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Mitohondrijske bolezni in epilepsija
David Neubauer PTON III – pomladni semester
2016
Dejstva
• Mitohondrijske motnje dihalne verige so relaBvno pogoste: prevalenca je 1:5000
• Genetsko so heterogene in do danes je odkriBh preko 130 genskih mutacij (mitohondrijske in jedrne DNA)
• Glavni genetski vzroki mitohondrijskih epilepsij so mutacije v mitohondrijski DNA
Developmental Medicine & Child Neurology 2012, 54: 397–406
Dejstva
• Epilespija je lahko prvi simptom, ponavadi pa je zgolj del mulBsistemske klinične prezentacije
• Ponavadi tako epilepsijo težko zdravimo in je napovedni znak slabega izida
• Do danes pravega zdravljenja nimamo – otroci potrebuejo ponavadi več PEZ, medtem ko podporna zdravljenja (vitamini, prehranska dopolnila, ketogena dieta) niso preverjena zdravila
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Molekularni mehanizmi, ki vodijo do epilepsije
FenoBp/ genoBp epilepsije
Izboljšanje simptomov po jemanju koencima Q10
0
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Motorični zaostanek
Sedenje
Stoja
Hoja
Stabilnost drže
Potresavanje z glavo in/ali trupom (ataksija)
Tresenje rok (tremor) pri doBkanju/prijemanju predmetov
Koordinacija gibov
Nehotni zgibki – Bki, stereoBpije
Oslabelost mišic
Hiperm
obilnost (laksnost) sklepov
Očesni kontakt (sledenje prstu)
Trzanje oči (nistagmus)
Vedenjska slika
Koncentracija
Govor (tekoče, razumljivo)
Spanje
Bolečina
Migrena (glavobol)
Obolevanje
Krvni tlak
Drugo (navedite)
Brez izboljšanja /niso bili pozorni Izboljšanje
Drugo
Počutje
ApeBt
Škiljenje
Požiranje hrane
Vsakodnevne akBvnosB
Kondicija
Energija
Moč
Volja
Volja do teka in gibanja
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Motorični simptomi z odličnim izboljšanjem
Motorični zaostanek
Sedenje
Stabilnost drže
Oslabelost mišic
Očesni kontakt
Mitohondrijske bolezni in EEG Even certain mitochondrial disorders may have rather typical EEG:
• Epilep8c seizures are the first symptom in more than half of the cases,
• More than 70% of these will present either with par8al seizures (with elementary motor symptoms) or with mul8focal epilep8form ac8vi8es
• MERRF = generalized myoclonic seizures • MELAS (?Leigh) = photoparoxysmal response
Canafoglia L et al. Neurology 2001;56:1340-‐6.
Leigh
Bilateralna straiatna nekroza
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Canafoglia L et al. Neurology 2001;56:1340-‐6
atypical myoclonus epilepsy with ragged-‐red fibers
Low frequency phoBc sBmulaBon – Bme-‐locked posterior sharp transients
+ larger amplitudes over RT
Naš primjer
• Nakon starosB od 5 godina generalizirani mioklonizmi kod umora ili jutranjeg buđenja;
• Mioklonizmi poput električnog udara, po cjelom tjelu • U serijama, u trajanju 2-‐3 sata • Osnovne pretrage, MRI glave, laktat, aminokiseline, organske kiseline – normalno
• Neuspjelo lječenje sa topiramatom, lamotriginom, valproatom
• Nešto manje napadaja nakon uvođenja mitohondrijskog koktejla
• EEGji – drugo mišljenje – MERRF?
