Razlika između verzija stranice "Spinalna mišićna atrofija"

'''Kičmena mišićna distrofija''', uobičajeno '''spinalna mišićna atrofija''' ('''SMA''') je rijedak [[neuromuskularni poremećaj]] koji rezultira gubitkom motornih [[neuron]]a i progresivnim [[mišićna slabost|slabljenjem mišića]].<ref>{{Cite web|date=2017-10-23. 10. 2017|title=Spinal muscular atrophy|url=https://www.nhs.uk/conditions/spinal-muscular-atrophy-sma/|access-date=2020-10-24. 10. 2020|website=nhs.uk|language=en}}</ref><ref name=":3">{{Cite web|title=Spinal muscular atrophy: MedlinePlus Genetics|url=https://medlineplus.gov/genetics/condition/spinal-muscular-atrophy/|access-date=2020-10-24. 10. 2020|website=medlineplus.gov|language=en}}</ref><ref>{{Cite web|title=Spinal Muscular Atrophy (SMA) {{!}} Boston Children's Hospital|url=https://www.childrenshospital.org/conditions-and-treatments/conditions/s/spinal-muscular-atrophy-sma|access-date=2020-10-25. 10. 2020|website=www.childrenshospital.org}}</ref> Obično se dijagnosticira u dobi puzanje ili ranom djetinjstvu i ako se ne liječi, najčešći je genetički uzrok smrti [[novorođenčad]]i.<ref name="FDA20192">{{cite web|date=24. May5. 2019|title=FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality|url=https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease|access-date=27. May5. 2019|website=FDA|language=en}}</ref> Može se pojaviti i kasnije u životu i tada imati blaži tok bolesti. Zajednička karakteristika je progresivna slabost voljnih mišića, pri čemu su prvozahvaćeni [[ruke]], [[noge]] i [[Mišići disanja|respiratorni mišići]].<ref name="NINDS20192">{{cite web|title=Spinal Muscular Atrophy Fact Sheet {{!}} National Institute of Neurological Disorders and Stroke|url=https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Spinal-Muscular-Atrophy-Fact-Sheet|access-date=27. May5. 2019|website=NINDS}}</ref><ref name="GHR20192">{{cite web|title=Spinal muscular atrophy|url=https://ghr.nlm.nih.gov/condition/spinal-muscular-atrophy|access-date=27. May5. 2019|website=Genetics Home Reference|language=en}}</ref> Povezani problemi mogu uključivati lošu kontrolu glave, poteškoće pri [[gutanje|gutanju]], [[skolioza|skoliozu]] i [[kontraktura zgloba|kotrakture zglobova]].<ref name="NORD20192">{{cite web|title=Spinal Muscular Atrophy|url=https://rarediseases.org/rare-diseases/spinal-muscular-atrophy/|access-date=27. May5. 2019|website=NORD (National Organization for Rare Disorders)}}</ref><ref name="GHR20192" />

Spinalna mišićna atrofija je uzrokovana [[genska mutacija|genskom mutacijom]] u [[gen]] u ''[[SMN1]]''.<ref>{{cite journal | vauthors = Brzustowicz LM, Lehner T, Castilla LH, Penchaszadeh GK, Wilhelmsen KC, Daniels R, Davies KE, Leppert M, Ziter F, Wood D | title = Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2–13.3 | journal = [[Nature]] | volume = 344 | issue = 6266 | pages = 540–1 | date = Aprilapril 1990 | pmid = 2320125 | doi = 10.1038/344540a0 | bibcode = 1990Natur.344..540B | s2cid = 4259327 }}</ref>

