GENERALIZED EPILEPSY AND FEBRILE SEIZURES CASE STUDY

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GENERALIZED EPILEPSY AND FEBRILE SEIZURES CASE
STUDY

• BLANCA VAZQUEZ,MD
• NYU COMPREHENSIVE EPILEPSY PROGRAM
• NYU MEDICAL CENTER
• NEW YORK, NEW YORK

2
Medical History

• ML 8-year-old boy with history of febrile
  seizures, myoclonic jerks and tonic-clonic
  seizures.
• Perinatal history normal
• Apgar scores normal
• Developmental milestones and language were normal

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1rst Seizure

• Age 2 years
• Viral illness
• Rapid rise in his temperature within 5-10 minutes
  from 99º to105
• Clinical description
• -generalized tonic-clonic activity
• -duration 5 minutes
• -no facility or post-ictal deficits
• -Diagnosis Febrile seizure
• - No treatment given

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Recurrent febrile seizures

• 4 febrile convulsions over the subsequent 18
  months(x1/6 months)
• Average duration 2-5 minutes
• One episode of 2 seizures in one day
• Possible head deviation to the left
• Symmetrical involvement

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1rst Non-Febrile seizure

• 2 years
• Clinical description
• -Myoclonic jerks
• -his eyes would roll up
• -trunk would flex forward
• -arms elevated with abduction and flexion at the
  elbows
• -Duration 1-2 seconds

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1rst Non-Febrile seizure (cont.)

• -Impairment in level of consciousness
• -Variable frequency (up to 3/day)
• -triggers loud noise and bright lights

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1rst Gtc

• Age 4 years
• Preceded by myoclonic jerks with a fall
• GTC lasting 2-3 minutes
• No focality
• Diagnosis Impact seizure

8
Family History

• Febrile seizures
• -Mother
• -Maternal grandmother
• -maternal aunt

9
Physical Examination

• Skin A single .8cm hypo-pigmented maculae
• No organomegally, No dysmorphic features
• Head circumference 53.4
• Neurological exam
• -Hyperactivity
• - decreased in rapid alternating movements
• -mild decreased in fine motor skills
• -The remainder of neurological examination was
  normal

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workup

• EEG Frequent generalized 3-4 Hz
  high-amplitude polyspike and spike and wave
  discharges
• MRI Normal
• Genetic testing Mutation in the brain
  sodium channel gene SCN1A

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Clinical Course

• Learning difficulties
• Hyperactive
• Seizure type and frequency
• -GTC 4/year
• -absence unknown
• -Myoclonic 50-100/day

12
Treatment

• Current Antiepileptic medications
• -Felbamate
• -Acetazolamide
• -Levetiracetam
• Previous Antiepileptic medications
• -Lamotrigine Valproic acid
• -Topiramate Zonisamide

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• Neonatal Epilepsy Syndromes
• Generalized Epilepsy with
• Febrile Seizures Plus (GEFS)
• Sunday December 5, 2004
• American Epilepsy Society Annual Course
• Ingrid E Scheffer MBBS PhD FRACPAssociate
  Professor, The University of Melbourne
• Austin Health, Monash Medical Centre, Royal
  Childrens Hospital, Melbourne

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Outline

• Autosomal Dominant Seizure Disorders of Infancy
• Generalized Epilepsy with Febrile Seizures Plus
  (GEFS)
• Severe Myoclonic Epilepsy of Infancy (SMEI)

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Autosomal Dominant Seizure Syndromes of Infancy

• Syndromes defined by age of onset
• Benign familial neonatal seizures (convulsions)
• Benign familial infantile seizures (convulsions)
• Benign familial neonatal-infantile seizures
• Syndromes characterized by
• Clusters of convulsive seizures over a few days
• Often focal clinical and EEG features
• (?Mis) classified as generalized syndromes by
  ILAE
• Development normal
• Good outcome - few have febrile seizures or
  epilepsy

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Benign Familial Neonatal Seizures

• Rett and Teubel 1964
• Well neonates until seizures begin on day 2 or 3
• Premature infants have delayed onset until term
• Seizures - tonic, apnoea, clonic, may have focal
  features, autonomic features
• EEG
• Interictal - normal or focal/multifocal
  abnormalities
• Ictal - diffuse flattening then focal or
  generalized spikes
• Autosomal dominant, penetrance 85
• Later Febrile Seizures 5, epilepsy 11

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Benign Familial Neonatal Seizures KCNQ2
mutation amino acid change R353G
Courtesy of Gregory Holmes
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M-Current Potassium ChannelsKCNQ2, KCNQ3
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Benign Familial Infantile SeizuresBFIS