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Canafoglia L et al. Neurology 2001;56:1340-‐6
Mitochondrial associated with PDH deficiency
PaBent 9 mos: Interictal EEG
MulBfocal sharp waves posteriorly
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Canafoglia L et al. Neurology 2001;56:1340-‐6 Mitochondrial associated with PDH deficiency
100 uV 1 sec
Ictal discharge Associated with clinical: ParBal seizure with lip protrusion and slight head version
Canafoglia L et al. Neurology 2001;56:1340-‐6 Mitochondrial associated with PDH deficiency
Brief eye versive seizure AWAKE
Canafoglia L et al. Neurology 2001;56:1340-‐6 Mitochondrial associated with PDH deficiency
ICTAL EEG: Short ictal run of fast acBvity
? Higher amplitudes Lt (= lateralized onset)
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Canafoglia L et al. Neurology 2001;56:1340-‐6 Mitochondrial associated with PDH deficiency
ICTAL EEG: Short ictal run of fast acBvity
? Higher amplitudes Lt (= lateralized onset)
Canafoglia L et al. Neurology 2001;56:1340-‐6 Mitochondrial associated with PDH deficiency
Hypsarrhythmic paoern with prominent
polymorphic slow acBvity and
rare sharp posteriorly SLEEP
Naša paciejnBca
• Težka epilepsija sa napadajima od 1. godine života
• U glavnom atonički napadaji • Težka psihomotorna retardacija • Bez reakcije na razlićite AED • Predvidena za operaciju epilepsije > biopsija mišića
• Težka deplecija piruvat dehidrogenaze
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EEG
MulBfocal & focal sharp
EEG
Ictal spikes with slight head version
EEG
generalized spikes without obvious clinical signs
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EEG
Tonic arm stretch
EEG Eye opening deep sigh
Canafoglia L et al. Neurology 2001;56:1340-‐6 Complex IV deficiency
At IPS 10 Hz sharp waves with massive myoclonus
Boy, aged 7 years
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Canafoglia L et al. Neurology 2001;56:1340-‐6
Boy, 7 years Complex IV def.
Rt posterior sharp
waves
Patogeneza
• Patogeneze mithondrijskih epilepsij še ne razumemo dovolj, kar doprinese do ogromnih težav pri zdravljenju teh stanj.
• Epilepsija je slab prognosBčen znak pri mitohondrijskih boleznih in
• nujno potrebujemo jasne klinične poskuse z različnimi kandidatnimi zdravili, vključno s koencimom Q10, ketogeno dieto in novimi terapevtskimi substancami.
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PEZ: praviloma se izogibamo valproatu -‐ Depakine
• Individuals at greatest risk of valproate-‐related toxicity are those with POLG mutaBons, in whom the drug may trigger fulminant and fatal hepaBc failure.
• For this reason, it is advisable to avoid valproate in individuals in whom there is a strong suspicion of mitochondrial disease, and especially in cases where pathogenic POLG mutaBons have been idenBfied.
• If valproate needs to be considered, for example because of lack of seizure control using alternaBve AEDs, then there is some evidence that prophylacBc co-‐treatment with L-‐carniBne may ameliorate the condiBon
• če že – potem v kombinaciji z L-‐karniBnom
PEZ
leveBracetam (Keppra) je sredstvo prvega izbora za mioklonus pri sindromu MERRF • tudi lamotrigine (Lamictal) ima lahko nevroprotekBvni učinek
• V veliki večini primerov bo treba uporabiB kombinacjo več PEZ, da dosežemo več ali manj dober nadzor nad epilepBčnimi napadi
PEZ • Studies in Japanese individuals with them.3243A>G mutaBon have suggested that arginine may reduce the severity and frequency of stroke-‐like episodes in individuals with MELAS syndrome
• There is some anecdotal evidence that seizures in the Kearns–Sayre syndrome may be related to white maoer lesions associated with cerebral folate (5-‐methyltetrahydrofolate) deficiency, and that folinic acid (Leucovorin) supplementaBon may lead to symptomaBc benefit in these individuals
Vloga arginina za preprečevanje števila in stopnje kapi pri sindromu MELAS
…In vloga folinične kisline (levkovorina) pri nadozru nad epi napadi
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PEZ
• Preliminary preclinical studies have suggested that ketogenic diet may be beneficial in a subgroup of mitochondrial disease,
• namely those with mtDNA deleBons
Ketogena dieta je lahko učinkovita zlasti pri delecijah mtDNA
Epilepsia. 2007 Jan;48(1):82-‐8. Safe and effecBve use of the ketogenic diet in children with epilepsy and mitochondrial respiratory chain complex defects. Kang HC, Lee YM, Kim HD, Lee JS, Slama A.
• 9 complex I • 1 complex II • 3 complex IV • 1 complex I and IV
• 7 paBents become seizure-‐free; 1 > 90% reducBon and 2 50%-‐90% reducBon
• 4 paBents (incl. 2 with Leigh sy) did not show good results
UČINKOVITOST KD
CoQ10
• DefecBve biosynthesis of the lipophilic electron carrier coenzyme Q10 (CoQ10) typically presents with combined deficiency of complexes I + III or II + III and is frequently associated with seizures.
• The most typical phenotype caused by CoQ10 deficiency was of recurrent rhabdomyolysis associated with an encephalopathy with prominent seizures.
• The molecular cause of this type of CoQ10 deficiency remains unknown, but seizures are also a feature of other phenotypes of CoQ10 deficiency in which the geneBc basis has recently been defined.
