Effect of high dose glyceryltriacetate in Canavan disease



Written on Thursday 11 April 2013

Canavan disease is a rare autosomal recessive neurodegenerative disorder, presenting in early infancy. The course of the disease is variable, but it is invariably fatal, and death usually occurs during the first and second decade of life.
Canavan disease is caused by mutations in the ASPA gene, which codes for the enzyme aspartoacylase (ASPA). ASPA normally breaks down N-acetylaspartate (NAA) to acetate and aspartic acid. The lack of NAA-degrading enzyme activity, leads to excess accumulation of NAA in the brain, and deficiency of acetate, which is necessary for myelin lipid synthesis.

Glyceryltriacetate (GTA) is a short-chain triglyceride with three acetate moieties on a glycerol backbone and is a proven effective acetate precursor. Intragastric administration of GTA to tremour mice results in greatly increased brain acetate levels, and improved motor functions. GTA given to infants with Canavan Disease at a low dose showed no improvement in their clinical status, but also no detectable toxicity was noted.

For the first time the safety profile of high dose GTA in 2 patients with Canavan Disease i spresented. Two 2 infants with Canavan Disease at ages 8 months and 1 year were treated with high dose GTA, for 4.5 and 6 months respectively. Treatment started at 0.5g/kg body weight daily, doubling the dose every 3 days until a maximum of 4.5 g/kg body weight /d was reached.

No significant side effects were observed except for possible increased gastric acidity at the highest dose for which Omeprazole was administrated. No toxicity was noted. Although the treatment resulted in no motor improvement, it was well tolerated. The lack of clinical improvement might be explained mainly by the late onset of treatment, when already significant brain damage was present. Better results may be achieved if therapeutic intervention starts at an earlier stage of CNS development, prior to 3 months of age. Further larger studies of Canavan Disease patients below age 3 months are required in order to test the long-term efficacy of this drug.

Disease: Canavan disease
Type of study: Therapeutic approach
Patients: Newborns suffering from Canavan disease.
Laboratory: Pr Gheona W. Altarescu, Institute of Medical Genetics, Shaare Zedek Medical Center, Jerusalem, Israel.

Source: R. Segel, Y. Anikster, S. Zevin, A. Steinberg, W.A. Gahl, D. Fisher, O. Staretz-Chacham, A. Zimran, G. Altarescu. A safety trial of high dose glyceryl triacetate for Canavan disease. Mol Genet Metab. 2011, 103(3):203-6.