title: Clinically Distinct Phenotypes of Canavan Disease Correlate with Residual Aspartoacylase Enzyme Activity.
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.
authors.affiliation: Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam Neuroscience, Amsterdam, The Netherlands.
authors.forename: Marisa I
authors.initials: MI
authors.lastname: Mendes
authors.affiliation: Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam Neuroscience, Amsterdam, The Netherlands.
authors.forename: Desirée Ec
authors.initials: DE
authors.lastname: Smith
authors.affiliation: Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam Neuroscience, Amsterdam, The Netherlands.
authors.forename: Ana
authors.initials: A
authors.lastname: Pop
authors.affiliation: Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam Neuroscience, Amsterdam, The Netherlands.
authors.forename: Pascal
authors.initials: P
authors.lastname: Lennertz
authors.affiliation: Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam Neuroscience, Amsterdam, The Netherlands.
authors.forename: Matilde R
authors.initials: MR
authors.lastname: Fernandez Ojeda
authors.affiliation: Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam Neuroscience, Amsterdam, The Netherlands.
authors.forename: Warsha A
authors.initials: WA
authors.lastname: Kanhai
authors.affiliation: Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam Neuroscience, Amsterdam, The Netherlands.
authors.forename: Silvy Jm
authors.initials: SJ
authors.lastname: van Dooren
authors.affiliation: Edmond and Lily Safra Children's Hospital, Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Israel.
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
authors.affiliation: Department of Pediatrics, University Hospital Center Zagreb & University of Zagreb, School of Medicine, Zagreb, Croatia.
authors.forename: Ivo
authors.initials: I
authors.lastname: Barić
authors.affiliation: Department of Pediatrics, Admiraal De Ruyter Ziekenhuis, Goes, Zeeland, The Netherlands.
authors.forename: Caroline
authors.initials: C
authors.lastname: Boelen
authors.affiliation: Neurology Department, CIBERER ISCIII, Hospital Sant Joan de Deu, University of Barcelona, Barcelona, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Campistol
authors.affiliation: Department of pediatrics, metabolic diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Lonneke
authors.initials: L
authors.lastname: de Boer
authors.affiliation: Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran.
authors.forename: Ariana
authors.initials: A
authors.lastname: Kariminejad
authors.affiliation: Medical Genetics Department, Koç University School of Medicine (KUSOM), Istanbul, Turkey.
authors.forename: Hulya
authors.initials: H
authors.lastname: Kayserili
authors.affiliation: Département de Neuropédiatrie, Hopital Gui de Chauliac, Montpellier, Languedoc-Roussillon, France.|INSERM U1051, Institut des Neurosciences de Montpellier, Montpellier, France.
authors.forename: Agathe
authors.initials: A
authors.lastname: Roubertie
authors.affiliation: Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Krijn T
authors.initials: KT
authors.lastname: Verbruggen
authors.affiliation: Centre de Biologie et de Pathologie Est CHU de Lyon, Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal, Lyon, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Vianey-Saban
authors.affiliation: Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam Neuroscience, Amsterdam, The Netherlands.
authors.forename: Monique
authors.initials: M
authors.lastname: Williams
authors.affiliation: Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam Neuroscience, Amsterdam, The Netherlands.
authors.forename: Gajja S
authors.initials: GS
authors.lastname: Salomons
mesh_terms: D000293:Adolescent; D000483:Alleles; D000581:Amidohydrolases / Q000737:chemistry / Q000378:metabolism*; D017825:Canavan Disease / Q000175:diagnosis* / Q000201:enzymology*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D011487:Protein Conformation
chemical_list: D000581:Amidohydrolases; C019751:aspartoacylase
keywords: ASPA; ASPA activity; Canavan disease; clinical phenotype; functional assay; missense variants