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

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)524-531
Number of pages8
JournalHuman Mutation
Volume38
Issue number5
DOIs
Publication statusPublished - 1 May 2017

Cite this

Mendes, Marisa I. ; Smith, Desirée E.C. ; Pop, Ana ; Lennertz, Pascal ; Fernandez Ojeda, Matilde R. ; Kanhai, Warsha A. ; van Dooren, Silvy J.M. ; Anikster, Yair ; Barić, Ivo ; Boelen, Caroline ; Campistol, Jaime ; de Boer, Lonneke ; Kariminejad, Ariana ; Kayserili, Hulya ; Roubertie, Agathe ; Verbruggen, Krijn T. ; Vianey-Saban, Christine ; Williams, Monique ; Salomons, Gajja S. / Clinically Distinct Phenotypes of Canavan Disease Correlate with Residual Aspartoacylase Enzyme Activity. In: Human Mutation. 2017 ; Vol. 38, No. 5. pp. 524-531.
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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.",
keywords = "ASPA, ASPA activity, Canavan disease, clinical phenotype, functional assay, missense variants",
author = "Mendes, {Marisa I.} and Smith, {Desir{\'e}e E.C.} and Ana Pop and Pascal Lennertz and {Fernandez Ojeda}, {Matilde R.} and Kanhai, {Warsha A.} and {van Dooren}, {Silvy J.M.} and Yair Anikster and Ivo Barić and Caroline Boelen and Jaime Campistol and {de Boer}, Lonneke and Ariana Kariminejad and Hulya Kayserili and Agathe Roubertie and Verbruggen, {Krijn T.} and Christine Vianey-Saban and Monique Williams and Salomons, {Gajja S.}",
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Mendes, MI, Smith, DEC, Pop, A, Lennertz, P, Fernandez Ojeda, MR, Kanhai, WA, van Dooren, SJM, Anikster, Y, Barić, I, Boelen, C, Campistol, J, de Boer, L, Kariminejad, A, Kayserili, H, Roubertie, A, Verbruggen, KT, Vianey-Saban, C, Williams, M & Salomons, GS 2017, 'Clinically Distinct Phenotypes of Canavan Disease Correlate with Residual Aspartoacylase Enzyme Activity' Human Mutation, vol. 38, no. 5, pp. 524-531. https://doi.org/10.1002/humu.23181

Clinically Distinct Phenotypes of Canavan Disease Correlate with Residual Aspartoacylase Enzyme Activity. / Mendes, Marisa I.; Smith, Desirée E.C.; Pop, Ana; Lennertz, Pascal; Fernandez Ojeda, Matilde R.; Kanhai, Warsha A.; van Dooren, Silvy J.M.; Anikster, Yair; Barić, Ivo; Boelen, Caroline; Campistol, Jaime; de Boer, Lonneke; Kariminejad, Ariana; Kayserili, Hulya; Roubertie, Agathe; Verbruggen, Krijn T.; Vianey-Saban, Christine; Williams, Monique; Salomons, Gajja S.

In: Human Mutation, Vol. 38, No. 5, 01.05.2017, p. 524-531.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Clinically Distinct Phenotypes of Canavan Disease Correlate with Residual Aspartoacylase Enzyme Activity

AU - Mendes, Marisa I.

AU - Smith, Desirée E.C.

AU - Pop, Ana

AU - Lennertz, Pascal

AU - Fernandez Ojeda, Matilde R.

AU - Kanhai, Warsha A.

AU - van Dooren, Silvy J.M.

AU - Anikster, Yair

AU - Barić, Ivo

AU - Boelen, Caroline

AU - Campistol, Jaime

AU - de Boer, Lonneke

AU - Kariminejad, Ariana

AU - Kayserili, Hulya

AU - Roubertie, Agathe

AU - Verbruggen, Krijn T.

AU - Vianey-Saban, Christine

AU - Williams, Monique

AU - Salomons, Gajja S.

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N2 - 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.

AB - 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.

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KW - ASPA activity

KW - Canavan disease

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KW - functional assay

KW - missense variants

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