{"id":2047,"date":"2020-05-05T22:24:40","date_gmt":"2020-05-05T20:24:40","guid":{"rendered":"https:\/\/www.newslab.sk\/potencialna-terapia-pre-alkaptonuriu-pribeh-spoluprace-vedy-kliniky-a-pacientov\/"},"modified":"2020-05-05T22:26:46","modified_gmt":"2020-05-05T20:26:46","slug":"potential-therapy-for-alkaptonuria-a-story-of-cooperation-among-science-clinic-and-patients","status":"publish","type":"post","link":"https:\/\/www.newslab.sk\/en\/potential-therapy-for-alkaptonuria-a-story-of-cooperation-among-science-clinic-and-patients\/","title":{"rendered":"Potential therapy for alkaptonuria \u2013 a story of cooperation among science, clinic and patients"},"content":{"rendered":"

*<\/strong>All tables, charts, graphs and pictures that are featured in this article can be found in the .pdf attachment at the end of the paper.<\/strong><\/span><\/p>\n

 <\/p>\n

Z hist\u00f3rie v\u00fdskumu AKU<\/strong><\/p>\n

AKU je ochorenie, pri ktor\u00e9ho defin\u00edcii bol na za\u010diatku minul\u00e9ho storo\u010dia prv\u00fdkr\u00e1t spomenut\u00fd pojem \u201evroden\u00e1 porucha metabolizmu\u201c s mendelistickou autozom\u00e1lne reces\u00edvnou dedi\u010dnos\u0165ou(2). Konkr\u00e9tny metabolick\u00fd blok pri AKU bol op\u00edsan\u00fd o 50 rokov nesk\u00f4r ako deficit homogentiz\u00e1t-1,2-dioxygen\u00e1zy (HGD), enz\u00fdmu zodpovedn\u00e9ho za \u0161tiepenie kyseliny homo\u2011 gentizovej (HGA) v metabolizme fenylalan\u00ednu a tyroz\u00ednu(3). O \u010fal\u0161\u00edch 40 rokov bola \u0161pecifikovan\u00e1 genetick\u00e1 podstata ochorenia u \u010dloveka a g\u00e9n k\u00f3duj\u00faci tento enz\u00fdm bol mapovan\u00fd v\u010faka v\u00e4zbovej anal\u00fdze v rodin\u00e1ch aj slovensk\u00fdch pacientov na chromoz\u00f3m 3q13.33(4,5). Kr\u00e1tko nato bola op\u00edsan\u00e1 \u0161trukt\u00fara g\u00e9nu a identifikovan\u00e9 prv\u00e9 mut\u00e1cie v rodin\u00e1ch pacientov(6). HGD <\/em>g\u00e9n pozost\u00e1va zo 14 ex\u00f3nov a celosvetov\u00e1 HGD <\/em>muta\u010dn\u00e1 datab\u00e1za (http:\/\/hgddatabase.cvtisr.sk), ktor\u00fa sme vytvorili a spravujeme, do dne\u0161n\u00fdch dn\u00ed eviduje 212 r\u00f4znych variantov tohto g\u00e9nu, identifikovan\u00fdch pribli\u017ene u 530 pacientov z cel\u00e9ho sveta(7,8).<\/p>\n

D\u00f4le\u017eit\u00fdm bodom v dejin\u00e1ch v\u00fdskumu AKU bol vznik AKU Society <\/em>(2003, www.akusociety.org), prvej AKU pacientskej organiz\u00e1cie na svete. Od za\u010diatku bolo jej cie\u013eom poskytova\u0165 podporu a inform\u00e1cie pacientom a rodin\u00e1m, ako aj umo\u017eni\u0165 vz\u00e1jomn\u00e9 stret\u00e1vanie a spozn\u00e1vanie AKU pacientov v Spojenom kr\u00e1\u013eovstve, ale aj na medzin\u00e1rodnej \u00farovni, aby sa tak zabr\u00e1nilo pocitom soci\u00e1lnej izolovanosti, ktorou pacienti so zriedkav\u00fdmi chorobami \u010dasto trpia. Pri zrode tejto organiz\u00e1cie bol Dr. Lakshminarayan Ranganath z Liverpoolu a pacient Robert Gregory, ku ktor\u00fdm sa \u010doskoro pridal aj Dr. Nicolas Sireau, otec dvoch det\u00ed s AKU. Ich dlhoro\u010dn\u00e1 pr\u00e1ca, ne\u00fanavn\u00e9 kampane, financovanie v\u00fdskumn\u00fdch projektov a budovanie partnerstiev viedli aj k vytvoreniu konzorcia DevelopAKUre a s\u00e9rii v\u00fdznamn\u00fdch medzin\u00e1rodn\u00fdch klinick\u00fdch sk\u00fa\u0161ok SONIA 1, SONIA 2 a SOFIA v Eur\u00f3pe (2012 \u2013 2019), o ktor\u00fdch budeme hovori\u0165 nesk\u00f4r.<\/p>\n

