TY - JOUR
T1 - Neurophysiological and Genetic Findings in Patients With Juvenile Myoclonic Epilepsy
AU - Stefani, Stefani
AU - Kousiappa, Ioanna
AU - Nicolaou, Nicoletta
AU - Papathanasiou, Eleftherios S.
AU - Oulas, Anastasis
AU - Fanis, Pavlos
AU - Neocleous, Vassos
AU - Phylactou, Leonidas A.
AU - Spyrou, George M.
AU - Papacostas, Savvas S.
N1 - Funding Information:
We thank the patients with epilepsy and their relatives for participating in this research. Special thanks to the patients with epilepsy and the controls who participated also in the Epi25 Collaborative (Cyprus cohort). We also thank the Epi25 Collaborative (principal investigators, local staff from individual cohorts, and all of the patients with epilepsy who participated in the study) for making possible this global collaboration and resource to advance epilepsy genetics research. This work is part of the Centers for Common Disease Genomics (CCDG) program, funded by the National Human Genome Research Institute (NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI). CCDG-funded Epi25 research activities at the Broad Institute, including genomic data generation in the Broad Genomics Platform, are supported by NHGRI grant UM1 HG008895 (PIs: Eric Lander, Stacey Gabriel, Mark Daly, and Sekar Kathiresan). The Genome Sequencing Program efforts were also supported by NHGRI grant 5U01HG009088-02. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We also thank the Stanley Center for Psychiatric Research at the Broad Institute for supporting the genomic data generation efforts. Funding. SS and SP were funded by the TELETHON (Grant No. 33173158)/Cyprus Institute of Neurology and Genetics. AO and GS were funded by the European Commission Research Executive Agency Grant BIORISE (Grant No. 669026), under the Spreading Excellence, Widening Participation, Science with and for Society Framework.
Publisher Copyright:
© Copyright © 2020 Stefani, Kousiappa, Nicolaou, Papathanasiou, Oulas, Fanis, Neocleous, Phylactou, Spyrou and Papacostas.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/8/20
Y1 - 2020/8/20
N2 - Objective: Transcranial magnetic stimulation (TMS), a non-invasive procedure, stimulates the cortex evaluating the central motor pathways. The response is called motor evoked potential (MEP). Polyphasia results when the response crosses the baseline more than twice (zero crossing). Recent research shows MEP polyphasia in patients with generalized genetic epilepsy (GGE) and their first-degree relatives compared with controls. Juvenile Myoclonic Epilepsy (JME), a GGE type, is not well studied regarding polyphasia. In our study, we assessed polyphasia appearance probability with TMS in JME patients, their healthy first-degree relatives and controls. Two genetic approaches were applied to uncover genetic association with polyphasia. Methods: 20 JME patients, 23 first-degree relatives and 30 controls underwent TMS, obtaining 10–15 MEPs per participant. We evaluated MEP mean number of phases, proportion of MEP trials displaying polyphasia for each subject and variability between groups. Participants underwent whole exome sequencing (WES) via trio-based analysis and two-case scenario. Extensive bioinformatics analysis was applied. Results: We identified increased polyphasia in patients (85%) and relatives (70%) compared to controls (47%) and significantly higher mean number of zero crossings (i.e., occurrence of phases) (patients 1.49, relatives 1.46, controls 1.22; p < 0.05). Trio-based analysis revealed a candidate polymorphism, p.Glu270del,in SYT14 (Synaptotagmin 14), in JME patients and their relatives presenting polyphasia. Sanger sequencing analysis in remaining participants showed no significant association. In two-case scenario, a machine learning approach was applied in variants identified from odds ratio analysis and risk prediction scores were obtained for polyphasia. The results revealed 61 variants of which none was associated with polyphasia. Risk prediction scores indeed showed lower probability for non-polyphasic subjects on having polyphasia and higher probability for polyphasic subjects on having polyphasia. Conclusion: Polyphasia was present in JME patients and relatives in contrast to controls. Although no known clinical symptoms are linked to polyphasia this neurophysiological phenomenon is likely due to common cerebral electrophysiological abnormality. We did not discover direct association between genetic variants obtained and polyphasia. It is likely these genetic traits alone cannot provoke polyphasia, however, this predisposition combined with disturbed brain-electrical activity and tendency to generate seizures may increase the risk of developing polyphasia, mainly in patients and relatives.
AB - Objective: Transcranial magnetic stimulation (TMS), a non-invasive procedure, stimulates the cortex evaluating the central motor pathways. The response is called motor evoked potential (MEP). Polyphasia results when the response crosses the baseline more than twice (zero crossing). Recent research shows MEP polyphasia in patients with generalized genetic epilepsy (GGE) and their first-degree relatives compared with controls. Juvenile Myoclonic Epilepsy (JME), a GGE type, is not well studied regarding polyphasia. In our study, we assessed polyphasia appearance probability with TMS in JME patients, their healthy first-degree relatives and controls. Two genetic approaches were applied to uncover genetic association with polyphasia. Methods: 20 JME patients, 23 first-degree relatives and 30 controls underwent TMS, obtaining 10–15 MEPs per participant. We evaluated MEP mean number of phases, proportion of MEP trials displaying polyphasia for each subject and variability between groups. Participants underwent whole exome sequencing (WES) via trio-based analysis and two-case scenario. Extensive bioinformatics analysis was applied. Results: We identified increased polyphasia in patients (85%) and relatives (70%) compared to controls (47%) and significantly higher mean number of zero crossings (i.e., occurrence of phases) (patients 1.49, relatives 1.46, controls 1.22; p < 0.05). Trio-based analysis revealed a candidate polymorphism, p.Glu270del,in SYT14 (Synaptotagmin 14), in JME patients and their relatives presenting polyphasia. Sanger sequencing analysis in remaining participants showed no significant association. In two-case scenario, a machine learning approach was applied in variants identified from odds ratio analysis and risk prediction scores were obtained for polyphasia. The results revealed 61 variants of which none was associated with polyphasia. Risk prediction scores indeed showed lower probability for non-polyphasic subjects on having polyphasia and higher probability for polyphasic subjects on having polyphasia. Conclusion: Polyphasia was present in JME patients and relatives in contrast to controls. Although no known clinical symptoms are linked to polyphasia this neurophysiological phenomenon is likely due to common cerebral electrophysiological abnormality. We did not discover direct association between genetic variants obtained and polyphasia. It is likely these genetic traits alone cannot provoke polyphasia, however, this predisposition combined with disturbed brain-electrical activity and tendency to generate seizures may increase the risk of developing polyphasia, mainly in patients and relatives.
KW - genetics
KW - juvenile myoclonic epilepsy
KW - neurophysiology
KW - polymorphism
KW - polyphasia
KW - transcranial magnetic stimulation
KW - whole exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85090188021&partnerID=8YFLogxK
U2 - 10.3389/fnint.2020.00045
DO - 10.3389/fnint.2020.00045
M3 - Article
AN - SCOPUS:85090188021
SN - 1662-5145
VL - 14
JO - Frontiers in Integrative Neuroscience
JF - Frontiers in Integrative Neuroscience
M1 - 45
ER -