Ljudski [[hromosom 5]] sadrži dva skoro identična gena na [[genski lokus|lokusu]] 5q13: [[telomera|telomerna]] kopija ''[[SMN1]]'' i [[centromera|centromerna]] kopija ''[[SMN2]]''. Kod zdravih osoba, gen ''SMN1'' kodira protein opstanka motornih [[neuron]]a (SMN) koji, kako mu ime kaže, igra ključnu ulogu u preživljavanju [[motorni neuron|motornih neurona]]. ''SMN2'' gen, s druge strane – zbog varijacije u jednom [[nukleotid]]u (840.C→T) – prolazi kroz [[alternativna prerada|alternativnu preradu]] na spoju [[intron]]a 6 do [[egzon]]a 8, sa samo 10-20% ''SMN2'' transkripata koji kodiraju potpuno funkcionalan [[SMN|protrin preživljavanja motornog neurona]] pr (SMN-fl) i 80-90% transkripata što rezultira skraćenim proteinskim [[varijante transkripta|varijantama transkripta]] (SMNΔ7) koje se brzo razgrađuju u ćeliji.<ref>{{cite web |url= https://ghr.nlm.nih.gov/condition/spinal-muscular-atrophy |title=Spinal muscular atrophy |website=Genetics Home Reference |access-date=2019-05-15. 5. 2019 }}</ref>

Kod osoba zahvaćenih SMA, gen ''SMN1'' je [[mutacija|mutiran]] na takav način da nije u stanju da ispravno kodira SMN protein – bilo zbog [[delecija (genetika)|delecije]]<ref name="ReferenceA">{{cite journal | vauthors = Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L, Benichou B, Cruaud C, Millasseau P, Zeviani M | title = Identification and characterization of a spinal muscular atrophy-determining gene | journal = Cell | volume = 80 | issue = 1 | pages = 155–65 | date = Januaryjanuar 1995 | pmid = 7813012 | doi = 10.1016/0092-8674(95)90460-3 | s2cid = 14291056 | doi-access = free }}</ref> na [[egzon]]u 7<ref>{{cite journal | vauthors = Passini MA, Bu J, Richards AM, Kinnecom C, Sardi SP, Stanek LM, Hua Y, Rigo F, Matson J, Hung G, Kaye EM, Shihabuddin LS, Krainer AR, Bennett CF, Cheng SH | title = Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy | journal = Science Translational Medicine | volume = 3 | issue = 72 | pages = 72ra18 | date = Marchmart 2011 | pmid = 21368223 | pmc = 3140425 | doi = 10.1126/scitranslmed.3001777 }}</ref> ili drge [[tačkasta mutacija|tačkaste mutacije]] (često rezultira funkcionalnom konverzijom sekvence ''SMN1'' u ''SMN2''). Skoro svi ljudi, međutim, imaju barem jednu funkcionalnu kopiju gena ''SMN2'' (od kojih većina ima 2–4) koji još uvijek kodira 10-20% uobičajenog nivoa SMN proteina, omogućavajući nekim [[neuron]]ima da prežive. Dugoročno, međutim, smanjena dostupnost SMN proteina rezultira postepenom smrću ćelija motornih neurona u [[kičmena moždina|prednjem rogu kičmene moždine]] i mozgu. [[Skeletni mišići]], koji svi zavise od ovih motornih neurona za nervni unos, sada imaju smanjenu inervaciju (također zvanu [[denervacija]]) i stoga imaju smanjen ulaz iz [[CNS|centralnog nervnog sistema]] (CNS). Smanjen prijenos impulsa kroz motorne neurone dovodi do smanjene kontraktilne aktivnosti denerviranog mišića. Posljedično, denervirani mišići prolaze kroz progresivnu [[atrofija|atrofiju]].

