Quand penser à une maladie mitochondriale devant une ... · Quand penser à une maladie...

Quand penser à une maladie

mitochondriale devant une

epilepsie chez l’enfant?

Brigitte Chabrol

Centre de référence, maladies héréditaires du métabolisme

Hôpital d’Enfants, CHU Timone

Marseille, France

Crise épileptique vs Epilepsie

ILAE: 2005

Une crise épileptique est une présence transitoire de signes et/ou

symptômes due à une activité neuronale excessive ou synchrone

anormale dans le cerveau.

L’épilepsie est un trouble cérébral caractérisé:

par une prédisposition durable à générer des crises épileptiques

par les conséquences neurobiologiques, cognitives, psychologiques

et sociales de cette affection.

La définition de l’épilepsie requiert la survenue d’au moins une crise

épileptique.

Enfants épileptiques:

France: 120.000 enfants

40.000 = épilepsie sévère

PACA: 12.000 enfants

4.000 = épilepsie sévère

Combien d’origine mitochondriale ?????

Etude UK: 213 enfants avec épilepsie pharmacorésistante : 2,3 % Mutation POL G (Uusimaa et al, 2013)

Mitochondrial DysfunctioninEpilepsy

DivyaS.Khurana, MD, IgnacioValencia, MD,Michael J.Goldenthal, PhD,

andAgustínLegido, MD, PhD, MBA

Epilepsyisthemostcommonneurologicdisorderworldwideandischaracterizedbyrecurrent

unprovokedseizures.Themitochondrial (mt)respiratorychainisthe nalcommonpathwayfor

cellularenergyproductionthroughtheprocessof oxidativephosphorylation.Asneuronsare

terminallydifferentiatedcellsthatlacksigni cantregenerativecapacityandhaveahighenergy

demand, theyaremorevulnerabletomt dysfunction. Therefore,epilepticseizureshavebeen

welldescribedinseveraldiseasessuchasmtencephalomyopathy, lacticacidosis,andstroke-

like episodes and myoclonic epilepsy and ragged red bers, which are caused by gene

mutationsinmtDNA,amongothers.MutationsinnuclearDNAregulatingmt functionarealso

being described (eg, POLG gene mutation). The role of mitochondria (mt) in acquired

epilepsies, whichaccount for about 60%of all epilepsies, isequally important but lesswell

understood. Oxidative stress is one of the possible mechanisms in the pathogenesis of

epilepsyresultingfrommtdysfunctiongraduallydisruptingtheintracellularCa2þ homeostasis,

which modulates neuronal excitability and synaptic transmission, making neurons more

vulnerable toadditional stress, and leading toenergy failureandneuronal loss inepilepsy.

Antiepilepticdrugs(AEDs)alsoaffectmtfunctioninseveralways.Theremustbecautionwhen

treatingepilepsyinpatientswithknownmt disordersassomeAEDsaretoxictothemt.This

reviewsummarizesourcurrentknowledgeoftheeffectofmtdisordersonepilepsy,ofepileptic

seizuresonmt,andofAEDsonmtfunctionandtheimplicationsofall theseinteractionsforthe

management of epilepsyinpatientswithorwithout mt disease.

SeminPediatr Neurol 20:176-187C2013Elsevier Inc.All rightsreserved.