• Benign Infantile Convulsions - Fukuyama, 1963
• Autosomal dominant families - Vigevano et al,
  1992
• Onset 4-7 months
• Seizures
• Complex partial
• Slow head and eye deviation, alternate in
  different attacks
• Unilateral clonic and bilateral, hypertonia
• EEG - parieto-occipital spikes and slowing
• ICCA - Infantile convulsions and choreoathetosis
• Onset infancy to adolescence
• Dystonic, with rest, exertion, anxiety

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Benign Familial Neonatal Seizures Benign Familial Infantile Seizures
Onset 2-3 d 6 m
Range 1 d - 6 m 2 - 20 m
Loci 8, 20 16, ?1, ?19
Genes KCNQ2KCNQ3 ?ATP1A2
Other features Myokymia Choreoathetosis
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Benign Familial Neonatal-Infantile Seizures

• Single family from Buffalo, US (Kaplan Lacey
  1983)
• Families with intermediate onset mean 3 months
• 2 families with SCN2A mutationsHeron et al, 2002

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BFNIS Mutations Alpha 2 subunit gene, SCN2A
Heron et al 2002 Berkovic et al 2004

• 8 / 13 families with mutations of SCN2A
• 0 / 105 other early childhood epilepsies
• More common than previously appreciated?

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Benign Familial Neonatal Seizures Benign Familial Neonatal-Infantile Seizures Benign Familial Infantile Seizures
Onset 2-3 d 11 w 6 m
Range 1 d - 6 m 2 d - 6 m 2 - 20 m
Loci 8, 20 2 16, ?1, ?19
Genes KCNQ2KCNQ3 SCN2A ?ATP1A2
Other features Myokymia Choreoathetosis
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Outline

• Autosomal Dominant Seizure Disorders of Infancy
• Generalized Epilepsy with Febrile Seizures Plus
  (GEFS)
• Severe Myoclonic Epilepsy of Infancy (SMEI)

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Febrile Seizures Plus - The funny name

• Little Johnny
• 13 months Convulsion with fever, otitis media
  
• Dx Febrile seizure Advice he will grow out
  of it
• 18 months Convulsion with ? fever, no obvious
  infection
• Dx Febrile seizure Advice he will grow
  out of it
• 3 years Convulsion with fever, throat infection
• Dx Febrile seizure Advice he will grow out
  of it
• 8 years Convulsion with fever, throat infection
• Dx Febrile seizure but doctor you said.

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Billy 18m - Febrile Seizures x 12 6 yrs - Last
tonic clonic seizure
Arthur 1 yr - Febrile Seizures x 12 5-9
yrs - Rare GTCS
Twins of William Lennox, 1945
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Generalized Epilepsy With Febrile Seizures Plus
(GEFS)

• New major clinical group
• Marked phenotypic heterogeneity
• Predominantly a condition of the first decade
• Recognized because of remarkable dominant
  pedigrees with 50-60 penetrance
• Generalized spike-wave discharges

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GEFS Phenotypes

• Age

3 m
Adolescence
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Myoclonic-Astatic EpilepsyDoose

• May begin with Febrile Seizures
• Multiple generalized seizure types
• Myoclonic, myoclonic-astatic, atonic, absence,
  GTCS
• Onset 1-5 years, boys gt girls
• Intellectual disability common
• Variable course

• Genetic predisposition
• 32 probands have family history of seizures
• Usually febrile and afebrile GTCS lt 5 years
• Aetiology polygenic with little non-genetic
  variability

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Focal Epilepsies in GEFS

• Temporal Lobe Epilepsy
• May follow FS or FS
• Rarely occurs without preceding FS
• May have Mesial Temporal Sclerosis
• Frontal Lobe Epilepsy (Baulac et al, 2001)
• Hemiclonic seizures
• Orofacial motor seizures

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GEFS - Clinical Genetics

• Familial genetic epilepsy syndrome
• Recognized because of remarkable large autosomal
  dominant pedigrees
• Penetrance 60-80
• Most cases not from large families
• Small families, sporadic cases
• Majority have complex inheritance
• Low risk to siblings
• Bilineal family trees

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Genes for GEFS

• Sodium channel subunits
• Alpha subunit genes - SCN1A, ?SCN2A
• Beta subunit gene - SCN1B

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Fundamental Neurology. Editor Larry R Squire,
Publisher Academic Press
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GEFS genes Neuronal Sodium Channel
Na
II
III
I
IV
Cell membrane
?
?2
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Genes for GEFS