Spinalna mišićna atrofija pogađa osobe svih [[etnička grupa|etničkih grupa]], za razliku od drugih dobro poznatih autosomno recesivnih poremećaja, kao što su [[anemija srpastih eritrocita|bolest srpastih ćelija]] i [[cistasta fibroza]], koji imaju značajne razlike u stopi pojavljivanja među etničkim grupama. Ukupna [[frekvencija|prevalencija]] SMA, svih tipova i među svim etničkim grupama, je u rasponu od 1/10.000 osoba; frekvencija gena je oko 1:100, dakle otprilike 1/50 osoba je nositej.<ref>{{cite journal | vauthors = Su YN, Hung CC, Lin SY, Chen FY, Chern JP, Tsai C, Chang TS, Yang CC, Li H, Ho HN, Lee CN | title = Carrier screening for spinal muscular atrophy (SMA) in 107,611 pregnant women during the period 2005–2009: a prospective population-based cohort study | journal = PLOS ONE| volume = 6 | issue = 2 | pages = e17067 | date = Februaryfebruar 2011 | pmid = 21364876 | pmc = 3045421 | doi = 10.1371/journal.pone.0017067 | veditors = Schrijver I | bibcode = 2011PLoSO...617067S | doi-access = free }}</ref><ref>{{cite journal | vauthors = Sugarman EA, Nagan N, Zhu H, Akmaev VR, Zhou Z, Rohlfs EM, Flynn K, Hendrickson BC, Scholl T, Sirko-Osadsa DA, Allitto BA | title = Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens | journal = European Journal of Human Genetics | volume = 20 | issue = 1 | pages = 27–32 | date = Januaryjanuar 2012 | pmid = 21811307 | pmc = 3234503 | doi = 10.1038/ejhg.2011.134 }}</ref> Ne postoje poznate zdravstvene posljedice koje ima nositelj. Osoba može imati status nositelja samo ako joj je dijete zahvaćeno SMA ili ako ima neeksprimirani gen ''SMN1''.

Ta liječenje spinalne mišićne atrofije koristi se [[Nusinersen]] (na tržištu kao Spinraza).<ref name="FDA Spinraza label">{{cite web | title=Spinraza- nusinersen injection, solution | website=DailyMed | date=30. June6. 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=dd70cd5f-b0fc-4ba4-a5ea-89a34778bd94 | access-date=8. August8. 2020}}</ref> To je antisensni [[nukleotid]] koji modifikuje [[alternativna prerada|altenativnu preradu]] proizvoda gena ''SMN2''.<ref name="FDA Spinraza label"/> Daje se direktno u [[CNS|centralni nervni sistem]] pomoću intratekne [[injekcija|injekcije]].<ref name="FDA Spinraza label" /><ref>{{cite news|url=https://www.wsj.com/articles/surprise-drug-approval-is-holiday-gift-for-biogen-1482856447|title=Surprise Drug Approval Is Holiday Gift for Biogen|last=Grant|first=Charley|date=2016-12-27. 12. 2016|newspaper=The Wall Street Journal|access-date=2016-12-27. 12. 2016|issn=0099-9660|name-list-style=vanc|url-access=subscription}}</ref> Nusinersen produžava preživljavanje i poboljšava motornu funkciju kod dojenčadi sa SMA.<ref>{{cite journal | vauthors = Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, Chiriboga CA, Saito K, Servais L, Tizzano E, Topaloglu H, Tulinius M, Montes J, Glanzman AM, Bishop K, Zhong ZJ, Gheuens S, Bennett CF, Schneider E, Farwell W, De Vivo DC | display-authors = 6 | title = Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy | journal = New England Journal of Medicine | volume = 377 | issue = 18 | pages = 1723–32 | date = Novembernovembar 2017 | pmid = 29091570 | doi = 10.1056/NEJMoa1702752 | s2cid = 4771819 | url = https://discovery.ucl.ac.uk/id/eprint/10046147/ }}</ref><ref>{{Cite journal|last1=Wadman|first1=Renske I.|last2=van der Pol|first2=W. Ludo|last3=Bosboom|first3=Wendy Mj|last4=Asselman|first4=Fay-Lynn|last5=van den Berg|first5=Leonard H.|last6=Iannaccone|first6=Susan T.|last7=Vrancken|first7=Alexander Fje|date=1. June6. 2020|title=Drug treatment for spinal muscular atrophy types II and III|journal=The Cochrane Database of Systematic Reviews|volume=1|pages=CD006282|doi=10.1002/14651858.CD006282.pub5|issn=1469-493X|pmc=6995983|pmid=32006461}}</ref> Za upotrebu u [[SAD]]-u, odobren je 2016., a u EU 2017. godine.<ref>{{cite web | title=Spinraza (nusinersen) Injection | website=U.S. Food and Drug Administration (FDA) | date=18. January1. 2017 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209531Orig1s000TOC.cfm | access-date=8. August8. 2020}}</ref><ref name="Spinraza EPAR">{{cite web | title=Spinraza EPAR | website=European Medicines Agency (EMA) | url=https://www.ema.europa.eu/en/medicines/human/EPAR/spinraza | access-date=8. August8. 2020}}</ref><ref>{{cite news|url=https://www.afp.com/en/news/1315/spinrazar-nusinersen-approved-european-union-first-treatment-spinal-muscular-atrophy|title=Spinraza (Nusinersen) Approved in the European Union as First Treatment for Spinal Muscular Atrophy|date=1. 6. 2017-06-01|access-date=1. 6. 2017-06-01|publisher=Agence France-Presse (AFP)}}</ref>