Na pomanjkanje oencima Q10 pomislimo ob kombinaciji: rabomioliza + encefalopatija s krči
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• Čeprav je to redko, je vendarle treba prepoznaB morebBne motnje v biosintezi CoQ10, kajB v teh primerih gre za podskupino mitohondrijskih bolezni, ki jih lahko uspešno (po)zdravimo.
• Zato so Shamima Rahman in sod. izdelali diagnosBčni algoritem klinične diagnoze pomanjkanjaCoQ10
Klinični znaki za poskus zdravljenja s CoQ10
• The most frequent presentation of CoQ10 deficiency appears to be ataxia that typically begins in childhood and is often associated with seizures Cerebellar ataxia and coenzyme Q10 deficiency. Lamperti C, Naini A, Hirano M, De Vivo DC, Bertini E, Servidei S, Valeriani M, Lynch D, Banwell B, Berg M, Dubrovsky T, Chiriboga C, Angelini C, Pegoraro E, DiMauro S
Neurology. 2003 Apr 8; 60(7):1206-8.
Na pomanjkanje pomslimo tudi ob kombinaciji ataksije in epileptičnih napadov
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Klinični znaki za poskus zdravljenja s CoQ10
Less frequently observed phenotypes include
• slowly progressive Leigh syndrome (initially reported in two adult sisters with encephalopathy and severe mental retardation associated with ataxia, deafness, growth retardation and
lactic acidosis) • and isolated myopathy .
Coenzyme Q10 deficiency and isolated myopathy. Horvath R, Schneiderat P, Schoser BG, Gempel K, Neuen-Jacob E, Plöger H, Müller-
Höcker J, Pongratz DE, Naini A, DiMauro S, Lochmüller H Neurology. 2006 Jan 24; 66(2):253-5.
Klinični znaki za poskus zdravljenja s CoQ10
Patients with the myopathic form have presented with • exercise intolerance between 6 and 33 years, • associated with proximal muscle weakness, • elevated CK (up to 20 times upper limit of normal) and • lactic acidosis (up to 10 times normal levels after
exercise) • and no evidence of disease affecting other organ
systems. • There is typically a dramatic response to exogenous
CoQ10.
Klinični znaki za poskus zdravljenja s CoQ10
The considerable overlap of the CoQ10 deficient phenotypes with other mitochondrial disorders makes clinical recognition of CoQ10 deficiency extremely challenging.
Nevertheless, it is important to be vigilant for clinical clues to diagnose patients so treatment can be initiated early in the disease.
It is important to suspect infantile-onset CoQ10 deficiency
V dojenčkovem obdobju moramo vedno pomisliti na pomanjkanje koencima Q10
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Sekundarna pomanjkanja CoQ10
• Mutations in the ETFDH gene: These patients presented with fluctuating proximal and axial myopathy, and exercise intolerance.
• The mechanism of CoQ10 deficiency in MADD remains unknown
• Ataxia with oculomotor apraxia type I (AOA1): clinical improvement with CoQ10
• Secondary CoQ10 deficiency has also been reported in a number of patients with primary mtDNA mutations
Zdravljenje Supplementation with oral CoQ10: • 10–30 mg/kg/day in children and • 1,200–3,000 mg/day in adults seems effective in patients with COQ2
mutations • Genetic diagnosis of CoQ10 deficiency
remains challenging because of the genetic heterogeneity of this disease group.
Tolerance of high-dose (3,000 mg/day) coenzyme Q10 in ALS. Ferrante KL, et al.
Neurology. 2005 Dec 13; 65(11):1834-6.
Zdravljenje Včash je bolje izbrati aktivno obliko
koencima Q10 = idebenon, ker lahko prečka krvno-možgansko pregrado
• CoQ10 does not cross the blood–brain barrier; therefore, it may have limited effect on the central nervous system. Idebenone is a CoQ10 analog that can cross the blood–brain barrier and has been shown to improve neurological complicaAons in some case reports
Lekoubou A et al. Effect of long-term oral treatment with L-arginine and idebenone on the prevention of strokelike episodes in an adult MELAS patient, Rev. Neurol. (Paris) 167 (2011) 852–855.
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Zaključek
• Danes še vedno ne vemo, katera od funkcij CoQ10 (electron transfer, antioxidant, pyrimidine biosynthesis, modulation of apoptosis or extramitochondrial roles) je najbolj relevantna za nastanek bolezni pomanjkanja pri ljudeh.
• Ko bomo enkrat to razumeli, bomo lahko napredovali na področju zdravljenja cele skupine teh bolezni/stanj, ki so potencialno lahko ozdravljive.