V roku 2013 v Liverpoole zalo\u017eili tie\u017e prv\u00e9 N\u00e1rodn\u00e9 centrum AKU Roberta Gregoryho (NAC) (so s\u00eddlom v Royal Uni\u2011 versity Hospital), pomenovan\u00e9 pr\u00e1ve po spoluzakladate\u013eovi AKU Society. NAC odvtedy poskytuje vy\u0161etrenia a lie\u010dbu \u013eu\u010fom s AKU \u017eij\u00facim v Anglicku a \u0160k\u00f3tsku. N\u00e1sledne bolo zriaden\u00fdch nieko\u013eko sestersk\u00fdch spolo\u010dnost\u00ed AKU vo viacer\u00fdch krajin\u00e1ch vr\u00e1tane Slovenska, aby sa tak zv\u00fd\u0161ila informovanos\u0165 o AKU (Klub \u010diernych kost\u00ed \u2013 Slovensko, AIMAKU \u2013 Taliansko, DSAKU \u2013 Nemecko, ALCAP \u2013 Franc\u00fazsko, AKU Society Netherlands, AKU Society Asia-Pacific, AKU Society North America, Jord\u00e1nska spolo\u010dnos\u0165 AKU, Braz\u00edlska spolo\u010d\u2011 nos\u0165 AKU a AKU Society India). Tieto spolo\u010dnosti zohr\u00e1vaj\u00fa k\u013e\u00fa\u010dov\u00fa \u00falohu pri vyh\u013ead\u00e1van\u00ed aj udr\u017eiavan\u00ed pacientov ochot\u2011 n\u00fdch zapoji\u0165 sa do biomedic\u00ednskeho v\u00fdskumu vr\u00e1tane klinic\u2011 k\u00fdch \u0161t\u00fadi\u00ed, \u010do je n\u00e1ro\u010dn\u00e9 zvl\u00e1\u0161\u0165 pri zriedkav\u00fdch ochoreniach.<\/p>\n

 <\/p>\n

AKU na Slovensku<\/strong><\/p>\n

V\u00fdskum AKU na Slovensku m\u00e1 svoju dlhoro\u010dn\u00fa trad\u00edciu v\u010faka vy\u0161\u0161iemu v\u00fdskytu tohto ochorenia u n\u00e1s. Prv\u00fd pr\u00edpad AKU na Slovensku op\u00edsal prof. Si\u0165aj v roku 1944 a v roku 1951 prof. Neuwirth objavil ve\u013ek\u00fd s\u00fabor pacientov na Kysuciach, ktor\u00fd potom \u010falej klinicky \u0161tudovali s kolegami prof. Si\u0165ajom a prof. Urb\u00e1nkom. Na z\u00e1klade ich pr\u00e1ce bola v roku 1956 publikovan\u00e1 ve\u013ek\u00e1 monografia Alkapton\u00faria <\/em>a ochron\u00f3za<\/em>(9), ktor\u00e1 predstavuje prv\u00fd ve\u013ek\u00fd komplexne spracovan\u00fd s\u00fabor chor\u00fdch s alkapton\u00fariou a ochron\u00f3zou vo svete.<\/p>\n

Na ich \u0161t\u00fadie nesk\u00f4r (po roku 1968) nadviazal \u010fal\u0161\u00ed v\u00fdznamn\u00fd slovensk\u00fd pediater, zakladate\u013e slovenskej lek\u00e1rskej genetiky, profesor \u0160tefan Sr\u0161e\u0148 spolu s man\u017eelkou docentkou Sr\u0161\u0148ovou a \u010fal\u0161\u00edmi spolupracovn\u00edkmi z Jesseniovej lek\u00e1rskej fakulty Univerzity Komensk\u00e9ho. Skr\u00edningom vy\u0161etrili 610 000 obyvate\u013eov Slovenska a do roku 1996 zaevidovali 204 pacientov s alkapton\u00fariou, z toho 106 det\u00ed do 15. roku \u017eivota, \u010do predstavuje najv\u00e4\u010d\u0161\u00ed s\u00fabor detsk\u00fdch pacientov na svete(10). Vykonali tie\u017e skr\u00edning v skupine 509 192 novorodencov, na z\u00e1klade ktor\u00e9ho odhadli incidenciu AKU na Slovensku na 1 : 19 000(1). V spolupr\u00e1ci s laborat\u00f3riom v M\u00fcnstri (Nemecko) uskuto\u010dnili aj prv\u00e9 genetick\u00e9 \u0161t\u00fadie u slovensk\u00fdch pacientov(11).<\/p>\n

Pri po\u010dte obyvate\u013eov asi 5 mili\u00f3nov sa odhaduje, \u017ee na Slovensku by malo v s\u00fa\u010dasnosti by\u0165 okolo 270 pacientov s AKU a asi 72 450 zdrav\u00fdch pren\u00e1\u0161a\u010dov. V s\u00fa\u010dasnosti sa AKU pacientom venuj\u00fa jednak miestni reumatol\u00f3govia, ale hlavne N\u00daRCH v Pie\u0161\u0165anoch, ktor\u00fd je neform\u00e1lnym centrom starostlivosti o AKU pacientov u n\u00e1s.<\/p>\n

