Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease

Authors: Lesca, Gaetan; Boutry-Kryza, Nadia¹; de Toffol, Bertrand²; Milh, Mathieu³; Steschenko, Dominique⁴; Lemesle-Martin, Martine⁵; Maillard, Louis⁶; Foletti, Giovanni⁷; Rudolf, Gabrielle⁸; Nielsen, Jørgen Erik; á Rogvi-Hansen, Bjarke⁹; Erdal, Jesper⁹; Mancini, Josette³; Thauvin-Robinet, Christel¹⁰; M'Rrabet, Amel¹¹; Ville, Dorothée¹²; Szepetowski, Pierre¹³; Raffo, Emmanuel⁴; Hirsch, Edouard⁸; Ryvlin, Philippe; Calender, Alain¹; Genton, Pierre

Source: Epilepsia, Volume 51, Number 9, September 2010 , pp. 1691-1698(8)

Publisher: Wiley-Blackwell

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Abstract:

Summary Purpose:

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. Discussion:

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.

Keywords: Lafora disease; EPM2A; EPM2B; NHLRC1

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1528-1167.2010.02692.x

Affiliations: 1: Service de génétique, hospices civils de Lyon et université Claude Bernard Lyon I, Lyon, France 2: Service de neurologie, CHU Bretonneau, Tours, France 3: Service de neurologie pédiatrique, hôpital Timone-enfants, Marseille, France 4: Médecine infantile 1, hôpital d'enfants, CHU de Nancy, Vandoeuvre-lès-Nancy, France 5: Laboratoire d'explorations du système nerveux, hôpital général, Dijon, France 6: Service de neurologie, hôpital central et centre de recherche en automatique de Nancy, UMR 7039, CNRS, université de Nancy, Nancy, France 7: Département de neurologie, institution de Lavigny, Lavigny, Switzerland 8: Service de neurologie, hôpitaux universitaires de Strasbourg, Strasbourg, France 9: Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark 10: Centre de génétique, hôpital d'enfant, CHU de Dijon, Dijon, France; †††Service de Neurologie, EPS Charles Nicolle, Tunis, Tunisia 11: Service de neuropédiatrie, Hôpital femme-mère-enfant, hospices civils de Lyon, Lyon, France 12: Service d'épileptologie, hospices civils de Lyon et université Claude Bernard Lyon 1, Lyon, France 13: Institut de neurobiologie de la Méditerranée (INMED), INSERM UMR901, université de la Méditerranée, Marseille, France

Publication date: 2010-09-01

Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease

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