Institut de Neurobiologie de la Méditerranée (INMED) P. Szepetowski Institut de Neurobiologie de la Méditerranée (INMED) INSERM U901 Epilepsies humaines et gènes, vingt ans après : points clés et points obscurs
Causes of the Epilepsies (1901) Gowers 1901 2
Causes of the Epilepsies (2014) slightly adapted from Thomas & Berkovic, Nat Rev Neurol 2014 3
www.ilae.org
Identification of the first ‘idiopathic epilepsy’ gene 1995 Identification of the first ‘idiopathic epilepsy’ gene in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) Onset: second decade of life Seizures: motor, mostly during non-REM sleep
Genetic heterogeneity and pleiotropy Steinlein et al. Nat Gen 1995 Kalachikov et al. Nat Gen 2002 Barcia et al. Nat Gen 2012 Dibbens et al. Nat Gen 2013 Ishida et al. Nat Gen 2013 Baulac, Prog Brain Res 2014
Genetic Epilepsy with Febrile Seizures Plus (GEFS+): SNC1A, SCN1B, GABRG2, STX1B Scheffer & Berkovic, Brain 1997 Escayg et al. Nat Gen 2000
SCN1A Variants Account for > 70% of Severe Myoclonic Epilepsy of Infancy (SMEI, Dravet Syndrome), a Much More Severe Phenotype than GEFS+ Catteral 2012 Missense, in-frame del Truncation
Single-gene epilepsies (non-exhaustive list) Autosomal dominant focal epilepsies CHRNA4, CHRNA2, CHRNB2, KCNT1, DEPDC5, LGI1, RELN Genetic epilepsy with febrile seizures plus (GEFS+) SCN1A, SCN1B, GABRG2, STX1B Benign familial neonatal seizures (BFNS) KCNQ2, KCNQ3 Juvenile myoclonic epilepsy, rare monogenic GABRA1 Epileptic encephalopathies KCNQ2, SCN1A, GRIN2A, PCDH19, STXBP1, … Early-onset absence epilepsy GLUT1 Benign familial infantile seizures (BFIS) PRRT2 Benign familial neonatal-infantile seizures (BFNIS) SCN2A Single-gene epilepsies (non-exhaustive list) 9
Several genetic epilepsies are channelopathies (as expected) Autosomal dominant focal epilepsies CHRNA4, CHRNA2, CHRNB2, KCNT1, DEPDC5, LGI1, RELN Genetic epilepsy with febrile seizures plus (GEFS+) SCN1A, SCN1B, GABRG2, STX1B Benign familial neonatal seizures (BFNS) KCNQ2, KCNQ3 Juvenile myoclonic epilepsy, rare monogenic GABRA1 Epileptic encephalopathies SCN1A, KCNQ2, GRIN2A, PCDH19, STXBP1, … Early-onset absence epilepsy GLUT1 Benign familial infantile seizures (BFIS) PRRT2 Benign familial neonatal-infantile seizures (BFNIS) SCN2A 10
Several genetic epilepsies are not channelopathies (as hoped) Autosomal dominant focal epilepsies CHRNA4, CHRNA2, CHRNB2, KCNT1, DEPDC5, LGI1, RELN Genetic epilepsy with febrile seizures plus (GEFS+) SCN1A, SCN1B, GABRG2, STX1B Benign familial neonatal seizures (BFNS) KCNQ2, KCNQ3 Juvenile myoclonic epilepsy, rare monogenic GABRA1 Epileptic encephalopathies KCNQ2, SCN1A, GRIN2A, PCDH19, STXBP1, … Early-onset absence epilepsy GLUT1 Benign familial infantile seizures (BFIS) PRRT2 Benign familial neonatal-infantile seizures (BFNIS) SCN2A 11
The monogenic epileptic encephalopathies: the genes McTague et al. Lancet Neurol 2015
The monogenic epileptic encephalopathies: the mechanisms (?) McTague et al. Lancet Neurol 2015
CURRENT GENETIC TESTING IN PATIENTS WITH EPILEPSY: Thomas & Berkovic, Nat Rev Neurol 2014 CURRENT GENETIC TESTING IN PATIENTS WITH EPILEPSY: Diagnosis, Counseling 14
CURRENT GENETIC TESTING IN PATIENTS WITH EPILEPSY: Therapeutic Implications Poduri et al., Nat Rev Neurol 2014 15
Epilepsies with Complex Inheritance 16
Complex Inheritance (II) SCN1A? SCN2A? ANO3? 17
Towards Personalized Pathogenicity? www.ilae.org Pathogenicity of a given variant in an ion channel subunit gene should be evaluated at least in the context of all other channel subunits Causality cannot be assigned to any particular variant - even when deleterious Expand this proposal to non-ion channel genes… Channotype Complexity and Heterogeneity in Epileptic and Control Individuals: Towards Personalized Pathogenicity?
