title: Paroxysmal exercise-induced dystonia within the phenotypic spectrum of ECHS1 deficiency.
abstract: ECHS1 encodes a mitochondrial enzyme involved in the degradation of essential amino acids and fatty acids. Recently, ECHS1 mutations were shown to cause a new severe metabolic disorder presenting as Leigh or Leigh-like syndromes. The objective of this study was to describe a family with 2 siblings affected by different dystonic disorders as a resulting phenotype of ECHS1 mutations.
  
  
  
  Clinical evaluation, MRI imaging, genome-wide linkage, exome sequencing, urine metabolite profiling, and protein expression studies were performed.
  
  
  
  The first sibling is 17 years old and presents with generalized dystonia and severe bilateral pallidal MRI lesions after 1 episode of infantile subacute metabolic encephalopathy (Leigh-like syndrome). In contrast, the younger sibling (15 years old) only suffers from paroxysmal exercise-induced dystonia and has very mild pallidal MRI abnormalities. Both patients carry compound heterozygous ECHS1 mutations: c.232G>T (predicted protein effect: p.Glu78Ter) and c.518C>T (p.Ala173Val). Linkage analysis, exome sequencing, cosegregation, expression studies, and metabolite profiling support the pathogenicity of these mutations. Expression studies in patients' fibroblasts showed mitochondrial localization and severely reduced levels of ECHS1 protein. Increased urinary S-(2-carboxypropyl)cysteine and N-acetyl-S-(2-carboxypropyl)cysteine levels, proposed metabolic markers of this disorder, were documented in both siblings. Sequencing ECHS1 in 30 unrelated patients with paroxysmal dyskinesias revealed no further mutations.
  
  
  
  The phenotype associated with ECHS1 mutations might be milder than reported earlier, compatible with prolonged survival, and also includes isolated paroxysmal exercise-induced dystonia. ECHS1 screening should be considered in patients with otherwise unexplained paroxysmal exercise-induced dystonia, in addition to those with Leigh and Leigh-like syndromes. Diet regimens and detoxifying agents represent potential therapeutic strategies. © 2016 International Parkinson and Movement Disorder Society.
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Simone
authors.initials: S
authors.lastname: Olgiati
authors.affiliation: Department of Neurology, Safarik University, Kosice, Slovakia.|Department of Neurology, University Hospital L. Pasteur, Kosice, Slovakia.
authors.forename: Matej
authors.initials: M
authors.lastname: Skorvanek
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Quadri
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Michelle
authors.initials: M
authors.lastname: Minneboo
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Josja
authors.initials: J
authors.lastname: Graafland
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Guido J
authors.initials: GJ
authors.lastname: Breedveld
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Ramon
authors.initials: R
authors.lastname: Bonte
authors.affiliation: Center for Biomics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Zeliha
authors.initials: Z
authors.lastname: Ozgur
authors.affiliation: Center for Biomics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Mirjam C G N
authors.initials: MC
authors.lastname: van den Hout
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Kees
authors.initials: K
authors.lastname: Schoonderwoerd
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Frans W
authors.initials: FW
authors.lastname: Verheijen
authors.affiliation: Center for Biomics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Wilfred F J
authors.initials: WF
authors.lastname: van IJcken
authors.affiliation: Department of Neurology, University of São Paulo, São Paulo, Brazil.
authors.forename: Hsin Fen
authors.initials: HF
authors.lastname: Chien
authors.affiliation: Department of Neurology, University of São Paulo, São Paulo, Brazil.
authors.forename: Egberto Reis
authors.initials: ER
authors.lastname: Barbosa
authors.affiliation: Neuroscience Research Center, Division of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors.forename: Hsiu-Chen
authors.initials: HC
authors.lastname: Chang
authors.affiliation: Neuroscience Research Center, Division of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors.forename: Szu-Chia
authors.initials: SC
authors.lastname: Lai
authors.affiliation: Neuroscience Research Center, Division of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors.forename: Tu-Hsueh
authors.initials: TH
authors.lastname: Yeh
authors.affiliation: Neuroscience Research Center, Division of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chin-Song
authors.initials: CS
authors.lastname: Lu
authors.affiliation: Human Molecular Genetics Laboratory, Department of Medical Research, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors.forename: Yah-Huei
authors.initials: YH
authors.lastname: Wu-Chou
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Anneke J A
authors.initials: AJ
authors.lastname: Kievit
authors.affiliation: Department of Neurology, Safarik University, Kosice, Slovakia.|Department of Neurology, University Hospital L. Pasteur, Kosice, Slovakia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Han
authors.affiliation: Department of Neurology, Safarik University, Kosice, Slovakia.|Department of Neurology, University Hospital L. Pasteur, Kosice, Slovakia.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Gdovinova
authors.affiliation: Department of Neurology, Charles University in Prague, First Faculty of Medicine, Prague, Czech Republic.
authors.forename: Robert
authors.initials: R
authors.lastname: Jech
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: George J G
authors.initials: GJ
authors.lastname: Ruijter
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: Mandemakers
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bonifati
mesh_terms: D000293:Adolescent; D020821:Dystonic Disorders / Q000235:genetics* / Q000503:physiopathology*; D004746:Enoyl-CoA Hydratase / Q000172:deficiency* / Q000235:genetics; D015444:Exercise; D006801:Humans; D008297:Male; D010375:Pedigree
chemical_list: C000600529:ECHS1 protein, human; D004746:Enoyl-CoA Hydratase
keywords: ECHS1; dystonia; exercise-induced; mutation; paroxysmal