Jelena Hyppönen1, Marja Äikiä2, Tarja Joensuu2, Petro Julkunen2, Nils Danner2, Päivi Koskenkorva2, Ritva Vanninen2, Anna-Elina Lehesjoki2, Esa Mervaala2, Reetta Kälviäinen2. 1. 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. 2. 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.
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.
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: Edoardo Ferlazzo; Dorothee Kasteleijn-Nolst Trenite; Gerrit-Jan de Haan; Felix Felix Nitschke; Saija Ahonen; Sara Gasparini; Berge A Minassian Journal: Curr Pharm Des Date: 2017 Impact factor: 3.116