[[Onasemnogene abeparvovec]] (na tržištu kao Zolgensma) je [[genska terapija]], tretman koji koristi samokomplementarni adeno-povezani virus tipa 9 (scAAV-9), kao vektor za isporuku [[transgeneza|transgena]] ''SMN1''.<ref>{{cite web|title=Zolgensma 2 x 1013 vector genomes/mL solution for infusion|url=https://www.medicines.org.uk/emc/product/11572/smpc|website=www.medicines.org.uk|access-date=8. August8. 2020}}</ref><ref name="FDA Zolgensma label">{{cite web | title=Zolgensma- onasemnogene abeparvovec-xioi kit | website=DailyMed | date=24. May5. 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=68cd4f06-70e1-40d8-bedb-609ec0afa471 | access-date=8. August8. 2020}}</ref> Terapija je prvi put odobrena u SAD u maju 2019. kao [[Intravenska primjena|intravenska]] formulacija za djecu mlađu od 24 mjeseca.<ref name="FDA2019">{{cite press release|title=FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality|url=https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease|website=U.S. Food and Drug Administration (FDA)|access-date=27. May5. 2019|date=24. May5. 2019}} {{PD-notice}}</ref><ref>{{cite web | title=Zolgensma | website=U.S. Food and Drug Administration (FDA) | date=24. May5. 2019 | url=https://www.fda.gov/vaccines-blood-biologics/zolgensma | access-date=8. August8. 2020}}</ref> Uslijedilo je odobrenje u [[Evropska Unija|Evropskoj Uniji]], [[Japan]]u i drugim zemljama, iako često s različitim obimima odobrenja.<ref name="Zolgensma EPAR">{{cite web | title=Zolgensma EPAR | website=European Medicines Agency (EMA) | date=24. March3. 2020 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/zolgensma | access-date=8. August8. 2020}}</ref><ref>{{Cite press release|url=https://www.novartis.com/news/media-releases/novartis-receives-approval-from-japanese-ministry-health-labour-and-welfare-zolgensma-only-gene-therapy-patients-spinal-muscular-atrophy-sma|title=Novartis receives approval from Japanese Ministry of Health, Labour and Welfare for Zolgensma the only gene therapy for patients with spinal muscular atrophy (SMA)|website=Novartis|access-date=8. August8. 2020}}</ref>

