Kufs disease, the major adult form of neuronal ceroid lipofuscinosis, caused by mutations in CLN6 |
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| Authors: | Arsov Todor Smith Katherine R Damiano John Franceschetti Silvana Canafoglia Laura Bromhead Catherine J Andermann Eva Vears Danya F Cossette Patrick Rajagopalan Sulekha McDougall Alan Sofia Vito Farrell Michael Aguglia Umberto Zini Andrea Meletti Stefano Morbin Michela Mullen Saul Andermann Frederick Mole Sara E Bahlo Melanie Berkovic Samuel F |
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| Institution: | 1Epilepsy Research Center, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia;2Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia;3Unit of Neurophysiopathology, IRCCS Foundation, C. Besta Neurological Institute, 20133 Milan, Italy;4Departments of Neurology and Neurosurgery and Human Genetics, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec H3A 2B4, Canada;5Département de Médecine, Université de Montréal, CHUM-Hôpital Notre-Dame, Montréal, Québec H2L 4M1, Canada;6Department of Clinical Genetics, Liverpool Hospital, Liverpool, New South Wales 1871, Australia;7Department of Neurology, Liverpool Hospital, Liverpool, New South Wales 1871, Australia;8Department of Neuroscience, University of Catania, 95123 Catania, Italy;9Department of Neuropathology, Beaumont Hospital, Dublin 9, Ireland;10Institute of Neurology, University Magna Græcia, Viale Europa, 88100 Catanzaro, Italy;11Department of Neuroscience, University of Modena and Reggio Emilia, Nuovo Ospedale Civile, 41100 Modena, Italy;12Neuropathology-Neurology 5, IRCCS Foundation, C. Besta Neurological Institute, 20133 Milan, Italy;13Departments of Neurology and Neurosurgery and Pediatrics, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec H3A 2B4, Canada;14Medical Research Council Laboratory for Molecular Cell Biology, Molecular Medicine Unit, Institute of Child Health and Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK;15Department of Mathematics and Statistics, University of Melbourne, Victoria 3010, Australia |
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| Abstract: | The molecular basis of Kufs disease is unknown, whereas a series of genes accounting for most of the childhood-onset forms of neuronal ceroid lipofuscinosis (NCL) have been identified. Diagnosis of Kufs disease is difficult because the characteristic lipopigment is largely confined to neurons and can require a brain biopsy or autopsy for final diagnosis. We mapped four families with Kufs disease for whom there was good evidence of autosomal-recessive inheritance and found two peaks on chromosome 15. Three of the families were affected by Kufs type A disease and presented with progressive myoclonus epilepsy, and one was affected by type B (presenting with dementia and motor system dysfunction). Sequencing of a candidate gene in one peak shared by all four families identified no mutations, but sequencing of CLN6, found in the second peak and shared by only the three families affected by Kufs type A disease, revealed pathogenic mutations in all three families. We subsequently sequenced CLN6 in eight other families, three of which were affected by recessive Kufs type A disease. Mutations in both CLN6 alleles were found in the three type A cases and in one family affected by unclassified Kufs disease. Mutations in CLN6 are the major cause of recessive Kufs type A disease. The phenotypic differences between variant late-infantile NCL, previously found to be caused by CLN6, and Kufs type A disease are striking; there is a much later age at onset and lack of visual involvement in the latter. Sequencing of CLN6 will provide a simple diagnostic strategy in this disorder, in which definitive identification usually requires invasive biopsy. |
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