Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd lcn h ako n nyeihbt hsctblcptwyadrslsi h cuuaino non-degraded of © accumulation the in results Artuch and Rafael pathway catabolic this inhibits enzyme any of lack The glycan. configurations: anomeric two and and or threonine one or in serine acids digested linked amino α the sugars the of six to groups O-linked of glycosidic or composed of asparagine acid majority are amino great the The to oligosaccharide. N-linked be- the the generally are Then, glycosidase, glycoproteins of proteases. specific end by a nonreducing core by protein degraded the sequentially the at are of ginning acids digestion amino the the is to step linked common chains carbohydrate first the pathway, catabolic this In tion. 2008). Sewell, 2014; al., spleen, et liver, heart, Casado lung, ( system, bones nervous dysfunction, central and cellular the joint to kidney, including leads tissues, ultimately multiple accumulation to This lipids damage organs. glycans, progressive and causing including tissues individ- intermediates, in affected catabolic accumulate of different can lysosomes enzyme, proteins, the lysosomal and in affected material catabolic the undigested these disor- on of genetic Depending encode accumulation 50 uals. over the that of by genes group characterized heterogeneous the are a which in (LSDs), ders, diseases Mutations polymers, storage lysosomal lipids. biological for hydrolysing and responsible of are polysaccharides enzymes capable RNA, are DNA, that proteins, enzymes as different such contain that organelles are Lysosomes Introduction Received: DOI: sequencing generation next with trometry detected be diagno- may in step that Keywords: first mutations a and of as sensibility pathogenicity both great diseases, the techniques. have these confirming tests of for These screening chromatography. or extended layer sis enabling alterna- thin automatable, good use are are the that and cases, and tests resolution all compounds, In screening abnormal disorders. traditional the these to identified of tives informative, characterization strongly and are identification pro- rapid profiles these the oligosaccharide summary, for In tools presented. powerful are are diseases) storage cedures disease (glycogen Schindler disorders aspartylglucosaminuria, related 3, and and galactosialydosis) 2 and type patients disease and storage controls glycogen (fucosidosis, healthy Sandhoff, from diseases type profiles gangliosidosis storage oligosaccharide lysosomal urine different The choice natural molecules. with a of is diagnosed class and very this mixtures versatility, of of analytical tolerant analysis is results, the spectrometry precise for Mass offer speed. high and and structures, precision oligosaccharide high sensitivity, im- of high are analysis analyses, the glycan optimal for for an tools tools offers powerful portant it as evolved system, have detector high techniques fluorescence a spectrometry laser-induced has Mass and a sensitivity. It to analytical oligosaccharidoses oligosaccharides. coupled urinary human is of it for analysis when screen and the efficiency, for resolution to suitable oligosaccharides is electrophoresis urinary Capillary of disorders. related analysis spec- the mass and for detection laser-induced techniques with electrophoresis trometry capillary of development the discusses review This 3 Spain Madrid, IDIPAZ, 2 1 oligosaccharidoses of diagnosis the for tests oligosaccharide Urine Casado Mecedes GRUYTER DE Abstract: lnclBohmsr eatet adarcRsac nttt-optlSn ond D de Joan Sant Institute-Hospital Research Paediatric Department, Biochemistry Clinical lnclBohmsr eatet optlSn ond D de Joan Sant Hospital Department, Biochemistry Clinical etod Diagn de Centro / acln,Spain Barcelona, 07Wle eGutrGb,Berlin/Boston. GmbH, Gruyter de Walter 2017 β lgschrdss(rgyortioi)aeasbru fLDcue ydfiin lcpoendegrada- glycoprotein deficient by caused LSD of subgroup a are glycoproteinosis) (or Oligosaccharidoses Naeyglcoaie( -N-acetylgalactosamine α 10.1515/revac-2016-0019 sai cd( acid -sialic aur ,2017; 9, January ailr lcrpoei,lssmlsoaedsae,MLITF lgschrdss asspec- mass oligosaccharidoses, MALDI-TOF, diseases, storage lysosomal electrophoresis, capillary stecrepnigauthor. corresponding the is ó tc eEfreae oeuae,Fcla eCeca,UiesddAut Universidad Ciencias, de Facultad Moleculares, Enfermedades de stico α 1 i) iue1sostemcaimb hc h yooa nye erd nN-linked an degrade enzymes lysosomal the which by mechanism the shows 1 Figure Sia). sa Ferrer-L Isaac / Accepted: α / β GalNAc), ó eray7 2017 7, February pez 2 er Ruiz-Sala Pedro / α / β glcoe( -galactose é ,Breoa pi,Emi:[email protected] E-mail: Spain, Barcelona, u, α / 2 β ei P Celia / Gal), α mnoioi,G1gnloioi,GM2 gangliosidosis, GM1 -mannosidosis, α / é β rez-Cerd mnoe( -mannose eiw nAayia hmsr.21;20160019 2017; Chemistry. Analytical in Reviews β Naeyguoaie( -N-acetylglucosamine é I-SD n CIBERER-ISCIII, and (IR-HSJD) u ó á oad ard CIBER-ER, Madrid, de noma 2 α aalArtuch Rafael / / β Man), α fcs ( -fucose β 3 GlcNAc), α Fuc) 1 Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd 2 1: Table 1: Figure profiles oligosaccharide urine gangliosides altered as present such by also biomolecules, 2008). may caused Sewell, different (GSDs) are ( on diseases that storage groups LSDs glycogen glycosidic other Some the abnormal are