• Sodium channel subunits
• Alpha subunit genes - SCN1A, SCN2A
• Beta subunit gene - SCN1B
• GABAA receptor subunits
• Gamma 2 subunit gene - GABRG2
• Delta subunit gene - GABRD

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GABAA receptor
Cl-
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g2 GABAA receptor subunit (GABRG2) mutations
R43Q CAE GEFS
NH2
K289M GEFS
C
C
COOH
M1
M2
M3
M4
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GABAA Receptor
?
b
?
b
?
Gamma subunit Mainly sub-synaptic Rapidly
desensitizing Mediate phasic inhibition
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Susceptibility gene?GABRD - GABAA delta subunit
(Dibbens et al, HMG, 2004)



Glu177Ala mutation
Febrile Seizures
Febrile Seizures Plus
Unclassified epilepsy
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Outline

• Autosomal Dominant Seizure Disorders of Infancy
• Generalized Epilepsy with Febrile Seizures Plus
  (GEFS)
• Severe Myoclonic Epilepsy of Infancy (SMEI)

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Severe Myoclonic Epilepsy of Infancy(SMEI)
Charlotte Dravet 1978

• Onset 5-6 months with febrile seizures
• Prolonged unilateral or generalized clonic
  seizures
• Other seizure types evolve by 1- 4 years
• myoclonus - usually by 4 years, not all patients
• partial seizures
• atonic seizures
• atypical absences
• Hyperthermia often precipitant (bathing, fever)

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Severe Myoclonic Epilepsy of Infancy

• Normal early development
• Psychomotor slowing gt 1 year
• Ataxia and pyramidal signs evolve
• Intellectual outcome poor, seizures refractory
• Up to 50 have family history of seizures
• Febrile Seizures
• Epilepsy
• GEFS spectrum (Singh et al, 2001)

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Severe Myoclonic Epilepsy of InfancyTreatment

• Lamotrigine may exacerbate seizures
• Stiripentol (unlicensed) - Chiron study (2000)
  showed 70 responders
• Anecdotal experience combination of topiramate
  and clobazam may be effective

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Alpha 1 sodium channel subunit SCN1A mutations

• Gene most commonly mutated in families with GEFS
  
• Only 10 families positive
• Missense mutations
• SMEI patients tested because seizures with fever
• Claes et al (2001) - 7 / 7 patients had SCN1A
  mutations
• Truncation of protein due to nonsense, frameshift
  mutations
• All de novo

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SMEI and SCN1AMutational analyses

• De novo truncation mutations of SCN1A in 70
  cases
• SMEI cases in GEFS families
• Familial SCN1A or GABRG2 mutations found rarely
• Account for up to 10 cases with SCN1A mutations
  (3/33 in French study)
• Only two familial GABRG2 SMEI cases reported
• High rate of de novo mutations does not explain
  family history data - other genes important

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Sodium Channel Alpha 1 Subunit Gene SCN1A
I
II
III
IV
NH2
COOH
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Severe Myoclonic Epilepsy of Infancy SCN1A
mutations
(Mulley, Harkin et al. in press)
I
II
III
IV
NH2
COOH
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SMEI and SCN1AGenotype-Phenotype Correlation
Phenotypic spectrum broader than classical SMEI

• SMEB - Severe Myoclonic Epilepsy of Infancy
  Borderland
• Missing key features of SMEI phenotype
• No GSW on EEG
• Absence of myoclonus
• Abnormal early development
• Subset Intractable Childhood Epilepsy with TCS
• Infantile Spasms (1 case)
• Single SMEB like case with SCN2A mutation

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Severe Myoclonic Epilepsy of Infancy
Borderland Intractable Childhood Epilepsy with
GTC
(Mulley, Harkin et al. in press)
I
II
III
IV







NH2
Infantile spasms
COOH
ICEGTC
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Generalized Epilepsy with Febrile Seizures
Plus GEFS
(Mulley, Harkin et al. in press)
I
II
III
IV
NH2
COOH
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GEFS

• Known genes identified in only 20 families
• Complex inheritance usual and is the basis of
  phenotypic heterogeneity
• Treatment implications not yet based on molecular
  findings
• AEDs with Na channel and GABA receptor effects
  not specifically effective with molecular defect

