title: Late onset Lafora disease and novel EPM2A mutations: breaking paradigms.
abstract: Lafora disease (LD) is an autosomal recessive progressive myoclonus epilepsy with classic adolescent onset of stimuli sensitive seizures. Patients typically deteriorate rapidly with dementia, ataxia, vegetative failure and death by 25 years of age. LD is caused by homozygous mutations in EPM2A or EPM2B genes. We found four novel mutations in EPM2A - three in exon 4 (Q247X, H265R G279C) and one in exon 1 (Y86D) - and a previously described mutation in exon 4 (R241X). These five EPM2A mutations were found in four index cases and affected relatives. Patient 1 with classic LD was doubly heterozygous for H265R and R241X in exon 4; while Patient 2, who also had classic LD, was homozygous for Q247X in exon 4. Patient 3 with classic LD was homozygous for Y86D in exon 1, but the same mutation in his affected brother manifested an atypical earlier childhood onset. For the first time, we describe a later onset and slower progression of EPM2A-deficient LD seen in Patient 4 and her three sisters who were doubly heterozygous for R241X and G279C in exon 4. In these sisters, seizures started later at 21 to 28 years of age and progressed slowly with patients living beyond 30 years of age. Our observations suggest that variations in phenotypes of EPM2A-deficient LD, like an earlier childhood or adolescent or later adult onset with a rapid or slower course, depend on a second modifying factor separate from pathogenicity or exon location of EPM2A mutations. A modifying gene amongst the patient's genetic background or environmental factors may condition age of onset and rapid or slow progression of LD.
authors.affiliation: Neurogenetics and Molecular Biology Department, National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Jara-Prado
authors.affiliation: Neurogenetics and Molecular Biology Department, National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico.
authors.forename: Adriana
authors.initials: A
authors.lastname: Ochoa
authors.affiliation: Neurogenetics and Molecular Biology Department, National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico.
authors.forename: María Elisa
authors.initials: ME
authors.lastname: Alonso
authors.affiliation: Neurogenetics and Molecular Biology Department, National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico.
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Lima Villeda
authors.affiliation: Experimental Pathology laboratory, National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico.
authors.forename: Francisca
authors.initials: F
authors.lastname: Fernández-Valverde
authors.affiliation: Experimental Pathology laboratory, National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico.
authors.forename: Luis
authors.initials: L
authors.lastname: Ruano-Calderón
authors.affiliation: Experimental Pathology laboratory, National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico.
authors.forename: Steven
authors.initials: S
authors.lastname: Vargas-Cañas
authors.affiliation: David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Reyna M
authors.initials: RM
authors.lastname: Durón
authors.affiliation: Epilepsy Genetics/Genomics Laboratories and Epilepsy Center of Excellence, Neurology and Research Services, VA GLAHS, Los Angeles, CA, USA; David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Antonio V
authors.initials: AV
authors.lastname: Delgado-Escueta
authors.affiliation: Epilepsy Clinic and Professor of Mexico City, Mexico. Electronic address: imartinez@innn.edu.mx.
authors.forename: Iris E
authors.initials: IE
authors.lastname: Martínez-Juárez
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis; D004569:Electroencephalography; D005192:Family Health; D005260:Female; D006801:Humans; D020192:Lafora Disease / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics*
chemical_list: D054558:Protein Tyrosine Phosphatases, Non-Receptor; C114990:EPM2A protein, human
keywords: Atypical phenotype; EPM2A; Lafora disease; Late onset; Slow progression