Computational Model of Various Firing Patterns of a Single Neuron Computational model of firing patterns of a single neuron upon two-hit gain or loss of function mutations in essential ionic currents Computational Model of Various Firing Patterns of a Single Neuron upon Different Combinations of Gain or Loss of Function Variants Sodium and Calcium Channels Sodium and Potassium Channels Klassen et al. Cell 2011
Paroxysmal Dyskinesia Epilepsy Migraine Speech/Language Disorders Intellectual Disability Autism Spectrum Depression Comorbidities 22
Paroxysmal Dyskinesia Epilepsy Migraine Speech/Language Disorders Intellectual Disability Autism Spectrum Depression Shared Genetic Defects 23
Infantile Convulsions with Paroxysmal Dyskinesia 1997 Infantile Convulsions with Paroxysmal Dyskinesia as a single Autosomal Dominant Disorder: the ICCA Syndrome in Families from Amiens Area Szepetowski et al. Am J Hum Genet 1997
PRRT2 identified by Exome and Genome Sequencing 2011-2012 PRRT2 identified by Exome and Genome Sequencing
Expanding the PRRT2 Phenotypic Spectrum to Hemiplegic Migraine PKD HM Unaffected Cloarec et al. Neurology 2012
PRRT2: Proline Rich Transmembrane Protein 2 Predominantly axonal Interaction with SNAP25 Low or no expression of mutant PRRT2 proteins Expression in the embryonic and postnatal murine brain (cerebral cortex, cerebellum, thalamus, basal ganglia…) PRRT2 MAP2 Lee et al. Cell Reports 2012 Chen et al. Nat Gen 2011
PRRT2 mutations: 70 different mutations (87% familial) in 1500 patients Recurrent p.217Pfs*8: 78% of all patients Ebrahimi-Fakhari et al. Brain 2015 Out In N C
PRRT2: another orientation predicts intracellular function Slightly modified from Rossi et al. J Biol Chem 2016 Out In Ebrahimi-Fakhari et al. Brain 2015 N C
Unexplained Phenotypic Variability Associated with p.R217Pfs*8 PKD only PKD/BFIC (ICCA) BFIC only PKD/HM More than two Dale et al. Dev Med Child Neurol 2012 Cloarec et al. Neurology 2012 Heron et al. Am J Hum Genet 2012 Lee et al. Cell Rep 2012
Gowers 1901 31
Speech/Language Disorders Epilepsy Speech/Language Disorders 32
Childhood Focal Epilepsies and Epileptic Encephalopathies with Speech and Language Dysfunction (Epilepsy-Aphasia Spectrum) Kingwell, Nat Rev Neurol 2013 33
Encephalopathies of the Epilepsy-Aphasia Spectrum LKS - Landau-Kleffner Syndrome, ’acquired’ epileptic aphasia Auditory verbal agnosia (‘word deafness’) Rare seizures Sleep-activated paroxysms, ESES Secondary deterioration of expressive language Psychomotor/behavioral issues (autistic features) Variable outcome CSWSS - Continuous Spike-and-Waves during Slow-Wave Sleep Syndrome Frequent seizures More global deterioration Neuroimaging structural abnormalities: not rare Encephalopathies of the Epilepsy-Aphasia Spectrum Birth Onset of disease: Language impairment, seizures… 4 7 years Neuropsychological deficits
Genetic defects of GRIN2A in 20% of sporadic cases or families with epilepsy-aphasia spectrum Lesca et al. Nat Gen 2013
More than 60 microdeletions, nonsense, frameshift and missense mutations of GRIN2A NR2A (GLUN2A) Burnashev & Szepetowski, Curr Opin Pharm 2015
GRIN2A GLUN2A: Glutamate NMDA Receptor Subunit Glutamate = most abundant excitatory neurotransmitter NMDARs subunit diversity Glutamate-gated and voltage-dependent cation channel Mature GLUN1/2A have faster kinetics than immature GLUN1/2B Paoletti et al. Nat Rev Neurosci 2013
GluN2A-p.Arg518His GluN2A-wt
Various functional effects of different GLUN2A missense mutations adapted from Burnashev & Szepetowski, Curr Opin Pharm 2015 Various functional effects of different GLUN2A missense mutations NR2A (GLUN2A) Impaired Zn++ Inhibition Decreased Close State Duration Increased Open State Duration Decreased Mg++ Block Reduced H+ sensitivity Increased Potency of Glutamate and Glycine
GLUN2A Mutations in Epilepsy-Aphasia Spectrum: Q1. Which early pathophysiological events associated with GRIN2A defects? hyperexcitability / epileptiform activity (activated by sleep?) altered ultrasonic vocalization? altered thalamo-cortical network? Q2. Which consequences for the GRIN2A mutations? altered NMDAR functioning in vitro? Q3. Which early rescue strategies? NMDAR-targeted – or not? GLUN2A Mutations in Epilepsy-Aphasia Spectrum: Insights into Pathophysiological Mechanisms 40
Paroxysmal Dyskinesia Epilepsy Migraine Speech/Language Disorders Intellectual Disability Autism Spectrum Depression Neurodevelopmental Origin Detect Early Events? Design Early Rescue Strategies? 41
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