Genetike AKU sa v laborat\u00f3riu genetiky \u010dloveka \u00daKTV, BMC SAV (predt\u00fdm \u00daMFG SAV) venujeme od roku 1998.\u00a0 V spolupr\u00e1ci s Dr. Bo\u0161\u00e1kom a nesk\u00f4r prof. Rovensk\u00fdm z N\u00da\u2011 RCH v Pie\u0161\u0165anoch sme uskuto\u010dnili komplexn\u00e9 genetick\u00e9 anal\u00fdzy v rodin\u00e1ch, ktor\u00e9 uk\u00e1zali, \u017ee na Slovensku m\u00e1me a\u017e 14 r\u00f4znych HGD <\/em>variantov sp\u00f4sobuj\u00facich toto zriedkav\u00e9 ochorenie (obr\u00e1zok 1)<\/em><\/strong>. Tento v\u00fdsledok nazna\u010duje, \u017ee zv\u00fd\u0161en\u00fa frekvenciu AKU u n\u00e1s nemo\u017eno vysvetli\u0165 len klasick\u00fdm efektom zakladate\u013ea, ako sa predpokladalo na z\u00e1klade identifik\u00e1cie zv\u00fd\u0161en\u00e9ho v\u00fdskytu ochorenia hlavne v oblasti b\u00fdval\u00fdch genetick\u00fdch izol\u00e1tov na Kysuciach(12-14).<\/p>\n

Anal\u00fdza haplotypov spojen\u00fdch s jednotliv\u00fdmi mut\u00e1ciami v rodin\u00e1ch nazna\u010duje, \u017ee \u010das\u0165 mut\u00e1ci\u00ed bola na Slovensko importovan\u00e1 po\u010das nieko\u013ek\u00fdch migr\u00e1ci\u00ed eur\u00f3pskej popul\u00e1cie, ktor\u00e9 sa roz\u0161\u00edrili do z\u00e1padnej Eur\u00f3py, pri\u010dom druh\u00fa skupinu tvoria mut\u00e1cie, ktor\u00e9 maj\u00fa svoj p\u00f4vod skuto\u010dne u n\u00e1s(12).<\/p>\n

Je mo\u017en\u00e9, \u017ee do\u0161lo k n\u00e1hodn\u00e9mu zv\u00fd\u0161eniu po\u010dtu mut\u00e1ci\u00ed na Slovensku, pri\u010dom k ich udr\u017eaniu a roz\u0161\u00edreniu prispela n\u00e1sledn\u00e1 genetick\u00e1 izol\u00e1cia a genetick\u00fd drift. K identifik\u00e1cii vy\u0161\u0161ieho po\u010dtu pacientov s AKU na Slovensku prispel aj akt\u00edvny sp\u00f4sob vyh\u013ead\u00e1vania chor\u00fdch, ktor\u00fd m\u00e1 u n\u00e1s dlhoro\u010dn\u00fa trad\u00edciu.<\/p>\n

Laborat\u00f3rium genetiky \u010dloveka BMC SAV sa v priebehu rokov stalo medzin\u00e1rodn\u00fdm centrom genetickej anal\u00fdzy AKU pacientov. V roku 2010 sme zriadili a spravujeme u\u017e spom\u00ednan\u00fa celosvetov\u00fa HGD <\/em>muta\u010dn\u00fa datab\u00e1zu (http:\/\/ hgddatabase.cvtisr.sk)(7,8). T\u00e1to datab\u00e1za obsahuje varianty identifikovan\u00e9 v na\u0161om laborat\u00f3riu, ale aj publikovan\u00fdch v celosvetovej odbornej literat\u00fare. V datab\u00e1ze s\u00fa k dispoz\u00edcii aj v\u00fdsledky anal\u00fdz predpokladan\u00e9ho efektu jednotliv\u00fdch missense mut\u00e1ci\u00ed g\u00e9nu na \u0161trukt\u00faru a funkciu HGD prote\u00ednu, aj jednotliv\u00e9 haplotypy spojen\u00e9 s HGD <\/em>mut\u00e1ciami na Slovensku a v in\u00fdch krajin\u00e1ch.<\/p>\n

 <\/p>\n

Klinick\u00e9 pr\u00edznaky ochorenia a mechanizmus vzniku ochron\u00f3zy<\/h4>\n

V d\u00f4sledku metabolick\u00e9ho bloku pri AKU doch\u00e1dza u\u017e od narodenia k hromadeniu kyseliny homogent\u00edzovej (HGA), ktor\u00e1 sa \u010diasto\u010dne vylu\u010duje mo\u010dom. Ke\u010f\u017ee HGA sa oxid\u00e1ciou men\u00ed na hnedo\u010dierny pigment, ako prv\u00fd pr\u00edznak je v\u00e4\u010d\u0161inou identifikovan\u00e9 tmavnutie mo\u010du na vzduchu (homogen\u2011 tiz\u00faria).<\/p>\n

Nevyl\u00fa\u010den\u00e1 HGA sa v priebehu rokov postupne hromad\u00ed v tele pacientov, a to hlavne v spojivovom tkanive. To vedie nesk\u00f4r k z\u00e1va\u017en\u00fdm multisyst\u00e9mov\u00fdm po\u0161kodeniam, ktor\u00e9 sa za\u010d\u00ednaj\u00fa prejavova\u0165 u\u017e medzi 20. \u2013 30. rokom \u017eivota. Ochron\u00f3za \u2013 tmav\u00e9 sfarbenie spojivov\u00fdch tkan\u00edv, hlavne chrupky \u2013 sa manifestuje na u\u0161niciach, v men\u0161om rozsahu aj na ko\u017ei a o\u010dn\u00fdch bielkach. Akumul\u00e1cia ochronotick\u00e9ho pigmentu v chrupk\u00e1ch vedie postupne k bolestivej degenerat\u00edvnej ochronotickej artropatii, po\u0161kodzuj\u00facej hlavne chrbticu, bedrov\u00e9, ramenn\u00e9 a kolenn\u00e9 k\u013aby. V\u00e1\u017enou komplik\u00e1ciou je kalci\u2011 fik\u00e1cia aort\u00e1lnych a mitr\u00e1lnych chlopn\u00ed. \u010casto sa vyskytuj\u00fa obli\u010dkov\u00e9 a prostatick\u00e9 kamene.<\/p>\n

