Biochemical and biological properties of glycoconjugates are strongly determined by the specific structure of its glycan parts. Glycosylation, the covalent attachment of sugars to proteins and lipids, is very complex and highly-coordinated process involving > 250 gene products. Deficiency of glycosylation enzymes or transporters results in impaired glycosylation, and consequently pathological modulation of many physiological processes. Inborn defects of glycosylation enzymes, caused by the specific mutations, lead to the development of rare, but severe diseases - congenital disorders of glycosylation (CDGs). Up today, there are more than 45 known CDGs. Their clinical manifestations range from very mild to extremely severe (even lethal) and unfortunately, only three of them can be effectively treated nowadays. CDG symptoms highly vary, though some are common for several CDG types but also for other unrelated diseases, especially neurological ones, leaving the possibility that many CDGs cases are under- or misdiagnosed. Glycan analysis of serum transferrin (by isoelectric focusing or more sophisticated methods, such as HPLC (high-performance liquid chromatography) or MALDI (matrix-assisted laser desorption/ionization)) or serum N-glycans (by MS), enzyme activity assays and DNA sequence analysis are the most frequently used methods for CDG screening and identification, since no specific tests are available yet. In this review we summarize the current knowledge on the clinical, biochemical and genetic characteristic of distinct CDGs, as well as existing diagnostic and therapeutic procedures, aiming to contribute to the awareness on the existence of these rare diseases and encourage the efforts to elucidate its genetic background, improve diagnostics and develop new strategies for their treatment.
Šećerni dijelovi glikokonjugata utječu na mnoga biokemijska i biološka svojstva tih molekula. Glikozilacija, kovalentno pripajanje šećera (glikana) proteinima i lipidima vrlo je složen i visokokoordiniran proces koji uključuje više od 250 različitih genskih produkata. Nedostatak enzima i transportera uključenih u glikozilaciju ima za posljedicu nedostatnu ili nepravilnu glikozilaciju te dovodi do patoloških promjena mnogih fizioloških procesa. Specifične mutacije gena čiji su proteinski produkti uključeni u glikozilaciju uzrokuju nastanak rijetkih, ali ozbiljnih bolesti – urođenih poremećaja glikozilacije (engl. congenital disorders of glycosylation, CDGs). Do danas je poznato 45 tipova CDGs. Kliničke manifestacije bolesti širokog su raspona (od vrlo blagih do smrti), a zasad se samo tri tipa CDGs mogu donekle uspješno liječiti. Simptomi CDGs vrlo su raznoliki, a premda su neki uobičajeni za više tipova CDGs, s obzirom na to da se javljaju i kod drugih, nevezanih bolesti (posebice neuroloških), sumnja se da postoje brojni slučajevi CDG koji još nisu dijagnosticirani ili su pogrešno dijagnosticirani. Premda ne postoje specifični testovi za dijagnosticiranje CDGs, u tu se svrhu najčešće koriste glikanske analize serumskog transferina (izoelektričnim fokusiranjem ili sofisticiranijim metodama kao što su HPLC (engl. high-performance liquid chromatography) i MALDI (engl. matrix-assisted laser desorption/ionization)) ili serumskih N-glikana (masenom spektrometrijom), analize enzimske aktivnosti i analize nukleotidnog slijeda DNA. U ovom preglednom članku predočene su trenutne spoznaje o kliničkim, biokemijskim i genetičkim osobinama pojedinih tipova CDGs, kao i postojeći dijagnostički i terapijski postupci, kako bi se proširila svijest o postojanju ovih rijetkih bolesti i potaknula nastojanja da se rasvijetli genetička osnova njihova nastanka, poboljša dijagnostika i razviju novi terapijski pristupi za njihovo liječenje.