Ataxia Series: Kuparadza ataxia idiopathic idiopathic ataxia iri kunonoka kutanga

Dr. José Luiz Pedroso: Maita basa Orlando. Ndinofara zvikuru kuva pano uye kuedza kutsanangura chirwere ichi chinonakidza chatinodaidza kuti ILOCA, idiopathic late occurrent cerebellar ataxia.

Purofesa Orlando Barsottini: Ndatenda [00:01:00] uye uyu ndiwo mubvunzo wangu wekutanga. Ndeipi tsanangudzo chaiyo ye idiopathic late occurrent cerebellar ataxia? Uye pane kubvumirana here nezvezera pakutanga kwechirwere ichi?

Dr. José Luiz Pedroso: Ehe. Uyu mubvunzo unonakidza zvikuru, asi kuti ndipindure mubvunzo uyu, ndinoda kutaura kukosha kwekuve nemi pano nekuti ndimi maive murairidzi wangu pano muBrazil uye ndimi makatanga kutsanangura nekuvaka division ye ataxia unit muyunivhesiti yedu makore makumi maviri apfuura.

Saka tine ruzivo rwakareba pamwe chete tichishanda nevarwere vane ataxia. Uye ichi chikomborero kwandiri kukupai podcast iyi. Uye [00:02:00] kuenda zvakananga kumubvunzo wenyu. ILOCA inyaya inonakidza nekuti kwenguva yakareba, kwemakore kana makumi emakore kana pamwe zana remakore, taisaziva matambudziko makuru eILOCA.

Izwi rekuti ILOCA ipfungwa isinganzwisisike yekunonoka kutanga kwecerebellar ataxia, uye tinoziva kuti idiopathic zvinoreva kuti hatizivi chikonzero. Zvakafanana ne essential kana primary tremble. Chii chinokonzera essential tremble? Zvinoreva kuti hatizivi chikonzero, asi tichifunga nezvekuvandudzwa kwese kwemajini tekinoroji yekuita genetic testing uye kuona majini matsva nemamiriro matsva.

Kunyanya nekutevera kwechizvarwa chinotevera, tinokwanisa [00:03:00] kuziva chimwe chikonzero cheILOCA. Uye pane dambudziko pano nekuti vanyori vazhinji, vanowanzo funga nezveILOCA kana varwere vanonoka kutanga, vane makore anopfuura makumi mana. Zvinoreva kuti chirwere ichi chinowanzo tanga mushure memakore makumi mana.

Asi ndine zvimwe zvandinofunga nezvazvo pano nekuti zvirwere zvakawanda zvemajini, zvakaita seFriedreich's ataxia neARSACS uye fragile-X zvinogona kutanga mushure memakore makumi mana. Saka ndinotenda kuti pfungwa yeILOCA inofanira kuva murwere ane ataxia yakaipa uye inononoka kutanga inowanzotanga mushure memakore makumi mashanu uye ane ataxia isina kunaka yecerebellar.

Saka aya ndiwo mafungiro angu tichifunga nezve [00:04:00] zvese zvakaoma kutsanangura uye kuisa muzvikamu zveILOCA.

Purofesa Orlando Barsottini: José Luiz, pamwe ILOCA inogona kunge iine chikonzero chakasiyana. Ndezvipi zvikonzero zvakajairika zve idiopathic late occurrent cerebellar ataxia?

Dr. José Luiz Pedroso: Tichifunga nezvemakore matanhatu kana manomwe apfuura, tava nemhando mbiri huru dze late octurnal cerebellar ataxia dzakadzidzwa zviri nani kuburikidza ne etiologies yemajini. Uye ikozvino tine majini maviri makuru anogona kukonzera late octurnal cerebellar ataxia, ayo ari RFC1 uye FGF 14.

Purofesa Orlando Barsottini: Zvakanaka. Kufungidzira neuroimaging kungabatsira sei mukuferefeta kwevarwere vane chirwere che [00:05:00] cerebellar ataxia?

Dr. José Luiz Pedroso: Ehe. Kazhinji kuongorora neuroimaging kunosungirwa kuti tiongorore varwere vane cerebellar ataxia nekuti tinofanira kubvisa matambudziko emuumbirwo wecerebellum akadai semabundu, malformation nezvimwe. Pfungwa yekutanga ndeyekubvisa mamwe mamiriro ezvinhu akadai sematambudziko emuumbirwo. Uye chechipiri, tinofanira kunzwisisa kuti kazhinji varwere vanoonekwa vaine cerebellar atrophy.

