title: A family with paroxysmal nonkinesigenic dyskinesias (PNKD): evidence of mitochondrial dysfunction.
abstract: BACKGROUND
  Paroxysmal nonkinesigenic dyskinesia (PNKD) is a rare movement disorder characterized by sudden attacks of involuntary movements. Familial PNKD is an autosomal dominant trait, caused by mutations in the myofibrillogenesis regulator 1 (MR-1) gene on chromosome 2q35. Three different mutations have been described; all of them reside in the N-terminal region common to isoforms L and S, that has been suggested to code for a mitochondrial targeting sequence, necessary for the correct sub-cellular localization of the protein into mitochondria.
  
  
  METHODS
  We report on four patients of the same family, affected by PNKD. Skin fibroblasts were used to analysed oxygen consumption and to measure mitochondrial matrix calcium response after agonist stimulation. Mitotracker-based visualization was also used to assess fragmentation of the mitochondrial network.
  
  
  RESULTS
  the paroxysmal movements were dystonic in two patients and dystonic/choreiform in the other ones; in three cases the symptoms started in one limb and then generalized, while in one case remained focal. Three had a very early onset, within the first two years of life. The frequency of episodes showed a great variability, ranging from 2 times a day to 3 times a year, while the duration of the attacks ranged from 2 min to 1,5 h, always with sudden onset and end and complete recover in between. All affected subjects harbored a heterozygous C to T substitution in MR-1, causing an Ala9Val amino acid change in the N-terminal region. A significant reduction of oxygen consumption and altered calcium homeostasis were found in mutant fibroblasts compared to controls, while no difference was detected in mitochondrial network.
  
  
  CONCLUSIONS
  The data on reduced oxygen consumption and altered calcium homeostasis obtained on mutant fibroblasts are the first evidences, in physiological conditions, of a mitochondrial dysfunction in PNKD.
authors.affiliation: Molecular Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Ghezzi
authors.affiliation: Neuropediatrics Unit, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Canavese
authors.affiliation: Department of Neurology, Institute for Mother and Child Health Care of Serbia, Serbia.
authors.forename: Gordana
authors.initials: G
authors.lastname: Kovacevic
authors.affiliation: Department of Neurology, Institute for Mother and Child Health Care of Serbia, Serbia.
authors.forename: Dragan
authors.initials: D
authors.lastname: Zamurovic
authors.affiliation: Molecular Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Barzaghi
authors.affiliation: Dept of Morphology, Surgery and Experimental Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation (ICSI), Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Giorgi
authors.affiliation: Neuropediatrics Unit, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zorzi
authors.affiliation: Molecular Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.affiliation: Dept of Morphology, Surgery and Experimental Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation (ICSI), Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
authors.affiliation: Molecular Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Garavaglia
authors.affiliation: Neuropediatrics Unit, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy. Electronic address: nardo.nardocci@istituto-besta.it.
authors.forename: Nardo
authors.initials: N
authors.lastname: Nardocci
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D020013:Calcium Signaling / Q000502:physiology; D002478:Cells, Cultured; D002648:Child; D002819:Chorea / Q000209:etiology / Q000503:physiopathology*; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D005190:Family; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000150:complications / Q000503:physiopathology*; D009069:Movement Disorders / Q000209:etiology; D009124:Muscle Proteins / Q000235:genetics; D010101:Oxygen Consumption / Q000502:physiology; D010375:Pedigree; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D009124:Muscle Proteins; C495444:PNKD protein, human
keywords: Mitochondrial dysfunction; Paroxysmal nonkinesigenic dyskinesias