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Kako se mitohondrijalne bolesti poput MERRF-a nasljeđuju?

Kako se mitohondrijalne bolesti poput MERRF-a nasljeđuju?


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Radim projekat o poremećaju MERRF u mitohondrijskoj DNK. Moram da napravim pedigre i objasnim kako se prenosi s generacije na generaciju. Znam da se nasljeđuje po majci, ali sam zbunjen kako se nasljeđuje. Da li bi se naslijedio kao autozomna DNK na mendelovski način? Ako jeste, da li bi ovaj gen bio dominantan ili recesivan? Ili bi djeca jednostavno automatski naslijedila gen koji imaju njihove majke? Takođe, kako bi se prikazali genotipovi za mitohondrijsku DNK? Bilo koja druga korisna informacija o mitohondrijskoj DNK ili MERRF-u bi takođe bila veoma zahvalna. Hvala.


Smatra se da su mitohondrije prvenstveno naslijeđene od majke, ali sada postoje dokazi da i otac može doprinijeti mitohondrijama (Schwartz i Vissing, 2002; Luo et al., 2018).

Čak i ako su mitohondrije čisto majčinski naslijeđene, stanica (uključujući oocit) obično sadrži mnogo mitohondrija i ne mogu svi mitohondriji imati (štetnu) mutaciju. Ovaj fenomen se naziva heteroplazmija.

MERRF je povezan s gubitkom funkcije mutacije u mitohondrijskim tRNA (vidi NIH, Genetics Home Reference). Stepen do kojeg će ćelija biti pogođena zavisiće od broja mutiranih mitohondrija koje sadrži. Stoga bi različite ćelije bile drugačije pogođene.

Stoga nasljeđivanje osobina ne bi bilo na tipičan mendelovski način.


Baza podataka o rijetkim bolestima

NORD zahvaljuje Kathryn Elliott, MS, uredničku pripravnicu NORD-a sa MS programa za ljudsku genetiku i genetičko savjetovanje Univerziteta Stanford, i Hannah Wand, MS, kliničku instruktoricu (pridružena), Odsjek za pedijatriju, Odsjek za medicinsku genetiku, Univerzitet Stanford, za pomoć u pripremi ovog izvještaja.

Sinonimi za MERRF sindrom

  • mioklonska epilepsija povezana sa ispucanim crvenim vlaknima
  • MERRF
  • Fukuhara sindrom
  • mioklonusna epilepsija povezana sa neravnim crvenim vlaknima
  • mioencefalopatija bolest crvenih vlakana

Opća diskusija

MERRF (myoclonus epilepsija sa rostarjeli-red fibers) je izuzetno rijedak poremećaj koji se javlja u djetinjstvu, adolescenciji ili odrasloj dobi nakon normalnog razvoja u ranom životu. MERRF sindrom utiče na nervni sistem, skeletne mišiće i druge sisteme tela. Karakteristična karakteristika MERRF-a su trzaji mišića (mioklonus), koji se sastoje od iznenadnih, kratkih grčeva koji mogu zahvatiti ruke, noge ili cijelo tijelo. Osobe sa MERRF sindromom mogu takođe imati napade (generalizovana epilepsija), oštećenu sposobnost koordinacije pokreta (ataksija), slabost mišića (miopatija), netoleranciju na fizičku aktivnost i spori pad intelektualne funkcije (demencija). Smanjena tjelesna visina (nizak rast), problemi s vidom (optička atrofija), gubitak sluha, srčana bolest srčanih mišića (kardiomiopatija) i abnormalna senzacija zbog oštećenja živaca (periferna neuropatija) su drugi uobičajeni simptomi. Osobe sa MERRF sindromom će takođe imati abnormalne mišićne ćelije koje se pojavljuju kao raščupana crvena vlakna (RRF) kada su obojene i gledane mikroskopski.

MERRF sindrom je mitohondrijski poremećaj. Mitohondrije su strukture koje se nalaze u ćeliji koje proizvode energiju. Poremećaji mitohondrija mogu nastati kada mitohondrijski genetski materijal (mtDNA) ima genetsku promjenu (mutaciju) koja sprečava mitohondrije da obavljaju svoju funkciju. Kao rezultat toga, dijelovi tijela poput mozga i mišića možda neće raditi ispravno zbog nedostatka energije. MERRF sindrom je uzrokovan mutacijama u mtDNK i naslijeđen je od majke.

Uvod

MERRF sindrom je prvi put prijavljen 1973. godine kada je opisana porodica sa trzajima mišića (mioklonus), napadima i abnormalnim mišićnim ćelijama koje pokazuju karakteristična raščupana crvena vlakna (RRF). Do 1988. identifikovano je 25 ljudi sa sličnom kolekcijom karakteristika. Iste godine utvrđeno je da je MERRF sindrom uzrokovan mutacijama u mitohondrijskoj DNK, a dvije godine kasnije, 1990. godine, otkrivena je prva uzročna genetska mutacija.

Danas se MERRF sindrom obično dijagnosticira kombinacijom kliničkih karakteristika (mioklonus, napadi i ataksija) i RRF koji se vidi na biopsiji mišića. Međutim, neće svi pojedinci kojima je dijagnosticiran MERRF sindrom imati ili razviti iste simptome. Molekularna dijagnoza MERRF-a se postavlja kada se identifikuje genetska mutacija u mitohondrijskom genu za koji se zna da je povezan sa ovim stanjem. Dijagnoza MERRF sindroma može pomoći u praćenju, liječenju simptoma i eventualno pomoći u prevenciji progresije bolesti. Genetska dijagnoza takođe može razjasniti rizik za braću i sestre, roditelje, članove šire porodice i biološko potomstvo, i može pomoći u planiranju porodice.

Znakovi i simptomi

Simptomi MERRF sindroma mogu početi u djetinjstvu, adolescenciji ili ranoj odrasloj dobi nakon perioda normalnog ranog razvoja. Znakovi, simptomi i fizički nalazi povezani sa MERRF sindromom mogu se uvelike razlikovati između pogođenih pojedinaca u istoj porodici i između različitih porodica. Starost početka i brzina napredovanja bolesti mogu se razlikovati među pojedincima.

Kratki, iznenadni grčevi mišića (mioklonus) obično su prvi simptom MERRF sindroma praćen napadima (generalizirana epilepsija), poremećenom sposobnošću koordinacije pokreta (ataksija), slabošću mišića (miopatija) i netolerancijom na vježbanje. Smanjena tjelesna visina (nizak rast), gubitak sluha, opadanje intelektualne funkcije (demencija) i izmijenjeni osjećaj (ubode i igle ili bol) zbog oštećenja živaca (periferna neuropatija) također su uobičajeni simptomi. Neke osobe mogu imati probleme s vidom ili gubitak vida, najčešće uzrokovane degeneracijom optičkog živca (optička atrofija). Oštećenje vida također može biti posljedica spuštanja gornjih kapaka (ptoza), progresivnog oštećenja receptora koji reaguju na svjetlost u mrežnjači oka (pigmentarna retinopatija) ili slabosti očnih mišića (oftalmoplegija). Mogu se pojaviti i problemi sa srcem, uključujući srčanu bolest srčanog mišića (kardiomiopatija) i probleme sa srčanim ritmom (aritmija) kao što je Wolff-Parkinson-White sindrom. Povremeno, ljudi sa MERRF sindromom imaju benigne tumore masnih ćelija (lipome) posebno oko vrata, previše šećera u krvi (dijabetes melitus) i nevoljnu ukočenost mišića (spastičnost) zajedno sa drugim razlikama u refleksima i pokretima (piramidalni znaci). Osobe s MERRF sindromom često imaju nakupljanje mliječne kiseline u krvi (laktacidozu) što može uzrokovati povraćanje, bol u trbuhu, smanjen apetit, neobičnu pospanost ili umor, bol u mišićima ili slabost i otežano disanje.

Uzroci

MERRF sindrom je uzrokovan genetskim promjenama (mutacijama) u mitohondrijskoj DNK (mtDNK). Mitohondrije, koje se nalaze u stotinama ili hiljadama u ćelijama tela, posebno u mišićnom i nervnom tkivu, nose nacrte za regulaciju proizvodnje energije. MtDNA kodira specifične gene koji su upute za stvaranje nekih od bitnih dijelova mitohondrija.

MERRF sindrom je uzrokovan mutacijama u mtDNK. Geni povezani sa MERRF sindromom su instrukcije za specifične molekule zvane transfer RNA. Transfer RNA (tRNA) pomažu u sklapanju proteina, koji zatim izvršavaju mitohondrijalnu funkciju proizvodnje energije. Mutacije u mtDNA genima povezanim sa MERRF dovode do abnormalnih tRNA i posljedično smanjuju sposobnost mitohondrija da grade proteine ​​i proizvode energiju za tijelo. Dijelovi tijela koji zahtijevaju puno energije, poput mišića i mozga, najviše će biti pogođeni ovim mutacijama.

Više od 90% slučajeva MERRF sindroma uzrokovano je mutacijama u jednom genu mtDNA, MT-TK. Jedan konkretan MT-TK mutacija, nazvana m.8344A>G, čini 80% slučajeva. Mutacije u MT-TF, MT-TH, MT-TI, MT-TL1, MT-TP, MT-TS1, i MT-TS2 takođe su povezani sa MERRF sindromom.