Po\u010diato\u010dn\u00e1 pigment\u00e1cia je pozorovan\u00e1 v jednotliv\u00fdch chondrocytoch kalcifikovanej chrupky a v ich okolitom matrixe(15). Toto sp\u00f4sobuje lo\u017eiskov\u00fa stuhnutos\u0165 chrupky a men\u00ed sa rozlo\u017eenie za\u0165a\u017eenia. N\u00e1sledne sa ochron\u00f3za \u0161\u00edri smerom do hyal\u00ednovej chrupky. Pigmentovan\u00e1 chrupka vytv\u00e1ra akoby \u0161krupinu, ktor\u00e1 je tuh\u00e1 a l\u00e1me sa, \u010do ma vplyv na podkladov\u00fa trabekul\u00e1rnu kos\u0165. Ochronotick\u00e1 chrupka nie je schopn\u00e1 poskytn\u00fa\u0165 potrebn\u00fa ochranu kosti pred norm\u00e1lnym mechanick\u00fdm za\u0165a\u017een\u00edm a za\u010d\u00edna jej agres\u00edvna resorpcia. Fragmenty chrupky s\u00fa pr\u00edtomn\u00e9 aj v kostnej dreni aj v synovi\u00e1lnom tkanive(15). Ochron\u00f3za teda sp\u00f4sobuje bolestiv\u00e9 ni\u010denie ve\u013ek\u00fdch k\u013abov nes\u00facich v\u00e1hu a f\u00fazie stavcov. Cel\u00fd proces sprev\u00e1dzaj\u00fa chronick\u00fd slab\u0161\u00ed z\u00e1pal a amyloid\u00f3za(16). <\/strong>Progreduj\u00face po\u0161kodenie vedie k invalidiz\u00e1cii.<\/p>\n

Preh\u013ead klinick\u00fdch pr\u00edznakov pri AKU sumarizuj\u00fa pr\u00e1ce(17,18) vr\u00e1tane opisu sp\u00f4sobu ur\u010denia sk\u00f3re AKUSSI (Alkaptonuria Severity Score Index) pou\u017e\u00edvan\u00e9ho na hodnotenie z\u00e1va\u017enosti a progresie pr\u00edznakov AKU.<\/p>\n

 <\/p>\n

Nov\u00e1 n\u00e1dej pre terapiu AKU<\/h4>\n

Kauz\u00e1lna lie\u010dba AKU moment\u00e1lne e\u0161te nie je k dispoz\u00edcii. Doposia\u013e boli mo\u017enosti lie\u010dby AKU limitovan\u00e9 a zameran\u00e9 len na zmiernenie pr\u00edznakov. Hlavn\u00fdm cie\u013eom je kontrola bo\u2011 lesti, fyzioterapia a rehabilit\u00e1cia a v pr\u00edpade nevyhnutnej potreby n\u00e1hrada po\u0161koden\u00fdch k\u013abov.<\/p>\n

S cie\u013eom zn\u00ed\u017ei\u0165 hladinu HGA a jej oxid\u00e1cie na ochronotick\u00fd pigment bolo v minulosti odpor\u00fa\u010dan\u00e9 aj po\u017e\u00edvanie r\u00f4znych kombin\u00e1ci\u00ed antioxidantov, ch\u00fdbaj\u00fa v\u0161ak d\u00e1ta potvrdzuj\u00face efekt\u00edvnos\u0165 t\u00fdchto postupov. Naopak, kyselina askorbov\u00e1 je kofaktorom dioxygen\u00e1zy 4-hydroxyfenylpyruv\u00e1tu, a teda m\u00f4\u017ee prispie\u0165 k zv\u00fd\u0161eniu produkcie HGA. Pacientom sa tie\u017e odpor\u00fa\u010da n\u00edzkoprote\u00ednov\u00e1 di\u00e9ta, dlhodob\u00e1 compliance je v\u0161ak problematick\u00e1.<\/p>\n