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GEFS and IGE inter-relationship Genetic insights
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Acknowledgments
John Mulley Leanne Dibbens, Sarah Heron, Hilary
Phillips, Robyn Wallace, Louise Harkin, Grant
Sutherland University of Adelaide Greg
Holmes Robert Kaplan Bob Macdonald Hua-Jun Feng
USA Eva Andermann, Canada Funding NHMRC,
Bionomics Consultant for Bionomics, Athena
Samuel Berkovic Rita Singh, Lata Vadlamudi,
Isabella Taylor, Nigel Tan, Chris Derry, Bronwyn
Grinton, Sam Turner, Jacinta MacMahon, Danya
Vears, Jodie MaloneEpilepsy Research Centre,
Austin, University of Melbourne Steve
Petrou University of Melbourne Federico Zara,
Lucio Giordano, Renzo Guerrini, Antonio
Gambardella, Lauro Bordo,Carla Marini Italy
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www.wcn2005.com
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Neonatal Syndromes and GEFS Mechanistic
Considerations
Daniel L. Burgess, Ph.D.
Baylor College of Medicine
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Outline
Genotypes, mechanisms, phenotypes
58
Mutation identification begins with a
phenotype and proceeds toward the genotype
genotype
phenotype
59
Mutation identification by linkage analysis and
positional cloning is largely a mathematical
process
3.0
2.5
2.0
1.5
(billion base pairs)
1.0
0.5
0.0
0
5
10
15
20
25
30
35
40
(number of meioses)
60
Mutation identification by linkage analysis and
positional cloning is largely a mathematical
process
61
Determination of how a genotype produces a
phenotype is not a simple reversal of the process
X
genotype
phenotype
62
Determination of how a genotype produces a
phenotype depends strongly on hypothesis testing
X
genotype
phenotype
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Annual Course Pre-Test Question
What is the most frequently observed abnormality
caused by mutations in Na channel alpha subunits
associated with GEFS?

