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

Gaetan Lesca; Nadia Boutry-Kryza; Bertrand de Toffol; Mathieu Milh; Dominique Steschenko; Martine Lemesle-Martin; Louis Maillard; Giovanni Foletti; Gabrielle Rudolf; Jørgen Erik Nielsen; Bjarke á Rogvi-Hansen; Jesper Erdal; Josette Mancini; Christel Thauvin-Robinet; Amel M'Rrabet; Dorothée Ville; Pierre Szepetowski; Emmanuel Raffo; Edouard Hirsch; Philippe Ryvlin; Alain Calender; Pierre Genton

doi:10.1111/j.1528-1167.2010.02692.x

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

Gaetan Lesca, Nadia Boutry-Kryza, Bertrand de Toffol, Mathieu Milh, Dominique Steschenko, Martine Lemesle-Martin, Louis Maillard, Giovanni Foletti, Gabrielle Rudolf, Jørgen Erik Nielsen, Bjarke á Rogvi-Hansen, Jesper Erdal, Josette Mancini, Christel Thauvin-Robinet, Amel M'Rrabet, Dorothée Ville, Pierre Szepetowski, Emmanuel Raffo, Edouard Hirsch, Philippe RyvlinAlain Calender, Pierre Genton

31 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Epilepsia
Volume	51
Issue number	9
Pages (from-to)	1691-8
Number of pages	8
ISSN	0013-9580
DOIs	https://doi.org/10.1111/j.1528-1167.2010.02692.x
Publication status	Published - 1 Sept 2010

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Lesca, G., Boutry-Kryza, N., de Toffol, B., Milh, M., Steschenko, D., Lemesle-Martin, M., Maillard, L., Foletti, G., Rudolf, G., Nielsen, J. E., á Rogvi-Hansen, B., Erdal, J., Mancini, J., Thauvin-Robinet, C., M'Rrabet, A., Ville, D., Szepetowski, P., Raffo, E., Hirsch, E., ... Genton, P. (2010). Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease. Epilepsia, 51(9), 1691-8. https://doi.org/10.1111/j.1528-1167.2010.02692.x

Lesca, G, Boutry-Kryza, N, de Toffol, B, Milh, M, Steschenko, D, Lemesle-Martin, M, Maillard, L, Foletti, G, Rudolf, G, Nielsen, JE, á Rogvi-Hansen, B, Erdal, J, Mancini, J, Thauvin-Robinet, C, M'Rrabet, A, Ville, D, Szepetowski, P, Raffo, E, Hirsch, E, Ryvlin, P, Calender, A & Genton, P 2010, 'Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease', Epilepsia, vol. 51, no. 9, pp. 1691-8. https://doi.org/10.1111/j.1528-1167.2010.02692.x

@article{74eab03907374f8da90de76ee2ae38e7,

title = "Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease",

abstract = "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.",

author = "Gaetan Lesca and Nadia Boutry-Kryza and {de Toffol}, Bertrand and Mathieu Milh and Dominique Steschenko and Martine Lemesle-Martin and Louis Maillard and Giovanni Foletti and Gabrielle Rudolf and Nielsen, {J{\o}rgen Erik} and {{\'a} Rogvi-Hansen}, Bjarke and Jesper Erdal and Josette Mancini and Christel Thauvin-Robinet and Amel M'Rrabet and Doroth{\'e}e Ville and Pierre Szepetowski and Emmanuel Raffo and Edouard Hirsch and Philippe Ryvlin and Alain Calender and Pierre Genton",

year = "2010",

month = sep,

day = "1",

doi = "10.1111/j.1528-1167.2010.02692.x",

language = "English",

volume = "51",

pages = "1691--8",

journal = "Epilepsia",

issn = "0013-9580",

publisher = "Wiley-Blackwell",

number = "9",

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TY - JOUR

T1 - Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease

AU - Lesca, Gaetan

AU - Boutry-Kryza, Nadia

AU - de Toffol, Bertrand

AU - Milh, Mathieu

AU - Steschenko, Dominique

AU - Lemesle-Martin, Martine

AU - Maillard, Louis

AU - Foletti, Giovanni

AU - Rudolf, Gabrielle

AU - Nielsen, Jørgen Erik

AU - á Rogvi-Hansen, Bjarke

AU - Erdal, Jesper

AU - Mancini, Josette

AU - Thauvin-Robinet, Christel

AU - M'Rrabet, Amel

AU - Ville, Dorothée

AU - Szepetowski, Pierre

AU - Raffo, Emmanuel

AU - Hirsch, Edouard

AU - Ryvlin, Philippe

AU - Calender, Alain

AU - Genton, Pierre

PY - 2010/9/1

Y1 - 2010/9/1

N2 - 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.

AB - 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.

U2 - 10.1111/j.1528-1167.2010.02692.x

DO - 10.1111/j.1528-1167.2010.02692.x

M3 - Journal article

SN - 0013-9580

VL - 51

SP - 1691

EP - 1698

JO - Epilepsia

JF - Epilepsia

IS - 9

ER -

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

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