N\u00e1dej pre AKU pacientov predstavuje nitizin\u00f3n. Tento liek je inhib\u00edtor enz\u00fdmu p-hydroxyfenylpyruv\u00e1tdioxygen\u00e1zy, zodpovedn\u00e9ho za premenu hydroxyfenylpyruv\u00e1tu na HGA. P\u00f4vodne indikovan\u00fd na lie\u010dbu heredit\u00e1rnej tyrozin\u00e9mie typ 1 (Orfadin(R) vyvinut\u00fd firmou SOBI). U\u017e v roku 2011 publikovan\u00e9 v\u00fdsledky klinickej \u0161t\u00fadie, uskuto\u010dnenej National Institute of Health (USA), uk\u00e1zali, \u017ee nitizin\u00f3n zni\u017euje hladinu HGA v mo\u010di a\u017e o 95 %(19). \u0160t\u00fadia v\u0161ak nepreuk\u00e1zala klinick\u00fa \u00fa\u010dinnos\u0165 nitizin\u00f3nu, preto\u017ee sa nepotvrdilo zlep\u0161enie pohyblivosti bedrov\u00e9ho k\u013abu AKU pacientov, \u010do bol hlavn\u00fd v\u00fdstupn\u00fd parameter \u0161t\u00fadie(19). V\u010faka aktivit\u00e1m AKU spolo\u010dnosti z Anglicka, ktor\u00e1 bola inici\u00e1torom novej vlny z\u00e1ujmu o toto zriedkav\u00e9 ochorenie, vzniklo v roku 2012 u\u017e spom\u00ednan\u00e9 DevelopAKUre konzorcium, ktor\u00e9 s podporou projektu 7RP Eur\u00f3pskej komisie za\u010dalo nov\u00fa \u0161t\u00fadiu s cie\u013eom testova\u0165 nitizin\u00f3n pre AKU. N\u00daRCH v Pie\u0161\u0165anoch, RLUH v Liverpoole a Hospital Necker v Par\u00ed\u017ei boli 3 centrami klinick\u00e9ho sk\u00fa\u0161ania, v ktor\u00fdch prebiehali postupne 3 \u0161t\u00fadie \u2013 SONIA 1, SONIA 2 a SOFIA (http:\/\/ www.developakure.eu\/). <\/a>Na projekte sa podie\u013ealo aj oddele\u2011 nie genetiky \u010dloveka \u00daKTV, BMC SAV, ktor\u00e9 bolo zodpovedn\u00e9 za muta\u010dn\u00fa anal\u00fdzu u v\u0161etk\u00fdch pacientov zapojen\u00fdch do \u0161t\u00fadi\u00ed.<\/p>\n

Prv\u00e1 \u0161t\u00fadia projektu, SONIA 1, bola realizovan\u00e1 v Liverpoole a v Pie\u0161\u0165anoch. I\u0161lo o kr\u00e1tku \u0161t\u00fadiu, trvala 4 t\u00fd\u017edne a ur\u010dila d\u00e1vku 8 mg nitizin\u00f3nu denne ako nejefekt\u00edvnej\u0161iu na zn\u00ed\u017eenie koncentr\u00e1cie HGA v mo\u010di pacientov(20).<\/p>\n

Do dlhodobej \u0161t\u00fadie SONIA 2 bolo u\u017e zapojen\u00fdch 138 pacientov a jej cie\u013eom bolo preuk\u00e1za\u0165, \u017ee nitizin\u00f3n je efekt\u00edvny a bezpe\u010dn\u00fd na pou\u017eitie u AKU pacientov. Kontroln\u00fa skupinu 69 pacientov, ktor\u00ed boli bez lie\u010dby, porovnali so 69 pacientmi, ktor\u00ed po\u010das 4 rokov u\u017e\u00edvali 10 mg nitizin\u00f3nu denne. Pacienti z oboch skup\u00edn pravidelne nav\u0161tevovali centr\u00e1 klinick\u00e9ho sk\u00fa\u0161ania a mali sledovan\u00e9 viacer\u00e9 parametre, ktor\u00e9 sa na z\u00e1ver \u0161t\u00fadie porovnali. Definit\u00edvne v\u00fdsledky tejto \u0161t\u00fadie, ktorej klinick\u00e1 \u010das\u0165 sa skon\u010dila v janu\u00e1ri 2019, e\u0161te neboli publikovan\u00e9, no v\u00fdrobca lieku, SOBI, u\u017e komunikoval svoj \u00famysel po\u017eiada\u0165 Eur\u00f3psku liekov\u00fa agent\u00faru (EMA) o povolenie pou\u017e\u00edva\u0165 liek pre AKU.<\/p>\n

Doteraj\u0161ie sk\u00fasenosti s nitizin\u00f3nom, \u010di u\u017e v \u0161t\u00fadii SONIA 2, alebo v pr\u00edpade off-label lie\u010dby, ukazuj\u00fa, \u017ee je nevyhnutn\u00fd multiodborov\u00fd pr\u00edstup k mana\u017ementu pacientov s AKU. Okrem prirodzenej \u00falohy reumatol\u00f3ga a klinick\u00e9ho genetika je potrebn\u00e9 komplexn\u00fd pr\u00edstup doplni\u0165 o kvalitn\u00e9 nutri\u010dn\u00e9 po\u2011 radenstvo. Pre mo\u017en\u00fd v\u00fdskyt keratopatie po\u010das lie\u010dby nitizin\u00f3nom ako hlavn\u00e9ho a o\u010dak\u00e1van\u00e9ho ne\u017eiaduceho \u00fa\u010dinku, bude potrebn\u00e9 zavies\u0165 pravideln\u00e9 biochemick\u00e9 monitorovanie koncentr\u00e1cie tyroz\u00ednu v s\u00e9re a sledovanie pacientov o\u010dn\u00fdm lek\u00e1rom. Vznik keratopatie sa d\u00e1va do s\u00favislosti pr\u00e1ve so zv\u00fd\u0161en\u00edm hladiny tyroz\u00ednu po\u010das lie\u010dby nitizin\u00f3nom, no presn\u00fd mechanizmus nie je \u00faplne jasn\u00fd. Z poh\u013eadu klinick\u00e9ho v\u00fdskumu bude preto potrebn\u00e9 zamera\u0165 sa na h\u013eadanie bio\u2011 markerov vzniku keratopatie.<\/p>\n