Semuenzaniso, murwere ane ILOCA, asina cerebellar atrophy, tinofanira kuongorora, semuenzaniso, Friedreich's ataxia. Uye zvechokwadi kune mamwe macheni chaiwo. Semuenzaniso, varwere vane ARSACS vanogona kuratidza macheni ezviratidzo mupons nezvimwe zvisingawanzoitiki. Semuenzaniso, varwere [00:06:00] vane X permutation isina kusimba.

Uye kudedera uye ataxia zvinogona kuuya nechirwere chakasiyana nechiratidzo chakanyanya, iyo dentate nucleus yecerebellum. Saka kazhinji tinoshandisa brain imaging zvakanyanya kubvisa chimwe chikonzero pane kusimbisa kuti murwere uyu anogona kuratidza imwe mhando ye idiopathic late occur cerebellar ataxia.

Purofesa Orlando Barsottini: Zvakanaka, ndinonzwisisa. Kana makafungidzira kuti pane chikonzero chemajini. Ndedzipi bvunzo dzemajini dzatinofanira kuraira varwere ava? Semuenzaniso, bvunzo chaiyo yeRFC1 kana FGF 14 kana exome yese kana genome. Chii chamunokurudzira panyaya iyi?

Dr. José Luiz Pedroso: Ehe. Ndinofunga kuti uyu ndiwo mubvunzo unonyanya kukosha [00:07:00] webvunzurudzo iyi nekuti tinoziva kuti majini anonyanya kutaurwa ane chekuita neILOCA ndiRFC1 neFGF 14, uye tinofanira kuyeuka kuti majini aya ane chekuita nekukura uye kunyanya RFC1, ari mukukura kwemukati uye chirwere chinokonzeresa hutachiona.

Saka muRFC1, tinowanzo kumbira PCR kuti iite long range PCR. Zvakakwana kuita diagnostic testing muRFC1 uye zvakare muFGF 14. Ichi chirwere chinotonga. Chinonziwo SCA 27 B. Pane musiyano pano pakati pezvirwere zviviri izvi. Semuenzaniso, RFC1 inowanzo kuve ne sensor neuropathy yakabatana [00:08:00] ne vestibular ocular reflex chains ine vestibular hypofunction kana hyporeflexia, uye FGF 14 inowanzova ne phenotype isina kusimba zvakanyanya uye inotanga kunonoka. Kazhinji RFC1 yedu inotanga pazera remakore makumi mashanu nepo FGF 14, inenge makore makumi matanhatu nemapfumbamwe, ine makore makumi matanhatu. FGF 14 inoda cerebellar ataxia inotanga kunonoka, uye cerebellar ataxia isina kunaka. Hazviwanzoitiki, asi zvinokwanisika kuva neuropathy uye vestibular reflexion muvarwere vane FGF 14.

Uye chikonzero chekuongorora FGF 14 ndiko kuchinja-chinja kwezviratidzo uye dzimwe nguva tinogona kuona nystagmus ichidzika uye dzimwe nguva tichifunga nezveRfC1, tinofanira kuyeuka kuti kukosora [00:09:00] kwakajairika muvarwere vane RFC1 mutations. Uye zvakakosha kuyeuka kuti exome sequencing haiongorore intronic expansions.

Zvakakosha kutaura kuti kazhinji kutevedzana kwemasero ese emuviri (whole exome sequencing) kunenge kusina kunaka patinoona varwere vane RFC1 neFGF14, tinofanira kuita PCR nekuferefeta bvunzo idzi dzekuwedzera. Uye yeuka kuti tine mhando mbiri dzekutevera majini. Tine kutevedzana kwemasero mapfupi ekuverenga majini uye kutevedzana kwemasero marefu ekuverenga majini.

Kuti tizive kukura uku kunowanzova kukura kwakanyanya. Tinofanira kuita kuverenga kwenguva refu genome sequencing. Nehunyanzvi uhu, tinogona kuziva kukura uku [00:10:00].

Purofesa Orlando Barsottini: Uyu mubvunzo wakakosha mukuona kwangu nekuti varwere vazhinji vane ataxia yekunonoka kutanga vanogona kunge vaine multiple system atrophy, kunyanya cerebral form. Mungataura here kuti munogona kusiyanisa sei multiple system atrophy ne idiopathic late sectaneous cerebellar ataxia?

Dr. José Luiz Pedroso: Ehe. Mubvunzo wakanaka nekuti multiple system atrophy, kunyanya cerebellar form, inyaya inokosha yekuongorora chirwere cheILOCA. Musiyano mukuru ndeupi? Chekutanga, kufambira mberi kwechirwere kunowanzoita kuti varwere vane MSA vawedzere nekukurumidza. Uye nepo varwere vane ILOCA, kunyanya vane chekuita nemajini maviri aya, RFC1 neFGF [00:11:00] 14, vanowanzo kufambira mberi zvishoma nezvishoma.