mucolipids. of present disorders or degradation related also the These that the in 1. of disorders Table defects identification in related enzymatic shown rapid and are the Oligosaccharidoses profiles for disease. oligosaccharide biomarkers the urine good causes are on that chains depends gene chains these non-degraded candidate therefore, these deficiency; of enzyme composition The specific fluids. the body and lysosomes the in oligosaccharides M agisdsseryifnie230500 defect Enzyme/protein OMIM infantile early gangliosidosis GM1 diseases Related Oligosaccharidoses Disease M agisdssaut230650 609242 609241 230600 256550 (EC A Aspartylglucosaminidase protein/cathepsin Protective 208400 256540 230000 adult gangliosidosis GM1 infantile late gangliosidosis GM1 disease Kanzaki disease Schindler Aspartylglucosaminuria Galactosialidosis Sialidosis Fucosidosis β α Mnoioi 248510 -Mannosidosis Mnoioi 248500 -Mannosidosis aaoe al. et Casado lgschrdssadrltddsreswt oligosacchariduria. with disorders related and Oligosaccharidoses aaoi aha fNlne oligosaccharides. N-linked of pathway Catabolic β 3.2.1.49) α 3.5.1.26) β (secondary α α β α Glcoiae(C3.2.1.23) (EC -Galactosidase deficiency) -galactosidase 3.2.1.25) (EC -Mannosidase Naeyglcoaiiae(EC -N-acetylgalactosaminidase 3.2.1.18) (EC -neuraminidase 3.2.2.51) (EC -Fucosidase 3.2.1.24) (EC -Mannosidase α nuaiiaeand -neuraminidase EGRUYTER DE Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd ad htaedtce yvsa xmnto.TCiae aebe eotdeswee(Pee,d og& Jong de Peelen, ( elsewhere reported been visualized have images then TLC are examination. bands 1994). visual Wevers, oligosaccharide by detected The are acid. that sulphuric bands in sprayed 100 orcinol and at dried of removed, heating finally solution by of is mixture prepared plate a pro- freshly The as this 2008). a such of development Sewell, processes, with variations ( development this are water third and deionized and There air, days. second and warm successive the n-propanol in two for nitromethane, solvents on dried n-butanol, organic solvent is different of same plate use mixture the that the prepared in day, cedure freshly more next a twice solvent, the repeated first On is water. the procedure in deionized can h glucotetrasaccharide, and 6 and acid over lactose acetic developed sialyl generally glacial lactose, is raffinose, as plate such The Standards, used. air. be warm of current a in dried McLaren 1978; al., et Friedman 1979). ( approach Sewell, this 1979; by Ng, detected ex- disorders to & and introduced profiles were from pathological modifications of Further data patho- range 1975). their the reported Collart, pand described & group and Humbel ( a method profiles later, this pa- oligosaccharide using from years urinary gangliosidosis logical oligosaccharides Three GM1 urine and 1972). of mannosidosis Savolainen, fucosidosis, screening & with the Palo patients for ( ago aspartylglucosaminuria decades several with described tients was method gel silica This (TLC) chromatography Thin-layer oligosacchariduria. present that disorders related and and oligosaccharidoses traditional of review screening will we and, the Here, for (HPLC) (CE). approaches chromatography electrophoresis new capillary liquid and few high-performance (MS) last detect spectrometry including the to mass recently, urine, able in more are in and that large improved, developed accumulate of been been have that screening have technologies the oligosaccharides analytical methods diverse for screening on it based biochemical apply procedures sensi- to reasons, different not impossible years, these it is For making method patients. days), this working of However, (three series (TLC). time-consuming chromatography is thin-layer it of by and oligosaccharides tive, onset urinary the the after of narrow ysis very be importance. may paramount of such therapies, be intervention, replacement may effective diagnosis an enzyme prenatal for Moreover, and window symptoms. transplantation and the clinical marrow because Early prognosis bone samples. patient as non-pathological to in crucial present is not patients recognition al- are from biochemical of that pattern samples the oligosaccharides characteristic in urine abnormal present However, excreted with oligosacchariduria difficult. be terations, displaying 2013). also be disorders al., other can may et and that diagnosis Leoz oligosaccharidoses fructooligosaccharides differential De with or ( conditions, galacto- milk these of breast variety Under 1 human large urine. from than a derived younger add oligosaccharides formulas children other particularly infant of Some children, excretion range breast-milk-fed its a and from contains populations, urine old, healthy from The month samples age. urine increasing ( in conditions 6- present with physiological is decreases tetrasaccharide tetrasaccharide under glycogen This the of 2012). al., degradation is intravascular et Sluiter the oligosaccharide from excreted derived amounts small is major contain which samples maltotriose, The urine oligosaccharides. non-pathological Usually, patient. some a of from samples urine random in rides X-linked. is which 9a, GSD of exception the with recessive, autosomal are diseases All GRUYTER DE infantile) 0, Variant gangliosidosis S ye9 000Hptcpopoyaekinase phosphorylase 2.4.1.18) Hepatic (EC enzyme Brancher 2.4.1.25) 306000 (EC enzyme Debrancher 232500 3.1.3.9) 232400 (EC Glucose-6-phosphatase 232200 252600 232300 N-acetylglucosamine- 252500 9a type GSD 4 type GSD 3 type GSD 1a type GSD 2) type (GSD disease Pompe 3 type Mucolipidosis 2 type Mucolipidosis (GM2 disease Sandhoff L spromdo 0c-ogslc e lts rn ape r ple sn ls ailr and capillary glass a using applied are samples Urine plates. gel silica 20-cm-long on performed is TLC anal- qualitative the is oligosaccharidoses of screening biochemical the for method used widely most The oligosaccha- abnormal of detection the on relies 1 Table in listed diseases the of diagnosis biochemical The ° o 0mn nhtai,ocnlrat ihteoioacaie,pouigcolour-stained producing oligosaccharides, the with reacts orcinol acid, hot In min. 10 for C 268800 ( α deficiency) enzyme lysosomal multiple (secondary 2.7.8.17) (EC 1-phosphotransferase ( β α α Hxsmnds n B and A -Hexosaminidase (,)guoiae(C3.2.1.20) (EC -(1,4)-glucosidase sbnt E 2.7.11.19) (EC -subunit) -subunit) α -D-glucopyranosyl- aaoe al. et Casado 3 Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd 4 Bruggink ( procedures MS in required addition frequently In is 2011). Wood, (SPE) & extraction Sowell solid-phase of- ( reaction, is efficiency derivatization derivatization ionization this analysis, poor glycan to for a display used procedures oligosaccharides is MS because and the necessary of glycocompounds ten most reducing In reagent studies. the glycomic derivation with in The oligosaccha- used reacts detection. commonly Because which LIF insert). before (APTS), kit required 8-aminopyrene-1,3,6-trisulphonate is the was derivatization and in used fluorescence, Labelling available native Carbohydrate are exhibit available procedure not commercially do the the rides of adapting (details module, (Beckman-Coulter) laser Kit ion Analysis argon 488-nm a with tion disor- related and oligosaccharidoses 2014). of al., diagnosis et Casado for ( validated MS a ders Recently, and tandem procedures. developed by (TOF) was flight indistinguishable procedure of are CE-LIF-based (MALDI)-time which desorption/ionization isomers, laser even matrix-assisted resolve to or and N-linked able (MS/MS) structures are analyse methods oligosaccharide These to related 2010a), al., developed closely et very Ruhaak been Novotny, Chen 2005; & Guttman, have Muzikar 1998; Evangelista, Mechref, laser-induced CE-LIF 1996; & Evangelista, a (Chen & on glycoproteins to from coupled based released enzymatically when are methods sensitivity that analytical oligosaccharides Some excellent (CE-LIF). offers and detector efficiency fluorescence resolution high a has CE (CE) electrophoresis Capillary of possibility the and resolution improved of offers profiles HPLC patterns. oligosaccharide TLC automatization. abnormal the reference, with compared this and In established were nm. 400 at detection 4-aminobenzoic α were UV with posterior reaction eluent derivatization and the post-column hydrazide a in by acid and oligosaccharides detection Separated amperometric urine pulsed separation. were by procedure, oligosaccharide gradients detected exchange Different this or anion eluents. In monosaccharide as high-pH acetate for (1994). by sodium analysis Wevers developed and separated for hydroxide and were sodium method Jong, of oligosaccharides HPLC solutions de an Then, using chromatography, Peelen, 1994, deproteinized. by In previously developed oligosaccharidoses. were was of samples urine screening in the oligosaccharides in used of also is technology HPLC (HPLC) chromatography liquid High-performance be may im- procedure it this making some in automatable, variations of between-run not forms the is Moreover, juvenile patients. it with of addition, patients number significant. In so large missed. a sensitive, screen very be to always may possible not phenotypes is slight It with 1986). limitations. Sewell, oligosaccharidoses ( important ( 4 has 2 type type it and GSD 1996) stances, de- Hommes, for glucotetrasaccharide & described Galvin-Parton characteristic been ( a have 3 of TLC type excretion on 1983), high al., patterns et a pathological Blom with These types glycogen. TLC, Several by accumulated from origin. urine profile from the and rived to abnormal origin, close an the migrating show at bands observed GSDs of is denselyof presence staining the and dense shows again, band aspartylglucosaminuria disease, brown/pink with Sandhoff characteristic patients In origin. a the excrete at pentasac- fucosidosis bands the stained with in Patients band heavily heptasaccharide). additional show an to gangliosidosis and charide octasaccharide, GM1 with an infantile Patients to with region. corresponding origin, charide Patients the profile. to characteristic close bands band the weaker stained a are and origin further the to migrated close band that stained densely a sialidosis, with patients In aspartylglucosaminuria. gangliosidosis, urine GM1 in sialidosis, observed of be profiles can pattern same oligosac- The the year. 1 cases, the to women. when these months lactating recommended In 6 or is from formulas. testing pregnant ages repeated milk from at and intake, infant profile, milk fortified pathological their some a decrease in with children confused as be fructooligosac- well could and as galacto- pattern of milk charide presence breast the to human due standard in raffinose