Otvoren\u00e1 prierezov\u00e1 \u0161t\u00fadia SOFIA, do ktorej sa zapojilo 32 pacientov s AKU a 30 kontroln\u00fdch jedincov, prebiehala len v Liverpoole. Cie\u013eom \u0161t\u00fadie bolo zisti\u0165, v akom veku sa po\u0161kodenie pri AKU za\u010d\u00edna, \u010do sa t\u00fdka klinicky manifestovan\u00fdch aj subklinick\u00fdch prejavov ochorenia(21). Prim\u00e1rnym v\u00fdsledkom bol sledovanie pr\u00edtomnosti ochron\u00f3zy v u\u0161nej biopsii. Sekund\u00e1rne v\u00fdsledky zah\u0155\u0148ali anal\u00fdzu fotografi\u00ed o\u010d\u00ed a u\u0161\u00ed, koncentr\u00e1ciu HGA v s\u00e9re a v mo\u010di aj markery po\u0161kodenia\/z\u00e1palu\/ oxid\u00e1cie tkan\u00edv, MRI, test ch\u00f4dze, kvality \u017eivota a index z\u00e1va\u017enosti sk\u00f3re alkapton\u00farie (qAKUSSI). Ochron\u00f3za v tkanive biopsie z ucha bola pr\u00edtomn\u00e1 u\u017e u 20-ro\u010dn\u00e9ho pacienta, \u010do nazna\u010duje, \u017ee subklinick\u00e9 prejavy s\u00fa pozorovate\u013en\u00e9 e\u0161te pred t\u00fdmto vekom.<\/p>\n

V s\u00fa\u010dasnosti prebiehaj\u00fa pr\u00edpravy na pediatrick\u00fa klinick\u00fa \u0161t\u00fadiu. Inform\u00e1cie z t\u00fdchto \u0161t\u00fadi\u00ed bud\u00fa d\u00f4le\u017eit\u00e9 pre rozhodovanie, v akom veku treba za\u010da\u0165 lie\u010dbu, aby sa zabr\u00e1nilo rozvoju pr\u00edznakov.<\/p>\n

 <\/p>\n

Zvierac\u00ed model AKU<\/h4>\n

D\u00f4le\u017eit\u00fa \u00falohu vo v\u00fdskume AKU zohralo vytvorenie experiment\u00e1lneho modelov\u00e9ho organizmu \u2013 AKU my\u0161i. Vyu\u017e\u00edva sa pri \u0161t\u00fadiu patofyziol\u00f3gie AKU a tie\u017e efektu potenci\u00e1lnej lie\u010dby. V roku 2014 bol publikovan\u00fd nov\u00fd my\u0161\u00ed model AKU(22), pri ktorom u\u017e od za\u010diatku \u017eivota mo\u017eno pozorova\u0165 line\u00e1rne st\u00fapaj\u00facu ochron\u00f3zu, pri\u010dom priemern\u00e9 celo\u017eivotn\u00e9 hladiny HGA v plazme zost\u00e1vaj\u00fa relat\u00edvne kon\u0161tantn\u00e9. Je zauj\u00edmav\u00e9, \u017ee u t\u00fdchto my\u0161\u00ed nebolo pozorovan\u00e9 kone\u010dn\u00e9\/ termin\u00e1lne \u0161t\u00e1dium pigment\u00e1cie kalcifikovan\u00fdch a hyal\u00ednov\u00fdch chrupiek, charakteristick\u00e9 pre AKU u \u013eud\u00ed, \u010do nazna\u010duje, \u017ee ochron\u00f3za u my\u0161i reprezentuje skor\u00e9 \u0161t\u00e1di\u00e1 pr\u00edtomn\u00e9 v k\u013aboch u \u010dloveka s AKU. Celo\u017eivotn\u00e9 pod\u00e1vanie nitizin\u00f3nu t\u00fdmto AKU my\u0161iam viedlo k 88% zn\u00ed\u017eeniu plazmatick\u00e9ho HGA a k \u00fapln\u00e9mu blokovaniu pigment\u00e1cie chondrocytov, \u010d\u00edm sa potvrdilo, \u017ee ak sa nitizin\u00f3n za\u010dne pod\u00e1va\u0165 v\u010das, m\u00f4\u017ee za\u2011 stavi\u0165 priebeh ochron\u00f3zy (22,23).<\/p>\n

 <\/p>\n

Variabilita z\u00e1va\u017enosti ochorenia<\/h4>\n

U pacientov s AKU bola pozorovan\u00e1 variabilita v z\u00e1va\u017enos\u2011 ti ochorenia. U\u017e v roku 2000 Rodriguez a kol.(24) pozorovali rozdielnu rezidu\u00e1lnu aktivitu HGD enz\u00fdmu nes\u00faceho r\u00f4zne missense mut\u00e1cie, \u010do sme n\u00e1sledne potvrdili aj v na\u0161ej pr\u00e1ci(8). Predpokladalo sa, \u017ee pr\u00e1ve rozdielna rezidu\u00e1lna aktivita ur\u010duje aj rozdiely v z\u00e1va\u017enosti ochorenia. V r\u00e1mci \u0161t\u00fadie SONIA 2 sme preto uskuto\u010dnili anal\u00fdzu korel\u00e1cie medzi genotypom a fenotypom, konkr\u00e9tne u pacientov s mut\u00e1ciou G161R, pri ktorej je zachovan\u00e9 len 1 % aktivity enz\u00fdmu, v porovnan\u00ed so skupinou nes\u00facou mut\u00e1cie M368V a A122V, ktor\u00e9, naopak, mali asi a\u017e 30 % aktivity divok\u00e9ho typu(8). Hoci medzi oboma skupinami bol pozorovan\u00fd rozdiel v hladine HGA vylu\u010dovanej mo\u010dom za 24 h, kompenzovanej na pr\u00edjem prote\u00ednov, tento rozdiel sa v\u0161ak neprejavil do signifikantn\u00fdch rozdielov v sledovan\u00fdch klinick\u00fdch parametroch(8).<\/p>\n

