Two novel aspartoacylase gene (ASPA) missense mutations specific to Norwegian and Swedish patients with Canavan disease

• aspartoacylase gene mutations
• Canavan disease

Canavan disease (CD) (OMIM 271900) is an autosomal recessive leucodystrophy characterised by swelling and spongy degeneration of the white matter of the brain. The biochemical marker for the disorder is increased level of N-acetylaspartic acid (NAA) in cerebrospinal fluid and urine owing to aspartoacylase (ASPA) deficiency.^1,2 The disease is caused by mutations in the gene encoding the enzyme aspartoacylase (EC 3.5.1.15) at 17p13-ter.^3,4

Clinical features are macrocephaly, head lag, and hypotonia from the age of 3-6 months followed by rapidly progressive severe mental retardation. Life expectancy is usually into the teens and development of optic atrophy is typical. Only symptomatic treatment is possible. The prevalence is highest among Ashkenazi Jews with a carrier frequency of 1 in 38 and two mutations, Y231X and E285A, constitute 98% of the CD alleles in this population.^3,5

Canavan disease is rare in non-Jewish populations and one mutation, A305E (914C→A), is found in about 40%⁶ to 60%⁵ of the disease alleles reported so far. Mutations are scattered all over the six exons of the aspartoacylase gene. In total, 38 different mutations have been reported of which 35 are listed in The Human Gene Mutation Data Base, Cardiff, UK.^7–10

Prenatal diagnosis by enzyme assay is complicated by technical difficulties.^11–15 Measurement of N-acetylaspartate concentration in amniotic fluid by stable isotope dilution is considered a reliable approach. However, for carrier detection and prenatal diagnosis, mutation detection should be performed. Our aim has been to study the mutational spectrum of the aspartoacylase gene in Norwegian and Swedish patients of non-Jewish origin. This knowledge is essential for patient management and for the design of rational molecular genetic diagnosis.