Geni za mitohondrije (mtDNK) su naslijeđeni od majke. MtDNK koja se nalazi u ćelijama sperme obično se gubi tokom oplodnje. Kao rezultat, sva ljudska mtDNK dolazi od majke. Majka sa neradnim genom u mtDNK će prenijeti neradni gen svoj djeci, ali će samo njene kćeri prenijeti neradni gen svojoj djeci.

Kako se ćelije dijele, broj normalne mtDNK i neradne (mutirane) mtDNK se distribuira na nepredvidiv način među različitim tkivima. Posljedično, mutirana mtDNK se akumulira različitom brzinom između različitih tkiva kod iste osobe. Stoga, članovi porodice koji imaju identičan nefunkcionalni gen u mtDNK mogu ispoljiti niz različitih simptoma u različito vrijeme i s različitim stupnjevima ozbiljnosti.

I normalna i mutirana mtDNK mogu postojati u istoj ćeliji, situacija poznata kao heteroplazmija. Broj mitohondrija sa nefunkcionalnim genom može biti veći od broja mitohondrija bez gena koji ne radi. Simptomi se možda neće pojaviti ni u jednoj generaciji sve dok značajan dio mitohondrija ne mutira mtDNK. Neravnomjerna distribucija normalne i mutirane mtDNK u različitim tkivima može utjecati na različite organe članova iste porodice. To može dovesti do raznih simptoma kod pogođenih članova porodice.

Općenito se smatra da veći broj mutirane mtDNK u odnosu na normalnu mtDNK odgovara težim simptomima. Međutim, broj mutirane mtDNK u odnosu na normalne mtDNK ne može se koristiti za precizno predviđanje da li će se simptomi pojaviti, koji se simptomi mogu pojaviti ili ozbiljnost simptoma.

Nekoliko rijetkih slučajeva MERRF sindroma dogodilo se kao rezultat nove spontane mutacije mitohondrijalnog gena kod oboljele osobe. Ove mutacije nisu naslijeđene, ali se mogu prenijeti na buduće generacije ako je zahvaćena osoba ženskog pola.

Pogođene populacije

MERRF sindrom je rijedak poremećaj koji pogađa muškarce i žene u jednakom broju. Početak simptoma MERRF sindroma može se javiti u djetinjstvu, adolescenciji ili ranoj odrasloj dobi. Obično se javlja nakon perioda normalnog ranog razvoja.

Prevalencija MERRF sindroma je nepoznata. Međutim, nekoliko studija o mitohondrijskim poremećajima u europskim populacijama otkrilo je da je uobičajeno MT-TK mutacija, m.8344A>G, ima prevalenciju između 0 i 1,5 na 100.000 odraslih u sjevernoj Finskoj, 0.39 na 100.000 odraslih u sjevernoj Engleskoj, između 0 i 0.25 na 100.000 djece u zapadnoj, 7 na sjeveroistoku Švedske i 10.00 pojedinaca u Engleskoj. U skladu sa ovim nalazima, široko se smatra da je prevalencija MERRF-a vjerovatno manja od 1 na 100.000 osoba.

Neki istraživači vjeruju da mitohondrijalne miopatije mogu ostati neprepoznate i nedovoljno dijagnosticirane u općoj populaciji, što otežava određivanje prave učestalosti poremećaja poput MERRF sindroma.

Related Disorders

MELAS sindrom (mitohondrijalna encefalopatija, laktacidoza i epizode slične moždanom udaru) je poremećaj koji počinje u djetinjstvu i pogađa uglavnom nervni sistem i mišiće. Najčešći rani simptomi su napadi, ponavljajuće glavobolje, gubitak apetita i ponavljano povraćanje. Mogu se javiti i epizode slične moždanom udaru s privremenom slabošću mišića na jednoj strani tijela (hemipareza), što može dovesti do promjene svijesti, gubitka vida i sluha, gubitka motoričkih sposobnosti i intelektualnog invaliditeta. Dijabetes melitus i paraliza očnih mišića (kronična progresivna vanjska oftalmoplegija) često su prisutni izolirano ili u kombinaciji s drugim simptomima. MELAS je uzrokovan mutacijama u mitohondrijskoj DNK (mtDNK). Neke mutacije koje uzrokuju MELAS nalaze se u genima mtDNA koji su također povezani sa MERRF sindromom. Kod jednog pacijenta, ovaj sindrom je povezan s mutacijama u nuklearnom genu, POLG1. (Za više informacija o ovom poremećaju, odaberite “MELAS” kao pojam za pretragu u bazi podataka o rijetkim bolestima.)

Kearns-Sayreov sindrom (KSS) je rijedak multisistemski poremećaj. Važna klinička simptomatska karakteristika je prisustvo spuštenih kapaka (ptoza) na jednom ili oba oka. Ovu bolest uglavnom karakteriziraju tri primarna nalaza: progresivna paraliza određenih mišića oka (kronična progresivna vanjska oftalmoplegija [CPEO]), abnormalno nakupljanje obojenog (pigmentiranog) materijala na živcima bogatoj membrani koja oblaže oči (atipični retinitis pigmentosa) ili pigmentno retinopatija, što dovodi do slabog noćnog vida i progresivnog gubitka vida i bolesti srca kao što je kardiomiopatija i/ili progresivna aritmija koja dovodi do potpunog srčanog bloka. Drugi nalazi mogu uključivati ​​slabost mišića, nizak rast, senzorneuralni gubitak sluha, endokrine probleme kao što su dijabetes melitus i hipoparatireoidizam (koji mogu uzrokovati hipokalcemiju) i/ili gubitak sposobnosti koordinacije voljnih pokreta (ataksija) zbog problema koji utječu na dio mozga (cerebelum). Kod nekih pacijenata, KSS može biti povezan sa drugim poremećajima i/ili stanjima. KSS pripada (djelimično) grupi rijetkih poremećaja poznatih kao mitohondrijalne encefalomiopatije. Mitohondrijalne encefalomiopatije su poremećaji kod kojih defekt genetskog materijala (DNK) nastaje iz dijela ćelijske strukture (mitohondrija), koji proizvodi energiju (u obliku adenozin trifosfata ili ATP) uzrokujući nepravilan rad mozga i mišića zbog nedostatak energije (encefalomiopatije). Kod ovih poremećaja prisutan je abnormalno veliki broj defektnih mitohondrija. Kod približno 80 posto pogođenih osoba sa KSS, testovi će otkriti nedostatak genetskog materijala (delecija) koji uključuje jedinstvenu DNK u mitohondrijima (mtDNA). (Za više informacija o ovom poremećaju, odaberite "Kearns Sayre" kao pojam za pretraživanje u rijetkim bolestima Baza podataka.)

Leighov sindrom je rijedak genetski neurometabolički poremećaj. Karakterizira ga degeneracija centralnog nervnog sistema (tj. mozga, kičmene moždine i optičkog živca). Simptomi Leighovog sindroma obično počinju u dobi od tri mjeseca do dvije godine, ali neki pacijenti ne pokazuju znakove i simptome tek nekoliko godina kasnije. Simptomi su povezani s progresivnim neurološkim pogoršanjem i mogu uključivati ​​gubitak prethodno stečenih motoričkih vještina, gubitak apetita, povraćanje, razdražljivost i/ili napade. Kako Leighov sindrom napreduje, simptomi mogu uključivati ​​i generaliziranu slabost, nedostatak mišićnog tonusa (hipotonija) i epizode laktacidoze, što može dovesti do oštećenja respiratorne i bubrežne funkcije. Nekoliko različitih genetski uvjetovanih enzimskih defekata može uzrokovati sindrom, koji je prvobitno opisan prije više od 60 godina. Većina osoba s Leighovim sindromom ima defekte u proizvodnji energije mitohondrija, kao što je nedostatak enzima kompleksa mitohondrijalnog respiratornog lanca ili kompleksa piruvat dehidrogenaze. Kod većine pacijenata, Leighov sindrom se nasljeđuje autosomno recesivno. Međutim, X-vezano recesivno i majčinsko nasljeđe, zbog mutacije mitohondrijske DNK, viđa se u nekim porodicama. (Za više informacija o ovom poremećaju, odaberite “Leigh” kao pojam za pretraživanje u bazi podataka o rijetkim bolestima.)

Kombinovani nedostatak oksidativne fosforilacije je bolest koja pogađa mnoge dijelove tijela. Početak se javlja na ili ubrzo nakon rođenja kod većine pacijenata, a karakteristike mogu uključivati ​​kašnjenje u rastu, malu glavu (mikrocefaliju), povećan tonus mišića, klonulost trupa i glave, bolest mozga (encefalopatiju), uvećani srčani mišić (kardiomiopatiju) i disfunkciju jetre . Postoji mnogo podtipova, uzrokovanih mnogo različitih genskih mutacija. Kombinovani nedostatak oksidativne fosforilacije 27 karakterizira juvenilna teška mioklonusna epilepsija nalik MERRF-u sa ataksijom, spastičnom slabošću koja zahvaća sva četiri uda (spastična tetrapareza), gubitkom vida, gubitkom sluha i kognitivnim opadanjem. Nasljeđuje se autosomno recesivno i uzrokovana je mutacijama u CARS2 gen. (Za više informacija o nedostacima kombinirane oksidativne fosforilacije, odaberite “Kombinirana oksidativna fosforilacija” kao pojam za pretraživanje u bazi podataka rijetkih bolesti).

