title: Elevated concentrations of sedoheptulose in bloodspots of patients with cystinosis caused by the 57-kb deletion: implications for diagnostics and neonatal screening.
abstract: Cystinosis is an autosomal recessive lysosomal storage disease caused by mutations in CTNS. The most prevalent CTNS mutation is a homozygous 57-kb deletion that also includes an adjacent gene named SHPK (CARKL), encoding sedoheptulokinase. Patients with this deletion have elevated urinary concentrations of sedoheptulose. Using derivatisation with pentafluorobenzyl hydroxylamine and liquid chromatography-tandem mass spectrometry (LC-MS/MS), we developed a new sensitive method for the quantification of sedoheptulose in dried blood spots. This method can be utilized as a quick screening test to detect cystinosis patients homozygous for the 57-kb deletion in CTNS; which is the most common mutation of cystinosis. Sedoheptulose concentrations in the deleted patients were 6 to 23 times above the upper limit for controls. The assessment of sedoheptulose in a bloodspot from a known cystinosis patient homozygous for the 57-kb deletion retrieved from the Dutch neonatal screening program showed that sedoheptulose was already elevated in the neonatal period. There was no overlap in sedoheptulose levels between cystinosis patients homozygous for the 57-kb deletion and cystinosis patients not homozygous for this deletion. Our presented method can be used prior to mutation analysis to detect cystinosis patients homozygous for the 57-kb deletion. We feel that the presented method enables fast (pre)-symptomatic detection of cystinosis patients homozygous for the 57-kb deletion, allowing early treatment.
authors.affiliation: VU University Medical Center, Department of Clinical Chemistry, Metabolic Unit, Amsterdam, The Netherlands. m.wamelink@vumc.nl
authors.forename: M M C
authors.initials: MM
authors.lastname: Wamelink
authors.forename: E A
authors.initials: EA
authors.lastname: Struys
authors.forename: E E W
authors.initials: EE
authors.lastname: Jansen
authors.forename: H J
authors.initials: HJ
authors.lastname: Blom
authors.forename: T
authors.initials: T
authors.lastname: Vilboux
authors.forename: W A
authors.initials: WA
authors.lastname: Gahl
authors.forename: M
authors.initials: M
authors.lastname: Kömhoff
authors.forename: C
authors.initials: C
authors.lastname: Jakobs
authors.forename: E N
authors.initials: EN
authors.lastname: Levtchenko
mesh_terms: D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics; D003554:Cystinosis / Q000097:blood / Q000175:diagnosis* / Q000201:enzymology* / Q000235:genetics; D017353:Gene Deletion; D006539:Heptoses / Q000097:blood*; D006801:Humans; D007231:Infant, Newborn; D015997:Neonatal Screening / Q000379:methods*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry; D014157:Transcription Factors / Q000235:genetics
chemical_list: D026921:Amino Acid Transport Systems, Neutral; C111445:CTNS protein, human; D006539:Heptoses; D014157:Transcription Factors; C003011:sedoheptulose; D017853:Phosphotransferases (Alcohol Group Acceptor); C404793:SHPK protein, human