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Validation of a newborn screening method for Cerebrotendinous Xanthomatosis


Uitbreiding neonatale hielprikscreening: onderzoek naar CTX screening

Cerebrotendineuze xanthomatose (CTX) is een erfelijke stofwisselingsziekte waarbij zonder behandeling progressieve lichamelijke en neurologische symptomen ontstaan. Een eenvoudige medicamenteuze behandeling kan dit voorkomen. Dit maakt CTX een geschikte aandoening voor hielprikscreening bij pasgeborenen.


Wij hebben recent een hielprikscreeningsmethode voor CTX ontwikkeld. Met het huidige onderzoek willen we bevestigen dat onze methode geschikt is voor hielprikscreening op CTX.


In dit onderzoek zullen we 20.000 geanonimiseerde hielprikkaarten van pasgeborenen analyseren om de nauwkeurigheid (specificiteit) van onze nieuwe ontwikkelde methode te bepalen en te testen hoe de screening in de praktijk moet gaan verlopen.

Verwachte resultaten

Naar verwachting toont deze studie aan dat onze methode nauwkeurig genoeg is om alleen patiënten met CTX te detecteren en krijgen we een goed beeld hoe de methode in de praktijk gaat functioneren. Hierna zullen we de methode voorgedragen voor toevoeging in het Nederlandse hielprikscreeningsprogramma.

Meer over preo- en neonatale screening


Titel: Newborn screening for Cerebrotendinous Xanthomatosis: A retrospective biomarker study using both flow-injection and UPLC-MS/MS analysis in 20,000 newborns
Auteur: Frédéric M Vaz, Youssra Jamal, Rob Barto, Michael H Gelb, Andrea E DeBarber, Ron A Wevers, Marcel R Nelen, Aad Verrips, Albert H Bootsma, Marelle J Bouva, Nick Kleise, Walter van der Zee, Tao He, Gajja S Salomons, Hidde H Huidekoper
Magazine: Clinica Chimica Acta
Titel: Toward newborn screening of cerebrotendinous xanthomatosis: results of a biomarker research study using 32,000 newborn dried blood spots
Auteur: Xinying Hong, Jessica Daiker, Martin Sadilek, Andrea E. DeBarber, John Chiang, Jie Duan, Albert H. Bootsma, Hidde H. Huidekoper, Frédéric M. Vaz, Michael H. Gelb
Magazine: Genetics in Medicine
Titel: CTX on the way to newborn screening: validation of two methods in 20.000 blood spots
Auteur: Dr. Hidde Huidekoper (Erasmus MC) Dr. Fred Vaz (Amsterdam UMC)
Titel: Results of Pilot Study Screening 20,000 Newborns for CTX and Progress Toward Adding CTX to Dutch NBS Panel
Auteur: Dr. Frederic Vaz Dr. Hidde Huidekoper


Samenvatting van de aanvraag

Cerebrotendinous xanthomatosis (CTX) is a treatable inherited metabolic disorder of bile acid synthesis. Without treatment progressive clinical symptoms develop including neonatal cholestasis, chronic diarrhea, bilateral cataract and developmental delay during childhood, and tendon xanthomas and various neuropsychiatric symptoms due to neurodegeneration towards adulthood. If started at an early age, development of symptoms can be prevented by bile acid replacement therapy (chenodeoxycholic acid supplementation) as this halts the accumulation of neurotoxic intermediates. This makes CTX an excellent candidate for newborn screening, which is why in 2015 the Dutch Health Council recommended that newborn screening for CTX should be considered upon availability of a suitable screening method. In addition, CTX is currently also considered for inclusion in the Recommended Uniform Screening Panel (RUSP) in the USA. We have developed a simple and sensitive one-tier newborn screening method for CTX based on the analysis of accumulating cholestanetetrol glucuronide (tetrol) and the deficiency of specific bile acids/bile acid intermediates in a dried blood spot (DBS). The power of our method is that the use of metabolite ratios enables disease-specific screening for CTX, thereby maximizing specificity, at least in a small scale pilot. In this proof-of-principle study we demonstrated that our method can distinguish CTX patients accurately from healthy newborns (both term and preterm), newborns with cholestasis and patients with Zellweger syndrome, another cause of inherited liver disease (see Vaz et al J Lipid Res. 2017;58(5):1002-1007 for details). After this study we optimized our method for use in the Dutch newborn screening laboratories in collaboration with the reference laboratory for newborn screening in the Netherlands at the Center for Health Protection, RIVM (RIVM-GZB). Before our method can be considered for inclusion in the Dutch (and other) newborn screening program(s), however, it needs to be validated by demonstrating that it has a high enough specificity for the detection of only CTX patients in a larger study. We therefore propose to perform a retrospective validation study based on the analysis of 20.000 anonymized newborn screening cards from the 2019 Dutch newborn screening cohort with the primary objective to demonstrate that no individuals with inherited or acquired liver disease are detected, but only potential patients with CTX. When we find a positive test result we will use a second 3.2 mm punch from the same newborn screening card to perform CYP27A1 mutation analysis, the gold standard for a CTX diagnosis, to differentiate between a true and false positive. We will consider our method suitable for use in the newborn screening program if we demonstrate a specificity of 99.9% or higher (as required for screening methods in the Dutch newborn screening program). In accordance with the consent given by the parents for anonymized scientific research at the time of material collection the anonymity of the individual with a positive screening test is guaranteed by the completely anonymized sampling procedure. Once our method is validated, the results will be presented to the RIVM-Centre for Population Screening (RIVM-CvB) who will evaluate if our method is suitable for implementation in the Dutch newborn screening program. The Health Council already has advised the Ministry of Health, Welfare and Sport to include CTX in the Dutch newborn screening program once a suitable method is available. In previous discussions on our proof-of-principle study and the current validation study with the scientific working group for newborn screening (WONHS) of the RIVM-CvB it was mentioned that if we successfully perform the validation study we propose here, the RIVM-CvB would very likely advice the Ministry of Health, Welfare and Sport to directly proceed with the introduction of CTX in the Dutch newborn screening program. This would also likely pave the way for inclusion of CTX in other newborn screening programs. This is also apparent from the fact that the USA-based working group on newborn screening for CTX has not only expressed great interest in our method but has included our method as the first-tier in their nomination proposal for inclusion of CTX to the RUSP. Newborn screening for CTX will greatly improve the prospects of patients as no symptoms are expected if treatment with chenodeoxycholic acid is started shortly after birth. Granting our proposal will enable validation of our CTX screening method on a relevant scale and will bring the first prospective newborn screening pilot for CTX one step closer to reality. Eventually, this will immensely improve the quality of life of otherwise severely ill children and adults.


Looptijd: 100%
Looptijd: 100 %
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Dr. H.H. Huidekoper
Verantwoordelijke organisatie:
Erasmus MC