Thedramaticclinical presentationof manyseizuredisor-

derswasdescribedbytheGreekswhodevelopedtheterm

“epilepsy”(meaning“seizedupon”),whichisstillused.1Epileptic

seizureisde nedbytheInternational LeagueAgainst Epilepsy

as “atransient occurrenceof signsand/or symptomsdueto

abnormal excessiveor synchronous neuronal activity in the

brain.”Toestablishthediagnosisof epilepsy, thepatient must

haveat least2nonfebrileseizuresoccurringdaysapartorwithin

24hours.2,3Epilepsyisthemostcommonneurologicdisorder,

affectingabout 0.5%-1.0%of thepopulationworldwide.1-3

Seizuresvary with respect toneurologic involvement and

severity,rangingfromminimalchangesor“staringepisodes”to

orid, generalizedmusclejerkingand lossof consciousness,

which maybelifethreatening.1 Aseizureinvolvesneuronal

dysfunction.Often,therearenostructuralchangesinthebrain

cells. Alternatively, evidence of earlier brain injury, gliosis,

vascular changes, andscarringinbrain tissuemaysuggest a

large-scalestructural problem.1

Theterm“mt disease” referstoanydisorder affectingthe

respiratory chain, or electron transport chain (ETC) and

oxidative phosphorylation (OXPHOS) system to generate

adenosine triphosphate (ATP). This pathway consists of

5multienzymecomplexesoftherespiratorychain(complexes

I-V)containing4 80proteinsandlocatedinthemitochondria

(mt) inner membrane.4-7

Mitochondrial (mt) diseases aremultisystemic disorders.8

However, themost commonclinical presentation isencepha-

lomyopathy, andepilepticseizurescanfrequentlyoccur asan

initial signor manifest duringthecourseof themt encephal-

opathy.9Different epilepsyphenotypeshavebeendescribedin

mt diseases secondary to mtDNA mutations, including mt

encephalomyopathy, lacticacidosis, and stroke-likeepisodes

(MELAS),myoclonicepilepsyandraggedred bers(MERRF),

progressiveexternal ophthalmoplegia, Leber hereditary optic

neuropathy,Kearns-Sayresyndrome,andLeighdisease,among

others.Newepilepsyphenotypesarebeingdescribedassociated

with newmtDNAmutationsand tomt-relatednuclear gene

mutations.3,10 Recently, several authors have reported the

clinicalmanifestationsofepilepsyinpatientswhodemonstrated

176 1071-9091/13/$-seefront matter&2013Elsevier Inc.All rightsreserved.

http://dx.doi.org/10.1016/j.spen.2013.10.001

Sectionof Neurology,Departmentsof PediatricsandNeurology,St. Christo-

pher's Hospital for Children, Drexel University College of Medicine,

Philadelphia, PA.

Addressreprint requeststo DivyaS. Khurana, MD, Section of Neurology,

St.Christopher'sHospital forChildren,3601ASt,Philadelphia,PA19134.

E-mail: divya.khurana@drexelmed.edu

Mitochondrial DysfunctioninEpilepsy

DivyaS.Khurana, MD, IgnacioValencia, MD,Michael J.Goldenthal, PhD,

andAgustínLegido, MD, PhD, MBA

Epilepsyisthemostcommonneurologicdisorderworldwideandischaracterizedbyrecurrent

unprovokedseizures.Themitochondrial (mt)respiratorychainisthe nalcommonpathwayfor

cellularenergyproductionthroughtheprocessof oxidativephosphorylation.Asneuronsare

terminallydifferentiatedcellsthatlacksigni cantregenerativecapacityandhaveahighenergy

demand, theyaremorevulnerabletomt dysfunction. Therefore,epilepticseizureshavebeen

welldescribedinseveraldiseasessuchasmtencephalomyopathy, lacticacidosis,andstroke-

like episodes and myoclonic epilepsy and ragged red bers, which are caused by gene

mutationsinmtDNA,amongothers.MutationsinnuclearDNAregulatingmt functionarealso

being described (eg, POLG gene mutation). The role of mitochondria (mt) in acquired

epilepsies, whichaccount for about 60%of all epilepsies, isequally important but lesswell

understood. Oxidative stress is one of the possible mechanisms in the pathogenesis of

epilepsyresultingfrommtdysfunctiongraduallydisruptingtheintracellularCa2þ homeostasis,

which modulates neuronal excitability and synaptic transmission, making neurons more

vulnerable toadditional stress, and leading toenergy failureandneuronal loss inepilepsy.

Antiepilepticdrugs(AEDs)alsoaffectmtfunctioninseveralways.Theremustbecautionwhen

treatingepilepsyinpatientswithknownmt disordersassomeAEDsaretoxictothemt.This

reviewsummarizesourcurrentknowledgeoftheeffectofmtdisordersonepilepsy,ofepileptic

seizuresonmt,andofAEDsonmtfunctionandtheimplicationsofall theseinteractionsforthe

management of epilepsyinpatientswithorwithout mt disease.

SeminPediatr Neurol 20:176-187C2013Elsevier Inc.All rightsreserved.