POLG-poremećaji povezani su niz stanja sa simptomima koji se preklapaju. Poremećaji uključuju: Alpers-Huttenlocherov sindrom (AHS), miocerebrohepatopatiju u djetinjstvu (MCHS), miokloničnu epilepsiju, miopatiju, senzornu ataksiju (MEMSA), spektar neuropatije ataksije (ANS), autosomno recesivnu progresivnu eksternu oftalmoplegiju (arPEO) i autosomno-recesivno progresivni vanjski ophtalmoplegiju (arPEO) adPEO). Simptomi i težina ovih stanja variraju, ali uobičajene karakteristike uključuju: poremećaj pokreta uključujući mišićne grčeve (mioklonus), napade (epilepsija), oštećenu sposobnost koordinacije pokreta (ataksija), abnormalni osjećaj oštećenja živaca (periferna neuropatija), kašnjenje u razvoju, smanjenje mišića tonus (hipotonija) i slabost mišića (miopatija). Ovi poremećaji se prvenstveno nasljeđuju autosomno recesivno, iako neki slijede autosomno dominantni obrazac nasljeđivanja. Sve su uzrokovane mutacijama u POLG gen.

Dijagnoza

MERRF sindrom se dijagnosticira na osnovu kliničkih nalaza i molekularnog genetskog testiranja.

Klinička dijagnoza MERRF-a može se postaviti na osnovu prisustva četiri karakteristike: mioklonus (mišićni grčevi), generalizirana epilepsija (napadi), ataksija (poremećena sposobnost koordinacije pokreta) i abnormalne mišićne ćelije koje pokazuju raščupana crvena vlakna (RRF) kada mišić biopsija se posmatra mikroskopski.

Klinička ispitivanja mogu otkriti i druge karakteristike MERRF sindroma. Koncentracije laktata i piruvata obično su povišene u krvi i tečnosti koja okružuje mozak i kičmenu moždinu (cerebrospinalna tečnost). Koncentracije laktata i piruvata mogu se značajno povećati nakon umjerene fizičke aktivnosti. Koncentracija proteina cerebrospinalne tečnosti (CSF) takođe može biti povišena kod MERRF sindroma. Tehnike snimanja mozga kao što je magnetna rezonanca (MRI) mogu pokazati lezije slične moždanom udaru ili degeneraciju stanica (atrofiju), a magnetska rezonantna spektroskopija (MRS) se koristi za traženje laktata u mozgu. Elektroencefalogram (EEG) mjeri električnu aktivnost u mozgu i može pomoći u dijagnosticiranju napadaja. Elektrokardiogram (EKG) se može koristiti za dijagnosticiranje abnormalnosti srčanog ritma. Studije brzine nervnog provođenja mogu biti u skladu s miopatijom ili neuropatijom kod osoba sa MERRF sindromom.

Molekularna dijagnoza MERRF sindroma se postavlja kada se utvrdi da osoba koja ima simptome u skladu sa sindromom ima mutaciju u mtDNA genu povezanom sa MERRF. Molekularna dijagnoza može potvrditi kliničku dijagnozu MERRF sindroma ili pomoći da se razjasni dijagnoza kada se klinička dijagnoza ne može postaviti jer se simptomi preklapaju s drugim povezanim poremećajima. Mutacije mtDNA povezane s MERRF-om obično se mogu otkriti u bijelim krvnim zrncima, ali zbog heteroplazme (vidi Uzroci), drugi uzorci tkiva kao što su koža, pljuvačka, folikuli dlake, urinarni sediment i skeletni mišići, mogu biti potrebni za postavljanje molekularne dijagnoze .

Kod osoba s kliničkom dijagnozom ili simptomima koji sugeriraju na MERRF sindrom, molekularno genetičko testiranje može započeti pristupom ciljanim na gen. Pojedinac se može prvo pregledati na uobičajenu mutaciju, m.8344A>G, u MT-TK gen. Ako se ova mutacija ne pronađe, može se naručiti šire genetsko testiranje koje uključuje sekvenciranje svih gena povezanih s MERRF sindromom i drugih gena koji uzrokuju srodne poremećaje (testiranje na više gena). Može biti potrebno i genetsko testiranje u drugim uzorcima tkiva.

Kod pojedinaca koji imaju opće simptome, kao što su napadi i slabost mišića koji se preklapaju s mnogim drugim naslijeđenim stanjima, molekularno genetičko testiranje može početi s vrlo širokim pristupom. Kod ovih pacijenata, genetsko testiranje može uključivati ​​sekvencioniranje cjelokupne mtDNK (mitohondrijalni genom) pored svih gena (sekvenciranje egzoma) ili cjelokupne DNK (sekvenciranje genoma).

Kliničko testiranje i obrada

Pojedince sa MERRF sindromom i njihove rizične rođake treba pratiti interdisciplinarni tim u redovnim intervalima kako bi pratio sve nove simptome i progresiju bolesti.

Nakon inicijalne dijagnoze, preporučene osnovne procjene uključuju: (1) mjerenje visine i težine radi otkrivanja niskog rasta, (2) neurološku procjenu pomoću MRI glave, MRS-a, EEG-a i neuropsihijatrijskih testova za otkrivanje razlika u mozgu, prisutnost napadaja i dokaz demencije, (3) slušna (audiološka) procjena za otkrivanje oštećenja sluha, (4) očna (oftalmološka) procjena za otkrivanje problema s vidom, (5) procjene fizikalne i radne terapije, (6) srčana evaluacija EKG-om i ehokardiogramom za otkrivanje srčanih abnormalnosti i (7) serum glukoze natašte i test tolerancije glukoze za otkrivanje dijabetes melitusa.

Genetsko savjetovanje se preporučuje za pogođene pojedince i njihove porodice.

Standardne terapije

Ne postoji poseban tretman za MERRF sindrom. Neki lijekovi i terapije mogu biti od pomoći u upravljanju simptomima.

Tradicionalni antikonvulzivni lijekovi se koriste za sprječavanje i kontrolu napadaja povezanih s MERRF sindromom. Valproičnu kiselinu treba izbjegavati u liječenju napadaja. Levetiracetam i klonazepam su bili efikasni u kontroli mioklonusa kod malog broja pacijenata. Standardno liječenje srčanih problema (kardiomiopatije i aritmije) može se koristiti prema preporuci kardiologa. Slušni aparati i kohlearni implantati mogu poboljšati oštećenje sluha. Fizikalna terapija, radna terapija i aerobne vježbe mogu pomoći u poboljšanju mišićne slabosti, ukočenosti i motoričke funkcije.

Terapije se ponekad koriste za povećanje proizvodnje energije od strane mitohondrija i usporavanje efekata stanja. Koenzim Q10 (CoQ10) i L-karnitin su bili korisni kod nekih pacijenata sa različitim mitohondrijalnim bolestima. Dodatno, suplementi kao što su ubikinol, karnitin, alfa lipoična kiselina, vitamin E, kompleks vitamina B i kreatin mogu biti od koristi nekim osobama sa mitohondrijskom bolešću sa zahvaćenošću mišića. Učinkovitost ovih dodataka se proučava u kliničkim ispitivanjima. Osobe s MERRF-om trebale bi izbjegavati mitohondrijske toksine kao što su aminoglikozidni antibiotici, linezolid, cigarete i alkohol.

Istražne terapije

Informacije o trenutnim kliničkim ispitivanjima objavljene su na Internetu na https://clinicaltrials.gov/ Sve studije koje su finansirane od strane američke vlade, a neke su podržane od strane privatne industrije, objavljene su na ovoj vladinoj web stranici.

Za informacije o kliničkim ispitivanjima koja se provode u Kliničkom centru NIH u Bethesdi, MD, kontaktirajte NIH Ured za regrutaciju pacijenata:

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Za informacije o kliničkim ispitivanjima sponzoriranim od privatnih izvora, kontaktirajte:
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Za informacije o kliničkim ispitivanjima koja se sprovode u Evropi, kontaktirajte:
https://www.clinicaltrialsregister.eu/

Organizacije članice NORD-a

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      Reference

      Sharma H, et al. Razvoj mitohondrijalne nadomjesne terapije: pregled. Heliyon. 2020 e04643.

      Finsterer J, et al. MERRF klasifikacija: implikacije za dijagnozu i klinička ispitivanja. Pedijatrijska neurologija. 2018 80, 8-23.

      Lorenzoni PJ, et al. Kada bi MERRF (mioklonusna epilepsija povezana sa neravnim crvenim vlaknima) trebala biti dijagnoza?. Arquivos de neuro-psiquiatria. 201472(10), 803-811.

      Mancuso M, et al. Fenotipska heterogenost 8344A> G mtDNA “MERRF” mutacije. Neurologija. 2013, 80(22), 2049-2054.

      Nissenkorn A, et al, Neurološke prezentacije mitohondrijalnih poremećaja. J Child Neurol. 200015:44-48.

      Velez-Bartolomei F, Lee C, Enns G. MERRF. 3. juna 2003. [Ažurirano 7. januara 2021.]. U: Adam MP, Ardinger HH, Pagon RA, et al., urednici. GeneReviews® [Internet]. Seattle (WA): Univerzitet Washington, Seattle 1993-2021. Dostupno na: https://www.ncbi.nlm.nih.gov/books/NBK1520/ Pristupljeno 5. maja 2021.

