Clinically Distinct Phenotypes of Canavan Disease Correlate with Residual Aspartoacylase Enzyme Activity

Marisa I. Mendes, Desirée E.C. Smith, Ana Pop, Pascal Lennertz, Matilde R. Fernandez Ojeda, Warsha A. Kanhai, Silvy J.M. van Dooren, Yair Anikster, Ivo Barić, Caroline Boelen, Jaime Campistol, Lonneke de Boer, Ariana Kariminejad, Hulya Kayserili, Agathe Roubertie, Krijn T. Verbruggen, Christine Vianey-Saban, Monique Williams, Gajja S. Salomons

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18 Citations (Scopus)


We describe 14 patients with 12 novel missense mutations in ASPA, the gene causing Canavan disease (CD). We developed a method to study the effect of these 12 variants on the function of aspartoacylase—the hydrolysis of N-acetyl-l-aspartic acid (NAA) to aspartate and acetate. The wild-type ASPA open reading frame (ORF) and the ORFs containing each of the variants were transfected into HEK293 cells. Enzyme activity was determined by incubating cell lysates with NAA and measuring the released aspartic acid by LC–MS/MS. Clinical data were obtained for 11 patients by means of questionnaires. Four patients presented with a non-typical clinical picture or with the milder form of CD, whereas seven presented with severe CD. The mutations found in the mild patients corresponded to the variants with the highest residual enzyme activities, suggesting that this assay can help evaluate unknown variants found in patients with atypical presentation. We have detected a correlation between clinical presentation, enzyme activity, and genotype for CD.

Original languageEnglish
Pages (from-to)524-531
Number of pages8
JournalHuman mutation
Issue number5
Publication statusPublished - 1 May 2017


  • ASPA
  • ASPA activity
  • Canavan disease
  • clinical phenotype
  • functional assay
  • missense variants

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