Thedramaticclinical presentationof manyseizuredisor-

derswasdescribedbytheGreekswhodevelopedtheterm

“epilepsy”(meaning“seizedupon”),whichisstillused.1Epileptic

seizureisde nedbytheInternational LeagueAgainst Epilepsy

as “atransient occurrenceof signsand/or symptomsdueto

abnormal excessiveor synchronous neuronal activity in the

brain.”Toestablishthediagnosisof epilepsy, thepatient must

haveat least2nonfebrileseizuresoccurringdaysapartorwithin

24hours.2,3Epilepsyisthemostcommonneurologicdisorder,

affectingabout 0.5%-1.0%of thepopulationworldwide.1-3

Seizuresvary with respect toneurologic involvement and

severity,rangingfromminimalchangesor“staringepisodes”to

orid, generalizedmusclejerkingand lossof consciousness,

which maybelifethreatening.1 Aseizureinvolvesneuronal

dysfunction.Often,therearenostructuralchangesinthebrain

cells. Alternatively, evidence of earlier brain injury, gliosis,

vascular changes, andscarringinbrain tissuemaysuggest a

large-scalestructural problem.1

Theterm“mt disease” referstoanydisorder affectingthe

respiratory chain, or electron transport chain (ETC) and

oxidative phosphorylation (OXPHOS) system to generate

adenosine triphosphate (ATP). This pathway consists of

5multienzymecomplexesoftherespiratorychain(complexes

I-V)containing4 80proteinsandlocatedinthemitochondria

(mt) inner membrane.4-7

Mitochondrial (mt) diseases aremultisystemic disorders.8

However, themost commonclinical presentation isencepha-

lomyopathy, andepilepticseizurescanfrequentlyoccur asan

initial signor manifest duringthecourseof themt encephal-

opathy.9Different epilepsyphenotypeshavebeendescribedin

mt diseases secondary to mtDNA mutations, including mt

encephalomyopathy, lacticacidosis, and stroke-likeepisodes

(MELAS),myoclonicepilepsyandraggedred bers(MERRF),

progressiveexternal ophthalmoplegia, Leber hereditary optic

neuropathy,Kearns-Sayresyndrome,andLeighdisease,among

others.Newepilepsyphenotypesarebeingdescribedassociated

with newmtDNAmutationsand tomt-relatednuclear gene

mutations.3,10 Recently, several authors have reported the

clinicalmanifestationsofepilepsyinpatientswhodemonstrated

176 1071-9091/13/$-seefront matter&2013Elsevier Inc.All rightsreserved.

http://dx.doi.org/10.1016/j.spen.2013.10.001

Sectionof Neurology,Departmentsof PediatricsandNeurology,St. Christo-

pher's Hospital for Children, Drexel University College of Medicine,

Philadelphia, PA.

Addressreprint requeststo DivyaS. Khurana, MD, Section of Neurology,

St.Christopher'sHospital forChildren,3601ASt,Philadelphia,PA19134.

E-mail: divya.khurana@drexelmed.edu

Mitochondrial DysfunctioninEpilepsy

DivyaS.Khurana, MD, IgnacioValencia, MD,Michael J.Goldenthal, PhD,

andAgustínLegido, MD, PhD, MBA

Epilepsyisthemostcommonneurologicdisorderworldwideandischaracterizedbyrecurrent

unprovokedseizures.Themitochondrial (mt)respiratorychainisthe nalcommonpathwayfor

cellularenergyproductionthroughtheprocessof oxidativephosphorylation.Asneuronsare

terminallydifferentiatedcellsthatlacksigni cantregenerativecapacityandhaveahighenergy

demand, theyaremorevulnerabletomt dysfunction. Therefore,epilepticseizureshavebeen

welldescribedinseveraldiseasessuchasmtencephalomyopathy, lacticacidosis,andstroke-

like episodes and myoclonic epilepsy and ragged red bers, which are caused by gene

mutationsinmtDNA,amongothers.MutationsinnuclearDNAregulatingmt functionarealso

being described (eg, POLG gene mutation). The role of mitochondria (mt) in acquired

epilepsies, whichaccount for about 60%of all epilepsies, isequally important but lesswell

understood. Oxidative stress is one of the possible mechanisms in the pathogenesis of

epilepsyresultingfrommtdysfunctiongraduallydisruptingtheintracellularCa2þ homeostasis,

which modulates neuronal excitability and synaptic transmission, making neurons more

vulnerable toadditional stress, and leading toenergy failureandneuronal loss inepilepsy.

Antiepilepticdrugs(AEDs)alsoaffectmtfunctioninseveralways.Theremustbecautionwhen

treatingepilepsyinpatientswithknownmt disordersassomeAEDsaretoxictothemt.This

reviewsummarizesourcurrentknowledgeoftheeffectofmtdisordersonepilepsy,ofepileptic

seizuresonmt,andofAEDsonmtfunctionandtheimplicationsofall theseinteractionsforthe

management of epilepsyinpatientswithorwithout mt disease.

SeminPediatr Neurol 20:176-187C2013Elsevier Inc.All rightsreserved.

