title: A safety trial of high dose glyceryl triacetate for Canavan disease.
abstract: Canavan disease (CD MIM#271900) is a rare autosomal recessive neurodegenerative disorder presenting in early infancy. The course of the disease is variable, but it is always fatal. CD is caused by mutations in the ASPA gene, which codes for the enzyme aspartoacylase (ASPA), which 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 has proven an effective acetate precursor. Intragastric administration of GTA to tremor mice results in greatly increased brain acetate levels, and improved motor functions. GTA given to infants with CD at a low dose (up to 0.25 g/kg/d) resulted in no improvement in their clinical status, but also no detectable toxicity. We present for the first time the safety profile of high dose GTA (4.5 g/kg/d) in 2 patients with CD. We treated 2 infants with CD at ages 8 months and 1 year with high dose GTA, for 4.5 and 6 months respectively. No significant side effects and no toxicity were observed. 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 significant brain damage was already present. Further larger studies of CD patients below age 3 months are required in order to test the long-term efficacy of this drug.
authors.affiliation: Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel. Reevals@szmc.org.il
authors.forename: Reeval
authors.initials: R
authors.lastname: Segel
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
authors.forename: Shoshana
authors.initials: S
authors.lastname: Zevin
authors.forename: Avraham
authors.initials: A
authors.lastname: Steinberg
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.forename: Drora
authors.initials: D
authors.lastname: Fisher
authors.forename: Orna
authors.initials: O
authors.lastname: Staretz-Chacham
authors.forename: Ari
authors.initials: A
authors.lastname: Zimran
authors.forename: Gheona
authors.initials: G
authors.lastname: Altarescu
mesh_terms: D001921:Brain / Q000187:drug effects / Q000473:pathology; D017825:Canavan Disease / Q000175:diagnosis / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D014215:Triacetin / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity
chemical_list: D018696:Neuroprotective Agents; D014215:Triacetin