title: Refining the phenotype of Unverricht-Lundborg disease (EPM1): a population-wide Finnish study.
abstract: OBJECTIVE
  This Finnish nationwide study aimed to refine the clinical phenotype variability and to identify factors that could explain the extensive variability in the clinical severity of the symptoms observed among patients with Unverricht-Lundborg disease (progressive myoclonus epilepsy type 1 [EPM1]) homozygous for the dodecamer expansion mutation in the cystatin B (CSTB) gene.
  
  
  METHODS
  The study population consisted of 66 (33 men and 33 women) patients with genetically confirmed EPM1 homozygous for the CSTB expansion mutation for whom the sizes of the expanded alleles were determined. The clinical evaluation included videorecorded Unified Myoclonus Rating Scale and retrospectively collected medical history. The navigated transcranial magnetic stimulation test was used to determine motor threshold (MT) and silent period (SP) of the motor cortex.
  
  
  RESULTS
  An earlier age at onset for EPM1 and longer disease duration were associated with more severe action myoclonus, lower performance IQ, increased MT, and prolonged SP. The number of dodecamer repeats in CSTB alleles varied between 38 and 77. On average, the size of the longer expanded alleles of patients was independently associated with MT, but exerted only a modulating effect on age at onset, myoclonus severity, and SP.
  