charides the below observed are bands many dren, mnoioi,G1gnloioi,G2gnloioi yeSnhff op ies and disease Pompe Sandhoff, type GM2-gangliosidosis GM1-gangliosidosis, -mannosidosis, nti td,aayi fteuieoioacaie a tnadzdfrtefis ieuigC-I detec- CE-LIF using time first the for standardized was oligosaccharides urine the of analysis study, this In circum- best the under even but oligosaccharidoses, screening for procedure used widely most the is TLC the described Sewell 2008, In described. well are diseases particular for specific patterns TLC Pathological chil- breast-milk-fed In urine. normal in detected usually are standard raffinose the below bands weak Only aaoe al. et Casado α mnoioi xrt eiso ans-otiigoioacaie (disac- oligosaccharides mannose-containing of series a excrete -mannosidosis α mnoioi,fcsdss M agisdsstp ado and Sandhoff type gangliosidosis GM2 fucosidosis, -mannosidosis, β -mannosidosis EGRUYTER DE Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd 0rn,wihaodcagsi h eeto iebtenec u fanalyses. of run polarity, each reverse between with time applied retention is the kV in 30 changes avoid of voltage which 14 separation runs, of a 10 procedures current and CE electrophoretic injected other an for is in as sample results rinsed The which is 2014). capillary al., the et injection, each Casado before ( and conditioned, are capillaries new the (for capillaries 20 N-CHO at maintained coated be neutrally CE in other separated but are USA), 50- compounds CA, a The Fullerton, example, purpose. (Beckman-Coulter, MDQ this P/ACE module for Beckman laser suitable a ion are using argon systems performed 488-nm were a experiments CE in- with The are equipped & analysis. they system Chen for before water apparatus ( deionized CE glycans in the of dilution onto amination undergo jected reductive from solutions the these residues derivatization, 37 for acid After at used sialic 1995). reaction commonly Evangelista, derivatization of are overnight loss conditions An derivatization the 2014). These avoid al., purpose. et to Casado 37 used ( a are chains on conditions oligosaccharide dark the labelling cyanoborohydride the mild sodium in and procedure, overnight solution derivatization reacted APTS are the the solutions with mixed mixed The are 150 tetrahydrofuran. solution containing in standard volume ladder urine per- dextran A are the samples. analyses 50 or urine at All ples heating stan- morning polymerization. by first ladder concentrated of is the the degree creatinine possible, of of the if nmol peaks represent samples, The and urine 2). markers random (Figure reference on standard size formed ladder as the used as be used may is dard units glucose are 15 procedure CE with the oligosaccharides for labelling and procedures. preparation sample MS various for required of labour those and to time similar the Thus, 2012). al., et GRUYTER DE ouino eihdoye eta otiiglna lcs oyesfo ooe lcs to glucose monomer from polymers glucose linear containing dextran semi-hydrolysed of solution A µ .. 02c oa eghada5-mdsac otedtco) h ailr atig must cartridge capillary The detector). the to distance 50-cm a and length total 60.2-cm a I.D., m ° sn iudcoatt vi hne ntertnintm ftegyoopud.Alof All glycocompounds. the of time retention the in changes avoid to coolant liquid using C µ .Tevaso ue r elcdwt e rs ue after buffer fresh new with replaced are buffer of vials The A. ° na vnfr5h hn 5 Then, h. 5 for oven an in C µ ftecnetae rn sam- urine concentrated the of l ° etn lc.Regarding block. heating C ° scoe o this for chosen is C aaoe al. et Casado 5 Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd 6 migration higher in 1995). result Pritchett, may & coil Guttman to ( structures oligosaccharides branched linear the of in with tendency discrepancies compared slight the times causes because difference times This migration structures. relative linear have their ladder the in oligosaccharides the whereas hexose reducing-end 2010). with al., sialylated moieties et carbohydrate of (Bruggink other residues products and a endo-beta-N-acetylglucosaminidase-cleaved moieties and to oligosaccharide A corresponding O-sulphated cathepsin N-glycans, 2I), protein (Figure enzyme/protective lysosomal disease a the in the defect a in to mutation greater secondary Other is 2H. which Figure in neuraminidase, state we as 2012), amounts detected. al., et also small Sluiter were Other ( octasaccharides) tetrasaccharide GSDs to 2G). the with (penta- (Figure patients of oligosaccharides in excretion Glc4 2009). described Increased al., been of detected. also et excretion Young also has were 2012; Glc4 the heptasaccharides) al., in to et Sluiter (penta- increment ( oligosaccharides remarkable therapy of replacement a enzyme showed the analysis after disease CE-LIF the of tetrasaccharide outcome the and of sion same excretion the urinary with increased an isomers 6- causes positional glycogen resolve accumulated to of degradation CE differ- travascular of These capacity 2013). the al., to et Xia due ( be described may weight. been profiles molecular have excretion oligosaccharides (Figure the hexasaccharides three and in only tetra- ences procedures, between ranging profile MS octasaccharide times in This the migration while with 2E). of 2F), 2013), Harzer, (Figure excretion & Sandhoff substantial units) ( with charides monosaccharide procedures, 12 MS to using 2013). 