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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.
Canavan Research
Foundation
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