1) Reduced selectivity for Na ions relative to Ca2 and K ions. 1) Reduced selectivity for Na ions relative to Ca2 and K ions.
2) Channel misfolding that results in cytoplasmic inclusion bodies.
3) Delayed inactivation of the channel following opening.
4) Altered confomation that prevents binding to essential b subunits.
64
Elucidation of a disease mechanism presents
a much more complex set of challenges
cell
protein
network
disease
mechanism
mRNA
genotype
phenotype
65
Not all potential defects arise from each mutation
cell
protein
network
disease
mechanism
mRNA
genotype
phenotype
66
Not all potential defects arise from each mutation
cell
protein
network
disease
mechanism
mRNA
T
genotype
phenotype
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cell
protein
network
disease
mechanism
mRNA
T
genotype
phenotype
68
Key points
Finding mutations is much simpler than solving
mechanisms
Complexity of the disease mechanism increases
exponentially, in parallel with the level of
biological complexity (DNA mRNA protein
cell network)
Proteins are logical targets for therapy and for
rational drug design
69
Rational drug design for epilepsy
M
T
70
Outline
Genotypes, mechanisms, phenotypes
Genes and mutations in neonatal syndromes and
GEFS
Methods for analyzing mechanisms in vitro
studies and animal models
GEFS, BFNC mechanisms
Future directions
71
Genes and mutations in neonatal syndromes and
GEFS
KCNQ2
Chr. 20q13.3
Benign familial neonatal convulsions (BFNC)
Benign neonatal epilepsy-1 (EBN1)
BFNC/myokymia syndrome
KCNQ3
Chr. 8q24
Benign familial neonatal convulsions (BFNC)
Benign neonatal epilepsy-2 (EBN2)
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SCN1B
Chr. 19q13
Generalized epilepsy with febrile seizures plus,
type 1 (GEFS type 1 GEFSP1)
SCN1A
Chr. 2q24
GEFS type 2 GEFSP2
Severe myoclonic epilepsy in infancy (SMEI)
GABRG2
Chr. 5q33-q34
GEFS type 3 GEFSP3
SMEI
SCN2A
Chr. 2q23-q24
Febrile seizures associated with afebrile seizures
Benign familial neonatal-infantile seizures
(BFNIS)
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Unknown
Chr. 19q12-q13.1
Benign familial infantile convulsions, type 1
(BFIS type 1 BFIC1)
Unknown
Chr. 16p12-q12
BFIS type 2 BFIC2
Infantile convulsions and paroxysmal
choreoathetosis (ICCA)
Paroxysmal kinesigenic choreoathetosis (PKC)
Unknown
Chr. 16p12-p11.2
Rolandic epilepsy, paroxysmal exercise-induced
dystonia, writer's cramp (RE-PED-WC)
Unknown
Chr. 16p13
Autosomal recessive (familial) benign idiopathic
myoclonic epilepsy of infancy (FIME)
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Traditional nomenclature of inherited epilepsy
Gene 1
Gene 2
Gene 3
Gene 4
Phenotype
Syndrome A
Syndrome B
Syndrome C
Syndrome D
Syndrome E
Syndrome F
Syndrome G
etc
75
Traditional nomenclature of inherited epilepsy
Different mutations in different genes can result
in different phenotypes
Different mutations in different genes can result
in similar phenotypes
Diferent mutations within one gene can result in
different phenotypes
An identical mutation within one gene can result
in different phenotypes in different individuals
(cause environment, other genes)
76
Gene-centric nomenclature of inherited epilepsy
Gene 1
Gene 2
Gene 3
Gene 4
Mutations
A
B
A
B
C
D
A
A
C
F,G
E
E
E
A
C
Phenotype
Gene 1
Phenotypic range A, B, C, D
Gene 2
Phenotypic range A, B, E, F, G
Gene 3
Phenotypic range A, S, E
Gene 4
Phenotypic range A, E
etc
Both Traditional and Gene-centric
nomenclatures have specific advantages and
disadvantages
77
Outline
Genotypes, mechanisms, phenotypes
Genes and mutations in neonatal syndromes and
GEFS
Methods for analyzing mechanisms in vitro
studies and animal models
GEFS, BFNC mechanisms
Future directions
78
in vitro methods and
animal models for
studying ion channels
expressed in
mutant
Xenopus laevis oocyte
gene
cultured cell (non-neuronal)
primary neuronal culture
brain slice culture
transgenic mouse
gene knock-out mouse
gene knock-in mouse
79
Mouse mutants of neonatal epilepsy syndrome and
GEFS genes
transgenic
knock-out
knock-in
v
KCNQ2
lethal
KCNQ3
v
seizures
SCN1B
SCN1A
v
GABRG2
lethal
v
v
SCN2A
seizures
lethal
Source http//www.informatics.jax.org/
10/30/2004
(lt18 days)
80
in vitro methods and
animal models for
studying ion channels
expressed in
mutant
gene
primary neuronal culture
brain slice culture
transgenic mouse
gene knock-out mouse
gene knock-in mouse
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Outline
Genotypes, mechanisms, phenotypes
Genes and mutations in neonatal syndromes and
GEFS
Methods for analyzing mechanisms in vitro
studies and animal models
GEFS, BFNC mechanisms
Future directions
83
SCN1B
SCN1A
SCN2A
GEFS
GEFS
GEFS
BFNIS
SMEI
a
N
C
Source http//www.ncbi.nlm.nih.gov/entrez/query.
fcgi?dbOMIM
84
SCN1B
(GEFS)
C121W
Slower inactivation and slower recovery from
inactivation.
(X. laevis oocytes)
Persistent inward Na currents, depolarized
membrane potential, hyperexcitability.
Wallace et al, 1998, Nat Genet 19366
Predicted effect hyperexcitable channel
Predicted effect hypo-excitable channel
85
SCN2A
(GEFS)
R187W
Slow channel inactivation
Increased inward Na currents, depolarized
membrane potential, hyperexcitability.
Sugawara et al, 1998, PNAS 986384
Predicted effect hyperexcitable channel
Predicted effect hypo-excitable channel
86
SCN1A
(GEFS)
Noninactivating inward currents
W1204R
T875M
tsA201 cells
R1648H
Lossin et al, 2002, Neuron 34877
Predicted effect hyperexcitable channel
Predicted effect hypoexcitable channel
87
Key points
These studies suggest that non-inactivating,
persistent inward sodium currents, caused by
mutations in SCN1B, SCN1A or SCN2A, are
associated with GEFS
However, there are now several exceptions to the
rule (e.g. GEFS mutations R1657C I1656M do not
produce a persistent, non-inactivating current,
while A1685V and V1353L exhibit complete loss of
function) (Lossin et al, 2003, J Neurosci
2311289)
88
Benign Familial Neonatal Convulsions (BFNC)
Neonatal seizures (possible intrauterine
convulsions too)
Seizures short duration (usually lt1
minute) generalized tonic seizures w/
autonomic features, often progressing to
clonic seizures. brief postictal state
Spontaneous remission in most by 6-8 weeks
Normal psychomotor development
Increased risk of epilepsy (10-15) in adulthood
89
Autosomal dominant w/locus heterogeneity
KCNQ2
(20q13.2)
(8q24)
KCNQ3
Molecular mechanism
altered inhibitory M-current (Muscarinic
regulated K current)
KCNQ2
KCNQ3
90
A developmental model of BFNC remission
GABA is excitatory (i.e. has depolarizing
effects) during early neuronal development
(Rivera et al., 1999, Nature 397251).
The developmental switch of GABA from excitatory
to inhibitory correlates with induction of the
neuronal K-Cl cotransporter (KCC2), which is
critical for establishing a mature Cl-gradient.
91
A developmental model of BFNC remission