  
  CONCLUSIONS
  As a group, earlier disease onset and longer duration are associated with more severe phenotype. Even though the vast majority of patients with EPM1 have a uniform genetic mutation, the actual size of the longer CSTB expansion mutation allele is likely to have a modulating effect on the age at disease onset, myoclonus severity, and cortical neurophysiology.
authors.affiliation: From Neurocenter (J.H., M.Ä., R.K.) and the Department of Clinical Neurophysiology (J.H., P.J., N.D., E.M.), Kuopio Epilepsy Center, and the Department of Clinical Radiology (P.K., R.V.), Kuopio University Hospital; Neuroscience Center and Research Programs Unit (T.J., A.-E.L.), Molecular Neurology, University of Helsinki; Folkhälsan Institute of Genetics (T.J., A.-E.L.), Helsinki; and the Institute of Clinical Medicine (N.D., R.V., E.M., R.K.), School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland. jelena.hypponen@kuh.fi.
authors.forename: Jelena
authors.initials: J
authors.lastname: Hyppönen
authors.affiliation: From Neurocenter (J.H., M.Ä., R.K.) and the Department of Clinical Neurophysiology (J.H., P.J., N.D., E.M.), Kuopio Epilepsy Center, and the Department of Clinical Radiology (P.K., R.V.), Kuopio University Hospital; Neuroscience Center and Research Programs Unit (T.J., A.-E.L.), Molecular Neurology, University of Helsinki; Folkhälsan Institute of Genetics (T.J., A.-E.L.), Helsinki; and the Institute of Clinical Medicine (N.D., R.V., E.M., R.K.), School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Marja
authors.initials: M
authors.lastname: Äikiä
authors.affiliation: From Neurocenter (J.H., M.Ä., R.K.) and the Department of Clinical Neurophysiology (J.H., P.J., N.D., E.M.), Kuopio Epilepsy Center, and the Department of Clinical Radiology (P.K., R.V.), Kuopio University Hospital; Neuroscience Center and Research Programs Unit (T.J., A.-E.L.), Molecular Neurology, University of Helsinki; Folkhälsan Institute of Genetics (T.J., A.-E.L.), Helsinki; and the Institute of Clinical Medicine (N.D., R.V., E.M., R.K.), School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Tarja
authors.initials: T
authors.lastname: Joensuu
authors.affiliation: From Neurocenter (J.H., M.Ä., R.K.) and the Department of Clinical Neurophysiology (J.H., P.J., N.D., E.M.), Kuopio Epilepsy Center, and the Department of Clinical Radiology (P.K., R.V.), Kuopio University Hospital; Neuroscience Center and Research Programs Unit (T.J., A.-E.L.), Molecular Neurology, University of Helsinki; Folkhälsan Institute of Genetics (T.J., A.-E.L.), Helsinki; and the Institute of Clinical Medicine (N.D., R.V., E.M., R.K.), School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Petro
authors.initials: P
authors.lastname: Julkunen
authors.affiliation: From Neurocenter (J.H., M.Ä., R.K.) and the Department of Clinical Neurophysiology (J.H., P.J., N.D., E.M.), Kuopio Epilepsy Center, and the Department of Clinical Radiology (P.K., R.V.), Kuopio University Hospital; Neuroscience Center and Research Programs Unit (T.J., A.-E.L.), Molecular Neurology, University of Helsinki; Folkhälsan Institute of Genetics (T.J., A.-E.L.), Helsinki; and the Institute of Clinical Medicine (N.D., R.V., E.M., R.K.), School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Nils
authors.initials: N
authors.lastname: Danner
authors.affiliation: From Neurocenter (J.H., M.Ä., R.K.) and the Department of Clinical Neurophysiology (J.H., P.J., N.D., E.M.), Kuopio Epilepsy Center, and the Department of Clinical Radiology (P.K., R.V.), Kuopio University Hospital; Neuroscience Center and Research Programs Unit (T.J., A.-E.L.), Molecular Neurology, University of Helsinki; Folkhälsan Institute of Genetics (T.J., A.-E.L.), Helsinki; and the Institute of Clinical Medicine (N.D., R.V., E.M., R.K.), School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Koskenkorva
authors.affiliation: From Neurocenter (J.H., M.Ä., R.K.) and the Department of Clinical Neurophysiology (J.H., P.J., N.D., E.M.), Kuopio Epilepsy Center, and the Department of Clinical Radiology (P.K., R.V.), Kuopio University Hospital; Neuroscience Center and Research Programs Unit (T.J., A.-E.L.), Molecular Neurology, University of Helsinki; Folkhälsan Institute of Genetics (T.J., A.-E.L.), Helsinki; and the Institute of Clinical Medicine (N.D., R.V., E.M., R.K.), School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Ritva
authors.initials: R
authors.lastname: Vanninen
authors.affiliation: From Neurocenter (J.H., M.Ä., R.K.) and the Department of Clinical Neurophysiology (J.H., P.J., N.D., E.M.), Kuopio Epilepsy Center, and the Department of Clinical Radiology (P.K., R.V.), Kuopio University Hospital; Neuroscience Center and Research Programs Unit (T.J., A.-E.L.), Molecular Neurology, University of Helsinki; Folkhälsan Institute of Genetics (T.J., A.-E.L.), Helsinki; and the Institute of Clinical Medicine (N.D., R.V., E.M., R.K.), School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
authors.affiliation: From Neurocenter (J.H., M.Ä., R.K.) and the Department of Clinical Neurophysiology (J.H., P.J., N.D., E.M.), Kuopio Epilepsy Center, and the Department of Clinical Radiology (P.K., R.V.), Kuopio University Hospital; Neuroscience Center and Research Programs Unit (T.J., A.-E.L.), Molecular Neurology, University of Helsinki; Folkhälsan Institute of Genetics (T.J., A.-E.L.), Helsinki; and the Institute of Clinical Medicine (N.D., R.V., E.M., R.K.), School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Esa
authors.initials: E
authors.lastname: Mervaala
authors.affiliation: From Neurocenter (J.H., M.Ä., R.K.) and the Department of Clinical Neurophysiology (J.H., P.J., N.D., E.M.), Kuopio Epilepsy Center, and the Department of Clinical Radiology (P.K., R.V.), Kuopio University Hospital; Neuroscience Center and Research Programs Unit (T.J., A.-E.L.), Molecular Neurology, University of Helsinki; Folkhälsan Institute of Genetics (T.J., A.-E.L.), Helsinki; and the Institute of Clinical Medicine (N.D., R.V., E.M., R.K.), School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Reetta
authors.initials: R
authors.lastname: Kälviäinen
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D055313:Cystatin B / Q000235:genetics*; D005260:Female; D005387:Finland / Q000453:epidemiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009044:Motor Cortex / Q000503:physiopathology*; D009154:Mutation; D009207:Myoclonus / Q000503:physiopathology*; D010641:Phenotype; D012720:Severity of Illness Index; D013997:Time Factors; D050781:Transcranial Magnetic Stimulation; D020194:Unverricht-Lundborg Syndrome / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology*; D055815:Young Adult
chemical_list: C524994:CSTB protein, human; D055313:Cystatin B