title: Expanding the phenotype in aminoacylase 1 (ACY1) deficiency: characterization of the molecular defect in a 63-year-old woman with generalized dystonia.
abstract: Aminoacylase 1 (ACY1) deficiency is an organic aciduria due to mutations in the ACY1 gene. It is considered much underdiagnosed. Most individuals known to be affected by ACY1 deficiency have presented with neurologic symptoms. We report here a cognitively normal 63-year-old woman who around the age of 12 years had developed dystonic symptoms that gradually evolved into generalized dystonia. Extensive investigations, including metabolic diagnostics and diagnostic exome sequencing, were performed to elucidate the cause of dystonia. Findings were only compatible with a diagnosis of ACY1 deficiency: the urinary metabolite pattern with N-acetylated amino acids was characteristic, there was decreased ACY1 activity in immortalized lymphocytes, and two compound heterozygous ACY1 mutations were detected, one well-characterized c.1057C>T (p.Arg353Cys) and the other novel c.325A>G (p.Arg109Gly). Expression analysis in HEK293 cells revealed high residual activity of the enzyme with the latter mutation. However, following co-transfection of cells with stable expression of the c.1057C>T variant with either wild-type ACY1 or the c.325A>G mutant, only the wild-type enhanced ACY1 activity and ACY1 presence in the Western blot, suggesting an inhibiting interference between the two variants. Our report extends the clinical spectrum of ACY1 deficiency to include dystonia and indicates that screening for organic acidurias deserves consideration in patients with unexplained generalized dystonia.
authors.affiliation: Department of Natural Sciences, Bioanalytics & Biochemistry, Bonn-Rhein-Sieg University of Applied Sciences, von-Liebig-Str. 20, D-53359, Rheinbach, Germany. joern.oliver.sass@h-brs.de.
authors.forename: Jörn Oliver
authors.initials: JO
authors.lastname: Sass
authors.affiliation: Clinical Chemistry & Biochemistry and Children's Research Center, University Children's Hospital, Zürich, Switzerland.
authors.forename: Jathana
authors.initials: J
authors.lastname: Vaithilingam
authors.affiliation: Clinical Chemistry & Biochemistry and Children's Research Center, University Children's Hospital, Zürich, Switzerland.
authors.forename: Corinne
authors.initials: C
authors.lastname: Gemperle-Britschgi
authors.affiliation: Department of Neurology, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Cathérine C S
authors.initials: CC
authors.lastname: Delnooz
authors.affiliation: Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Leo A J
authors.initials: LA
authors.lastname: Kluijtmans
authors.affiliation: Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Bart P C
authors.initials: BP
authors.lastname: van de Warrenburg
authors.affiliation: Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
mesh_terms: D000581:Amidohydrolases / Q000172:deficiency* / Q000235:genetics; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics*; D004252:DNA Mutational Analysis; D020821:Dystonic Disorders / Q000235:genetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype
chemical_list: D000581:Amidohydrolases; C019672:aminoacylase I
keywords: Aminoacylase 1; Aspartoacylase; Canavan disease; Dystonia; Movement disorder; N-acylated amino acids