Thedramaticclinical presentationof manyseizuredisor-

derswasdescribedbytheGreekswhodevelopedtheterm

“epilepsy”(meaning“seizedupon”),whichisstillused.1Epileptic

seizureisde nedbytheInternational LeagueAgainst Epilepsy

as “atransient occurrenceof signsand/or symptomsdueto

abnormal excessiveor synchronous neuronal activity in the

brain.”Toestablishthediagnosisof epilepsy, thepatient must

haveat least2nonfebrileseizuresoccurringdaysapartorwithin

24hours.2,3Epilepsyisthemostcommonneurologicdisorder,

affectingabout 0.5%-1.0%of thepopulationworldwide.1-3

Seizuresvary with respect toneurologic involvement and

severity,rangingfromminimalchangesor“staringepisodes”to

orid, generalizedmusclejerkingand lossof consciousness,

which maybelifethreatening.1 Aseizureinvolvesneuronal

dysfunction.Often,therearenostructuralchangesinthebrain

cells. Alternatively, evidence of earlier brain injury, gliosis,

vascular changes, andscarringinbrain tissuemaysuggest a

large-scalestructural problem.1

Theterm“mt disease” referstoanydisorder affectingthe

respiratory chain, or electron transport chain (ETC) and

oxidative phosphorylation (OXPHOS) system to generate

adenosine triphosphate (ATP). This pathway consists of

5multienzymecomplexesoftherespiratorychain(complexes

I-V)containing4 80proteinsandlocatedinthemitochondria

(mt) inner membrane.4-7

Mitochondrial (mt) diseases aremultisystemic disorders.8

However, themost commonclinical presentation isencepha-

lomyopathy, andepilepticseizurescanfrequentlyoccur asan

initial signor manifest duringthecourseof themt encephal-

opathy.9Different epilepsyphenotypeshavebeendescribedin

mt diseases secondary to mtDNA mutations, including mt

encephalomyopathy, lacticacidosis, and stroke-likeepisodes

(MELAS),myoclonicepilepsyandraggedred bers(MERRF),

progressiveexternal ophthalmoplegia, Leber hereditary optic

neuropathy,Kearns-Sayresyndrome,andLeighdisease,among

others.Newepilepsyphenotypesarebeingdescribedassociated

with newmtDNAmutationsand tomt-relatednuclear gene

mutations.3,10 Recently, several authors have reported the

clinicalmanifestationsofepilepsyinpatientswhodemonstrated

176 1071-9091/13/$-seefront matter&2013Elsevier Inc.All rightsreserved.

http://dx.doi.org/10.1016/j.spen.2013.10.001

Sectionof Neurology,Departmentsof PediatricsandNeurology,St. Christo-

pher's Hospital for Children, Drexel University College of Medicine,

Philadelphia, PA.

Addressreprint requeststo DivyaS. Khurana, MD, Section of Neurology,

St.Christopher'sHospital forChildren,3601ASt,Philadelphia,PA19134.

E-mail: divya.khurana@drexelmed.edu

Mitochondrial DysfunctioninEpilepsy

DivyaS.Khurana, MD, IgnacioValencia, MD,Michael J.Goldenthal, PhD,

andAgustínLegido, MD, PhD, MBA

Epilepsyisthemostcommonneurologicdisorderworldwideandischaracterizedbyrecurrent

unprovokedseizures.Themitochondrial (mt)respiratorychainisthe nalcommonpathwayfor

cellularenergyproductionthroughtheprocessof oxidativephosphorylation.Asneuronsare

terminallydifferentiatedcellsthatlacksigni cantregenerativecapacityandhaveahighenergy

demand, theyaremorevulnerabletomt dysfunction. Therefore,epilepticseizureshavebeen

welldescribedinseveraldiseasessuchasmtencephalomyopathy, lacticacidosis,andstroke-

like episodes and myoclonic epilepsy and ragged red bers, which are caused by gene

mutationsinmtDNA,amongothers.MutationsinnuclearDNAregulatingmt functionarealso

being described (eg, POLG gene mutation). The role of mitochondria (mt) in acquired

epilepsies, whichaccount for about 60%of all epilepsies, isequally important but lesswell

understood. Oxidative stress is one of the possible mechanisms in the pathogenesis of

epilepsyresultingfrommtdysfunctiongraduallydisruptingtheintracellularCa2þ homeostasis,

which modulates neuronal excitability and synaptic transmission, making neurons more

vulnerable toadditional stress, and leading toenergy failureandneuronal loss inepilepsy.

