title: New T530C mutation in the aspartoacylase gene caused Canavan disease with no correlation between severity and N-acetylaspartate excretion.
abstract: OBJECTIVE
  Canavan disease (OMIM 271900) is a severe autosomal recessive neurodegenerative disorder characterized by spongy degeneration of the brain and caused by mutations in the gene encoding for aspartoacylase (ASPA). The enzyme is responsible for the catalyses of the brain-specific compound N-acetylaspartate (NAA).
  
  
  METHODS
  We report the case of two Egyptian sibling patients suspected of Canavan disease (CD) showing clinical deterioration, white matter degeneration, megalencephaly and severe intellectual impairment. The patients underwent magnetic resonance imaging (MRI) and biochemical analysis of NAA in biological fluid samples (serum and urine). Subsequently, in order to determine the mutation responsible for CD in these two sibs, a molecular biological examination was performed.
  
  
  RESULTS
  MRI findings and quantification of high NAA excretion (1378.5 and 680.1μmolNAA/mmolcreatinine in urine of 4months and 4years old patients, respectively) confirmed the diagnosis of CD and prompted a search for the responsible mutation. The molecular biological analysis revealed homozygosity for the substitution T530C (Ile177Thr) in the exon 4 of the ASPA gene in both sibs. A total loss of enzymatic activity was also recorded.
  
  
  CONCLUSIONS
  The substitution T530C (Ile177Thr) results in a novel missense mutation causing a CD phenotype with severe clinical characteristics. This mutation was not previously described in the literature. In these two sibs, urinary concentration of NAA appears to correlate inversely to symptom severity and CD progression.
authors.affiliation: School of Clinical & Experimental Medicine, College of Medical & Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Valentina
authors.initials: V
authors.lastname: Di Pietro
authors.forename: Ugo
authors.initials: U
authors.lastname: Cavallari
authors.forename: Angela M
authors.initials: AM
authors.lastname: Amorini
authors.forename: Giacomo
authors.initials: G
authors.lastname: Lazzarino
authors.forename: Salvatore
authors.initials: S
authors.lastname: Longo
authors.forename: Carlo
authors.initials: C
authors.lastname: Poggiani
authors.forename: Pietro
authors.initials: P
authors.lastname: Cavalli
authors.forename: Barbara
authors.initials: B
authors.lastname: Tavazzi
mesh_terms: D000581:Amidohydrolases / Q000235:genetics*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000652:urine; D017825:Canavan Disease / Q000201:enzymology* / Q000209:etiology* / Q000235:genetics; D002675:Child, Preschool; D006720:Homozygote; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D020125:Mutation, Missense
chemical_list: D001224:Aspartic Acid; C000179:N-acetylaspartate; D000581:Amidohydrolases; C019751:aspartoacylase
keywords: Aspartoacylase; Canavan disease; HPLC; Novel missense mutation; Urinary N-acetylaspartate