To znamen\u00e1, \u017ee pri AKU sa nepotvrdil priamy efekt typu mut\u00e1cie HGD <\/em>g\u00e9nu na variabilitu fenotypu ochorenia. Preto\u2011 \u017ee je pozorovan\u00e1 vysok\u00e1 intra aj interindividu\u00e1lna variabilita hlad\u00edn HGA v mo\u010di, predpoklad\u00e1me, \u017ee je z\u00e1visl\u00e1 hlavne od celkov\u00e9ho pr\u00edjmu bielkov\u00edn v strave (t. j. tyroz\u00ednu) a od ren\u00e1lnych funkci\u00ed(25).<\/p>\n

Nevylu\u010dujeme v\u0161ak, \u017ee m\u00f4\u017eu prispieva\u0165 aj \u010fal\u0161ie faktory \u2013 genetick\u00e9 alebo biomechanick\u00e9. V bud\u00facnosti sa bude treba zamera\u0165 na identifik\u00e1ciu t\u00fdchto potenci\u00e1lnych faktorov, a to anal\u00fdzou s\u00farodeneck\u00fdch p\u00e1rov, u ktor\u00fdch je rozdielnos\u0165 fenotypu pozorovan\u00e1. Z\u00e1rove\u0148 bude potrebn\u00e9 identifikova\u0165 faktory, ktor\u00e9 prispievaj\u00fa k rozvoju keratopatie po\u010das lie\u010dby nitizin\u00f3nom a vypracova\u0165 komplexn\u00fd protokol mana\u017ementu pacientov s AKU.<\/p>\n

 <\/p>\n

LITERAT\u00daRA<\/strong><\/p>\n

    \n
  1. Srsen S, Koska L, Kapralik [Alkaptonuria in the Upper Hron Region in Slovakia (author\u2019s transl)]. Cas Lek Cesk 1978; 117(49): 1517-1522.<\/li>\n
  2. Garrod The incidence of alkaptonuria: a study in chemical individuality. 1902. Lancet 1902; 2: 1616-1620.<\/li>\n
  3. La Du Alkaptonuria. In: Scriver CR, Beauder AL, Sly W, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York: McGraw Hill; 1958: 1371-1386.<\/li>\n
  4. Janocha S, Wolz W, Srsen S, et The human gene for alkaptonuria (AKU) maps to chromosome 3q. Genomics 1994; 19(1): 5-8.<\/li>\n
  5. Pollak MR, Chou YH, Cerda JJ, et Homozygosity mapping of the gene for alkaptonuria to chromosome 3q2. Nat Genet 1993; 5(2): 201-204.<\/li>\n
  6. Fern\u00e1ndez-Ca\u00f1\u00f3n JM, Granadino B, Beltr\u00e1n-Valero de Bernab\u00e9 D, et The molecular basis of alkaptonuria. Nat Genet 1996; 14(1): 19-24.<\/li>\n
  7. Zatkova A, Sedlackova T, Radvansky J, et Identification of 11 Nov\u2011 el Homogentisate 1,2 Dioxygenase Variants in Alkaptonuria Patients and Establishment of a Novel LOVD-Based HGD Mutation Database. JIMD Re\u2011 ports 2012; 4: 55-65.<\/li>\n
  8. Ascher DB, Spiga O, Sekelska M, et Homogentisate 1,2-dioxygenase (HGD) gene variants, their analysis and genotype-phenotype correlations in the largest cohort of patients with AKU. Eur J Hum Genet 2019; 27(6): 888-902.<\/li>\n
  9. Si\u0165aj \u0160, \u010cerve\u0148ansk\u00fd J, Urb\u00e1nek Alkapton\u00faria a ochron\u00f3za. Vol 1. Bratislava: Slovensk\u00e1 akad\u00e9mia vied; 1956.<\/li>\n
  10. Srsen S, Muller CR, Fregin A, Srsnova Alkaptonuria in Slovakia: thirty-two years of research on phenotype and genotype. Mol Genet Metab 2002; 75(4): 353-359.<\/li>\n
  11. Gehrig A, Schmidt SR, Muller CR, Srsen S, Srsnova K, Kress Molec\u2011 ular defects in alkaptonuria. Cytogenet Cell Genet 1997; 76(1-2): 14-16.<\/li>\n
  12. Zatkova A, Beltr\u00e1n-Valero de Bernab\u00e9 D, Polakova H, et High frequency of alkaptonuria in Slovakia: evidence for the appearance of multi\u2011 ple mutations in HGO involving different mutational hot spots. Am J Hum Genet 2000; 67(5): 1333-1339.<\/li>\n
  13. Zatkova A, Beltr\u00e1n-Valero de Bernab\u00e9 D, Polakova H, et Allele heter\u2011 ogeneity of alkaptonuria causing mutations and possible reasons for high incidence of this disease in Slovakia. Lekarsky Obzor 2000; 49: 347-352.<\/li>\n
  14. Zatkova An update on molecular genetics of Alkaptonuria (AKU). J Inherit Metab Dis 2011; 34(6): 1127-1136.<\/li>\n
  15. Gallagher JA, Taylor AM, Boyde A, et Recent advances in under\u2011 standing the pathogenesis of ochronosis. Reumatologia 2012; 50(4): 316\u2011323.<\/li>\n
  16. Millucci L, Braconi D, Bernardini G, et Amyloidosis in alkaptonuria. J Inherit Metab Dis 2015; 38(5): 797-805.<\/li>\n
  17. Ranganath LR, Cox Natural history of alkaptonuria revisited: analyses based on scoring systems. J Inherit Metab Dis 2011; 34(6): 1141-1151.<\/li>\n
  18. Ranganath LR, Norman BP, Gallagher Ochronotic pigmentation is caused by homogentisic acid and is the key event in alkaptonuria leading to the destructive consequences of the disease-A review. J Inherit Metab Dis 2019; 42(5): 776-792.<\/li>\n
  19. Introne WJ, Perry MB, Troendle J, et A 3-year randomized therapeutic trial of nitisinone in alkaptonuria. Mol Genet Metab 2011; 103(4): 307-314.<\/li>\n
  20. Ranganath LR, Milan AM, Hughes AT, et Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1): an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study to investigate the effect of once daily nitisinone on 24-h urinary homogentisic acid excretion in patients with alkaptonuria after 4 weeks of treatment. Ann Rheum Dis 2016; 75(2): 362-367.<\/li>\n
  21. Cox TF, Psarelli EE, Taylor S, et Subclinical Ochronosis Features In Alkaptonuria: A Cross-Sectional Study. BMJ Innovations (in press). 2019.<\/li>\n
  22. Preston AJ, Keenan CM, Sutherland H, et Ochronotic osteoarthropathy in a mouse model of alkaptonuria, and its inhibition by nitisinone. Ann Rheum Dis 2014; 73(1): 284-289.<\/li>\n
  23. Keenan CM, Preston AJ, Sutherland H, et al. Nitisinone Arrests but Does Not Reverse Ochronosis in Alkaptonuric JIMD Rep 2015; 24: 45-50.<\/li>\n
  24. Rodriguez JM, Timm DE, Titus GP, et Structural and functional anal\u2011 ysis of mutations in alkaptonuria. Hum Mol Genet 2000; 9(15): 2341-2350.<\/li>\n
  25. Ranganath LR, Khedr M, Milan AM, et Nitisinone arrests ochronosis and decreases rate of progression of Alkaptonuria: Evaluation of the effect of nitisinone in the United Kingdom National Alkaptonuria Centre. Mol Genet Metab 2018; 125(1-2): 127-134.<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

