Disease relevance of Canavan Disease

• Finally, we performed the first in vivo gene transfer study for a human neurodegenerative disease in 2 children with Canavan disease to assess the in vivo toxicity and efficacy of ASPA gene delivery [1].
• No mutations were found for Bloom syndrome, BRCA1, BRCA2, Canavan disease, Fanconi anemia complementation group C, or Tay-Sachs disease [2].
• The Ashkenazi Jewish population is at increased risk for several recessively inherited disorders (Tay-Sachs disease, Cystic fibrosis, Canavan disease, Gaucher disease, Familial Dysautonomia, Niemann-Pick disease, Fanconi anemia, and Bloom syndrome) [3].
• Mental retardation and hypotonia seen in the knock out mouse for Canavan disease is not due to succinate semialdehyde dehydrogenase deficiency [4].
• Clinical trials using rAAV2 for the treatment of hemophilia B, cystic fibrosis, alpha-1-antitrypsin deficiency, and Canavan disease have begun, and reports from these phase I trials support the safety seen in preclinical trials [5].

High impact information on Canavan Disease

• Cloning of the human aspartoacylase cDNA and a common missense mutation in Canavan disease [6].
• In vitro expression of mutant cDNA clones demonstrated that all of these mutations led to a deficiency of ASPA and should therefore result in Canavan disease [7].
• Restoration of aspartoacylase activity in CNS neurons does not ameliorate motor deficits and demyelination in a model of Canavan disease [8].
• Canavan disease (CD) is an autosomal recessive leukodystrophy caused by deficiency of aspartoacylase (ASPA) [9].
• Although the exact role of this enzymatic reaction has not yet been completely elucidated, the metabolism of NAA appears to be necessary in the formation of myelin lipids, and defects in this enzyme lead to Canavan disease, a fatal neurological disorder [10].

Chemical compound and disease context of Canavan Disease

• Canavan disease, an autosomal recessive leukodystrophy, is caused by deficiency of aspartoacylase and accumulation of N-acetylaspartic acid in brain [6].
• In controls, the mean V(NAA) was 9.2 +/- 3.9 nmol/min/g. In Canavan disease, where [NAA] is increased (p < 0.001) and [aspartate] is deceased (p < 0.001), V(NAA) was significantly reduced to 3.6 +/- 0.1 nmol/min/g (p < 0.001) [11].
• We found high concentrations of N-acetylaspartic acid, citric acid, and succinic acid in CSF from a patient with Canavan disease [12].
• In patients with Canavan disease, NAA signal intensity was markedly increased, but no choline signal was found [13].
• In a patient diagnosed with Canavan disease, examined four times, glutamate was reduced to 46% of normal, 4.6 +/- 0.5 mmol/kg [14].

Biological context of Canavan Disease

• While the dysmyelinating disorder was clearly differentiated from Canavan disease by an absence of elevated NAA and differing histopathologic findings and autosomal-dominant inheritance pattern, there were similarities to this disease in the presentation and, to some extent, in the initial imaging findings [15].

Gene context of Canavan Disease

• CONCLUSION: The newly created ASPA deficient mouse establishes an important animal model of Canavan disease [16].
• Canavan disease, an autosomal-recessive neurogenetic disorder, is caused by mutations in aspartoacylase, an enzyme that deacetylates N-acetylaspartate to generate free acetate in the brain [17].
• Autosomal recessive megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare childhood-onset spongiform leukodystrophy with macrocephaly and slowly progressive deterioration of motor functions [18].
• Effects of ethanol and of alcohol dehydrogenase inhibitors on the reduction of N-acetylaspartate levels of brain in mice in vivo: a search for substances that may have therapeutic value in the treatment of Canavan disease [19].

Analytical, diagnostic and therapeutic context of Canavan Disease

• The aspartoacylase assay is a new tool for determining both the prenatal and antenatal diagnosis of Canavan disease [20].

References