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La SiNDROME di DRAVET OGGI

Charlotte Dravet,Rome, Marseille

Pavia, 19 Novembre 2016

Prima 2001

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* inizio prima 1 anno

* crisi convulsive severe

* febbrile poi senza febbre

* mioclonie ++ ,

* assenze atipiche,

* crisi parziali

* rallentamento dello sviluppo psicomotorio

* EEG normale ➜➜➜➜ PO gen. + foc/multifoc

* neuroimagerie normale

Epilessia Mioclonica Severa dell’ Infanzia

Evoluzione :

* crisi farmacoresistente

* stati di male epilettici

* fotosensibilita

* handicap mentale

� Encefalopatia

senza eziologia conosciuta

∆∆∆∆g differenziale : sd di Lennox-Gastaut

���� Epilessia mioclonica severa del lattante

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FORME BORDERLINE

(SMEB)

� senza mioclonie/assenze atipiche

� « Intractable childhood epilepsies with frequent

GTCS » (Watanabe 1989, Fujiwara, 1992, Kanazawa,2001)

� « Severe idiopathic generalized epilepsy of

infancy with generalized tonic-clonic seizures »

(Doose & al, 1998 )

2001

SMEI diventava la sindrome di Dravet

Perchè?

- alcuni bambini presentavano lo stesso quadro senza crisi miocloniche

- l’epilessia non scompariva in adolescenza e persisteva in età adulta

- “mioclonica” e “infanzia” non erano più appropriate(ILAE

(Classificazione Lega Internazionale , 2001)

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Dopo 2001

1978-2001SMEI2001 Claes et al

SCN1A mutations

2002 Harkin et al. GABRG2

Dravetsyndrome spectrum

PCDH19 protocadherinin girls Dibbens et al 2008 Depienne et al 2009

CHD2 Suls et al 2013

Other close epilepsy

types

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� Dravet syndrome is a genetic encephalopathy with epilepsy, cognitive, behavioral and motor impairment

� In most patients it is caused by a mutation in the SCN1A gene.

� However, the diagnosis is based on clinical characteristics

Where are we now ?

Clinical general featuresNo big changes from the first descriptions

�semiological particularities : onset with afebrile seizures or focal seizures, scarcity of febrile seizures, absence of focal seizuresabsence of neurological signs, almost normal psychomotor development in the first 4 years.

�Variety of seizure types

� less patients with photo/pattern-sensitivity but eye-closure as triggering factor of micro-absences

�better knowledge of the motor and orthopedic impairments

�better knowledge of sleep, food, autonomic disorders

�occurrence of SUDEP

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Variety of seizure types

Video

Clonic seizure

Obtundation status

Are they true atonic seizures in Dravet syndrome ?

Video

1 true atonic seizure and 1 myoclono-atonic seizure in a patient with Epilepsy with myoclonic- atonicseizures (Doose syndrome)

1 atypical absence with atonic component elicited by ILS in a girl with Dravet syndrome (by Dr Cantaloupe courtesy)

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5 y. generalized myoclonic seizures

5y. Multifocal S and SW

� Photo and pattern sensitivity :

Variable during the time

ILS, patterns, eye closure, environmental light intensity

Very high convulsive susceptibility

Z.A. 3yrs

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Motor and orthopedic impairment

Video

Genetic background

SCN1A mutations

Sindrome di Dravet 70/80 %GEFS+ 10-20 %

Migrating partial seizures (Carranza et al, 2011, Freilich et al, 2011)

Epilessie focali altre (Shi et al, 2012, McDonald et al, 2016)

Sd di Panayiotopoulos (Grosso et al, 2007, Livingston et al, 2009)

Familial hemiplegic migraine (Thomsen et al, 2007, Vahedi et al, 2009)

Familial autism (Weiss et al, 2003)

Sd di Rasmussen (Ohmori et al, 2008)

...

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Differential diagnosis

- is not present in all patients with Dravet syndrome

- can be present in other epilepsy types, for example :

Can be difficult knowing that an SCN1A mutation

* Genetic Epilepsy with Febrile Seizures plus (GEFS+ ) syndrome

* focal epilepsies but sharing common traits with Dravetsyndrome

• In the first two years of life

• In childhood

Differential Diagnosis

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• Dravet syndrome

– Onset before the age of 1 year

– Febrile (<38.5°C) and afebrile seizures

– Long seizures, unilateral or with signs of lateralisation

– Cognitive decline

– For 80%: SCN1A mutation

• Febrile seizures

– Onset rather after the age of 1 year

– Only febrile seizures

– brief seizures

- Normal cognitive outcome

– Possible SCN1A mutation (GEFS+ spectrum)

