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From the Program in Genetics and Genomic Biology (H.L., J.T., X.C.Z., S.P., L.I., B.A.M.), Hospital for Sick Children, Toronto, Ontario, Canada; Folkhälsan Institute of Genetics and Program in Molecular Medicine (H.L.), University of Helsinki, Finland; Laboratory of Medical Genetics (L.I.), Mauro Baschirotto Institute for Rare Diseases, Vicenza, Department of Clinical Neurophysiology, National Neurologic Institute C. Besta (S.F.), Milan, and Institute of Neurology (F.Z.), University Magna Graecia, Cantanzaro, Italy; Neurology Service (M.Y.), Specialties Hospital, Rabat, Morocco; Department of Pediatrics and Adult and Pediatric Epilepsy Program (M.A.M.), American University of Beirut Medical Center, Lebanon; and Sobell Department of Motor Neuroscience and Movement Disorders (N.P.Q.), Institute of Neurology, London, UK.
Address correspondence and reprint requests to Dr Minassian, Program in Genetics and Genomic Biology and Division of Neurology, Hospital for Sick Children, 555 University Ave., Toronto, Ontario, Canada M5G 1X8; e-mail: bminass{at}sickkids.ca
Lafora disease (LD) can be diagnosed by skin biopsy, but this approach has both false negatives and false positives. Biopsies of other organs can also be diagnostic but are more invasive. Genetic diagnosis is also possible but can be inconclusive, for example, in patients with only one heterozygous EPM2A mutation and patients with apparently homozygous EPM2B mutations where one parent is not a carrier of the mutation. We sought to identify occult mutations and clarify the genotypes and confirm the diagnosis of LD in patients with apparent nonrecessive disease inheritance. We used single nucleotide polymorphism, quantitative PCR, and fluorescent in situ hybridization analyses. We identified large EPM2A and EPM2B deletions undetectable by PCR in the heterozygous state and describe simple methods for their routine detection. We report a coding sequence change in several patients and describe why the pathogenic role of this change remains unclear. We confirm that adult-onset LD is due to EPM2B mutations. Finally, we report major intrafamilial heterogeneity in age at onset in LD.
Editorial, see page 975
Funded by the Canadian Institutes of Health Research (CIHR). B.A.M. holds the Canada Research Chair in Pediatric Neurogenetics. H.L. is supported by the Academy of Finland, Biocentrum Helsinki, the Sigrid Juselius, and the Emil Aaltonen Foundations, Finland. J.T. is supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) Graduate Scholarship. L.I. is supported by a Marie Curie European Reintegration Grant within the 6th European Community Framework Programme.
Disclosure: The authors report no conflicts of interest.
Received May 11, 2006. Accepted in final form January 9, 2007.
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