3 al., obtained with et results Xia oligosaccharides ( Gal2-GlcNAc2-Man3-GlcNAc the (eight to 2012) similar al., trisaccharide was the et in peak Sluiter a had ( and 2013) al., Man3-5-GlcNAc. et for Xia peaks 1998; smaller al., several et as (Man2-GlcNAc), Klein area ( patterns described 2013). previously al., to et similar Xia 2005; al., Fuc-Gal-GlcNAc- corresponding et Ramsay hexasaccharide, mobility ( n fucosidosis the electrophoretic with to patients an of corresponding urine with standard the in peak ladder excreted abnormal is the which Man2-GlcNAc, an in shows hexa-heptasaccharide 2C) the to (Figure profiles CE-LIF impaired by show clearly obtained galactosialydosis and 3 type GSD 2, 2C type (Figure GSD Sandhoff, type gangliosidosis the in disappear peaks intake. which several milk 2B), Figure their month), and decrease 2A <1 (Figure children (age cases the most infants in as detected young peak be very may a area In peaks, pentasaccharide to observed. these trisaccharide is After glycogen, 2014). of al., degradation et travascular 6- Casado oligosaccharide ( the disaccharides to several corresponding and monosaccharides of Quality excretion ERNDIM high the from program galac- educational and disease oligosaccharide presented. from Schindler are the and aspartylglucosaminuria, Scheme in old) Control 3, years included type 16 samples GSD to and 2, week tosialydosis), type 1 GSD (from subjects Sandhoff, (fucosidosis, control type diseases from gangliosidosis lysosomal samples different Urine with 2014). diagnosed al., patients et Casado ( CE-LIF ing corresponding the in residues) maltotriose, glucose 3: the maltose, of 2: (number glucose, maltooligosaccharide degrees (1: the polimeration oligosaccharide of showladder the separation Arrows indicate the trace). numbers shows The (middle and electrophoregram patient. control standard, each the age-matched ladder in from an trace profile with lower urinary compared The the is oligosaccharides. Galactosialido- shows disease abnormal (I) trace each profile. upper for 3 the pattern type urines, excretion GSD pathological oligosaccharide (H) of profile. electrophoregrams disease) (Pompe In 2 profile. type sis GSD (G) profile. (D) Sandhoff profile. gangliosidosis-type Fucosidosis (C) old. year >1 children children from profile non-pathological Representative (A) 2: Figure ≥ α ) hc r xrtdi rn ihlk li,19) h atr bandb ELF(iue2)was 2D) (Figure CE-LIF by obtained pattern The 1999). Klein, & Michalski ( urine in excreted are which 2), Dguoyaoy-attis Gc) diinly rnr l4i imre o oioigteprogres- the monitoring for biomarker a is Glc4 urinary Additionally, (Glc4). -D-glucopyranosyl-maltotriose motnl,i hudb oe htptooia lgschrdsuulyhv rnhdstructures, branched have usually oligosaccharides pathological that noted be should it Importantly, GM1 of deficiency combined a by caused is that LSD rare a is Galactosialidosis in- the disease, this In lysosomes. the in glycogen accumulate disease) (Pompe 2 type GSD with Patients oligosac- different eight of consisting pattern oligosaccharide urine a present disease Sandhoff with Patients oligosaccharides galactosylated of excretion the in increase an present gangliosidosis GM1 with Patients with Patients profile The urine. in excreted are which oligosaccharides, reducing accumulate fucosidosis with Patients fucosidosis, with patients samples, pathological the Regarding display electropherograms Typical 2. Figure in presented are samples urine non-pathological of Examples us- documented been have disease a with individuals and controls healthy of profiles oligosaccharide The aaoe al. et Casado rnr lgschrd rfie yCE-LIF. by profiles oligosaccharide Urinary – I). CTSA α mnoioi cuuaehg-ans-otiigoioacaie (Mann-GlcNAc, oligosaccharides high-mannose-containing accumulate -mannosidosis ee lal mardpol a eetdi aewt eei ofimto of confirmation genetic with case a in detected was profile impaired clearly A gene. α Dguoyaoy-attis Gc) hc sdrvdfo h in- the from derived is which (Glc4), -D-glucopyranosyl-maltotriose α Mnoioi rfie E M1gnloioi rfie F GM-2 (F) profile. gangliosidosis GM-1 (E) profile. -Mannosidosis ≤ erod B ersnaiennptooia rfiefrom profile non-pathological Representative (B) old. year 1 … :Glucose n: , α α n mnoioi,G1gnloioi,GM2 gangliosidosis, GM1 -mannosidosis, mnoioi,G1gnloioi,GM2 gangliosidosis, GM1 -mannosidosis, ) β glcoiae( -galactosidase EGRUYTER DE β gl and -gal) Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd l,21b aauh ta. 04 op,21) oto hs eiaiainratoscnb copihdby be accomplished also 2009). be could Callea, oligosaccharides can & However, reactions Duse oligosaccharides. Verardo, derivatization the ( of these derivatization end without of (Kapkov reducing analysed Most the literature 2010). with the Volpi, reagents facil- 2014; in the to 2005; al., coupling reported and et al., widely ionization Sakaguchi et oligosaccharide been Ramsay 2010b; have enhance ( al., to quantification disease) dis- strategies (Tay-Sachs subsequent Gaucher labelling GM2 sialidosis, their different disease, and itate Other I-cell GM1 2011). III, gangliosidoses Wood, type and & and disease Sowell II storage type acid mucolipidosis 4), sialic Figure ease, fol- in the shown in are patterns diseases identify four could method ESI-MS/MS this diseases: using lowing oligosaccharides of reten- Identification ratio chromatographic 