title: Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease.
abstract: OBJECTIVE
  Lafora disease (LD) is an autosomal recessive form of progressive myoclonus epilepsy with onset in childhood or adolescence and with fatal outcome caused by mutations in two genes: EPM2A and NHLRC1. The aim of this study was to characterize the mutation spectrum in a cohort of unrelated patients with presumed LD.
  
  
  METHODS
  Sequencing of the two genes and search for large rearrangements was performed in 46 unrelated patients with suspected LD, 33 originating from France and the others from different countries. Patients were classified into two groups according to the clinical presentation.
  
  
  RESULTS
  Mutations of various types were found in EPM2A in 10 patients and in NHLRC1 in 4 patients. Mutations were found in 14 (93%) of 15 patients with classical clinical and electroencephalography (EEG) presentation of LD and in no patients with an atypical presentation. Ten mutations were novel, including the first substitution reported in a donor splice site of EPM2A, leading to the deletion of exon 2 at the RNA level. Four large deletions, including two deletions of exon 2 with different sizes and breakpoints, were found in EPM2A, corresponding to 20% of the alleles of this gene.
  
  
  CONCLUSIONS
  We described several novel mutations of EPM2A and NHLRC1 and brought additional data to the genetic epidemiology of LD. This study emphasized the high mutation rate in patients with classical LD as well as the high negativity rate of skin biopsy.
authors.affiliation: Service de génétique, hospices civils de Lyon et université Claude Bernard Lyon I, Lyon, France. gaetan.lesca@chu-lyon.fr
authors.forename: Gaetan
authors.initials: G
authors.lastname: Lesca
authors.forename: Nadia
authors.initials: N
authors.lastname: Boutry-Kryza
authors.forename: Bertrand
authors.initials: B
authors.lastname: de Toffol
authors.forename: Mathieu
authors.initials: M
authors.lastname: Milh
authors.forename: Dominique
authors.initials: D
authors.lastname: Steschenko
authors.forename: Martine
authors.initials: M
authors.lastname: Lemesle-Martin
authors.forename: Louis
authors.initials: L
authors.lastname: Maillard
authors.forename: Giovanni
authors.initials: G
authors.lastname: Foletti
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Rudolf
authors.forename: Jørgen Erik
authors.initials: JE
authors.lastname: Nielsen
authors.forename: Bjarke
authors.initials: B
authors.lastname: á Rogvi-Hansen
authors.forename: Jesper
authors.initials: J
authors.lastname: Erdal
authors.forename: Josette
authors.initials: J
authors.lastname: Mancini
authors.forename: Christel
authors.initials: C
authors.lastname: Thauvin-Robinet
authors.forename: Amel
authors.initials: A
authors.lastname: M'Rrabet
authors.forename: Dorothée
authors.initials: D
authors.lastname: Ville
authors.forename: Pierre
authors.initials: P
authors.lastname: Szepetowski
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Raffo
authors.forename: Edouard
authors.initials: E
authors.lastname: Hirsch
authors.forename: Philippe
authors.initials: P
authors.lastname: Ryvlin
authors.forename: Alain
authors.initials: A
authors.lastname: Calender
authors.forename: Pierre
authors.initials: P
authors.lastname: Genton
mesh_terms: D000293:Adolescent; D000328:Adult; D001706:Biopsy; D002352:Carrier Proteins / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D020192:Lafora Disease / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics*; D012867:Skin / Q000473:pathology; D044767:Ubiquitin-Protein Ligases
chemical_list: D002352:Carrier Proteins; D005819:Genetic Markers; C478960:NHLRC1 protein, human; D044767:Ubiquitin-Protein Ligases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C114990:EPM2A protein, human