Saka ichi chiratidzo chakakosha. Uye chimwe chinhu chakakosha ndechekufungidzira kweuropi. Kazhinji mukufungidzira kweuropi, tinogona kuona chiratidzo che "hot cross bun" muMSA nedzimwe mafambiro asina kunaka akadai sekutetemeka neParkinsonism nezvimwe zvinhu, asi kunyanya kusagadzikana kwemuviri. Kana tiine kusagadzikana kwemuviri, tinofanira kufunga nezveMSA.

Chimwe chinoratidza kurara, nekuti REM sleep behavior disorder inowanikwa zvakanyanya mu alpha synucleinopathy, senge MSA, asi haina kuwanda muILOCA.

Purofesa Orlando Barsottini: Watotaura nezve majini eRFC1 neFGF 14. Asi mumaonero angu, mumwe mubvunzo unokosha, tine nzira ipi zvayo yekurapa [00:12:00] kune varwere ava here kana kuti kune imwe nzira chaiyo yekurapa kwekupedzisira kwe cerebellar ataxia?

Dr. José Luiz Pedroso: Ehe, chinhu chakakosha chine chekuita nekurapwa nekuti, tinofanira kufunga kuti tine miganhu pakurapwa kwacho kune varwere vane nhaka ye cerebellar ataxias. Asi kunyanya paFGF 14, tinogona kushandisa 4-Aminopy ridine uye varwere vanogona kuratidza kuvandudzika pakufamba uye pakuchinja-chinja kwezviratidzo.

Saka nyatsoteererai kuti muone kana paine chirwere ichi nekuti 4-aminopyridine inogona kubatsira varwere kuti vafambire mberi. Saka ichi chiratidzo chakakosha.

Purofesa Orlando Barsottini: Uye ndinoziva kuti une maonero chaiwo nezvenyaya iyi [00:13:00]. Mukufunga kwako, uri nyanzvi yeataxia. Sei tichifanira kupatsanura izwi rekuti idiopathic late mwanzo ataxia.

Dr. José Luiz Pedroso: Ehe, mubvunzo wakanaka kwazvo. Ndinoda kupindura mubvunzo uyu nekuti ndine zvimwe zvandinotsoropodza nezvetsanangudzo iyi, ILOCA. Ndinofunga kuti tinofanira kurega kushandisa ILOCA nekuti nyaya dzakawanda hadzisisiri idiopathic. Dzinoda kuferefetwa, kuferefetwa kwemajini. Vazhinji vevarwere ava vatinoona nhasi vane RFC1 neFGF 14 vaive varwere vakamboonekwa vaine ILOCA kare.

Saka mushure mekunge majini akura nemajini matsva azvitsanangura, ndinofunga kuti tinofanira kuchinja [00:14:00] maonero edu pavarwere vane late opening cerebellar ataxia. Tichifunga kuti tine majini akawanda ane chekuita nevarwere ava, ndinofunga kuti hazvisi zve idiopathic zvakare. Saka ndosaka ndichiwanzoda izwi rekuti deconstruct reILOCA nekuti ikozvino tine chirwere chaicho, kwete RFC1 neFGF 14 chete, tinogona kunge tine varwere vane Friedreich's ataxia vane late opening fragile-x premutation pamwe ne tremor uye ataxia.

Mamwe marudzi eSCA, mamwe ma point mutations, SCAs anogona kuuya nekunonoka kutanga, semuenzaniso, SCA 45. Saka kune mamwe marudzi emajini. Kune mamwe marudzi emajini eARSACS anouya nekunonoka kutanga kwechirwere nevarwere vachitanga zviratidzo mushure memakore makumi mana. Saka ndosaka ndichiwanzoti [00:15:00] tinofanira kubvisa izwi rekuti ILOCA.

Purofesa Orlando Barsottini: Zvino nezvevarwere vane ILOCA uye kuongororwa kwemajini asina kunaka. Mungatiudzewo here nezvemaitiro enyu ekurapa uye kuti mungaongorora sei murwere ane chirwere checerebellar ataxia chinokonzerwa ne idiopathic late occurrent?

Dr. José Luiz Pedroso: Zvakakwana. Uyu mubvunzo unoshanda, uye pandinoona murwere ane cerebellar ataxia yekunonoka kutanga, kunyanya mushure memakore makumi mana. Kuti ndakadzivisa izwi rekuti ILOCA late set cerebellar ataxia. Kutanga tinofanira kuita mu deep phenotyping. Saka kana uine sensorial neuropathy, vestibular areflexia, unobvumirwa kuita bvunzo chaiyo ye [00:16:00] RFC1.