      Hameed S, Tadi P. (Ažurirano 7. februara 2021.). Mioklonična epilepsija i raščupana crvena vlakna. U: StatPearls Objavljeno januara 2021. Dostupno na https://www.ncbi.nlm.nih.gov/books/NBK555923/. Pristupljeno 5. maja 2021.

      McKusick VA, ur. Online Mendelsko nasljeđivanje kod čovjeka (OMIM). Baltimore. MD: The Johns Hopkins University Entry No:545000 Zadnja izmjena: 19.11.2014. https://www.omim.org/entry/545000 Pristupljeno 5. maja 2021.

      MedlinePlus. Nacionalna medicinska biblioteka. Mioklonična epilepsija sa neravnim crvenim vlaknima. Recenzirano 1. maja 2014. http://ghr.nlm.nih.gov/condition/myoclonic-epilepsy-with-ragged-red-fibers. Pristupljeno 5. maja 2021.

      Years Published

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      Nacionalna organizacija za rijetke poremećaje (NORD)
      55 Kenosia Ave., Danbury CT 06810 &bull (203)744-0100


      Mutacije u MT-TK geni su najčešći uzrok MERRF-a, koji se javlja u više od 80 posto svih slučajeva. Rjeđe, mutacije u MT-TL1, MT-TH, i MT-TS1 prijavljeno je da geni uzrokuju znakove i simptome MERRF-a. Ljudi sa mutacijama u MT-TL1, MT-TH, ili MT-TS1 gen obično ima znakove i simptome drugih mitohondrijalnih poremećaja, kao i onih MERRF-a.

      The MT-TK, MT-TL1, MT-TH, i MT-TS1 geni su sadržani u mitohondrijskoj DNK (mtDNK). Mitohondrije su strukture unutar ćelija koje koriste kiseonik za pretvaranje energije iz hrane u oblik koji ćelije mogu koristiti kroz proces koji se naziva oksidativna fosforilacija. Iako je većina DNK upakovana u hromozome unutar jezgre, mitohondrije također imaju malu količinu vlastite DNK. Geni povezani sa MERRF-om daju uputstva za stvaranje molekula zvanih transfer RNK, koji su hemijski rođaci DNK. Ove molekule pomažu u sklapanju proteinskih gradivnih blokova zvanih aminokiseline u funkcionalne proteine ​​pune dužine unutar mitohondrija. Ovi proteini izvode korake oksidativne fosforilacije.

      Mutacije koje uzrokuju MERRF narušavaju sposobnost mitohondrija da stvaraju proteine, koriste kisik i proizvode energiju. Ove mutacije posebno utiču na organe i tkiva sa visokim energetskim zahtevima, kao što su mozak i mišići. Istraživači nisu utvrdili kako promjene u mtDNK dovode do specifičnih znakova i simptoma MERRF-a.

      Mali postotak slučajeva MERRF uzrokovan je mutacijama u drugim mitohondrijalnim genima, au nekim slučajevima uzrok stanja je nepoznat.

      Saznajte više o genima i kromosomima povezanim s miokloničnom epilepsijom s isprekidanim crvenim vlaknima

      Dodatne informacije od NCBI Gene:


      Nasljedstvo

      Ovo stanje se nasljeđuje u mitohondrijskom uzorku, koji je također poznat kao nasljeđe po majci. Ovaj obrazac nasljeđivanja odnosi se na gene sadržane u mtDNK. Budući da jajne ćelije, ali ne i spermatozoidi, doprinose mitohondrijima u razvoju embrija, djeca mogu naslijediti samo poremećaje koji su rezultat mutacija mtDNA od svoje majke. Ovi poremećaji se mogu pojaviti u svakoj generaciji porodice i mogu zahvatiti i muškarce i žene, ali očevi ne prenose osobine povezane s promjenama mtDNK na svoju djecu.

      U većini slučajeva, ljudi sa MELAS-om nasljeđuju izmijenjeni mitohondrijski gen od svoje majke. Ređe, poremećaj je rezultat nove mutacije mitohondrijalnog gena i javlja se kod ljudi bez porodične istorije MELAS-a.


      Upravljanje i liječenje

      Kako se liječe mitohondrijalne bolesti?

      Ne postoje lijekovi za mitohondrijalne bolesti, ali liječenje može pomoći u smanjenju simptoma ili usporiti opadanje zdravlja.

      Liječenje se razlikuje od pacijenta do pacijenta i ovisi o specifičnoj dijagnosticiranoj mitohondrijskoj bolesti i njenoj težini. Međutim, ne postoji način da se predvidi pacijentov odgovor na liječenje ili da se predvidi kako će bolest dugoročno utjecati na tu osobu. Ne postoje dvije osobe na isti način reagiranja na isti tretman, čak i ako imaju istu bolest.

      Tretmani za mitohondrijsku bolest mogu uključivati:

      • Vitamini i suplementi, uključujući vitamine B kompleksa koenzima Q10, posebno tiamin (B1) i riboflavin (B2), alfa lipoinsku kiselinu L-karnitin (Carnitor) kreatin i L-arginin. , uključujući i vježbe izdržljivosti i trening otpora/snage. Ovo se radi kako bi se povećala veličina i snaga mišića. Vježbe izdržljivosti uključuju hodanje, trčanje, plivanje, ples, vožnju bicikla i druge. Trening otpora/snage uključuje vježbe kao što su trbušnjaci, savijanje ruku, ekstenzije koljena, dizanje utega i druge.
      • Očuvanje energije. Ne pokušavajte da uradite previše u kratkom vremenskom periodu. Tempirajte se.
      • Ostali tretmani. To može uključivati ​​logopedsku terapiju, fizikalnu terapiju, respiratornu terapiju i radnu terapiju.

      Izbjegavajte situacije koje mogu pogoršati vaše zdravstveno stanje. To uključuje: izlaganje hladnoći i/ili toploti gladovanje nedostatak sna stresne situacije i korištenje alkohola, cigareta i mononatrijum glutamata (MSG, pojačivač okusa koji se obično dodaje kineskoj hrani, konzerviranom povrću, supama i prerađenom mesu).


      Pripadnosti

      Odsjek za neurologiju, Medicinski centar Univerziteta Columbia, 630 West 168th Street, New York, 10032, New York, SAD

      Eric A. Schon, Salvatore DiMauro i Michio Hirano

      Odjel za genetiku i razvoj, Medicinski centar Univerziteta Columbia, 701 West 168th Street, New York, 10032, New York, SAD

      Takođe možete tražiti ovog autora u PubMed Google Scholar-u

      Takođe možete tražiti ovog autora u PubMed Google Scholar-u

      Takođe možete tražiti ovog autora u PubMed Google Scholar-u

      Dopisni autor


      Zaključak

      Dugi niz godina smatralo se da je nasljeđivanje mtDNK jednostavno i jednostavno kod ljudi. Međutim, nedavno otkriće skoro univerzalne heteroplazme, složenost koju uvodi usko grlo mtDNK i dokazi selekcije za i protiv varijanti u određenim regijama mtDNK pokazuju da je situacija daleko složenija nego što smo ranije mislili. S obzirom na nove dokaze koji impliciraju mutacije mtDNA u patogenezi uobičajenih kasnih bolesti i njihov mogući doprinos procesu starenja, dublje razumijevanje ovih procesa je ključno ako želimo iskoristiti ovo znanje i spriječiti i liječiti ljudske poremećaje uzrokovane mutacijama. mitohondrijalne DNK manipulisanjem njihovim nasleđem.


      Zaključak

      In summary, seizures occur frequently in mitochondrial disease. They may be the presenting feature but are often part of a multisystem presentation. Mitochondrial epilepsies are biochemically and genetically heterogeneous, but some of the more common causes are mtDNA mutations and mutations in POLG. A rapidly increasing number of nuclear gene defects have been linked to mitochondrial epilepsy (Table I). The pathogenesis of mitochondrial epilepsy remains poorly understood, contributing to the immense difficulties in treating this condition. Epilepsy is a poor prognostic sign in mitochondrial disease, and there is an urgent need for formal clinical trials of candidate treatments, including the ketogenic diet and novel therapeutic agents.


      A mitochondrial bioenergetic etiology of disease

      Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

      Address correspondence to: Douglas C. Wallace, Colket Translational Research Building, Room 6060, Children’s Hospital of Philadelphia, University of Pennsylvania, 3501 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-4302, USA. Phone: 267.425.3034 Fax: 267.426.0978 E-mail: [email protected]

      Find articles by Wallace, D. in: JCI | PubMed | Google Scholar

      The classical Mendelian genetic perspective has failed to adequately explain the biology and genetics of common metabolic and degenerative diseases. This is because these diseases are primarily systemic bioenergetic diseases, and the most important energy genes are located in the cytoplasmic mitochondrial DNA (mtDNA). Therefore, to understand these “complex” diseases, we must investigate their bioenergetic pathophysiology and consider the genetics of the thousands of copies of maternally inherited mtDNA, the more than 1,000 nuclear DNA (nDNA) bioenergetic genes, and the epigenomic and signal transduction systems that coordinate these dispersed elements of the mitochondrial genome.

