Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease.
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.
Lesca
Gaetan
G
Service de génétique, hospices civils de Lyon et université Claude Bernard Lyon I, Lyon, France. gaetan.lesca@chu-lyon.fr
Boutry-Kryza
Nadia
N
de Toffol
Bertrand
B
Milh
Mathieu
M
Steschenko
Dominique
D
Lemesle-Martin
Martine
M
Maillard
Louis
L
Foletti
Giovanni
G
Rudolf
Gabrielle
G
Nielsen
Jørgen Erik
JE
á Rogvi-Hansen
Bjarke
B
Erdal
Jesper
J
Mancini
Josette
J
Thauvin-Robinet
Christel
C
M'Rrabet
Amel
A
Ville
Dorothée
D
Szepetowski
Pierre
P
Raffo
Emmanuel
E
Hirsch
Edouard
E
Ryvlin
Philippe
P
Calender
Alain
A
Genton
Pierre
P
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
D002352:Carrier Proteins; D005819:Genetic Markers; C478960:NHLRC1 protein, human; D044767:Ubiquitin-Protein Ligases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C114990:EPM2A protein, human