    *All tables, charts, graphs and pictures that are featured in this article can be found in the .pdf attachment at the end of the paper.   Z hist\u00f3rie v\u00fdskumu AKU AKU je ochorenie, pri ktor\u00e9ho defin\u00edcii bol na za\u010diatku minul\u00e9ho storo\u010dia prv\u00fdkr\u00e1t spomenut\u00fd pojem \u201evroden\u00e1 porucha metabolizmu\u201c s mendelistickou autozom\u00e1lne reces\u00edvnou dedi\u010dnos\u0165ou(2). Konkr\u00e9tny metabolick\u00fd blok<\/p>\n","protected":false},"author":7,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_mi_skip_tracking":false,"footnotes":""},"categories":[290],"tags":[1536,1541,1542,1544,1543],"class_list":["post-2047","post","type-post","status-publish","format-standard","hentry","category-genetics","tag-alkaptonuria-en","tag-hgd-gene","tag-metabolic-disorder","tag-nitisinone","tag-treatment-of-rare-diseases","typ_clanku-review-article"],"acf":{"abstrakt":"

    Over the past 10 years, we have witnessed an increased interest in the rare disease alkaptonuria (AKU, OMIM, No. 203500), which has a primate in Slovakia. While the worldwide incidence of AKU is 1: 250 000 to 1: 500 000, the disease is much more common in Slovakia \u2013 1: 19000(1). In January 2019 a clinical part of the DevelopAKUre project (FP7 EU) finished, which included the SONIA2 study to test the effectiveness and safety of nitizinone in the treatment of the disease. The research was conducted under the leadership of scientists at the Royal University Hospital in Liverpool (RLUH) and the British Alkaptonuria Society (AKU Society). However, two teams from Slovakia as well as many Slovak patients were actively involved in the international consortium, so we want to bring a closer story of AKU to readers of Newslab. The results of the SONIA2 study have not been published yet, but the drug manufacturer, SOBI (Swedish Orphan BIovitrum) has already communicated its intention to ask the European Medicines Agency (EMA) for permission to use the medicine for AKU. It gives many patients the hope that AKU is likely to be one of the diseases, for which we will have therapy in 2020. This drug is currently being used off-label in several countries.<\/p>\n

    Keywords: <\/strong>alkaptonuria, HGD gene, metabolic disorder, treatment of rare diseases, nitisinone<\/p>\n","casopis":[{"ID":1893,"post_author":"7","post_date":"2020-05-05 11:32:54","post_date_gmt":"2020-05-05 09:32:54","post_content":"

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