      The application of Mendelian genetic principles, using the most sophisticated technologies, has failed to adequately explain the genetics or pathophysiology of many common metabolic and degenerative diseases. This shortcoming can now be understood through the discovery that mutations in the maternally inherited mtDNA can cause many of the symptoms associated with “complex” diseases and that the mtDNA codes for the central genes of the mitochondrial energy–generating process oxidative phosphorylation (OXPHOS). Therefore, the common metabolic and degenerative diseases must be bioenergetic in origin and non-Mendelian in inheritance.

      The central player in bioenergetics is the mitochondrion. Mitochondria produce about 90% of cellular energy, regulate cellular redox status, produce ROS, maintain Ca 2+ homeostasis, synthesize and degrade high-energy biochemical intermediates, and regulate cell death through activation of the mitochondrial permeability transition pore (mtPTP). The mitochondrial genome consists of thousands of copies of the maternally inherited mtDNA plus between 1,000 and 2,000 nDNA genes. mtDNA codes for 13 OXPHOS polypeptides, plus the 22 transfer RNAs (tRNAs) and the 12S and 16S rRNAs necessary for the bacteria-like mitochondrial protein synthesis. mtDNA polypeptides encompass seven of the 45 polypeptides of OXPHOS complex I (ND1, ND2, ND3, ND4, ND4L, ND5, and ND6), one of the 11 polypeptides of complex III (cytochrome b), three of the 13 polypeptides of complex IV (COI, COII, and COIII), and two of the approximated 17 polypeptides of complex V (ATPase6 and ATPase8). Complexes I, III, and IV constitute the electron transport chain (ETC), which oxidizes the reducing equivalents (hydrogen-derived electrons) from food with the oxygen we breathe. As the electrons flow sequentially through complexes I, III, and IV, protons are pumped out across the mitochondrial inner membrane through these complexes to generate an electrochemical gradient. This mitochondrial capacitor is the vital force and can be used to drive many biological processes, including the condensation of ADP and Pi to form ATP via complex V. Thus oxidation is coupled with phosphorylation in OXPHOS. The 1,000–2,000 nDNA mitochondrial genes, scattered across the chromosomes, code for the remaining approximately 80 OXPHOS subunits, the intermediary metabolism enzymes, and the mitochondrial biogenesis proteins ( 1 – 3 ).

      Three factors can perturb mitochondrial bioenergetics and result in disease: variation in the mtDNA sequence, variation in the sequences of nDNA-coded mitochondrial genes or in the expression of these genes, or variation in environmental calories and the caloric demands made on the organism. Since different tissues rely on mitochondrial energy to different extents, partial systemic energy deficiency can result in tissue-specific symptoms. The brain, which represents only 2% of the body weight but consumes 20% of the oxygen, is the organ most sensitive to subtle energy diminution. Other high-energy demand tissues include the heart, muscle, kidney, and endocrine system, the organs commonly affected in metabolic and degenerative diseases (Figure 1).

      Bioenergetic paradigm for metabolic and degenerative diseases, cancer, and aging. Mitochondrial OXPHOS can be perturbed by nDNA genetic alterations and/or epigenomic regulation, by mtDNA ancient adaptive of recent deleterious mutations, or by variation in the availability of calories and in caloric demands. Alterations in mitochondrial structure and function can impair OXPHOS, which in turn can reduce energy production, alter cellular redox state, increase ROS production, deregulate Ca 2+ homeostasis, and ultimately activate the mtPTP, leading to apoptosis. These and other consequences of OXPHOS perturbation can destabilize mtDNA. This results in progressive accumulation of somatic mtDNA mutations and decline of mitochondrial function, which accounts for aging and the delayed-onset and progressive course of degenerative diseases. As energy output declines, the most energetic tissues are preferentially affected, resulting in degenerative diseases of the central nervous system, heart, muscle, and kidney. Aberrant mitochondrial caloric metabolism also leads to metabolic deregulation, endocrine dysfunction, and symptoms such as diabetes, obesity, and cardiovascular disease. The release into the blood stream of mtDNA mutant N-formylmethionine polypeptides plus the mtDNA can initiate the inflammatory response, contributing to autoimmune diseases (e.g., multiple sclerosis and type I diabetes) and possibly also to the inflammatory component of late-onset degenerative diseases. Finally, cancer cells must manage energy resources to permit rapid replication ( 95 ). Figure adapted with permission from Cold Spring Harbor Press ( 55 ).

      Since the first report of an inherited mtDNA disease mutation 25 years ago ( 4 ), hundreds of clinically relevant mtDNA mutations have been identified. These can either be polypeptide mutations or protein synthesis mutations, the latter altering the tRNA or rRNA genes ( 3 , 5 ). There are three clinically relevant classes of mtDNA mutations: recent deleterious mutations that result in matrilineal disease, ancient adaptive variants that predispose to the common diseases, and somatic mutations that accumulate in tissues with age and provide the aging clock (Figure 1).

      Recent deleterious mutations and maternally inherited diseases. A prime example of a pathogenic mtDNA polypeptide missense mutation is the NADH dehydrogenase subunit 4 (ND4) nt 11,778 G>A mutation (histidine 340 to arginine), or ND4 G11778A (R340H), that causes Leber hereditary optic neuropathy (LHON) ( 4 ). LHON is characterized by acute or subacute midlife blindness that is two to five times more likely to affect males than females, even though all maternal relatives generally have close to 100% mutant mtDNAs (homoplasmic) ( 6 ).

      The two most common mtDNA protein synthesis mutations cause myoclonic epilepsy and ragged red fiber disease (MERRF) (tRNA Lys A8344G) ( 7 , 8 ) and mitochondrial encephalomyopathy and stroke-like episodes (MELAS) (tRNA Leu(UUR) A3243G) ( 9 ). These more severe mtDNA mutations produce multisystem neuromuscular diseases, and the mutant mtDNAs are generally mixed within the cell with normal (wild-type) mtDNAs (heteroplasmic) ( 3 , 5 ). As a heteroplasmic cell replicates, the percentages of mutant and normal mtDNAs are randomly distributed into the daughter cells (replicative segregation). Consequently, the mtDNA genotype can drift during both meiotic and mitotic cell division. Meiotic replicative segregation can cause maternal relatives to harbor different percentages of mutant mtDNAs, have different degrees of the energetic defect, and manifest widely different phenotypes. For example, when the MELAS-causing tRNA Leu(UUR) A3243G mutant is present in 10%–30% of the mtDNAs, the individual will develop type I or type II diabetes mellitus, but when the mutant is present at higher percentages, myopathy, cardiomyopathy, and stroke-like episodes will develop. Mitotic segregation can give rise to an individual with significantly different percentages of mutant mtDNAs in different tissues when derived from a heteroplasmic oocyte, further contributing to phenotypic variability ( 3 , 5 , 7 , 8 ).

      The milder mtDNA variants can affect caloric metabolism and result in metabolic abnormalities such as diabetes and obesity and/or affect the most energy-demanding organs such as the brain and lead to late-onset degenerative diseases, such as psychiatric disorders, Parkinson disease (PD), and Alzheimer disease (AD). The more severe mtDNA mutations, like MERRF and MELAS, cause progressive multisystem diseases, frequently resulting in premature death. The most severe mtDNA mutations can lead to lethal childhood diseases, such as Leigh syndrome ( 3 ).

      Ancient adaptive mtDNA variants: common variants that predispose to common diseases. Population-specific mtDNA polymorphisms have been linked to predisposition to a broad range of metabolic and degenerative diseases ( 3 , 10 , 11 ). These variants are generally ancient, having accumulated along radiating maternal lineages during the human expansion out of Africa. By superimposing the human mtDNA mutational tree on the geographic locations of indigenous populations that harbor the various mtDNA types, mtDNA polymorphisms have been used to reconstruct the origins and ancient migrations of women (Figure 2).

      Radiation of human mtDNA as women migrated out of Africa to colonize Eurasia, Australia, and the Americas. The uniparentally inherited mtDNA can only change by sequential accumulation of mutations along radiating female lineages. Therefore, the mtDNA mutational tree and ancient migrations of women were reconstructed by sequencing mtDNAs from indigenous populations and correlating their regional clusters of related haplotypes (haplogroups) with the population’s geographic location. The haplogroups are regional because they were founded by regionally adaptive functional variants. The mtDNA tree originates in Africa, and all African mtDNAs are classified together as macrohaplogroup L. From haplogroup L3, two mtDNA lineages, M and N, arose in Ethiopia and successfully left Africa to colonize the rest of the world about 65,000–70,000 YBP. The founder mtDNA of macrohaplogroup N harbored two mtDNA missense mutations, ND3 G10398A (A114T) and ATP6 G8701A (A59T), whereas the founder of macrohaplogroup M did not harbor major functional mutations ( 3 , 15 ). Early M and N emigrants from Africa moved through Southeast Asia, ending in Australia ( 96 , 97 ). N mtDNAs also moved north from Africa into the Middle East to generate submacrohaplogroup R and European-specific haplogroups H, J, T, U, Uk, and V (from R) and I, W, and X (from N). N and R gave rise to Asian haplogroups A+Y and B+F, respectively. M moved north out of Southeast Asia to colonize Asia, generating haplogroups C and D and multiple M haplogroups. Haplogroups A, B, C, D, and X subsequently migrated to the Americas. The mtDNA mutation rate is 2.2%–2.9% per million years (numbers within the figure denote YBP). Figure adapted with permission from MITOMAP ( 5 ).

      mtDNA has a very high mutation rate, yet codes for the most important mitochondrial energy genes. This should be a lethal combination. However, mammalian females have evolved an intraovarian selection system that destroys the proto-oocytes with the most severe mitochondrial defects ( 12 , 13 ), a process that may account for atresia. Therefore, mild mtDNA variants are continuously being introduced into populations with minimum genetic load. Those variants can be beneficial for a population within a specific regional energetic environment and be selectively enriched in that regional population. Since different mtDNA variants are adaptive in different environments, different mtDNAs became enriched in different populations. The subsequent accumulation of random mtDNA mutations on the founding adaptive mtDNA produced regional clusters of related mtDNA haplotypes, known as haplogroups.