Antiepilepticdrugs(AEDs)alsoaffectmtfunctioninseveralways.Theremustbecautionwhen

treatingepilepsyinpatientswithknownmt disordersassomeAEDsaretoxictothemt.This

reviewsummarizesourcurrentknowledgeoftheeffectofmtdisordersonepilepsy,ofepileptic

seizuresonmt,andofAEDsonmtfunctionandtheimplicationsofall theseinteractionsforthe

management of epilepsyinpatientswithorwithout mt disease.

SeminPediatr Neurol 20:176-187C2013Elsevier Inc.All rightsreserved.

Thedramaticclinical presentationof manyseizuredisor-

derswasdescribedbytheGreekswhodevelopedtheterm

“epilepsy”(meaning“seizedupon”),whichisstillused.1Epileptic

seizureisde nedbytheInternational LeagueAgainst Epilepsy

as “atransient occurrenceof signsand/or symptomsdueto

abnormal excessiveor synchronous neuronal activity in the

brain.”Toestablishthediagnosisof epilepsy, thepatient must

haveat least2nonfebrileseizuresoccurringdaysapartorwithin

24hours.2,3Epilepsyisthemostcommonneurologicdisorder,

affectingabout 0.5%-1.0%of thepopulationworldwide.1-3

Seizuresvary with respect toneurologic involvement and

severity,rangingfromminimalchangesor“staringepisodes”to

orid, generalizedmusclejerkingand lossof consciousness,

which maybelifethreatening.1 Aseizureinvolvesneuronal

dysfunction.Often,therearenostructuralchangesinthebrain

cells. Alternatively, evidence of earlier brain injury, gliosis,

vascular changes, andscarringinbrain tissuemaysuggest a

large-scalestructural problem.1

Theterm“mt disease” referstoanydisorder affectingthe

respiratory chain, or electron transport chain (ETC) and

oxidative phosphorylation (OXPHOS) system to generate

adenosine triphosphate (ATP). This pathway consists of

5multienzymecomplexesoftherespiratorychain(complexes

I-V)containing4 80proteinsandlocatedinthemitochondria

(mt) inner membrane.4-7

Mitochondrial (mt) diseases aremultisystemic disorders.8

However, themost commonclinical presentation isencepha-

lomyopathy, andepilepticseizurescanfrequentlyoccur asan

initial signor manifest duringthecourseof themt encephal-

opathy.9Different epilepsyphenotypeshavebeendescribedin

mt diseases secondary to mtDNA mutations, including mt

encephalomyopathy, lacticacidosis, and stroke-likeepisodes

(MELAS),myoclonicepilepsyandraggedred bers(MERRF),

progressiveexternal ophthalmoplegia, Leber hereditary optic

neuropathy,Kearns-Sayresyndrome,andLeighdisease,among

others.Newepilepsyphenotypesarebeingdescribedassociated

with newmtDNAmutationsand tomt-relatednuclear gene

mutations.3,10 Recently, several authors have reported the

clinicalmanifestationsofepilepsyinpatientswhodemonstrated

176 1071-9091/13/$-seefront matter&2013Elsevier Inc.All rightsreserved.

http://dx.doi.org/10.1016/j.spen.2013.10.001

Sectionof Neurology,Departmentsof PediatricsandNeurology,St. Christo-

pher's Hospital for Children, Drexel University College of Medicine,

Philadelphia, PA.

Addressreprint requeststo DivyaS. Khurana, MD, Section of Neurology,

St.Christopher'sHospital forChildren,3601ASt,Philadelphia,PA19134.

E-mail: divya.khurana@drexelmed.edu

Cause ou conséquence ????

Cause ou conséquence ????

Role du stress oxydatif :

Modification de l’excitabilité

synaptique, et de la transmission synaptique ,

Entrainant une plus grande

vulnérabilité neuronale

Déficit énérgetique secondaire

Perte neuronale

Cause ou conséquence ????

