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Canavan disease

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Canavan Disease...

  Canavan disease is an autosomal genetic disorder that results in progressive leukodystrophy, paralysis and death, usually between 3 and 10 years of age. Currently there is no effective treatment for this fatal disorder. Canavan disease is caused by mutations in the gene that codes for the enzyme aspartoacylase (ASPA; EC 3.5.1.15) (1). ASPA deacetylates the highly concentrated nervous system specific molecule, N-acetylaspartate (NAA). The primary metabolic effects of mutations in the gene for ASPA in Canavan disease patients are a lack of NAA deacetylation leading to buildup of NAA in the brain (2), decreased brain acetate levels and impaired myelin lipid synthesis (3), and greatly increased excretion of NAA in urine. Two hypotheses have been put forward concerning the etiology of Canavan disease (reviewed in 4) and the two hypotheses suggest disparate treatment strategies.

One treatment strategy is predicated on the hypothesis that NAA is an osmolyte involved in the active regulation of neuronal water balance (5). In this hypothesis, the lack of ASPA activity leads to an inability to control osmolarity in axons, resulting in damage to myelin sheaths and a progressive leukodystrophy (6). Treatment for Canavan disease under this hypothesis has focused on ASPA gene transfer to reduce brain NAA levels (7;8). To date, ASPA gene transfer therapy has not proven successful in improving motor functions. Based on findings that NAA-derived acetate is responsible for as much as 1/3 of the lipid synthesis that occurs during postnatal myelination, we have proposed that metabolic therapy using acetate supplementation during postnatal myelination might be an effective treatment for Canavan disease (3;9). Glyceryltriacetate (GTA), the acetate triester of glycerol, was used for acetate supplementation in the current study because it is well tolerated when given orally (10) and intravenously (11;12) is distributed to the brain rapidly due to its hydrophobic nature (13).


Reference List

(1) 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; 29:463-471.
(2) Kvittingen EA, Guldal G, Borsting S, Skalpe IO, Stokke O, Jellum E. N-acetylaspartic aciduria in a child with a progressive cerebral atrophy. Clin Chim Acta 1986; 158(3):217-227.
(3) 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(14):5221-5226.
(4) Moffett JR, Ross B, Arun P, Madhavarao CN, Namboodiri AM. N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology. Prog Neurobiol 2007; 81(2):89-131.
(5) Baslow MH. Molecular water pumps and the aetiology of Canavan disease: a case of the sorcerer's apprentice. J Inherit Metab Dis 1999; 22(2):99-101.
(6) Baslow MH. Brain N-acetylaspartate as a molecular water pump and its role in the etiology of Canavan disease: a mechanistic explanation. J Mol Neurosci 2003; 21(3):185-190.
(7) Janson C, McPhee S, Bilaniuk L, Haselgrove J, Testaiuti M, Freese A et al. Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain. Hum Gene Ther 2002; 13(11):1391-1412.
(8) 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(1):27-38.
(9) 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(3):318-329.
(10) 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; 32:640-650.
(11) Bailey JW, Haymond MW, Miles JM. Triacetin: a potential parenteral nutrient. JPEN J Parenter Enteral Nutr 1991; 15(1):32-36.
(12) Bailey JW, Barker RL, Karlstad MD. Total parenteral nutrition with short- and long-chain triglycerides: triacetin improves nitrogen balance in rats. J Nutr 1992; 122(9):1823-1829.
(13) Mathew R, Arun P, Madhavarao C, Moffett J, Namboodiri A. Progress toward acetate supplementation therapy for Canavan disease: Glyceryl triacetate administration increases acetate, but not N-acetylaspartate levels in brain. J Pharmacol Exp Ther 2005; 315(1):297-303.



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