Be concerned : prescribe rectal diazepam

Hattori et al, 2008. A screening test for prediction of Dravet syndrome before one year

Video

1st clonic seizure after vaccination in a 6 m-old boy

2nd clonic seizure triggered by fever in the same boy

at 10m

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� Progressive myoclonus epilepsies:

• in the 2nd year when the neurological and behavioural signs appear

• one ceroïd lipofuscinosis can be eliminated throughout :

- interictal myoclonus characteristics

- absence of visual impairment

- absence of fundus abnormalities

- absence of posterior evoked potentials elicited by the

Intermittent Photic Stimulation (IPS) low frequencies

- negative results of biological and genetic investigations

for NCL

4 years Necker Enfants Malades

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• Dravet syndrome– No perinatal history– Generalised /alternating unilateral

seizures

– Febrile and afebrile seizures

– Other seizure types appear later on:• atypical absences• myoclonic seizures• focal seizures

– EEG: general/multifocal S and SW

– Cognition: normal then global delay

– For 80%: SCN1A mutation

– Aggravated by carbamazepine

– Normal MRI

• Focal epilepsy– With/without perinatal history – Unilateral seizures, always on the

same side

– Febrile and afebrile seizures

– Later on • no atypical absences • no myoclonic seizures• seizures become more focal

- EEG: focal spikes

- Cognition: normal or specific deficits

– Generally no SCN1A mutation

– Normal/abnormal MRI

(Sarisjulis et al; 2OOO)

If you should have any doubts, avoid CBZ and obtain a precise description of the seizures

(home video)

* Other myoclonic epilepsies:

Epilepsy with myoclonic-atonic seizures

(Doose syndrome)

* Other epilepsies

Early Lennox-Gastaut syndrome (not

relevant)

� Relationship with the GEFS+ syndrome

� Relationship with Protocadherin 19 (PCDH19)

In Childhood

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Video

Doose syndrome: - drop-attack (atonic seizure)

- myoclonic-atonic seizure

LGS: - atonic-tonic atypical absence

- nocturnal axial tonic seizure

� Relationship with GEFS+

(Genetic epilepsy with febrile seizures +)

1/ Family context: several members with FS, FS+, epilepsy

→ GTCS, absences, focal seizures,

rarely myoclonic-astatic epilepsy

* with usually benign outcome, no mental impairment

* SCN1A mutation in 10-20%.

* “There is a possibility of simultaneous involvement of multiple genes for seizure phenotypes.” (Ito et al, 2006)

2/ One patient with Dravet syndrome may be a member

of a GEFS+ family

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� Relationship with Protocadherin 19 gene

• an almost similar semiology with slight variations

- later onset (mean 7.5 months)

- seizures in clusters

- less frequent

status epilepticus,

myoclonic and atypical absence seizures,

- less severe epilepsy in childhood

• is observed in girls without SCN1A mutation

with PCDH19 mutation on X chromosome

(Dibbens et al;2008 - Marini et al; 2010 - Depienne et al; 2012)

SCN1A-POSITIVE VERSUS PCDH19-POSITIVE

Unpublished data from Leguern et al.

Normal Development before seizure onset

Age at onset ≤ 1 an

Association of febrile /afebrile seizures

Association of generalised / focal seizures

Prolonged seizures or seizures in cluster n=66n=113

SCN1A PCDH19

Mean age at onset: 6 months (1-12)

Highly frequent status epilepticus (82%)

Pharmacoresistance persisting

over time

Highly polymorphic seizures:

Frequent myoclonic jerks (50%)

Frequent atypical absences (85%)

Mean age at onset: 10 months (3-60)

Less frequent status epilepticus (52%)

Intractable seizures at the beginning

Frequency decreases with age

Less polymorphic seizures:

Infrequent myoclonic jerks (20%)

Infrequent atypical absences (20%)

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The American Journal of Human Genetics 93, 1–9, November 7, 2013

De Novo Loss-of-Function Mutations in CHD2 Cause

a Fever-Sensitive Myoclonic Epileptic Encephalopathy

Sharing Features with Dravet Syndrome

Arvid SULS and the EuroEPINOMICS RES Consortium

Nat Genet. 2013 July ; 45(7): . doi:10.1038/ng.2646.

Targeted resequencing in epileptic encephalopathies

identifies de novo mutations in CHD2 and SYNGAP1

Gemma L. Carvill1, Sinéad B. Heavin2, Simone C. Yendle2, Jacinta M. McMahon2, Brian J.