      Because of the complexity of mitochondrial physiology, a mtDNA variant might be beneficial early in reproductive life, but deleterious postreproductively. Such variants are said to be antagonistically pleiotropic. For example, increased ROS production might help fight infection in the young but cause lifelong chronic oxidative stress that predisposes to development of age-related degenerative diseases.

      The human mtDNA tree originated in Africa about 130,000–200,000 years before present (YBP) and gave rise to a series of African-specific haplogroups, which in aggregate form African macrohaplogroup L (Figure 2). Of all the African mtDNAs, only two mtDNA lineages, macrohaplogroups M and N, successfully left Africa (about 65,000–70,000 YBP) and colonized the rest of the world. In one migration, M and N left Africa and traveled along the tropical Southeast Asian coast, ultimately reaching Australia.

      Macrohaplogroup N mtDNAs also moved north into the Middle East and radiated to create submacrohaplogroup R. Both N and R lineages spread into Europe to generate the eight to nine European-specific haplogroups.

      In Asia, macrohaplogroup N radiated to form haplogroups A and Y, and the N-derived R lineage generated haplogroups B and F. From Southeast Asia, macrohaplogroup M moved northward to form an array of Asian-specific mtDNA haplogroups (C, D, and M1∼M40). Ultimately, haplogroups A, B, C, D, and X migrated into the Americas to found the Native American populations (Figure 2).

      A major environmental barrier to the migration of sub-Saharan Africans into Eurasia must have been the cold of the northern latitudes. To survive, early humans would have needed to produce more core body heat. This might have been achieved by mtDNA mutations that decreased the “coupling efficiency” of OXPHOS. This would require that more calories be burned to generate the same amount of ATP. Since a calorie is a unit of heat, reduced coupling efficiency would increase the core body temperature and resistance to cold, but would necessitate a higher-calorie diet ( 2 , 14 ).

      Prior to moving out of Ethiopia, the founding macrohaplogroup N mtDNA acquired two functional variants, ND3 G10398A (A114T) and ATP6 G8701A (A59T) ( 3 , 15 ), which changed the mitochondrial membrane potential and Ca 2+ metabolism (ref. 16 and Figure 3). These mutations likely contributed to cold resistance in the temperate zone. Macrohaplogroup M, in contrast, stayed in the tropics, so cold-adaptive variants were not initially fixed in this lineage.

      Relationship between ancient adaptive mtDNA variants and predisposition to metabolic and degenerative diseases. African haplogroup L3 gave rise to macrohaplogroups M and N, which colonized Europe and Asia. N differed from M in harboring the ND3 G10398A (A114T) and ATP6 G8701A (A59T) variants. In Europe, N gave rise to haplogroup H, and H acquired the tRNA Gln A4336G variant to generate H5a, which predisposes to AD, PD, and both AD and PD ( 17 ). The ND1 A3397G (M31V) missense mutation arose twice in Europeans, once on H5a and once independently, and in both cases was associated with predisposition to both AD and PD ( 17 ). Oba tRNA Gln A4336G and ND1 A3397G (M31V) mutations are likely to reduce mitochondrial complex I activity, augmenting the founding N variants. The ND1 T3394C (Y30H) mutation, which is adjacent to the ND1 M31 codon, arose on N and M mtDNAs. When arising on N haplogroups B and F, the ND1 T3394C (Y30H) variant is associated with complex I deficiency and increased penetrance of the primary LHON mutations. However, complex I activity is also modulated by N haplogroup background, with haplogroup F mtDNAs having lower complex I activity than haplogroup B mtDNAs, consistent with haplogroup F predisposition to diabetes ( 23 ). The ND1 T3394C (Y30H) mutation has arisen on several M mtDNAs, with all haplogroup M9 mtDNAs having the 3394C allele. Both M9 and 3394C mtDNAs increase in frequency with altitude in Tibet. Finally, M9 complex I activity is equal to or greater than that of any of the N haplogroups with the wild-type T3394 allele ( 20 ). Asterisks indicate that the stated complex I activity is predicted, based on the known genotype and complex I activities determined for cell lines harboring ND1 T3394C (Y30H)–containing mtDNAs.

      The most common European N-R–derived mtDNA haplogroup is H. In Europe, haplogroup H acquired additional functional variants, one of which arose between 8,500 and 17,000 YBP in the tRNA Gln gene (tRNA Gln A4336G), creating subhaplogroup H5a. Today, this variant is found in only 0.4% of the general European population, but is present in 3.3% of AD patients, 5.3% of PD patients, and 6.8% of patients with both AD and PD (ref. 17 and Figure 3). The retention of this variant in the European population may be an example of antagonistic pleiotropy. A second European mtDNA variant observed in patients with both AD and PD is a missense mutation in the ND1 gene: ND1 A3397G (M31V). This variant arose twice, once in the tRNA Gln A4336G lineage, and once independently (ref. 17 and Figure 3).

      A related ND1 variant, ND1 T3394C (Y30H), changes the amino acid adjacent to M31. When arising on macrohaplogroup N mtDNAs, this variant is associated with increased penetrance of the milder primary LHON mtDNA mutations ( 18 , 19 ). Yet when this same ND1 T3394C (Y30H) variant arose on macrohaplogroup M mtDNAs, it became enriched in high-altitude Tibetans. Haplogroup M9 mtDNA with the ND1 T3394C (Y30H) variant is present at less than 2% at sea level, but increases to about 35% of the mtDNAs in the highest Tibetan villages (ref. 20 and Figure 3).

      The ND1 T3394C (Y30H) variant results in a 15%–28% reduction in complex I–specific activity when arising on macrohaplogroup N mtDNAs, which explains its enhancement of LHON mutation penetrance. However, the specific activity of complex I can also vary among different macrohaplogroup N haplogroups by up to 30%, independent of their 3394 allele. Even more surprising, the 3394C allele, when present in the M9 haplogroup mtDNA, is associated with complex I activity equal to or greater than any of the macrohaplogroup N mtDNAs with the wild-type T3394 (Y30) variant (ref. 20 and Figure 3).

      Similar physiological differences have been documented between European haplogroup H and Uk mtDNAs ( 11 , 21 ). Therefore, the metabolic consequences of a particular mtDNA nucleotide variant can be strongly influenced by genetic and environmental context.

      The clinical relevance of mtDNA haplogroup variation has been repeatedly demonstrated through case-control studies on a wide variety of metabolic and degenerative diseases, cancer, and aging ( 3 , 10 , 11 , 22 ), and the physiological associations are being elucidated. For example, haplogroup F mtDNAs are associated with low complex I activity ( 20 ) and predilection to diabetes ( 23 ). Hence, ancient mtDNA variants and haplogroups are likely the long-sought common variants that predispose to common diseases.

      Somatic mtDNA mutations. mtDNA also accumulates mutations within tissues with age. mtDNA deletions that occur early in development can become widely disseminated throughout the body and cause spontaneous mitochondrial myopathy ( 24 ). However, mtDNA deletions ( 25 – 28 ) and base substitutions ( 29 , 30 ) can arise in tissues throughout life, and their accumulation has been shown to modulate aging and longevity ( 31 – 33 ). Therefore, the accumulation of somatic mtDNA mutations may be the aging clock.

      The rate of accumulation of somatic mtDNA mutations can be modulated by nuclear or cytoplasmic genetic variants and by environmental factors (Figure 1). For example, factors that increase mitochondrial ROS production would increase the mtDNA mutation rate and lead to premature organ failure. Increased mtDNA somatic mutation levels have been documented in ischemic heart disease ( 34 ), AD brains ( 35 – 37 ), PD brains ( 38 , 39 ), Huntington disease brains ( 40 ), and Down syndrome with dementia (DSAD) brains ( 37 ). In AD and DSAD brains, elevated somatic mtDNA base substitution mutations have been correlated with reduced mtDNA copy number and ND6 transcript levels ( 37 ).

      As somatic mtDNA mutations accumulate, they change the amino acid sequences of the mtDNA-coded mitochondrial N-formylmethionine–initiated polypeptides. These bacterial-like variant polypeptides can then be seen as foreign and initiate an inflammatory response. This may contribute to the inflammation frequently observed in late-stage degenerative diseases (Figure 1 and refs. 38 , 41 – 43 ).

      Bioenergetic disease can also result from mutations in any one of the hundreds of nDNA genes that code for mitochondrial proteins. Mutations in more than 200 nDNA gene loci have already been reported to cause mitochondrial bioenergetic dysfunction ( 3 , 44 ).

