1. 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

2. Causes of the Epilepsies (1901)
Gowers 1901 2

3. Causes of the Epilepsies (2014)
slightly adapted from Thomas & Berkovic, Nat Rev Neurol 2014 3

5. 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

6. 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

7. Genetic Epilepsy with Febrile Seizures Plus (GEFS+): SNC1A, SCN1B, GABRG2, STX1B
Scheffer & Berkovic, Brain 1997
Escayg et al. Nat Gen 2000

8. 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

9. 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

10. 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

11. 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

12. The monogenic epileptic encephalopathies: the genes
McTague et al. Lancet Neurol 2015

13. The monogenic epileptic encephalopathies: the mechanisms (?)
McTague et al. Lancet Neurol 2015

14. CURRENT GENETIC TESTING IN PATIENTS WITH EPILEPSY:
Thomas & Berkovic, Nat Rev Neurol 2014
CURRENT GENETIC TESTING
IN PATIENTS WITH EPILEPSY:
Diagnosis, Counseling 14

15. CURRENT GENETIC TESTING IN PATIENTS WITH EPILEPSY:
Therapeutic Implications
Poduri et al., Nat Rev Neurol 2014 15

16. Epilepsies with Complex Inheritance16

17. Complex Inheritance (II)
SCN1A?
SCN2A?
ANO3? 17

19. Towards Personalized Pathogenicity?
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?

20. 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

22. Paroxysmal Dyskinesia Epilepsy
Migraine
Speech/Language Disorders
Intellectual Disability
Autism Spectrum
Depression
Comorbidities 22

23. Paroxysmal Dyskinesia Epilepsy
Migraine
Speech/Language Disorders
Intellectual Disability
Autism Spectrum
Depression
Shared Genetic Defects 23

24. 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

25. PRRT2 identified by Exome and Genome Sequencing
PRRT2 identified by Exome and Genome Sequencing

26. Expanding the PRRT2 Phenotypic Spectrum to Hemiplegic Migraine
PKD HM
Unaffected
Cloarec et al. Neurology 2012

27. 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

28. 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

29. 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

30. 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

31. Gowers 1901 31

32. Speech/Language Disorders
Epilepsy
Speech/Language Disorders 32

33. Childhood Focal Epilepsies and Epileptic Encephalopathies
with Speech and Language Dysfunction
(Epilepsy-Aphasia Spectrum)
Kingwell, Nat Rev Neurol 2013 33

34. 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

35. Genetic defects of GRIN2A in 20% of sporadic cases or families
with epilepsy-aphasia spectrum
Lesca et al. Nat Gen 2013

36. More than 60 microdeletions, nonsense, frameshift and missense mutations
of GRIN2A
NR2A (GLUN2A)
Burnashev & Szepetowski, Curr Opin Pharm 2015

37. 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

38. GluN2A-p.Arg518His
GluN2A-wt

39. 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

40. 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

41. Paroxysmal Dyskinesia Epilepsy
Migraine
Speech/Language Disorders
Intellectual Disability
Autism Spectrum
Depression
Neurodevelopmental Origin
Detect Early Events?
Design Early Rescue Strategies? 41

42. Mediterranean Institute of Neurobiology (INMED)
Mediterranean Institute of Neurobiology (INMED)