Saka zvinoenderana nemafambiro ezvinhu uye zviratidzo zvekurapa. Kana uine murwere anotanga kunonoka, semuenzaniso anotanga pamakore makumi matanhatu. Tinofanira kuona kana murwere uyu aine zvimwe zviratidzo zvinochinja-chinja zvinogona kuwedzera necaffeine kana kuti zvinogona kuwedzera nefodya, uye zvinogona kuwedzera zviratidzo uye kufamba zvakanyanya.

Varwere ava vanogonawo kuva nechirwere che phenomenology chatinodaidza kuti downbeat nystagmus. Saka izvi zvimwe zvekuongorora kwe phenomenology zvinogona kubatsira kuferefeta zvirwere zviviri izvi, RFC1 neFGF 14 zvichiteerana. Asi zvechokwadi tine chimwe chikonzero, kana tikaita ongororo isina kunaka, nhasi uno zvinokwanisika kuita ongororo ye genome yakaverengwa kwenguva refu.

Kana [00:17:00] usina genome sequencing iripo, unogona kuita exome sequencing nekuti pane mamwe ma point mutations anogona kukonzera late occurrent cerebellar ataxia. Saka tinofanira kutanga taongorora, majini maviri makuru ane chekuita ne expansions dzakadai seRFC1 neFGF 14. Kana usina kuwana chinhu paongororo iyi, unobvumirwa kuita exosome sequencing kana zviri nani kuverenga kwenguva refu genome sequencing kana iripo. Saka izvi ndizvo zvandinofunga nezvazvo kana tichiongorora. Uye yeuka kuti tichiri ne late occurrent Friedreich's at axia. VLOCA very late occurrent ata xia inowanzotanga mushure memakore makumi mana, saka inokonzerwa ne expansion, ungangoda [00:18:00] kuita genetic testing kuna Friedreich's ataxia kuti ubvisewo chirwere ichi, VLOCA.

Saka kune zvikonzero zvakawanda, asi tinowanzo tanga nezviitiko uye nemajini maviri aya, RFC1 yakatsanangurwa makore manomwe apfuura uye FGF 14 yakatsanangurwa makore mana apfuura.

Purofesa Orlando Barsottini: Tava pedyo nekupera kwekubvunzurudzwa kwedu. Ndeipi meseji yatinofanira kuendesa kumba kune vateereri vedu?

Dr. José Luiz Pedroso: Ehe. Ndinofunga kuti shoko guru rinotorwa kumba nderokuti unowanzo sangana nevarwere vane cerebellar ataxia vasati vatanga chirwere mushure memakore makumi mana. Uye yeuka kuti tinofanira kutanga tabvisa mhando dze ataxia dzakawanikwa. Saka iyi ndiyo nhanho yekutanga [00:19:00]. Musakanganwa dzimwe mhando dze syndromic dze late beginning cerebellar ataxias, dzakadai se fragile-x ataxia.

Sezvine chekuita nekuchinja kwemuviri mujini reFMR1. Uyewo, tinofanira kubvisa Friedreich's ataxia pamwe nejini reARSACS, uye tinofanira kurangarira chimwe chirwere chinogona kuitika nekunonoka kutanga kwechirwere ichi chinonzi SPG7, spastic paraplegia type seven. Uye ILOCA yekare ine chekuita nevarwere vane cerebellar ataxia isina kunaka iyo inowanzoonekwa nekufambira mberi uye kunonoka kweataxia kunotanga mushure memakore makumi mana kana makumi mashanu.

Uye yeukai zvikuru majini maviri achangobva kutsanangura RFC1 neFGF 14. Musakanganwa kuferefeta varwere ava nemiedzo iyi chaiyo [00:20:00]. Uye zvechokwadi, exome sequence inogona kubatsira, asi zvakaoma kuwana point mutations mune iyi phenotype. Asi genome yakaverengwa kwenguva refu inogona kubatsira kuwana majini matsva uye zvakare kuferefeta zviri nani ma genetic features ese emurwere ane idiopathic late occurrent cerebellar ataxia.

Purofesa Orlando Barsottini: Tinotenda Jose Luiz nekugovana pfungwa idzi uye tinotenda vateereri vedu nekubatana nesu. Tinovimba kuti chikamu chino chichakubatsira kutaura nevarwere vecerebellar vanotanga kurwara nechirwere ichi nechivimbo chikuru. Tinotenda. [00:21:00]