      Structural and metabolic nDNA-coded mitochondrial genes. In addition to mutations in the nDNA-coded enzymes of mitochondrial intermediary metabolism, which exhibit classical Mendelian transmission, pathogenic mutations have been identified in multiple nDNA-coded OXPHOS structural and assembly factor genes. When both copies of a chromosomal gene are mutated, severe OXPHOS defects can occur and cause devastating pediatric disease, the most commonly recognized phenotype being Leigh syndrome ( 3 , 44 ).

      Diseases of nDNA-mtDNA interactions. Mutations in the nDNA-coded mtDNA biogenesis genes can cause degenerative diseases by destabilizing mtDNA biogenesis, resulting in multiple mtDNA deletions and/or mtDNA depletion ( 3 , 44 ). Pathogenic mutations have been reported in mtDNA polymerase γ (POLG) ( 45 ), Twinkle helicase ( 46 ), mitochondrial deoxyguanosine kinase and thymidine kinase 2 ( 47 , 48 ), cytosolic thymidine phosphorylase ( 49 ), and the heart-muscle adenine nucleotide (ADP/ATP) translocator (ANT1) ( 50 , 51 ), to name a few ( 3 ). Mitochondrial disease can also result from the incompatible interaction of two otherwise nonpathogenic nDNA and mtDNA genetic variants ( 52 ).

      Alterations in nDNA-coded mitochondrial gene expression and the epigenome. While mtDNA mutations have permitted humans to adapt to stable regional environmental energetic differences, many energy resources and demands fluctuate cyclically, for example, seasonal changes in temperature and food supply. Adaptation to this type of energetic variation is accomplished by changes in the levels of mitochondrially generated high-energy intermediates, such as acetyl-CoA and ATP, and in the mitochondrial modulation of the cellular redox state. As these mitochondrial bioenergetic parameters fluctuate with the environment, they drive posttranslational modification of the proteins of the epigenome and the signal transduction pathways. In this way, the expression of the hundreds of nDNA-coded bioenergetic genes is coupled to environmental fluctuations through mitochondrial energy flux ( 53 – 55 ).

      This new bioenergetic perspective provides a framework to reevaluate the genetics and pathophysiology of “complex” diseases, such as PD, AD, autism spectrum disorders (ASDs), and psychiatric disorders. In PD, numerous nDNA loci that have been linked to developing movement disorders are directly involved in modulating mitochondrial integrity and function ( 38 ). For example, mutations in parkin (PARK2) and PTEN-induced kinase 1 (PINK1 also known as PARK6) impede mitochondrial autophagy (mitophagy), which leads to the accumulation of mitochondrial damage ( 38 , 56 , 57 ). The resulting increased mtDNA somatic mutation rate degrades the mtDNA in the basal ganglion and substantia nigra, ultimately resulting in neuronal dysfunction, cell death, and movement disorders ( 26 , 39 , 58 ).

      In AD, Aβ toxicity is generally assumed to be the cause, yet systemic mitochondrial defects have been repeatedly reported ( 1 ). At high concentrations, Aβ oligomerizes and is toxic ( 59 ), specifically inhibiting mitochondrial function ( 38 , 60 ). However, at low concentrations, monomeric Aβ is protective of mitochondrial function ( 38 ). Therefore, Aβ appears to be bifunctional. From this perspective, under normal conditions, Aβ functions to protect the mitochondria and associated neurons and synapses and is induced in response to mitochondrial stress, possibly mitochondrial ROS production. However, when mitochondrial dysfunction becomes so severe that neuronal function is irreversibly impaired, Aβ induction becomes excessive and leads to Aβ oligomerization. The oligomerized Aβ then inhibits mitochondrial function, activates the mtPTP, and destroys the neuron with the defective mitochondria, thus eliminating noise from the neuronal information network.

      Early-onset AD, then, is the result of mutations in APP or the presenilins, which aberrantly increase Aβ levels, leading to premature Aβ aggregation and destruction of potentially repairable mitochondria, neurons, and synapses. Late-onset AD, in contrast, is the result of chronic mitochondrial stress, perhaps mediated by ROS toxicity, Ca 2+ overload, or other factors. Increased chronic mitochondrial oxidative stress can result from a variety of factors that partially inhibit OXPHOS, including the tRNA Gln A4336G and ND1 A3397G (M31V) variants. Excessive mitochondrial Ca 2+ exposure can also increase mitochondrial ROS production and activate the mtPTP. Mitochondrially destined Ca 2+ is released from the endoplasmic reticulum within the mitochondria-associated membranes (MAMs), and MAMs harbor the presenilin complexes ( 61 , 62 ). Inappropriate MAM Ca 2+ regulation can cause chronic mitochondrial stress by increasing mitochondrial ROS production and Ca 2+ activation of the mtPTP. These and other stressors could cause the premature accumulation of neuronal somatic mtDNA mutations, bioenergetic decline, mutant mtDNA peptide–induced inflammation, synaptic loss, and dementia ( 38 ).

      ASDs have also proven enigmatic when viewed from a classical Mendelian perspective. Yet the genetics and pathophysiology of ASDs are fully consistent with the expectations for mild mitochondrial dysfunction. Like LHON ( 6 ), in ASDs, males are four times more likely than females to be affected ( 63 , 64 ). Mitochondrial metabolic defects have been repeatedly reported in ASD patients, and mtDNA mutations have been found in several ASD pedigrees ( 63 , 65 – 67 ).

      Elevated Ca 2+ levels have also been observed in ASD brains, and the excess Ca 2+ could activate the neuronal aspartate/glutamate carrier of the mitochondrial NADH shuttle system ( 68 ) and the tricarboxylic acid cycle dehydrogenases ( 69 , 70 ). Both of these effects would drive excessive reducing equivalents into the ETC, stimulating mitochondrial ROS production, oxidative stress, mitochondrial damage, and synaptic loss. Mutacije u CACNA1C Ca 2+ channel gene have been shown to cause the syndromic ASD Timothy syndrome ( 71 ), and mutations in the CACNA1F Ca 2+ channel gene have been reported in ASD patients ( 72 ).

      Copy number variants (CNVs) are also increased in number in autism patients ( 73 , 74 ), and CNVs that remove a copy of the PARK2 or ubiquitin protein ligase E3A (UBE3A) genes have been observed repeatedly ( 75 , 76 ). Since loss of PARK2 would impair mitochondrial quality control ( 77 ), and mutations in UBE3A are associated with hippocampal mitochondrial defects in Angelman syndrome, another syndromic ASD ( 78 ), these observations also implicate bioenergetics in ASDs.

      Since there are more than 1,000 nDNA mitochondrial genes, and partial mitochondrial defects can be sufficient to cause neurodegenerative disease, random CNVs that delete one copy of a nDNA mitochondrial gene could be sufficient to predispose to the neurological symptoms of ASD. Indeed, in one study, an ASD subject with one CNV had near-normal OXPHOS function, while another patient with 13 CNVs had a severe OXPHOS defect ( 67 ).

      Another surprise from the Mendelian perspective has been that genetic elements linked to ASDs are also associated with other neuropsychiatric disorders ( 79 , 80 ). However, this would be predicted if neuropsychiatric disorders share a common bioenergetic pathophysiological mechanism. Mitochondrial dysfunction has been documented in psychiatric disorders ( 81 ), evidence of matrilineal bias in transmission has been reported ( 82 , 83 ), and mtDNA haplogroups and brain mtDNA somatic mutations have been observed in patients with psychiatric conditions ( 21 , 28 ).

      To prove that mitochondrial defects cause metabolic and degenerative diseases, mitochondrial gene mutations have been introduced into the mouse, and metabolic and degenerative disease phenotypes have been observed ( 84 ). The introduction of mtDNA mutations into the mouse germline has proven particularly instructive.

      To introduce a mtDNA mutation into the mouse, an appropriate mtDNA mutation must be isolated in a cultured mouse cell line and the mutant mtDNA transferred into the mouse female germline, most commonly mediated by mouse female embryonic stem cell (mfESC) transmitochondrial cybrids ( 85 ). Introduction into the mouse of a mtDNA harboring a 12S rRNA chloramphenicol resistance (CAP R ) mutation ( 86 , 87 ) resulted in chimeric CAP R mice with cataracts, retinal dysfunction, and optic nerve hamartomas. Homoplasmic CAP R transgenic mice had stunted growth, mitochondrial myopathy, and cardiomyopathy and died prematurely ( 87 ).

      Introduction of mtDNAs harboring a homoplasmic mtDNA with a COI T6589C (V421A) missense mutation that were also heteroplasmic for a ND6 13886 insertion C frameshift mutation resulted in animals that rapidly and directionally lost the frameshift mtDNA within three generations. This observation revealed the existence of the prefertilization ovarian selective system, which eliminates proto-oocytes with the most deleterious mtDNA mutations ( 12 , 88 ). The mice that remained after segregation of the ND6 13886 insertion C frameshift mtDNA were homoplasmic for the COI T6589C (V421A) missense mutation. These animals had a 50% reduction in complex IV activity and developed mitochondrial myopathy and cardiomyopathy ( 12 ).