Inhibitory System
P3
P7
P30
P90
92
Outline
Genotypes, mechanisms, phenotypes
Genes and mutations in neonatal syndromes and
GEFS
Methods for analyzing mechanisms in vitro
studies and animal models
GEFS, BFNC mechanisms
Future directions
93
Future Directions
Reverse engineering of epilepsy mutations
Pyramidal neurons and interneurons, Cajal 1900
94
Case Presentation
Familial TLE with auditory features

• Fernando Cendes, MD, PhD
• Department of Neurology
• University of Campinas - UNICAMP
• Campinas, SP, Brazil

95
Familial TLE with auditory features

• LGI1 mutation IVS7-2AgtG on chromosome 10q.
• 22 evaluated with MRI 16 affected, 6
  asymptomatic
• MRI lateral temporal lobe dysgenetic features
  45

Kobayashi et al, Arch Neurol 2003
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Patient III-13 (proband)

• 42 years old woman
• First seizure at 24 years
• Generalized tonic-clonic seizure during sleep
• She then developed simple partial seizures with
  auditory features
• described as a radio or a motorcycle running
  noise
• or as if there were people talking on TV
  something she could not understand
• This could be followed or accompanied by
  distorted vision peoples face became
  disfigured

98
Patient III-13 (proband) - continued

• She has good seizure control
• Routine EEG normal
• MRI enlargement of left lateral temporal lobe
  and absence of 1st and 2nd temporal sulci,
  abnormal shape and axis of hippocampus

99
III-13
100
III-4

• 53 years old man had a single seizure at 35 yrs.
• Funny noise in the left ear followed by loss of
  consciousness and generalized tonic-clonic seizure

101
Familial TLE with auditory features

• III-7 51 yr. old woman seizure onset at 34 yrs.
• Buzzing noise aphasia visual distortions
• had only one episode of secondary generalization
• III-9 49 yr. old woman seizure onset at 26 yrs.
• Visual distortions
• had two generalized seizures
• III-10 47 yr. old man seizure onset at 16 yrs.
• Funny noise (like clapping hands) volume
  changes
• complex partial and a few generalized seizures

102
Discussion
Recognizing Familial TLE with auditory features

• A good family history
• Characteristic clinical picture (Ottman et al)
• Auditory auras buzzing, ringing, or clicking
  distortions such as volume changes
• Ictal sensory aphasia
• Visual auras may occur
• Absence of MRI signs of MTS
• Age at onset varies
• 50 of the families have the LGI1 mutation

103
Genetic focal epilepsiesState of the art and
paths to the future

• Frederick Andermann, MD, FRCP(C),
• Eliane Kobayashi, MD, PhD
• Eva Andermann, MD, PhD, FCCMG, Montreal
  Neurological Hospital and Institute, McGill
  University

104
Genetics of the epilepsies
Historical

• Generalized epilepsies have a strong genetic
  component
• Partial epilepsies are largely due to
  environmental factors
• Although some multiplex families had been
  recognized in partial epilepsy, they were
  considered compatible with complex inheritance

105
Genetics of the epilepsies
Actual

• Most generalized epilepsies have complex or
  multifactorial inheritance
• A number of partial epilepsies with single gene
  inheritance have recently been identified

106
Benign rolandic epilepsy
   Autosomal dominant inheritance
suggested (Heijbel et al, 1975)    EEG
abnormalities in siblings (Degen and Degen,
1992)    Genetic relationship to
migraine    Twin studies no concordance in MZ
or DZ twins (Vadlamudi et al, 2004)    Most
likely complex inheritance
107
Benign rolandic epilepsy
   Co-occurrence of benign neonatal seizures
and BECTS, but no linkage to EBN1 and EBN2
(Neubauer et al, 1997)    Linkage to chr15q
for EEG abnormalities (Neubauer et al, 1998), but
no mutations in the potassium chloride
cotransporter KCC3 (Steinlein et al, 2001)
108
Benign rolandic epilepsy single gene variants
   Autosomal dominant rolandic epilepsy with
speech dyspraxia (Scheffer et al, 1995)   
Autosomal recessive rolandic epilepsy with
paroxysmal exercise-induced dystonia and writer's
cramp linked to chr 16p (Guerrini et al,
1998)    Partial epilepsy with pericentral
spikes, linked to chr 4p (Kinton et al, 2002)
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Partial epilepsies with single gene inheritance
Common features

• Onset usually in childhood or adolescence
• Usually but not always benign and easily
  controlled
• Genetic heterogeneity
• Some are channelopathies

