraborty G, Mekala P, Yahya D, Wu G, Ledeen RW. Intraneuronal N-acetylaspartate supplies acetyl groups for myelin lipid synthesis: evidence for myelin-associated aspartoacylase. J Neurochem 2001; 78: 736–45.
69. Madhavarao CN, Arun P, Moffett JR, Szucs S, Surendran S, Matalon R, et al. Defective N-acetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan's disease. Proc Natl Acad Sci U S A 2005; 102: 5221–6.
70. Namboodiri AM, Peethambaran A, Mathew R, Sambhu PA, Hershfield J, Moffett JR, et al. Canavan disease and the role of N-acetylaspartate in myelin synthesis. Mol Cell Endocrinol 2006; 252: 216–23.
71. Mathew R, Arun P, Madhavarao CN, Moffett JR, Namboodiri MA. Progress toward acetate supplementation therapy administration increases acetate, but not N-acetylaspartate, levels in brain. J Pharmacol Exp Ther 2005; 315: 297–303.
72. D'Adamo AF JR, Gidez LI, Yatsu FM. Acetyl transport mechanisms. Involvement of N-acetyl aspartic acid in de novo fatty acid biosynthesis in the developing rat brain. Exp Brain Res 1968; 5: 267–73.
73. Madhavarao CN, Arun P, Anikster Y, Mog SR, Staretz- Chacham O, Moffett JR, et al. Glyceryl triacetate for Canavan disease: a low-dose trial in infants and evaluation of a higher dose for toxicity in the tremor rat model. J Inherit Metab Dis 2009;32:640–50.
74. Arun P, Madhavarao CN, Moffett JR, Hamilton K, Grunberg NE, Ariyannur PS, et al. Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease. J Inherit Metab Dis 2010.
75. Baslow MH, Kitada K, Suckow RF, Hungund BL, Serikawa T. The effects of lithium chloride and other substances on levels of brain N-acetyl-L-aspartic acid in Canavan disease-like rats. Neurochem Res 2002;27:403–6.
76. Janson CG, Assadi M, Francis J, Bilaniuk L, Shera D, Leone P. Lithium citrate for Canavan disease. Pediatr Neurol 2005;33:235–43.
77. Assadi M, Janson C, Wang DJ, Goldfarb O, Suri N, Bilaniuk L, et al. Lithium citrate reduces excessive intra- cerebral N-acetyl aspartate in Canavan disease. Eur J Paediatr Neurol 2009.
78. Matalon R, Surendran S, Rady PL, Quast MJ, Campbell GA, Matalon KM, et al. Adeno-associated virus-mediated aspartoacylase gene transfer to the brain of knockout mouse for canavan disease. Mol Ther 2003;7:580–7.
79. McPhee SW, Francis J, Janson CG, Serikawa T, Hyland K, Ong EO, et al. Effects of AAV-2-mediated aspartoacylase gene transfer in the tremor rat model of Canavan disease. Brain Res Mol Brain Res 2005; 135: 112–21.
80. Klugmann M, Leichtlein CB, Symes CW, Serikawa T, Young D, During MJ. Restoration of aspartoacylase activity in CNS neurons does not ameliorate motor deficits and demyelination in a model of Canavan disease. Mol Ther 2005; 11: 745–53.
81. Sass JO, Mohr V, Olbrich H, Engelke U, Horvath J, Fliegauf M, et al. Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error. Am J Hum Genet 2006;78:401–9.
82. Van Coster RN, Gerlo EA, Giardina TG, Engelke UF, Smet JE, De Praeter CM, et al. Aminoacylase I deficiency: a novel inborn error of metabolism. Biochem Biophys Res Commun 2005;338:1322–6.
83. Sass JO, Olbrich H, Mohr V, Hart C, Woldseth B, Krywawych S, et al. Neurological findings in aminoacylase 1 deficiency. Neurology 2007;68:2151–3.
84. Wiame E, Tyteca D, Pierrot N, Collard F, Amyere M, Noel G, et al. Molecular identification of aspartate N- acetyltransferase and its mutation in hypoacetylaspartia. Biochem J 2010;425:127–36.