3. mass-to-charge their Figure a in with and fragment oligosaccharides common of a produces efficiency oligosaccharides. and ionization tion neutral poor and inherently Derivatiza- sialylated structures. the analyse improves their to of PMP used elucidation was the 2008), facilitate (PMP) 1-phenyl-3-methyl-5-pyrazolone Morelle, and & with MS Michalski in tion Faid, oligosaccharides their ( of oligosaccharides reduces ionization acidic oligosaccharides, the and enhance basic neutral to and for acidic sensibility the for improves ionization and uniform polarity enables which permethylation, as such oligosac- analyse to chromatography 1994). liquid Wevers, with & combined Jong often de Peelen, is MS/MS. might ( MS by features charides approach. structural characterization this different deriva- by structural but but distinguished mass detailed efficiencies, not same supports be ionization the and with poor oligosaccha- isomers sensitivity their carbohydrate the to MS containing of samples due enhances mass However, MS the sample in to as the field problems decreases of electric ESI cause tization strong of analytes a sensitivity these into the and Generally, capillary increases, droplets. a charged rides through sprayed of mist and charged fine highly a is form solution sample the ESI-MS, In ESI-MS/MS are that structures isobaric separating by complexity reduce The to structures. is MS. oligosaccharide elec- by characterizing techniques resolved capillary in coupled not or MS these chromatographic of of use liquid function with the exchange, analyser main increased ion mass has exclusion, powerful methods size a separation of carbon, trophoretic use graphited The porous 2014). phase, MS al., al., mal oligosac- or et the et TOF/TOF) Kailemia of Xia quadrupole, ( structures (triple ( MS/MS detailed MS/MS MALDI by The modes. and obtained ionization 2009) are negative Linhardt, molecules and positive charide & in Zhang performed ( are (ESI) which 2013), ionization molecules. electrospray of are class this analyses of oligosaccharide tolerant and analysis is oligosaccharides the MS for of speed. choice analysis high natural structural and a precision the a is high for and as sensitivity, evolved mixtures tool high have of important very versatility, which an analytical techniques, is results, MS precise MS offers character- include analysis. developments accurate glycan and technological for rapid these tool the powerful of enabled Many have LSDs. analysis of carbohydrate ization in advances technological recent Other techniques MS 1999). Klein, & Michalski 2014; the al., by et derivatized Casado be ( cannot expected is diseases signal two fluorescence these no in thus, de- excreted and, be glycocomponus reagent cannot APTS The disease, procedure. Schindler this and aspartylglucosaminuria using as tected such urine, in glycocompounds non-reducing GRUYTER DE hsooia ape uie lsa re lo ptadanoi ud utudroderivatization, undergo must fluid) amniotic and spot blood dried plasma, (urine, samples Physiological for methods ionization applied frequently most The analysis. MS for ionized be must Oligosaccharides excrete that defects the that is analysis oligosaccharide urinary for procedure CE-LIF this of limitation A α -fucosidosis, α mnoioi,Pmedsae agisdssG2(ado ies)(these disease) (Sandhoff GM2 gangliosidosis disease, Pompe -mannosidosis, n inta)cpblte ncnucinwt ees-hs,nor- reverse-phase, with conjunction in capabilities trap) (ion m/z f15i l rdc o cn,a shown as scans, ion product all in 175 of á 09 uaket Ruhaak 2009; , aaoe al. et Casado 7 Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd 8 standard internal an as served MeLac use). drug and pregnancy nutrition, parenteral diet, of ( result the be could at variation series Hex4 to Hex2 at (Hex), the sialyllactose hexose including pentose, observed, as are such oligosaccharides monosaccharides other contain at samples) acid urine uronic pathological and N-acetylhesoxamine, the of many (like samples control. Control a from urine PMP-derivatized the on 3: Figure m/z 8.,i red). in 686.7, aaoe al. et Casado S-SM rfieo rcro o cnof scan ion precursor a of profile ESI-MS/MS m/z 6..Mn esitnesgasaepeeti h oto rns n hs aidsbtnily(this substantially varied these and urines, control the in present are signals intense less Many 964.0. m/z aus413(aantson,515 5.,ad545rsetvl.Various respectively. 524.5 and 551.6, 511.5, shown), not (data 481.3 values m/z 7 npstv o oe cnrange scan mode, ion positive in 175 m/z 7.,852 n 9.,rsetvl;and respectively; 997.0, and 835.2, 672.7, m/z 475 – 70 performed 1700, EGRUYTER DE Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd ae u ncnrs oeetohrss tietfisteoioacaie ytermlclrin.I ambiguous In ions. dis- molecular Schindler their or by oligosaccharides aspartylglucosaminuria the of identifies diagnosis it the electrophoresis, to enable [M-H] contrast not as in does but registered method ease, were This with ANTS-oligosaccharides was group. 