Chez le rat, induction état de mal temporal par acide kainique deficits en complexes I et 3 observés à H3

Chez des patients avec epilepsie temporale et sclérose de l’hippocampe : anomalies ultrastrucurales des mitochondries, et déficit de la chaiîne respiratoire, surtout du complexe 1 ,dans la région C1 de l’hippocampe mais pas dans le reste du tissu cérébral

Atteinte spécifique du complexe 1=

témoin de la mort neuronale induite par les crises

rôle crucial dans l’épileptogénèse

56 patients (1990-2006)

Autres signes précédant l’épilepsie dans 82, 5 % des cas :

Retard de croissance,

Anomalies du développement psychomoteur

Ataxie

Atteinte multisystémique

60 % des patients répartis en 6 groupes

Etat de mal dans le cadre d’une atteinte néonatale multiviscérale (2 patients),

Encéphalopathie myoclonqique néonatale ( 3 patients)

Spasmes infantiles(8 patients),

Etat de mal réfractaire ou récurrent (21 patients),

Epilepsie partielle continue (4 patients),

Epilpesie myoclonique (18 patients).

Epilepsie difficile à traiter dans 95% des cas

Valproate : 25 patients, un seul insuffisance hépatique aigue à J6.

Epilepsie = facteur pronostique sevère: 45% décès, ( la moitié dans les 9 mois aprés le début de l’Epilespie)

Intêret de la PBH

1995 et 2010: 53 enfants épileptiques

groupe 1: présence d’un dysfonctionnement de la

chaîne respiratoire mitochondriale

groupe 2: absence de pathologie mitochondriale.

Archives de Pédiatrie 2012;19:794-802

En pratique :

Epilepsie : trés rarement signe inaugural et isolé

Nombreuses autres atteintes d’organes:

Retard de croissance ( parfois anténatal)

Anomalies du développement psychomoteur

Ophtalmologiques à type d’apraxie oculomotrice, atrophie

optique, rétinite pigmentaire

Auditives: surdité , hypo-acousie

Hépatiques: cytolyse, hépatomégalie

Atteinte plurisystémique ++++++

En pratique: EEG

Pas de tracés pathognomoniques

( contrairement à NCL 2)

En pratique:

IRM +SRM : anomalies chez + de 90 %

Atteinte corticale, ,

Atteinte cérébelleuse

Atteinte des noyaux gris

Atteinte de la SB

en SRM, pic de lactates

Exceptionellement normal

En pratique:

Pas de corrélation nette entre le type d’epilepsie et

le déficit de la chaine respiratoire mitochondriale

Intêret de la PBH

Nombreuses mutations nucléaires +++ ou DNAmt

Tout n’est pas mitochondrial

Encéphalopathies épileptiques précoces :

2 gènes dominants majeurs fréquents :

STXBP1 et KCNQ2

2 gènes récessifs avec une clinique particulière :

TBC1D24 et SLC13A5

XXX autres gènes : CDKL5, PIGQ, PIGO, SCN2A,GNAO1, KCNT1, SLC25A22, PNKP, PLCB1, DOCK7, SLC35A2, GABRB3, HDAC4, SCN8A, SPTAN1, GRIN2A, GRIN2B…

EMP

Ohtahara

Dr Martine Gavaret- CINAPSE

Service de réanimation néonatale. La conception.

Tout n’est pas mitochondrial

STXBP1 KCNQ2

Age début 0-6 semaines 1ere semaine

Type Orage / crises

focales

Orage de crises

toniques

EEG SB / focal SB

Evolution de

l’épilepsie

Rémission Rémission

Evolution EEG Rythmes rapides Anomalies

« fonctionnelles »

PC Normal Normal

Mouvements

anormaux

+++ ++

KCNQ2 (46 cas publiés)

STXBP1 (40 cas)

0

5

10

15

20

25

30

35

40

45

50

0,5 1 2 3 4 5 6 >6

Déficit chaîne respiratoire parfois retrouvé:= secondaire

Tout n’est pas mitochondrial

Mutation RANBP2: Encephalopathie aigue nécrosante

Tout n’est pas mitochondrial

1er enfant: décés à 9 mois: état de mal fébrile,

défaillance multiviscérale en 1 semaine

2eme enfant tableau identique à 9 mois, séquelles

majeures, décès à 3 ans

3eme enfant même tableau à 9 mois,

Etat de mal épileptique

Atteinte hepatique sévère

Coma

Deficit complexe 5

Actuellement: Retard mental, Epilepsie partielle

Au total:

Maladie mitochondriale rarement cause d’une épilepsie

Epilepsie sévère fréquente au cours des maladies

mitochondriales ( 30 %)

Chez l’enfant, epilepsie généralisée

Chez adulte: épilespie partielle

Facteur de mauvais pronostic

Equipe pluridiisciplinaire indispensable = neuropédiatre,

métabolicien, généticien , biochimiste…..

Au total

Pluridisciplinarité=

Filière Maladies Héréditaires du Métabolisme