[[Risdiplam]] (na tržištu kao Evrysdi) je lijek koji se uzima [[Oralna primjena|na usta]] u tečnom obliku.<ref name="FDA risdiplam" /><ref name="Evrysdi label">{{cite web |url=https://www.gene.com/download/pdf/evrysdi_prescribing.pdf | publisher=Genentech | title=Evrysdi (risdiplam) for oral solution | access-date=8. August8. 2020}}</ref> To je izvedenica [[piridazin]]a koja povećava količinu proteina za preživljavanje [[neuron]]a koji su produkt kodiranja iz gena ''[[SMN2|]]''SMN2'']] putem [[alternativna prerada|alternativne prerade]] [[splajsing]] obrasca.<ref>{{cite web| url=https://smanewstoday.com/rg7916-rg7800-roche-ptc-smaf | title=RG7916 | author=Maria Joao Almeida | publisher=BioNews Services | date=8. 9. 2016-09-08 | access-date=2017-8. 10-08. 2017 }}</ref><ref>{{cite journal | vauthors = Zhao X, Feng Z, Ling KK, Mollin A, Sheedy J, Yeh S, Petruska J, Narasimhan J, Dakka A, Welch EM, Karp G, Chen KS, Metzger F, Ratni H, Lotti F, Tisdale S, Naryshkin NA, Pellizzoni L, Paushkin S, Ko CP, Weetall M | display-authors = 6 | title = Pharmacokinetics, pharmacodynamics, and efficacy of a small-molecule SMN2 splicing modifier in mouse models of spinal muscular atrophy | journal = Human Molecular Genetics | volume = 25 | issue = 10 | pages = 1885–1899 | date = Maymaj 2016 | pmid = 26931466 | pmc = 5062580 | doi = 10.1093/hmg/ddw062 }}</ref> Risdiplam je prvi put odobren za medicinsku upotrebu u Sjedinjenim Državama u augustu 2020<ref name="FDA risdiplam">{{cite press release | title=FDA Approves Oral Treatment for Spinal Muscular Atrophy | website=U.S. Food and Drug Administration (FDA) | date=7. August8. 2020 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-oral-treatment-spinal-muscular-atrophy | access-date=7. August8. 2020}}</ref> i od tada je odobren u preko 30 zemalja.

Ako se ne liječi, većina djece s dijagnozom SMA tipa 0 i 1 ne navrši 4 godine, a ponovljeni respiratorni problemi su primarni uzrok smrti.<ref>{{cite journal | vauthors = Yuan N, Wang CH, Trela A, Albanese CT | title = Laparoscopic Nissen fundoplication during gastrostomy tube placement and noninvasive ventilation may improve survival in type I and severe type II spinal muscular atrophy | journal = Journal of Child Neurology | volume = 22 | issue = 6 | pages = 727–31 | date = Junejuni 2007 | pmid = 17641258 | doi = 10.1177/0883073807304009 | s2cid = 38799022 }}</ref> Uz odgovarajuću njegu, blaži slučajevi SMA tipa I (koji čine oko 10% svih slučajeva SMA1) žive i u odrasloj dobi.<ref>{{cite journal | vauthors = Bach JR | title = Medical considerations of long-term survival of Werdnig-Hoffmann disease | journal = American Journal of Physical Medicine & Rehabilitation | volume = 86 | issue = 5 | pages = 349–55 | date = Maymaj 2007 | pmid = 17449979 | doi = 10.1097/PHM.0b013e31804b1d66 | s2cid = 39989993 }}</ref> Dugotrajno preživljavanje kod SMA tipa I nije dovoljno dokazano; međutim, od 2007. godine čini se da je napredak u respiratornoj podršci smanjio smrtnost.<ref>{{cite journal | vauthors = Oskoui M, Levy G, Garland CJ, Gray JM, O'Hagen J, De Vivo DC, Kaufmann P | title = The changing natural history of spinal muscular atrophy type 1 | journal = Neurology | volume = 69 | issue = 20 | pages = 1931–6 | date = Novembernovembar 2007 | pmid = 17998484 | doi = 10.1212/01.wnl.0000290830.40544.b9 | s2cid = 7528894 }}</ref>

* {{cite journal | vauthors = Parano E, Pavone L, Falsaperla R, Trifiletti R, Wang C | title = Molecular basis of phenotypic heterogeneity in siblings with spinal muscular atrophy | journal = Annals of Neurology | volume = 40 | issue = 2 | pages = 247–51 | date = Augustaugust 1996 | pmid = 8773609 | doi = 10.1002/ana.410400219 | s2cid = 42514712 }}

* {{cite journal | vauthors = Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, Aloysius A, Morrison L, Main M, Crawford TO, Trela A | title = Consensus statement for standard of care in spinal muscular atrophy | journal = Journal of Child Neurology | volume = 22 | issue = 8 | pages = 1027–49 | date = Augustaugust 2007 | pmid = 17761659 | doi = 10.1177/0883073807305788 | s2cid = 6478040 }}

[[Kategorija: Geni na hromosomu 5]]

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