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Clinically Distinct Phenotypes of Canavan Disease Correlate with Residual Aspartoacylase Enzyme Activity
Author(s) -
Mendes Marisa I,
Smith Desirée EC,
Pop Ana,
Lennertz Pascal,
Fernandez Ojeda Matilde R,
Kanhai Warsha A,
Dooren Silvy JM,
Anikster Yair,
Barić Ivo,
Boelen Caroline,
Campistol Jaime,
Boer Lonneke,
Kariminejad Ariana,
Kayserili Hulya,
Roubertie Agathe,
Verbruggen Krijn T,
VianeySaban Christine,
Williams Monique,
Salomons Gajja S
Publication year - 2017
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23181
Subject(s) - missense mutation , biology , genotype , enzyme , orfs , open reading frame , enzyme assay , phenotype , gene , microbiology and biotechnology , biochemistry , genetics , peptide sequence
ABSTRACT 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.