3-Aminoquinoline the derivatized sulphonic column. and were the carbon the matrix SPE on oligosaccharides a the anal- with depends as were The purification derivatives which used after obtained MALDI-TOF group. controls, the and healthy and electrophoresis blood by tag, of ysed or fluorescent urine a neonates) the (ANTS), showed acid fortified-milk-fed in also 8-aminonaphtalene-1,3,6-trisulphonic even authors or The profile, (breast- disease. oligosaccharide Pompe diet the galactosialido- as such beta-mannosidoses, of oligosaccharidurias, and complexity other (alpha- the and defects gangliosidosis) lysosomal GM1 four and in sis oligosaccharidosis oligosaccharidosis. identify each for to an pattern provide used specific can a MALDI-TOF/TOF, of as diagnosis such the MS/MS, to and contribute MS), and quadrupole signature the to oligosaccharide by contrast (in imparted resolution energy high the with that consider acid. sialic to as necessary and such is potassium majority groups, or It The labile sodium formed. generated. fragment with could also ions adducts however, MALDI of are mode; type ions positive the and deprotonated negative on or in matrix. effects protonated charged the different singly by are the assisted ions of ionized, the are because of oligosaccharides studied the being finally, and are laser, matrices a Several using irradiated is mixture columns. dry carbograph The separation and Permethylation online C18 formed. with mainly adduct MALDI needed, of couple are to type methods difficult purification the is offline and it Therefore, agent The but techniques. derivatizing analysis, interpret. of chromatography to type liquid easier the the improve step, not would derivatization are a spectra of the use but the func- pro- oligosaccharides, to the basic ( believed on and ratio is (depending acidic mass-to-charge Methylation oligosaccharides (permethylation). for methylation native ionization chemical both uniform after of vide present and oligosacchari- analysis Positive those 2013). of the and Rinaldo, for groups) diagnosis & used tional Raymond the ( are in method modes TLC improvements ionization challenging the negative the to with comparison contributing in particularly also doses, is (MALDI-TOF) MS MALDI-TOF MALDI-TOF of screening the for MS improved in developments for further need for driver The a benefits. as induce serve oligosaccharidoses. its possibly will decreasing could oligosaccharides analyse potentially procedures to thereby derivatization methods contamination, the However, detec- and the ease. deterioration allows relative and sample with oligosaccharides of oligosaccharidoses quantification of the tion enables it because laboratories screening newborn lower their to are due removed oligosaccharides be derivatized can the reagents phase, derivatization stationary excess could hydrophilic hydrophilicity. the 0.1% the and acid In interactions, hydrophilic residues. trifluoroacetic by acid using perfor- are retained sialic good elution used shows of but phases phase loss oligosaccharides, stationary stationary the underivatized carbon of cause of the types Briefly, purification 2014). major the al., two in et the mance Zhang and ( simple SPE, and materials rapid of carbon its and phases to hydrophilic due stationary oligosaccharides diverse labelled are of purification detec- There the oligosaccharide operation. for facilitate employed and widely interference been the has remove SPE to tion. implemented be must procedure clean-up a and green). in respectively, ( Hex3-HexNAc4 1647.6, HexNAc and and Hex3-HexNAc3, terminal 1445.4, Hex3-HexNAc2, with Hex2-HexNAc2, 1242.2, oligosaccharides compositions: 1080.1, were following disease the disease Pompe Sandhoff with in with and present patient residue oligosaccharides a The of disease. urine Sandhoff the with ( in Glc4 present tetrasaccharide excretion glucose oligosaccharide the major was The disease. Pompe with patient a ( with series NAc patient a the from fu- in urine PMP-derivatized the present of in oligosaccharides scan present 175 oligosaccharides Precursor The (B) fucosidosis. respectively. Fuc-Hex-HexNAc, at with oligosaccharides patient fucosylated a were from ( sample urine standard PMP-derivatized cosidosis internal of an scan as 175 served Precursor MeLac (A) oligosaccharidurias. with patients from urine 4: Figure GRUYTER DE li ta.(98 ecie AD-O ehdfraayigoioacaie nuieta ol be could that urine in oligosaccharides analysing for method MALDI-TOF a >2000 described range (1998) mass al. a et and Klein measurement mass accurate an derives analyser mass as TOF the of use The dried. and target MALDI a on spotted matrix, a with mixed solvent organic an in dissolved are samples The many in oligosaccharides of determination the for method analytical used widely most the is ESI-MS/MS excess, large a in present are reagents derivatization and solvents salts, reaction, derivatization the During S-SM rfie fpeusrinsa of scan ion precursor of profiles ESI-MS/MS m/z 1.,859 080 202 n 334 ngen.()Peusr15sa fPPdrvtzduiefrom urine PMP-derivatized of scan 175 Precursor (C) green). in 1363.4; and 1200.2, 1038.0, 875.9, 713.7, m/z ftepedmlclrino pcfi lgschrd ilcag eedn on depending change will oligosaccharide specific a of ion pseudomolecular the of ) α mnoioi apewr ans-ihoioacaie fte(Man)n the of oligosaccharides mannose-rich were sample -mannosidosis m/z 9. ngen.