Canavan disease (OMIM # 271900) is an inherited leukodystrophy caused by deficiency of aspartoacylase (ASPA) (Matalon, et al., 1988) a cytosolic enzyme found in oligodendrocytes (Madhavarao, et al., 2004). It hydrolyzes ^-acetylaspartic acid (NAA) to acetate and aspartic acid. In Canavan disease (CD), NAA concentrations in brain increase causing vacuolization in the lower layers of the cerebral cortex and subcortical white matter with intramyelinic swelling and myelin loss. Symptoms of this rare antosomal recessive disease appear within two to four months of birth, consisting of poor head control, truncal hypotonia, developmental delay, and lack of visual tracking. Subsequently, progressive macrocephaly, limb spasticity and seizures develop. With gastrostomy feedings and close nursing care, some of these children will remain interactive for a number of years although they are unable to sit alone, speak or walk.
The human ASPA gene maps to 17pter-p13 and covers a span of ~30 kb of genomic DNA. The cDNA is 1435 bp in length and contains 6 exons encoding a protein of 313 amino acids (Kaul et al., 1993). CD is especially prevalent among individuals of Ashkenazi Jewish ancestry in which the carrier frequency approximates 1 in 37-57 (Feigenbaum et al., 2004). Nearly all (98%) of the mutant alleles in this population are due to two founder mutations, E285A and Y231X. A third mutation, A305E, accounts
Department of Neurology, New York University School of Medicine 550 First Avenue, New York, NY 10016 USA
for approximately 40 percent of mutant alleles in non-Jewish patients. Most other mutations appear to be private, confined to single families or to small geographic areas.
A total of 53 mutations of the ASPA gene are listed in the Human Gene Mutation Database (http://archive.uwcm.ac.uk/uwcm/mg/search/231014.html). Our laboratory first reported 14 of these mutations (Zeng et al., 2002), and has recently discovered another 10 novel mutations, all in non-Jewish families. These mutations were found in the course of our study of 38 non-Jewish families with CD. This report reviews the ASPA mutations we have observed in these families and illustrates the importance of molecular genotyping for the prenatal diagnosis of CD.
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