111
Partial epilepsies with single gene inheritance

• Autosomal dominant nocturnal frontal lobe
  epilepsy (ADNFLE)
• Familial benign temporal lobe epilepsy
• Familial mesial temporal lobe epilepsy (FMTLE)

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Partial epilepsies with single gene inheritance

• Familial lateral temporal lobe epilepsy (FLTLE)
  or familial partial epilepsy with auditory
  features (FPEAF)
• Familial partial epilepsy with variable foci
  (FPEVF)

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Autosomal dominant nocturnal frontal lobe epilepsy

•    Age of onset 2m 35y (mean 12y median 8y)
•    Clusters of nocturnal frontal seizures
  (median 6 per night)
• aura on awakening (70)
• tonic spasms or hyperkinetic motor seizures
• rare tonic-clonic seizures
•    Interictal EEG abnormalities very rare

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Autosomal dominant nocturnal frontal lobe epilepsy

• Clinical Genetics
•    Autosomal dominant penetrance 75
•    Marked intra-familial variation in severity
•    Inherited nature easy to overlook as
  relatives may be only mildly affected

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Autosomal dominant nocturnal frontal lobe epilepsy

• How many genes?
•    Chromosome 20 locus, mutations in the ?4
  subunit of the neuronal nicotinic acetylcholine
  receptor
•    Chromosome 15 locus, gene unknown
•    Chromosome 1 locus, mutations in the ?2
  subunit of the neuronal nicotinic acetylcholine
  receptor

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Berkovic et al.
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Definition of familial temporal lobe epilepsy
(FTLE)

•    Familial recurrence of TLE in 2 or more
  family members
•    Absence of any suggestion of other
  generalized or partial epilepsy syndromes
•    Due to decreased penetrance, may have 2 or
  more affected family members who are second or
  third degree relatives, not only first degree

Kobayashi, Andermann and Andermann, 2004
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FTLE - Epidemiology

•    No predominance in any particular ethnic
  group
•    FMTLE Australia, Canada, Brazil, Italy,
  Belgium, France
•    FLTLE Australia, Brazil, France, Germany,
  Italy, Japan, USA
•    Underestimation of FTLE worldwide,
  especially in families with predominantly good
  outcomes

Kobayashi, Andermann and Andermann, 2004
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Familial temporal lobe epilepsy

• SEVERITY AGE AT FEBRILE MRI
• SEIZURE SEIZURES
• ONSET
• Berkovic et al, 1994, 1996 Benign Adolescence
  - No HA
• (population-based) or adulthood or MTS
• Cendes et al, 1998 Variable Variable /-
  Variable
• Kobayashi et al, 2001 HA
• (hospital based)

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Population based familial TLE
Berkovic et al, 1994
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Hospital based familial TLE
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Benign FTLE Déjà vu is over- represented
Déjà-vu
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Benign FTLE Conclusions
   The inheritance pattern fits an autosomal
dominant model with reduced penetrance   
Autosomal recessive or sex-linked
inheritance cannot be ruled out in some
families    Linkage studies have excluded the
known loci for partial epilepsies on 10q,15q,
20q, 22q
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Differential diagnosis of FTLE

•    FMTLE AD with ? penetrance
•    FLTLE or ADPEAF AD with ? penetrance
•    FPEVF AD with ? penetrance
•    GEFS AD with ? penetrance

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Differential diagnosis of FTLE

•    Sporadic temporal or pseudotemporal
•    Familial neuronal migration disorders
• - double cortex syndrome
  X-linked dominant
• - periventricular nodular heterotopia
  X-linked dominant
•    Mild form of tuberous sclerosis AD
•    Chorea-acanthocytosis AR or AD
•    Pallister-Hall syndrome AD
• hypothalamic hamartoma

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Familial mesial temporal lobe epilepsy (FMTLE)

•    Seizures with mesial temporal semiology
  (epigastric aura, psychic and experiential
  phenomena)
•    Complex partial seizures with oral and
  manual automatisms
•    Prominent post-ictal confusion
•    Secondarily generalized GTC can occur
•    Seizures can be refractory in up to 29

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Familial mesial temporal lobe epilepsy (FMTLE)

•    EEG - unilateral or bilateral epileptiform
  discharges over mesio-temporal regions
•    MRI - varying degrees of HA and hyperintense
  T2 signal, more frequent and more severe in
  patients with refractory seizures
•    These findings, especially HA, can also be
  found in asymptomatic family members
• The imaging and pathological features of MTLE
  are identical in sporadic and familial cases

