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Canavan`s disease or spongy degeneration of the central nervous system or aspartoacylase deficiency is an autosomal recessive neurological degeneration that usually causes early death. Patients appear to be normal at birth and during their first month. Axial hypotonia and macrocephaly appear between the 2nd and 4th months in infantile forms, later on in the juvenile form. Neurological degeneration continues with spasticity, opisthotonos, loss of contact with the outer world, sleep disorders, blindness, and convulsions. Imaging of the brain evidences leukodystrophy. Increased urinary output of N-acetylaspartate (x50) is diagnostic. Histopathology shows spongy degeneration of the brain. The disease is due to aspartoacylase deficiency. The enzyme is localised in the oligodendrocytes- the myelin synthesizing cells- its gene is on the short arm of chromosome 17. Aspartoacylase converts N-acetylaspartate to aspartate and acetic acid. It can be found in white substance and can be dosed in cultured fibroblasts. The enzyme is coded by 6 exons and the gene spans 29kb of the genome. The protein is a 55kDa monomere with 313 aminoacids. Two mutations have been identified in Ashkenasi Jews (A854G and C692A) and account for 97% of cases in this particular population. Other mutations that are not related to a foundation effect have been found among other populations. Prenatal diagnosis is easily made by measuring N-acetylaspartate in amniotic fluid or, when the mutation has been pinpointed, by identifying it in the chorionic villi. Physiopathology of the disease is still unclear: N-acetylaspartate that accumulates in the white substance because of enzyme deficiency is specifically synthesized in the neurons of grey matter, where aspartoacylase has very little activity. The role of N-acetylaspartate in the brain is related either as a molecular water pump in mylinated neurons or as acetyl groups donor for synthesis of myelin lipids. |