O’Roak3, Joseph Cook1, Adiba Khan1, Michael O Dorschner4,5, Molly Weaver4,5, Sophie

Calvert6, Stephen Malone6, Geoffrey Wallace6, Thorsten Stanley7, Ann M. E. Bye8, Andrew

Bleasel9, Katherine B. Howell10, Sara Kivity11, Mark T. Mackay10,12,13, Victoria Rodriguez-

Casero14, Richard Webster15, Amos Korczyn16, Zaid Afawi17, Nathanel Zelnick18, Tally

Lerman-Sagie19, Dorit Lev19, Rikke S. Møller20, Deepak Gill15, Danielle M. Andrade21,

Jeremy L. Freeman10,12, Lynette G. Sadleir7, Jay Shendure3, Samuel F. Berkovic2, Ingrid E.

Scheffer2,10,13,22,*, and Heather C. Mefford1,*

CHD2 syndrome

More heterogeneous

- Variable onset age , most often after 1 year (12m-5years)

- Inconstant fever-sensitivity

- Possible delayed development before seizure onset

- Multiple seizure types including myoclonic seizures

- Frequent and strong photosensitivity with autostimulation

- Predominance of generalized anomalies on EEG

This syndrome is clearly different from Dravet syndrome,

even in its incomplete forms

Video

2 brief myoclonic seizures in a boy with CHD2 syndrome,

published by Carvill et al,2013

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� All the authors have failed to find any significant

correlations genotype / phenotype (Fontana et al, 2004,

Oguni et al, 2005 Akiyama et al, 2010, Brunkhaus et al,

2012...)

Except an earlier age at onset in patients with

truncation, splice site mutation, genomic deletion

(Marini et al, 2010 )

� Researches are ongoing in order to discover other

mutations, variants, modifiers, epigenetic factors

capable to explain the negative cases, and the

variability in the correlation genotype/ phenotype

Genotype/ phenotype correlations

Not consistently found

Clinical outcome

1/ Epilepsy severity

2/ Occurrence of acute encephalopathies

3/ Ocurrence of SUDEP

4/ Different cognitive outcomes

Role of genetics in the different outcomes?

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Recent clinical studies (Chieffo et al,2011, Nabbout et al, 2013, Villeneuve et al, 2014) are in favour of the effect of mutations rather than epilepsy, supported by experimental studies (Bender et al, 2013, 2016, Tsai et al,2015, Maeda et al, 2016 ) but the mechanisms of these effects are still not well known.

Our findings suggest that SCN1A mutation leads to changes in the dopamine system that may contribute to the behavioral abnormalities in DS.

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Conversely, other recent studies are in favour of the effect of epilepsy (Ragona et al,2011, Olivieri et al, 2016)

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Group 1: 19 children onset

5,3 ± months

Group 2: 7 children

onset 6,5 ± months

Mean decrease

12.08 ± 5

Mean

decrease

39.8 ± 16

Mean decrease

32.3 + 18.9Total group; 26

children Ragona et al,

2011

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Comments of this slide in the article by Ragona et al, 2011

The analysis of individual cognitive profiles showed that

- 19 pts exhibited a steep decrease in GQ (group 1),

- whereas in 7 pts who had been assessed at comparable ages, the

decrease was less steep, and the differential (d)GQ was lower than

20 points (group 2).

On the basis of this arbitrary cut-off of 20 points of dGQ, we

observed that,

although the difference was statistically non significant,

absences and myoclonus during the first 3 years of life

were present in 12 of 19 patients of group 1 (63%)

and in only 1 patient of group 2 (14%).

the higher incidence of complete forms among the cases with more severe neurological and neuropsychological findings,together with more severe epileptic severity in the lastyears (in particular, background EEG abnormalities) would suggest a possible responsibility of some epileptic disorders(early myoclonic seizures and atypical absences, aswell as persistent background slowness) in worsening theneuropsychological outcome, as others already stressed.

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Cerebellar and extra-striate dorsal stream?

Where are we going to?

???????????

New technologies give us great hope but also great perplexity : next generation sequencing, genome analysis, experimental studies ...

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New treatment approaches

1/ Fenfluramine

3/ Could we consider the possibility of a true cure through a genic treatment?

2/ Cannabinoids ?Several trials are ongoing and the preliminary results are encouraging

C0NCLUSION

� In 1978, SMEI was only a syndrome

� In 2016, Dravet syndrome is a disease comprising epilepsy, cognitive, behavioral and motor impairment

� due to genetic alterations mainly consisting of mutations in the SCN1A gene, exceptionally in other genes

� The phenotype/genotype relationship remains unclear

� A part of the cases remain without known genetic etiology

� New therapeutic perspectives are now opening

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My colleagues and friends

In Marseille

J.RogerM.BureauB.Dalla BernardinaC.A. TassinariC.Cassé-PerrotG.Delahaye

In Italy

D.Battaglia R.Guerrini F.Guzzetta D.Chieffo

Château d’If in the Marseille gulf