DIAGNOSIS AND FOLLOW-UP OF PATIENTS WITH ANDERSON-FABRY DISEASE

Anderson-Fabryjeva bolest (AFB) je X-vezan poremećaj nakupljanja supstrata u lizosomima uzrokovan mutacijama gena za galaktozidazu (GLA). Znatno smanjena ili odsutna aktivnost enzima α-galaktozidaza A (α-Gal A) rezultira progresivnim nakupljanjem glikolipida, prije svega globotriaosilceramida (Gb3) u cirkulaciji i brojnim stanicama, tkivima i organima, posljedica je višestruko zatajivanje organskih sustava. Bolesnici s tim genetskim poremećajem imaju veliki rizik od razvoja neuropatije malih vlakana, uglavnom ishemijskog moždanog udara, kronične bolesti bubrega, fibrotske srčane bolesti što rezultira poremećajima srčanog ritma i provođenja, kao i progresivnom hipertrofičnom kardiomiopatijom. Iako je AFB povezan s X-kromosomom, obolijevaju osobe oba spola. Dijagnoza AFB-a zahtijeva odlično poznavanje te bolesti i vrlo osnovanu kliničku sumnju, dobar detaljan fizikalni pregled, laboratorijske i slikovne preglede za pojedine organe, a potvrđuje se nalazom bitno smanjene aktivnosti enzima α-Gal A homozigotnih muškaraca i tipizacijom gena u heterozigotnih žena. Enzimska nadomjesna terapija (ENT), oralna terapija šapronom i ciljano liječenje poremećaja pojedinih organskih sustava može dovesti do bitnog kliničkog poboljšanja. Međutim, u današnjoj medicinskoj literaturi možemo naći podatke o liječenju (ENT-om, šapronom, simptomatska terapija) bolesnika s uznapredovalim AFB-om, što znači da je već došlo do značajnog oštećenja organa. Uspjeh u liječenju bolesnika s AFB-om ovisi o personaliziranom pristupu skrbi za bolesnika (odražava fenotip genetske bolesti), sveobuhvatnoj procjeni oštećenja organa prije početka liječenja s ENT-om ili šapronom, odgovor na terapiju, kao i temeljitu prosudbu možebitnih oštećenja organa asimptomskih bolesnika. Bolesnike treba istovremeno liječiti zbog organ-specifičnih oštećenja (živčani sustav, srce, bubrezi, probava i dr.). Budući da je AFB multisistemska bolest, skrb o pacijentima treba povjeriti iskusnom multidisciplinskom timu. Nakon početne procjene bolesti, učestalost kontrolnih pregleda ovisi o kliničkoj slici i stupnju zahvaćenosti pojedinih organskih sustava. Početnu procjenu bolesti treba obaviti za oba spola. U žena s potvrđenom dijagnozom potrebno je utvrditi stupanj zahvaćenosti pojedinih organa. Kontrolni pregled žena koje nemaju simptome bolesti treba obaviti svake 2 godine (starenjem bolesnica povećava se učestalost kontrola), dok žene s izraženim simptomima treba, kao i muškarce s AFB-om, kontrolirati svakih 6 mjeseci. Unatoč značajnom napretku u liječenju i skrbi za bolesnike s AFB-om potrebno je dodatno pojasniti patofiziologiju bolesti i odrediti idealni trenutak za početak liječenja bolesnika različitih fenotipova. Treba uložiti dodatne napore u razvijanju učinkovitijih specifičnih lijekova.Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by mutations in the galactosidase (GLA) gene. Markedly reduced or absent activity of the α-galactosidase A (α-Gal A) enzyme results in progressive accumulation of glycolipids, primarily globotriaosylceramide (Gb3) in the circulation and a wide range of cells, tissues and organs, resulting in the development of a multisystem disorder. Affected patients are at a high risk of developing small-fiber neuropathy, mostly ischemic cerebrovascular stroke, chronic kidney disease, fibrotic cardiac disease resulting in rhythm and conduction disturbances, and progressive hypertrophic cardiomyopathy. Alhough the disease is X-linked, both males and females are affected. Diagnosing AFD requires high clinical suspicion, good physical examination, organ specific tests, and is confirmed by demonstrating low enzyme assays in homozygous males and gene typing in heterozygous females. Enzyme replacement therapy (ERT), oral chaperone therapy and adjunctive treatments can provide significant clinical benefit. However, much of the current literature report on outcomes after late initiation of ERT, once substantial organ damage has already occurred. In AFD patients, the success of management depends on personalized approach to care (reflecting the natural history of the specific disease phenotype), comprehensive evaluation of disease involvement prior to early ERT or chaperone initiation, and thorough routine monitoring for evidence of organ involvement in non-classic asymptomatic patients and response to therapy in treated patients. It is also very important to treat patients with adjuvant therapies for specific disease manifestations. Since AFD is a multisystem disease, the patients should be managed by an experienced multidisciplinary team. After initial evaluation, the frequency of follow-ups depends on clinical severity and involvement of different organs. The initial baseline assessment should be performed for both sexes. In women with confirmed diagnosis, organ involvement needs to be determined clinically. Asymptomatic women may be evaluated every 2 years by increasing the frequency to annual in adulthood, but symptomatic women should be monitored every 6 months, as recommended for men. Despite marked advances in patient care and improved overall outlook, there is the need for better understanding the pathogenesis of AFD and to determine appropriate age to initiate therapy in all types of patients. The need to develop more effective specific therapies was also emphasized