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Title: Kufs disease due to mutation of CLN6: clinical, pathological and molecular genetic features.
Austin Authors: Berkovic, Samuel F ;Oliver, Karen L;Canafoglia, Laura;Krieger, Penina;Damiano, John A;Hildebrand, Michael S ;Morbin, Michela;Vears, Danya F;Sofia, Vito;Giuliano, Loretta;Garavaglia, Barbara;Simonati, Alessandro;Santorelli, Filippo M;Gambardella, Antonio;Labate, Angelo;Belcastro, Vincenzo;Castellotti, Barbara;Ozkara, Cigdem;Zeman, Adam;Rankin, Julia;Mole, Sara E;Aguglia, Umberto;Farrell, Michael;Rajagopalan, Sulekha;McDougall, Alan;Brammah, Susan;Andermann, Frederick;Andermann, Eva;Dahl, Hans-Henrik M;Franceschetti, Silvana;Carpenter, Stirling
Affiliation: Department of Neuropathology, Beaumont Hospital, Dublin 9, Ireland
Epilepsy Research Group, Montreal Neurological Hospital and Institute, Montreal, Quebec, Canada
Institute of Molecular Bioimaging and Physiology of the National Research Council (IBFM-CNR) Germaneto, CZ, Italy
Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Departments of Neurology and Neurosurgery and Paediatrics, McGill University, Montreal, Quebec, Canada
Department of Medical and Surgical Sciences, University Magna Græcia Catanzaro, Italy
Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Central Sydney Electron Microscope Unit, Concord Repatriation General Hospital, Concord, New South Wales, Australia
Department of Neurology, Liverpool Hospital, Liverpool, New South Wales Australia
Department of Clinical Genetics, Liverpool Hospital, Liverpool, New South Wales Australia
MRC Laboratory for Molecular Cell Biology and UCL GOS Institute of Child Health, Department of Genetics, Evolution and Environment, University College London, London, UK
Clinical Genetics, Royal Devon and Exeter Hospital, Gladstone Road, Exeter, UK
University of Exeter Medical School, St Luke's Campus, Magdalen Road, Exeter EX1 2LU, UK
Department of Neurophysiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Department of Medical and Surgical Sciences and Advanced Technologies "G.F. Ingrassia", Section of Neurosciences, University of Catania, Catania, Italy
Medical Genetics and Neurogenetics Unit, Bicocca Laboratories, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy
Department of Neuroscience, Biomedicine, Movement-Neurology and Neuropathology, Policlinico GB Rossi, P.le LA Scuro, Verona, Italy
Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa, Italy
Institute of Neurology, University Magna Græcia Catanzaro, Italy; Institute of Molecular Bioimaging and Physiology of the National Research Council (IBFM-CNR) Germaneto, CZ, Italy
Neurology Unit, S. Anna Hospital, Como, Italy
Unit Genetics of Neurodegenerative and Metabolic Diseases, IRCCS Foundation C. Besta Neurological Institute, Milan, Italy
Istanbul University-Cerrahpasa, Medical Faculty, Department of Neurology, Istanbul, Turkey
Department of Neurophysiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Consultant in Neuropathology, Centro Hospitalar São João, Porto, Portugal
Issue Date: 1-Jan-2019
Publication information: Brain : a journal of neurology 2019; 142(1): 59-69
Abstract: Kufs disease is the major adult form of neuronal ceroid lipofuscinosis, but is rare and difficult to diagnose. Diagnosis was traditionally dependent on the demonstration of characteristic storage material, but distinction from normal age-related accumulation of lipofuscin can be challenging. Mutation of CLN6 has emerged as the most important cause of recessive Kufs disease but, remarkably, is also responsible for variant late infantile ceroid lipofuscinosis. Here we provide a detailed description of Kufs disease due to CLN6 pathogenic variants. We studied 20 cases of Kufs disease with CLN6 pathogenic variants from 13 unrelated families. Mean age of onset was 28 years (range 12-51) with bimodal peaks in teenage and early adult life. The typical presentation was of progressive myoclonus epilepsy with debilitating myoclonic seizures and relatively infrequent tonic-clonic seizures. Patients became wheelchair-bound with a mean 12 years post-onset. Ataxia was the most prominent motor feature. Dementia appeared to be an invariable accompaniment, although it could take a number of years to manifest and occasionally cognitive impairment preceded myoclonic seizures. Patients were usually highly photosensitive on EEG. MRI showed progressive cerebral and cerebellar atrophy. The median survival time was 26 years from disease onset. Ultrastructural examination of the pathology revealed fingerprint profiles as the characteristic inclusions, but they were not reliably seen in tissues other than brain. Curvilinear profiles, which are seen in the late infantile form, were not a feature. Of the 13 unrelated families we observed homozygous CLN6 pathogenic variants in four and compound heterozygous variants in nine. Compared to the variant late infantile form, there was a lower proportion of variants that predicted protein truncation. Certain heterozygous missense variants in the same amino acid position were found in both variant late infantile and Kufs disease. There was a predominance of cases from Italy and surrounding regions; this was partially explained by the discovery of three founder pathogenic variants. Clinical distinction of type A (progressive myoclonus epilepsy) and type B (dementia with motor disturbance) Kufs disease was supported by molecular diagnoses. Type A is usually caused by recessive pathogenic variants in CLN6 or dominant variants in DNAJC5. Type B Kufs is usually associated with recessive CTSF pathogenic variants. The diagnosis of Kufs remains challenging but, with the availability of genetic diagnosis, this will largely supersede the use of diagnostic biopsies, particularly as biopsies of peripheral tissues has unsatisfactory sensitivity and specificity.
DOI: 10.1093/brain/awy297
ORCID: 0000-0003-4580-841X
PubMed URL: 30561534
Type: Journal Article
Appears in Collections:Journal articles

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