Progressive Myoclonus Epilepsies: Diagnostic Yield With Next-Generation Sequencing in Previously Unsolved Cases
Laura Canafoglia1, Silvana Franceschetti1, Antonio Gambardella1
1Neurophysiopathology (L.C., S.F.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan; Department of Medical and Surgical Sciences (A.G., E.F.), Magna Graecia University, Catanzaro; IRCCS Istituto "G. Gaslini" (P.S., F.Z.), Genova; Department of Neurosciences (P.S., F.Z.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genova; Department of Human Neurosciences (T.G., C.D.B., M.F.), Sapienza University of Rome, Viale dell'Università, Rome; IRCCS Istituto delle Scienze Neurologiche di Bologna (P.T., L.L.), Epilepsy Center, Bologna; Department of Biomedical and Neuromotor Sciences (P.T., L.L.), University of Bologna; IRCCS Istituto delle Scienze Neurologiche di Bologna (R.M., P.R.), Unit of Neurology, Bellaria Hospital, Bologna; Regional Epilepsy Centre (E.F.), BMM Great Metropolitan Hospital, Via Melacrino, Reggio Calabria; Department of Pediatric Neuroscience (T.G.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan; Epilepsy Center (A.M.), Department of Clinical and Experimental Medicine, AOU Policlinico "G. Martino", Messina; Department of Neuroscience (A.F.), Reproductive, and Odontostomatological Sciences, University of Naples Federico II, Naples; Department of Basic Medical Sciences (A.L.N.), Neuroscience and Sense Organs, University of Bari "Aldo Moro", Piazza Giulio Cesare 11, Bari ; Perugia Hospital (T.A.C,), Neurophysiopathology Unit, Azienda Ospedaliera di Perugia, S. Andrea delle Fratte, Perugia; Unit of Genetics of Neurodegenerative and Metabolic Diseases (B.C., C.G.), IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Population Health and Immunity Division (M.B., K.L.O.), The Walter and Eliza Hall Institute of Medical Research, Parkville; Department of Medical Biology (M.B., K.L.O.), The University of Melbourne; Folkhälsan Research Center (C.C., A.E.L.); Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Finland; and Epilepsy Research Centre (K.L.O., S.F.B), Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
Background And Objectives:
To assess the current diagnostic yield of genetic testing for the progressive myoclonus epilepsies (PMEs) of an Italian series described in 2014 where Unverricht-Lundborg and Lafora diseases accounted for ∼50% of the cohort.
Methods:
Of 47/165 unrelated patients with PME of indeterminate genetic origin, 38 underwent new molecular evaluations. Various next-generation sequencing (NGS) techniques were applied including gene panel analysis (n = 7) and/or whole-exome sequencing (WES) (WES singleton n = 29, WES trio n = 7, and WES sibling n = 4). In 1 family, homozygosity mapping was followed by targeted NGS. Clinically, the patients were grouped in 4 phenotypic categories: "Unverricht-Lundborg disease-like PME," "late-onset PME," "PME plus developmental delay," and "PME plus dementia."
Results:
Sixteen of 38 (42%) unrelated patients reached a positive diagnosis, increasing the overall proportion of solved families in the total series from 72% to 82%. Likely pathogenic variants were identified in NEU1 (2 families), CERS1 (1 family), and in 13 nonfamilial patients in KCNC1 (3), DHDDS (3), SACS, CACNA2D2, STUB1, AFG3L2, CLN6, NAXE, and CHD2. Across the different phenotypic categories, the diagnostic rate was similar, and the same gene could be found in different phenotypic categories.
Discussion:
The application of NGS technology to unsolved patients with PME has revealed a collection of very rare genetic causes. Pathogenic variants were detected in both established PME genes and in genes not previously associated with PME, but with progressive ataxia or with developmental encephalopathies. With a diagnostic yield >80%, PME is one of the best genetically defined epilepsy syndromes.
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