Jelle van den Ameele1, Ivana Jedlickova2, Anna Pristoupilova2, Anne Sieben2, Sara Van Mossevelde2, Chantal Ceuterick-de Groote2, Helena Hůlková2, Radoslav Matej2, Alfred Meurs2, Christine Van Broeckhoven2, Samuel F Berkovic2, Patrick Santens2, Stanislav Kmoch2, Bart Dermaut1. 1. From the Department of Neurology (J.v.d.A., A.S., A.M., P.S., B.D.) and Center for Medical Genetics (B.D.), Ghent University Hospital, Belgium; Institute for Inherited Metabolic Disorders (I.J., A.P., H.H., S.K.), Prague, First Faculty of Medicine, Charles University in Prague, Czech Republic; Neurodegenerative Brain Diseases Group (A.S., S.V.M., C.V.B.), Center for Molecular Neurology, VIB; Neuropathology and Laboratory of Neurochemistry and Behavior (A.S.), Laboratory of Neurogenetics (S.V.M., C.V.B.), and Laboratory of Neuromuscular Pathology and Translational Neurosciences (C.C.-d.G.), Institute Born-Bunge, University of Antwerp, Belgium; Institute of Pathology, First Faculty of Medicine (H.H., R.M.), Charles University and General University Hospital; Department of Pathology and Molecular Medicine (R.M.), National Reference Laboratory for Diagnostics of Human Prion Diseases, Thomayer Hospital, Prague, Czech Republic; Epilepsy Research Centre, Department of Medicine (S.F.B.), University of Melbourne, Austin Health, Heidelberg, Australia; and Inserm U1167 (B.D.), Laboratoire d'Excellence Distalz, Institut Pasteur de Lille, Longevity Research Center, Université de Lille, France. J.v.d.A. is currently affiliated with the Department of Clinical Neurosciences and WT/CRUK Gurdon Institute, University of Cambridge, UK. jv361@cam.ac.uk bart.dermaut@ugent.be. 2. From the Department of Neurology (J.v.d.A., A.S., A.M., P.S., B.D.) and Center for Medical Genetics (B.D.), Ghent University Hospital, Belgium; Institute for Inherited Metabolic Disorders (I.J., A.P., H.H., S.K.), Prague, First Faculty of Medicine, Charles University in Prague, Czech Republic; Neurodegenerative Brain Diseases Group (A.S., S.V.M., C.V.B.), Center for Molecular Neurology, VIB; Neuropathology and Laboratory of Neurochemistry and Behavior (A.S.), Laboratory of Neurogenetics (S.V.M., C.V.B.), and Laboratory of Neuromuscular Pathology and Translational Neurosciences (C.C.-d.G.), Institute Born-Bunge, University of Antwerp, Belgium; Institute of Pathology, First Faculty of Medicine (H.H., R.M.), Charles University and General University Hospital; Department of Pathology and Molecular Medicine (R.M.), National Reference Laboratory for Diagnostics of Human Prion Diseases, Thomayer Hospital, Prague, Czech Republic; Epilepsy Research Centre, Department of Medicine (S.F.B.), University of Melbourne, Austin Health, Heidelberg, Australia; and Inserm U1167 (B.D.), Laboratoire d'Excellence Distalz, Institut Pasteur de Lille, Longevity Research Center, Université de Lille, France. J.v.d.A. is currently affiliated with the Department of Clinical Neurosciences and WT/CRUK Gurdon Institute, University of Cambridge, UK.
Abstract
BACKGROUND: The progressive myoclonic epilepsies (PME) are a heterogeneous group of disorders in which a specific diagnosis cannot be made in a subset of patients, despite exhaustive investigation. C9orf72 repeat expansions are emerging as an important causal factor in several adult-onset neurodegenerative disorders, in particular frontotemporal lobar degeneration and amyotrophic lateral sclerosis. An association with PME has not been reported previously. OBJECTIVE: To identify the causative mutation in a Belgian family where the proband had genetically unexplained PME. RESULTS: We report a 33-year old woman who had epilepsy since the age of 15 and then developed progressive cognitive deterioration and multifocal myoclonus at the age of 18. The family history suggested autosomal dominant inheritance of psychiatric disorders, epilepsy, and dementia. Thorough workup for PME including whole exome sequencing did not reveal an underlying cause, but a C9orf72 repeat expansion was found in our patient and affected relatives. Brain biopsy confirmed the presence of characteristic p62-positive neuronal cytoplasmic inclusions. CONCLUSION: C9orf72 mutation analysis should be considered in patients with PME and psychiatric disorders or dementia, even when the onset is in late childhood or adolescence.
BACKGROUND: The progressive myoclonic epilepsies (PME) are a heterogeneous group of disorders in which a specific diagnosis cannot be made in a subset of patients, despite exhaustive investigation. C9orf72 repeat expansions are emerging as an important causal factor in several adult-onset neurodegenerative disorders, in particular frontotemporal lobar degeneration and amyotrophic lateral sclerosis. An association with PME has not been reported previously. OBJECTIVE: To identify the causative mutation in a Belgian family where the proband had genetically unexplained PME. RESULTS: We report a 33-year old woman who had epilepsy since the age of 15 and then developed progressive cognitive deterioration and multifocal myoclonus at the age of 18. The family history suggested autosomal dominant inheritance of psychiatric disorders, epilepsy, and dementia. Thorough workup for PME including whole exome sequencing did not reveal an underlying cause, but a C9orf72 repeat expansion was found in our patient and affected relatives. Brain biopsy confirmed the presence of characteristic p62-positive neuronal cytoplasmic inclusions. CONCLUSION:C9orf72 mutation analysis should be considered in patients with PME and psychiatric disorders or dementia, even when the onset is in late childhood or adolescence.