Subtle Brain Developmental Abnormalities in the Pathogenesis of Juvenile Myoclonic Epilepsy

Maxime Gilsoul, Thierry Grisar, Antonio V. Delgado-Escueta, Laurence de Nijs, Bernard Lakaye*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

12 Citations (Web of Science)

Abstract

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 Frontiers during development. These alterations may explain "microdysgenesis" neuropathology, impulsivity, executive dysfunctions, EEG polyspike waves, and awakening m-t-c convulsions observed in JME patients.

Original languageEnglish
Article number433
Number of pages15
JournalFrontiers in Cellular Neuroscience
Volume13
DOIs
Publication statusPublished - 27 Sep 2019

Keywords

  • development
  • juvenile myoclonic epilepsy
  • brain imaging
  • genes
  • physioparhology
  • IDIOPATHIC-GENERALIZED EPILEPSY
  • CALCIUM SENSING RECEPTOR
  • MAGNETIC-RESONANCE-SPECTROSCOPY
  • INTESTINAL-CELL KINASE
  • WHITE-MATTER ABNORMALITIES
  • TEMPORAL-LOBE
  • PSYCHIATRIC-DISORDERS
  • PERSONALITY-TRAITS
  • MICE LACKING
  • FUNCTIONAL CONNECTIVITY

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