Kobayashi et al
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Genetic basis of FMTLE

•    No single gene molecular basis identified to
  date
•    Most likely, FMTLE will be found to have a
  major gene leading to hippocampal abnormalities
•    The phenotype could then be influenced by
  additional genetic and environmental modifying
  factors

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Genetic basis of FMTLE

•    Over-representation of a GABA B receptor 1
  polymorphism (G1465A) in patients with FMTLE as
  compared to the normal population (Gambardella et
  al, 2003)
•    This may suggest an increased
  susceptibility to TLE related to GABA receptors
•    Several other polymorphisms have been
  described

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Familial lateral temporal lobe epilepsy (FLTLE)

•    Benign epilepsy syndrome
•    Auditory auras (buzzing, roaring,
  distortions of sounds and words)
•    Other less frequent manifestations
• psychic
• cephalic and other sensory and motor phenomena

   Occasional ictal aphasia and visual
misperceptions    Secondary generalization can
occur    No refractory patients reported to
date
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FLTLE - Etiology

•    Mutations in LGI-1 are found in
  approximately half of all families, suggesting
  genetic heterogeneity
•    LGI-1 codes for a putative membrane-anchored
  protein of unknown function
•    LGI-1 was cloned from a glioblastoma cell
  line, and possibly represents a tumour suppressor
  gene

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• Association of lateral temporal malformation
  patterns in some families
• suggests a probable role for LGI-1 in the
  development of the
• temporal lobes

Kobayashi et al
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FPEVFClinical Characteristics

•    The seizures are usually of frontal or
  temporal origin, but may also be occipital
•    Overall, age of onset is variable, but there
  seem to be two peaks the first at around 5
  years of age, and the second at around 25 years
•    Most affected individuals have exclusively or
  predominantly nocturnal seizures

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FPEVFClinical Characteristics

•    Different foci are seen in different family
  members, but the foci remain consistent in the
  same individuals
•    The EEGs are relatively inactive, showing at
  most occasional spikes in the frontal and/or
  temporal areas
•    Some family members have cognitive symptoms,
  such as déjà vu and/or jamais vu

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FPEVFClinical Characteristics

•    In family members, there is a high frequency
  of parasomnias in childhood, including
  nightmares, night terrors, and somnambulism
•    No visible pathological lesions in affected
  individuals

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Xiong et al, 1999
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Berkovic et al, 2004
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Familial or sporadic?
   In all familial syndromes, the clinical
presentation is similar to that in sporadic
patients    In all familial partial
epilepsies, there are families that do not show
the known molecular pattern, suggesting genetic
heterogeneity    Therefore, all patients could
be familial, some with single gene inheritance
and incomplete penetrance and others with
complex inheritance    Should molecular studies
be carried out in apparently sporadic
patients? eg SMEI, ADNFLE
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Paths to the future clinical practice
   Greater awareness of possible genetic
etiologies in clinical practice    Detailed
family histories and review of medical records
are still crucial    Detailed imaging,
electrodiagnostic and pathological studies in
family members may provide clues    Are there
more unrecognized single gene syndromes?
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Paths to the future

•    Continued search for major genes in large
  families linkage studies
•    Association studies in large patient
  populations with homogeneous genetic
  backgrounds and ethnically matched controls
•    Pathological studies
• PET receptor studies (Reutens and Fedi, 2004)
•    Integration of all these aspects
•    Animal models

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Paths to the future

•    Search for susceptibility genes
• non-parametric linkage studies
• association studies with large numbers of
  patients, improved methodologies and suitable
  controls
• whole genome association studies
• candidate gene studies

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The future

•    Knowing the gene, can we identify the steps
  from molecular changes to epileptogenesis?
•    Knowing the mechanisms, is it possible to
  reverse them?
•    If it is not possible to reverse them, can we
  create more adequate treatment options?

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The future

•  
•    How does the mutant protein produce
  epilepsy?
•  
•    Specific treatment counteracting the effect
  of the mutant protein?
•  
•    Replacement of the mutated gene ???

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Genetic counseling in familial focal epilepsies
Single gene inheritance

•    In the single gene syndromes, the phenotype
  is often benign and the epilepsy self-limited
•    There is usually decreased penetrance and
  variable expressivity
•    Are molecular diagnostic tests in asympto-
  matic relatives and prenatal diagnosis
  justified?

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Genetic counseling in familial focal epilepsies
Complex inheritance

•    In epilepsies with complex inheritance, the
  recurrence risks are much lower, and to date
  can only be determined empirically
•    We may never be able to identify all the
  susceptibility genes and environmental factors
  acting in any one individual or family