      Introduction into the mouse of an ND6 G13997A (P25L) mtDNA mutation, which is functionally equivalent to the human ND6 G14600A (P25L) mutation reported to cause optic atrophy when heteroplasmic and Leigh syndrome when homoplasmic ( 89 ), resulted in animals with all of the anatomically possible physiological and pathological features of LHON. The physiological effects of the mutation on neurons were analyzed using synaptosomes from the mouse LHON model brain. This revealed that the optic atrophy mutation did not diminish synaptic ATP levels, but instead chronically increased mitochondrial ROS production. If this is the case for other LHON mutations, it suggests that the delayed onset of acute vision loss may be the result of cumulative oxidative damage ( 90 ).

      A heteroplasmic mtDNA rearrangement mutation has also been introduced into the mouse. This resulted in mice with complex IV–negative (COX-negative) muscle and heart myofibers, renal dysfunction ( 91 ), and infertility ( 92 ). Therefore, both base substitution and mtDNA rearrangement mutations are sufficient to cause degenerative diseases.

      To determine the consequences of much milder mitochondrial defects, mice were created in which two normal but different mouse mtDNAs were mixed within the female germline, thus subverting maternal inheritance. The mtDNAs were from NZB and 129 mice and differed at 91 nt positions encompassing 15 missense mutations, 5 tRNA mutations, 7 rRNA mutations, and 11 control region mutations. All mice were maintained on the C57BL/6J nuclear background ( 93 ). As previously observed ( 94 ), the heteroplasmy levels within the tissues of individual animals segregated, with NZB mtDNAs predominating in liver and kidney, and 129 mtDNAs in spleen and pancreas. However, the tail, muscle, heart, and brain heteroplasmy levels remained relatively stable. In mating experiments, the NZB mtDNAs were progressively lost from the maternal lineage, with the rate of segregation being greatest when the mtDNAs were at relatively equal percentages.

      By random segregation and selective breeding, the heteroplasmic mice were used to derive three mouse lines: homoplasmic NZB, homoplasmic 129, and heteroplasmic NZB-129. These three different mtDNA genotype strains were then examined for behavioral alterations. While the homoplasmic NZB and homoplasmic 129 mice were essentially the same and phenotypically normal, the heteroplasmic NZB-129 mice were markedly different. The heteroplasmic NZB-129 animals were hypoactive during the normally active dark period, in association with reduced food intake and respiratory exchange ratio, but were hyperexcitable under stress conditions. Even more remarkably, the heteroplasmic mice showed a striking learning defect, being slow to learn and quick to forget ( 93 ).

      Extensive biochemical studies of the heteroplasmic NZB-129 mice have failed to detect a significant OXPHOS defect. Therefore, even extremely subtle bioenergetic dysfunction is sufficient to cause neuropsychiatric symptoms. This can account for why maternal inheritance of the mtDNA is strictly imposed throughout most of the eukaryotic kingdom and might explain why it has been so difficult to determine the pathophysiological basis of neuropsychiatric disorders.

      Elucidation of the novel genetics of mtDNA and the demonstration of its central role in bioenergetics has provided a new set of genetic rules and physiological parameters for understanding the intraspecific genetic variation of relevance to human health and disease. This bioenergetic perspective not only provides a coherent theory for the etiology of the “complex” metabolic and degenerative diseases, it suggests powerful new approaches for their presymptomatic diagnoses, reliable prognosis, and effective treatment and prevention ( 10 ). However, reaping the benefits of these new insights will require a major redirection of the way we think about medical genetics and origin of disease. If we can change, the bioenergetic perspective promises to reduce the burden of chronic diseases and markedly improve global health span.

      The author thanks Marie Lott for assistance. This work was supported by NIH grants NS21328, NS070298, AG24373, and DK73691 and by Simon Foundation grant 205844 awarded to D.C. Wallace.

      Sukob interesa: The author’s research has received some support from Glaxo-Smith Kline.

      Referentne informacije: J Clin Invest. 2013123(4):1405–1412. doi:10.1172/JCI61398.


      Three-Parent Babies and The Truth Behind Mitochondrial Replacement Therapy

      Most of us have heard in a biology class that DNA is found in the cell’s nucleus. While this statement is mostly true, some DNA also resides in the mitochondria. The human nuclear genome consists of more than 3 billion base pairs, while the human mitochondrial genome clocks in at slightly fewer than seventeen thousand base pairs. It is clear that in terms of quantity, mitochondrial DNA (mtDNA) pales in comparison to nuclear DNA. However, mitochondrial DNA is nevertheless an integral part of the genetic code. So what exactly is it that makes mitochondrial DNA so special?

      For one, it is obično passed exclusively from mother to child. However, in contradiction to this, a recent study has shown that fathers are also capable of passing on mtDNA to their children in some cases. Dr. Taosheng Huang, a pediatrician at Cincinnati Children’s Hospital Medical Center, discovered that a four-year-old patient of his carried two sets of mtDNA—one from his mother and one from his father. Despite this new discovery, Sophie Breton, a mitochondrial geneticist, explains that “maternal inheritance of mitochondrial DNA is still the norm.” It is easy to think that because mtDNA has historically been maternally inherited, everyone has the same mtDNA. However, this is not true, due to mutations being picked up over time as mtDNA was passed down. Eventually, this led to the existence of slightly different mtDNA sequences across individuals.

      Due to the way mtDNA is passed on, there are certain diseases which can only be inherited maternally. One example is mitochondrial myopathies, encephalopathy, lactic acidosis, and stroke (MELAS), which causes serious nervous and muscular system problems. Mutations in mtDNA can also cause myoclonic epilepsy with ragged red fibers (MERRF), which is characterized by sudden spasms, and Leber’s hereditary optic neuropathy (LHON), which results in vision loss during childhood or young adulthood. To further complicate matters, mtDNA exhibits heteroplasmy, meaning that each cell may contain several variants of mtDNA. Because of this, mitochondrially inherited conditions can vary widely in severity, age of onset, and symptoms because each cell may contain a different ratio of normal mtDNA to abnormal mtDNA. This also creates a lot of variance between organs, as organs throughout the body may have differing levels of heteroplasmy.

      Fortunately, the advent of mitochondrial replacement therapy (MRT) has proven to be very promising for couples who would like to have biological children without passing on a mitochondrial disease. MRT involves using healthy mitochondria from a donor egg from which the nucleus is removed. The mother’s nucleus is then transferred into the cell, and in vitro fertilization (IVF) is used to produce “ an embryo that contains nuclear DNA from the father and the mother with healthy mtDNA from the donor.” This way, women with mtDNA mutations are still able to have children of their own who will almost certainly not inherit said mutations. Due to the fact that genetic material from three individuals is combined during MRT, the resultant offspring is sometimes referred to as a “three-parent baby.”

      As of now, MRT is only legal in the United Kingdom. The FDA in the United States has not approved human clinical trials for IVF involving donor mitochondria. However, for some couples, this procedure is their only chance to have a healthy biological child of their own. Evan and Kristelle Shulman are one of these couples. They lost their son Noah soon after his birth due to a mitochondrial disease and later found out that his condition was a result of mutations present in seventy to eighty percent of Kristelle’s mitochondria, though she herself is not symptomatic. The Shulmans’ only option to guarantee a healthy child is through MRT, but they are unable to undergo the procedure, since it is currently illegal in the United States. Dr. Michio Hirano is able to perform MRT for the Shulmans and five other couples in similar situations, but unfortunately, he cannot transfer the embryos for fertilization with the current laws in place. Until then, the embryos will remain frozen.

      Why is it such a big deal to legalize MRT? After all, it has the potential to help so many couples, right? Though this is true, there are also several associated ethical concerns which lead to the technique being viewed with apprehension by many scientists and bioethicists. For one, there is, as with any procedure, the possibility of unforeseen effects down the road. Though these repercussions are not known at the moment, Professor Joanna Poulton at the University of Oxford explains that “replacing the nucleus [of an egg cell] d oes not prevent development into a baby, but it causes damage to the cell that probably requires radical reorganization.” She goes on to state that this replacement could possibly result in an increased risk of diabetes later on in life. Another ethical concern regarding MRT is that its effects will be passed down through multiple generations, giving it the potential to change the human gene pool over time. Though nucleotide sequences are not being altered as in the case of CRISPR, MRT and its associated alterations will nevertheless persist throughout future generations. A safeguard currently being discussed in order to minimize the risk of future complications of MRT is to, following the procedure, implant only male embryos for possible pregnancy. This way, potential adverse effects of MRT on the mtDNA will be less likely to be passed on to future generations. A third concern relates to the high costs of MRT. With the procedure ranging from $25k-50k, a societal divide may form between those able to afford this therapy and improve their children’s lives, and those who would like to have this opportunity but cannot afford it. Also related to MRT’s price point is the concern regarding the donors themselves. Mitochondrial donors receive significant compensation, and this might fuel the exploitation of disadvantaged women in the donor business.

      All in all, mitochondrial DNA accounts for only a small portion of the human genome, but mutations within it can be just as adverse as those occurring in nuclear DNA. The breakthrough of mitochondrial replacement therapy appears to be a solution to diseases inherited mitochondrially however, as with any new biotechnology, it is accompanied by several ethical concerns. Stringent regulation of the use of MRT, as well as delving deeper into its possible side effects, will hopefully allow a balanced and ethical use of this technology in the coming years.


      Pogledajte video: #7 Mitochondria الميتوكوندريا. Biology (Februar 2023).