Subtle Brain Developmental Abnormalities in the Pathogenesis of Juvenile Myoclonic Epilepsy
Juvenile myoclonic epilepsy (JME), a lifelong disorder that starts during adolescence, is the most common of genetic generalized epilepsy syndromes. JME is characterized by awakening myoclonic jerks and myoclonic-tonic-clonic (m-t-c) grand mal convulsions. Unfortunately, one third of JME patients ha...
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doaj-6cafc5c2679a4c95a646216250a0815e2020-11-25T02:05:23ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022019-09-011310.3389/fncel.2019.00433465519Subtle Brain Developmental Abnormalities in the Pathogenesis of Juvenile Myoclonic EpilepsyMaxime Gilsoul0Maxime Gilsoul1Maxime Gilsoul2Thierry Grisar3Antonio V. Delgado-Escueta4Antonio V. Delgado-Escueta5Laurence de Nijs6Laurence de Nijs7Bernard Lakaye8Bernard Lakaye9Bernard Lakaye10GIGA-Stem Cells, University of Liège, Liège, BelgiumGIGA-Neurosciences, University of Liège, Liège, BelgiumGENESS International Consortium, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United StatesGENESS International Consortium, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United StatesGENESS International Consortium, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United StatesEpilepsy Genetics/Genomics Lab, Neurology and Research Services, VA Greater Los Angeles Healthcare System, Los Angeles, CA, United StatesGENESS International Consortium, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United StatesSchool for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, NetherlandsGIGA-Stem Cells, University of Liège, Liège, BelgiumGIGA-Neurosciences, University of Liège, Liège, BelgiumGENESS International Consortium, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United StatesJuvenile myoclonic epilepsy (JME), a lifelong disorder that starts during adolescence, is the most common of genetic generalized epilepsy syndromes. JME is characterized by awakening myoclonic jerks and myoclonic-tonic-clonic (m-t-c) grand mal convulsions. Unfortunately, one third of JME patients have drug refractory m-t-c convulsions and these recur in 70–80% who attempt to stop antiepileptic drugs (AEDs). Behavioral studies documented impulsivity, but also impairment of executive functions relying on organization and feedback, which points to prefrontal lobe dysfunction. Quantitative voxel-based morphometry (VBM) revealed abnormalities of gray matter (GM) volumes in cortical (frontal and parietal) and subcortical structures (thalamus, putamen, and hippocampus). Proton magnetic resonance spectroscopy (MRS) found evidence of dysfunction of thalamic neurons. White matter (WM) integrity was disrupted in corpus callosum and frontal WM tracts. Magnetic resonance imaging (MRI) further unveiled anomalies in both GM and WM structures that were already present at the time of seizure onset. Aberrant growth trajectories of brain development occurred during the first 2 years of JME diagnosis. Because of genetic origin, disease causing variants were sought, first by positional cloning, and most recently, by next generation sequencing. To date, only six genes harboring pathogenic variants (GABRA1, GABRD, EFHC1, BRD2, CASR, and ICK) with Mendelian and complex inheritance and covering a limited proportion of the world population, are considered as major susceptibility alleles for JME. Evidence on the cellular role, developmental and cell-type expression profiles of these six diverse JME genes, point to their pathogenic variants driving the first steps of brain development when cell division, expansion, axial, and tangential migration of progenitor cells (including interneuron cortical progenitors) sculpture subtle alterations in brain networks and microcircuits during development. These alterations may explain “microdysgenesis” neuropathology, impulsivity, executive dysfunctions, EEG polyspike waves, and awakening m-t-c convulsions observed in JME patients.https://www.frontiersin.org/article/10.3389/fncel.2019.00433/fulldevelopmentjuvenile myoclonic epilepsybrain imaginggenesphysioparhology |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Maxime Gilsoul Maxime Gilsoul Maxime Gilsoul Thierry Grisar Antonio V. Delgado-Escueta Antonio V. Delgado-Escueta Laurence de Nijs Laurence de Nijs Bernard Lakaye Bernard Lakaye Bernard Lakaye |
