title: Severer phenotype in Unverricht-Lundborg disease (EPM1) patients compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutation in the CSTB gene.
abstract: OBJECTIVE
  Unverricht-Lundborg disease (EPM1) is caused by mutations in the cystatin B (CSTB) gene. Most patients are homozygous for the expanded dodecamer repeat mutation alleles, but 9 other EPM1-associated mutations have also been identified. We describe the clinical, cognitive and imaging characteristics of 5 Finnish EPM1 patients who are compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutations.
  
  
  METHODS
  Five compound heterozygous patients and 21 patients homozygous for the expansion mutation, participating in an ongoing nationwide clinical and molecular genetics study, were evaluated using the Unified Myoclonus Rating Scale test and comprehensive neuropsychological testing. All patients underwent MR imaging. The MR data were also compared with those of 24 healthy control subjects.
  
  
  RESULTS
  Age at onset of symptoms was significantly lower in the compound heterozygotes than in the homozygous EPM1 patients. They also had severer myoclonus and drug-resistant tonic-clonic seizures. Moreover, they had lower cognitive performance. In MRI a voxel-based morphometry analysis of primary and premotor cortex, supplementary motor cortex and thalami revealed gray matter volume loss when compared with the healthy controls, similar to patients homozygous for the expansion mutation.
  
  
  CONCLUSIONS
  Patients compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutations seem to have a severer form of EPM1 than patients homozygous for the expansion mutation. These findings have implications for counseling of EPM1 patients with different genetic defects.
authors.affiliation: Department of Clinical Radiology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Koskenkorva
authors.forename: Jelena
authors.initials: J
authors.lastname: Hyppönen
authors.forename: Marja
authors.initials: M
authors.lastname: Aikiä
authors.forename: Esa
authors.initials: E
authors.lastname: Mervaala
authors.forename: Tuula
authors.initials: T
authors.lastname: Kiviranta
authors.forename: Kai
authors.initials: K
authors.lastname: Eriksson
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
authors.forename: Ritva
authors.initials: R
authors.lastname: Vanninen
authors.forename: Reetta
authors.initials: R
authors.lastname: Kälviäinen
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000927:Anticonvulsants / Q000627:therapeutic use; D055313:Cystatin B / Q000235:genetics*; D018450:Disease Progression; D004569:Electroencephalography; D004830:Epilepsy, Tonic-Clonic / Q000188:drug therapy / Q000209:etiology; D005091:Exons / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007361:Intelligence Tests; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics / Q000502:physiology; D009483:Neuropsychological Tests; D010641:Phenotype; D020449:Repetitive Sequences, Amino Acid; D020194:Unverricht-Lundborg Syndrome / Q000235:genetics* / Q000473:pathology; D014706:Verbal Learning; D016138:Walking; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; C524994:CSTB protein, human; D055313:Cystatin B