title: A step toward essential tremor gene discovery: identification of extreme phenotype and screening of HTRA2 and ANO3.
abstract: BACKGROUND
  Essential tremor (ET) is characterized by a frequent family history. No monogenic form of ET has been identified. We aimed at exploring ET patients to identify distinct subgroups and facilitate the identification of ET genes. We tested for the presence of HTRA2 p.G399S, and ANO3 p. W490C, p. R484 W and p. S685G mutations.
  
  
  METHODS
  Between June 2011 and November 2013, all consecutive patients suspected with ET were prospectively included in a prospective, monocentric study. Family history, age at onset (AAO), features of tremor, benefit of alcohol and drugs, electrophysiological recording findings were collected. Sanger sequencing was performed for HTRA2 and ANO3 mutations screening.
  
  
  RESULTS
  Sixty eight patients were investigated. Fourteen diagnosed with psychogenic (5) or dystonic tremor (9) were excluded. Regarding the 54 ET patients, mean AAO was 48 years (6-77), and mean disease duration 15 years (1-55). Bimodal distribution of AAO was consistent with phenotypic subgroups. In patients with AAO before 30 years, marked benefit of alcohol (p < 0.01) and ET family history (p < 0.01) were more frequent and the disease progression less severe (p < 0.0001). Neither HTRA2 nor ANO3 mutation were identified in our patients.
  
  
  CONCLUSIONS
  Our data support that distinct ET phenotypic subgroups may be encountered. We recommend to study separately extreme phenotypes of ET, particularly autosomal dominant families with early AAO (<30 years) and marked benefit of alcohol, to facilitate the identification of ET genes. Electromyographic recording remains a support to distinguish ET from differential diagnosis. HTRA2 and ANO3 mutations are not common causes of ET.
authors.affiliation: Service of Neurology, University Hospital of Strasbourg, Hospital of Hautepierre, 1 avenue Molière, 67098, Strasbourg Cedex, France.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.|Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, 67404, Illkirch, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Renaud
authors.affiliation: Service of Neurology, University Hospital of Strasbourg, Hospital of Hautepierre, 1 avenue Molière, 67098, Strasbourg Cedex, France.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Marcel
authors.affiliation: Service of Neurology, University Hospital of Strasbourg, Hospital of Hautepierre, 1 avenue Molière, 67098, Strasbourg Cedex, France.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.|Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, 67404, Illkirch, France.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Rudolf
authors.affiliation: Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.|Département d'informations médicales, Hôpitaux universitaires de Strasbourg, Hôpital civil, 1 place de l'Hôpital, 67000, Strasbourg, France.
authors.forename: Mickaël
authors.initials: M
authors.lastname: Schaeffer
authors.affiliation: Service of Neurology, University Hospital of Strasbourg, Hospital of Hautepierre, 1 avenue Molière, 67098, Strasbourg Cedex, France.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
authors.forename: Ouhaïd
authors.initials: O
authors.lastname: Lagha-Boukbiza
authors.affiliation: Service of Neurology, University Hospital of Strasbourg, Hospital of Hautepierre, 1 avenue Molière, 67098, Strasbourg Cedex, France.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Chanson
authors.affiliation: Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.|Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, 67404, Illkirch, France.|Service de Diagnostic génétique, Nouvel hôpital civil, 67000, Strasbourg Cedex, France.
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.affiliation: Service of Neurology, University Hospital of Strasbourg, Hospital of Hautepierre, 1 avenue Molière, 67098, Strasbourg Cedex, France.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.|Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, 67404, Illkirch, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Anheim
authors.affiliation: Service of Neurology, University Hospital of Strasbourg, Hospital of Hautepierre, 1 avenue Molière, 67098, Strasbourg Cedex, France. christine.tranchant@chru-strasbourg.fr.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France. christine.tranchant@chru-strasbourg.fr.|Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, 67404, Illkirch, France. christine.tranchant@chru-strasbourg.fr.
authors.forename: Christine
authors.initials: C
authors.lastname: Tranchant
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000075368:Anoctamins; D018118:Chloride Channels / Q000235:genetics; D020821:Dystonic Disorders / Q000235:genetics*; D020329:Essential Tremor / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics; D009154:Mutation; D011446:Prospective Studies; D012697:Serine Endopeptidases / Q000235:genetics; D055815:Young Adult
chemical_list: C577591:ANO3 protein, human; D000075368:Anoctamins; D018118:Chloride Channels; D024101:Mitochondrial Proteins; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2
keywords: ANO3; Electrophysiological recording; Essential tremor; Extreme phenotype; HTRA2