PerspectivesAre you interested in submitting a Perspective Article? Be sure to read The Science Advisory Board's Editorial Guides for Perspective Articles. Click here. Progress in Canavan disease by Sankar Surendran, Ph.D. and Reuben Matalon, M.D., Ph.D. Canavan disease (CD) is an autosomal recessive disorder, characterized by spongiform degeneration throughout the white matter of the brain (1). ASPA deficiency (2) caused by mutations in the gene affects normal hydrolysis of N-acetylaspartic acid (NAA) to aspartate and acetate and thus leads to accumulation of NAA in the brain. Therefore, patients with CD have elevated excretion of urinary NAA and this has been used as a marker to test these patients. Macrocephaly, hypotonia and head lag are common clinical features of CD (3). Developmental delay occurs in later stage of life. As infants get older, hypotonia gives way to spasticity and developmental delay becomes more prominent. Seizures often develop in the second year of life and optic atrophy can be found. However, they are not blind and can follow objects with their eyes. Gastroesophageal reflux leads feeding difficulties when the disease progresses and poor weight gain also observed. Although mortality rate is high during first few years of life, improved medical and nursing care may reach the children with CD to their teens. How a single gene defect causes all these abnormalities seen in CD is not known. Animal models have been used to understand molecular mechanisms involved in human diseases. The knockout mouse for CD shows pathophysiology similar to patients with CD (4) and therefore used to understand molecular mechanisms involved in CD. Research on CD mouse brain showed that ASPA gene knockout affected normal expression of several other genes, including down-regulation of glutamate transporter (EAAT4), GABA-A receptor subunit alpha (GABRA6) and up-regulation of serine proteinase inhibitor 2 (Spi2) and caspase 11(5-6). The down-regulation of EAAT4 and GABRA6 are associated with the low levels of glutamate and GABA. The low level of these neurotransmitters leads to abnormal cortical excitability in the CD mouse (5). The downregulation of EAAT4 and GABRA6 resulting pathology in the cerebellar compartment, leads to hypotonia and muscle weakness (5). These are major clinical features seen in patients with CD. Succinic semialdehyde dehydrogenase (SSADH) deficiency also leads to hypotonia (7). However, SSADH activity was normal in the CD mouse brain (8). The product of NAA, aspartate is converted to glutamate by aspartate aminotransferase (ASAT) activity. A low activity of this enzyme is one of the factors of inducing a low glutamate level (9). Glutamate dehydrogenase (GDH), which converts glutamate to alpha-ketoglutarate, is lower in the hind brain of the CD mouse brain. A low activity of GDH results sensorimotor dysfunction (8). alpha-ketoglutarate is converted to succinyl CoA by alpha-ketoglutarate dehydrogenase complex (KGDHC). Activity of KGDHC is lower in the CD mouse brain to cause motor abnormalities (8). Osteoporosis is also one of the events in the CD mouse, as the bone mineral density has decreased in the adult mouse (9). From these studies it is obvious that a single gene defect alters other genes expression to produce abnormal protein (proteome). The resulting proteome affecting normal metabolome determines the phenotype in the knockout mouse. References: 1. JH. Globus, I. Strauss, Archs. Neurol. Psychiatry 20, 1190 (1928). 2. R. Matalon et al., Am. J. Med. Genet. 29, 463 (1988). 3. L. van Bogaert, I. Bertrand, Acta Neurol. Belg. 49, 572 (1949). 4. R. Matalon et al., J. Gene Med. 2, 165 (2000). 5. S. Surendran et al., Brain Res. Bull. 61, 427 (2003). 6. S. Surendran et al., Mol. Genet. Metab. 80, 74 (2003). 7. K.M. Gibson et al., J. Inherit. Metab. Dis. 16, 704 (1988). 8. S. Surendran et al., Neurosci. Lett. 358, 29-32 (2004). 9. S. Surendran et al., J. Child Neurol. 18, 611-615 (2003). ### The authors are from the Department of Pediatrics, The University of Texas Medical Branch, Galveston, Texas. Dr. Surendran has been a member of The Science Advisory Board since March 2004. To discuss progress in understanding the biology of this disease, please participate in The Science Advisory Board Forum. ### << Previous Next >> [ View All Perspectives ] |
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