spellingShingle |
Maxime Gilsoul Maxime Gilsoul Maxime Gilsoul Thierry Grisar Antonio V. Delgado-Escueta Antonio V. Delgado-Escueta Laurence de Nijs Laurence de Nijs Bernard Lakaye Bernard Lakaye Bernard Lakaye Subtle Brain Developmental Abnormalities in the Pathogenesis of Juvenile Myoclonic Epilepsy Frontiers in Cellular Neuroscience development juvenile myoclonic epilepsy brain imaging genes physioparhology |
author_facet |
Maxime Gilsoul Maxime Gilsoul Maxime Gilsoul Thierry Grisar Antonio V. Delgado-Escueta Antonio V. Delgado-Escueta Laurence de Nijs Laurence de Nijs Bernard Lakaye Bernard Lakaye Bernard Lakaye |
author_sort |
Maxime Gilsoul |
title |
Subtle Brain Developmental Abnormalities in the Pathogenesis of Juvenile Myoclonic Epilepsy |
title_short |
Subtle Brain Developmental Abnormalities in the Pathogenesis of Juvenile Myoclonic Epilepsy |
title_full |
Subtle Brain Developmental Abnormalities in the Pathogenesis of Juvenile Myoclonic Epilepsy |
title_fullStr |
Subtle Brain Developmental Abnormalities in the Pathogenesis of Juvenile Myoclonic Epilepsy |
title_full_unstemmed |
Subtle Brain Developmental Abnormalities in the Pathogenesis of Juvenile Myoclonic Epilepsy |
title_sort |
subtle brain developmental abnormalities in the pathogenesis of juvenile myoclonic epilepsy |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cellular Neuroscience |
issn |
1662-5102 |
publishDate |
2019-09-01 |
description |
Juvenile myoclonic epilepsy (JME), a lifelong disorder that starts during adolescence, is the most common of genetic generalized epilepsy syndromes. JME is characterized by awakening myoclonic jerks and myoclonic-tonic-clonic (m-t-c) grand mal convulsions. Unfortunately, one third of JME patients have drug refractory m-t-c convulsions and these recur in 70–80% who attempt to stop antiepileptic drugs (AEDs). Behavioral studies documented impulsivity, but also impairment of executive functions relying on organization and feedback, which points to prefrontal lobe dysfunction. Quantitative voxel-based morphometry (VBM) revealed abnormalities of gray matter (GM) volumes in cortical (frontal and parietal) and subcortical structures (thalamus, putamen, and hippocampus). Proton magnetic resonance spectroscopy (MRS) found evidence of dysfunction of thalamic neurons. White matter (WM) integrity was disrupted in corpus callosum and frontal WM tracts. Magnetic resonance imaging (MRI) further unveiled anomalies in both GM and WM structures that were already present at the time of seizure onset. Aberrant growth trajectories of brain development occurred during the first 2 years of JME diagnosis. Because of genetic origin, disease causing variants were sought, first by positional cloning, and most recently, by next generation sequencing. To date, only six genes harboring pathogenic variants (GABRA1, GABRD, EFHC1, BRD2, CASR, and ICK) with Mendelian and complex inheritance and covering a limited proportion of the world population, are considered as major susceptibility alleles for JME. Evidence on the cellular role, developmental and cell-type expression profiles of these six diverse JME genes, point to their pathogenic variants driving the first steps of brain development when cell division, expansion, axial, and tangential migration of progenitor cells (including interneuron cortical progenitors) sculpture subtle alterations in brain networks and microcircuits during development. These alterations may explain “microdysgenesis” neuropathology, impulsivity, executive dysfunctions, EEG polyspike waves, and awakening m-t-c convulsions observed in JME patients. |
topic |
development juvenile myoclonic epilepsy brain imaging genes physioparhology |
url |
https://www.frontiersin.org/article/10.3389/fncel.2019.00433/full |
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