()Peusr15sa fPPdrvtzduiefo patient a from urine PMP-derivatized of scan 175 Precursor (D) green). in 998.0 m/z m/z 7 npstv o oepromdo h PMP-derivatized the on performed mode ion positive in 175 9. n 5. i re) ihcmoiinFcHxA and Fuc-HexNAc composition with green), (in 859.9 and 697.7 m/z − 8.,i red). in 686.7, nngtv o oe u to due mode, ion negative in α mnoioi.The -mannosidosis. aaoe al. et Casado α -Man β 1-4Glc- m/z m/z 9 Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd 10 in oligosaccharides of chromatography Thin-layer (1983). C. M. Loonen, & G. J. Huijmans, H., H. Kelholt-Dijkman, C., J. Luteyn, W., Blom, References sequencing generation next with detected be may diagnosis that in and mutations step sensibility first of a great pathogenicity as have the techniques. both are methods diseases, of technologies these These confirmation These of TLC. for subjects. screening using or extended control test enabling the automatable, screening from are traditional samples and urine resolution the the to different of abnormal alternatives with showed any good and in patients informative very present strongly in are not oligosaccharides profiles are oligosaccharide urinary that character- the compounds of cases, and all patterns identification In rapid characteristic described. the are The diseases for disorders. and tools oligosaccharidoses these powerful of of are study izations oligosacchariduria the present for that used diseases procedures MALDI-TOF related and ESI-MS/MS, CE-LIF, summary, In Conclusions deuterated of use the suggest data. authors quantitative obtain The identified to studied. only excretion be were species creatinine also and for the could correcting indistinguishable of and residues are identification standards fucosyl Gal the and and to asparaginyl contributing Man, However, respectively. detected, Glc, hexoses, as and well N-acetylhexosamines as GalNAc as were and GlcNAc oligosaccharides that Sialylated ion mind interpret. positive to the easier [M-H] was for as mode that better ion profile negative was in oligosaccharide analysed latter an 9-aminoacridine obtain as positive the in and such Na] detected and adducts were matrices, + glycans mode Other Neutral [M results. ion twice. as poor analysed negative mode produced were and the studied patient were for 1,5-diaminonaphtalene, each or better from samples was Therefore, matrix mode. first the III). that and II mucolipidosis aspartylglucosamin- (fucosidosis, and samples alfa-mannosidosis control disease, included Sandhoff that less GM1, series sialidosis, analysis much blind uria, is a method in al. training this as et used that Xia were by remarked reported well method is the It than MALDI-TOF. min) in (30 salts shorter for and laborious tolerance IIb). the glycosylation of of disorder be advantage (congenital could taking deficiency oligosaccharides I of glucosidase excretion as first-tier such the the analysis, by for same tool characterized the reliable diseases a in is screened Other method disorders. these the lysosomal of that some suggesting of oligosac- of presentations, screening authors subtypes clinical studied the the between mild Finally, similar. authors differentiated or of very severe and The were end with oligosaccharidoses required. profiles diseases 10 reducing the also of that the profiles is found diagnostic permethylation of and 43 ranges from derivatization identified age acid different the seven sialic on at terminal samples based the control are of acids protection methods glycoamino The the which charide. in when aspartylglucosaminuria, diagnosing detected diseases). aspartyl- of au- be possibility Gaucher sialidosis, The a cannot columns). be and alpha-mannosidosis, may carbograph Pompe there and GM2, that (C18 and suggest purification and thors fucosidosis offline two-step (GM1 galactosialidosis, after permethylated samples III, are urine Oligosaccharides and of II analysis mucolipidoses single glucosaminuria, a in TOF/TOF other which in profile observed. a be of must part are ions oligosaccharides intense these less course, Of respectively. GM1, and galactosialidosis in at signals highest alpha- The GlcNAc. For identification. at Man2GlcNAc correct to at HexHexNAc corresponding the The Hex2HexNAc, achieve 911. trisaccharide the to was help compound could major the exoglycosidades mannosidosis, selective with digestion the cases, rn sarpdidcto o h igoi flssmlai ats ecec (Pompe deficiency maltase acid lysosomal of diagnosis the for indication rapid a as urine in bearing spectra, MALDI-TOF the in obtained peaks relevant more the identify to used was TOF/TOF showed and 3-aminoquinoline, and acid 2,5-dihydroxybenzoic matrices, different two tried authors The which samples, diagnosed previously in oligosaccharidoses different eight identify to able were authors The (10 samples urine analysed (2014) al. et Bonesso MALDI- by diseases different 11 of patterns oligosaccharide the identify to able was (2013) al. et Xia aaoe al. et Casado + n M+K] + [M and m/z 4 a oeipratmre fbt-ansdssadcrepne oMan- to corresponded and beta-mannosidosis of marker important more a was 749 m/z + hrfr,sdu at eeaddt eueteocrec fsodium of occurrence the reduce to added were salts sodium therefore, ; 57(eAHxHxA2 and (NeuACHex3HexNAc2) 1567 − u oimadptsimadcswr loobserved. also were adducts potassium and sodium but , µ )wtotayperamn oioaeoligosaccharides, isolate to pretreatment any without l) m/z ’ disease). s 83(e5eNc)wr observed were (Hex5HexNAc3) 1803 lnc hmc Acta Chimica Clinica 3,221 134, , EGRUYTER DE – 227. m/z Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd lie,W,vndnBsh .C,Guran .A,vnGle,C . eVis .M,Himn,J . esr .J,vndrPog .T Ruijter, & T. 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