A blood test for cerebrotendinous xanthomatosis with potential for disease detection in newborns

DeBarber, Andrea E.; Luo, Jenny; Star-Weinstock, Michal; Purkayastha, Subhasish; Geraghty, Michael T.; Chiang, John; Merkens, Louise S.; Pappu, Anuradha S.; Steiner, Robert D.

doi:10.1194/jlr.p043273

Cited by 41 publications

(51 citation statements)

References 41 publications

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“…Several hundred cases have been reported, but the number of undiagnosed and possibly misdiagnosed cases is unknown (DeBarber et al 2014b). Although epidemiologic data are limited and methodology differs among studies, available data suggest that CTX may be substantially underdiagnosed.…”

Section: Epidemiologymentioning

confidence: 99%

Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX)

Salen

Steiner

2017

J of Inher Metab Disea

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Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid synthesis caused by mutations in the cytochrome P450 CYP27A1 gene that result in production of a defective sterol 27‐hydroxylase enzyme. CTX is associated with abnormally high levels of cholestanol in the blood and accumulation of cholestanol and cholesterol in the brain, tendon xanthomas, and bile. Hallmark clinical manifestations of CTX include chronic diarrhea, bilateral cataracts, tendon xanthomas, and neurologic dysfunction. Although CTX is a rare disorder, it is thought to be underdiagnosed, as presenting signs and symptoms may be nonspecific with significant overlap with other more common conditions. There is marked variability in signs and symptoms, severity, and age of onset between patients. The disease course is progressive and potentially debilitating or fatal, particularly with respect to neurologic presentations that can include intellectual disability, autism, behavioral and psychiatric problems, and dementia, among others. Treatment with chenodeoxycholic acid (CDCA; chenodiol) is the current standard of care. CDCA can help restore normal sterol, bile acid, bile alcohol, and cholestanol levels. CDCA also appears to be generally effective in preventing adverse clinical manifestations of the disease from occurring or progressing if administered early enough. Improved screening and awareness of the condition may help facilitate early diagnosis and treatment.

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Section: Epidemiologymentioning

confidence: 99%

Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX)

Salen

Steiner

2017

J of Inher Metab Disea

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139

150

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“…Az epesavak eltérései a vizeletben és a szérumban, valamint a plazma és a szövetek emelkedett kolesztanolszintjének meghatározása egy fontos diagnosztikai lehetőség, és alkalmas a betegség terápiájának követésére is. A korai diagnózis jelentőség e olyan nagy, hogy nemrégiben egy új, bár igen költséges módszert is kifejlesztettek kifejezetten az újszülöttkori szűrés céljából az emelkedett epesav prekurzor ketoszterol szintjének meghatározására szárított vércseppből [29]. A molekuláris biológiai módszerek szükségesek a végleges diagnózis felállításához, a hordozó családtagok azonosításához és elengedhetetlenek a praenatalis diagnosztika alkalmazásához.…”

Section: A Korai Diagnosztika Jelentőségeunclassified

Laboratory diagnosis of a rare congenital neurodegenerative disease: cerebrotendinous xanthomatosis

et al. 2014

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A cerebrotendinosus xanthomatosis egy ritka, ataxiával, spasticitassal, korai mentális hanyatlással és pszichiátriai tüne-tekkel járó neurodegeneratív betegség, amelyet a koleszterin és a kolesztanol agyban és az inakban történő felszaporodása jellemez az epesavszintézisben részt vevő szterol-27-hidroxiláz (CYP27A1) génjének mutációja miatt. A diagnózis gyakran hibás vagy megkésett a változatos klinikai megjelenés miatt. A laboratóriumi diagnosztika rutinszerűen az emelkedett kolesztanolszint kimutatását végzi gázkromatográf-tömegspektrométer alkalmazásával, majd a diagnó-zist a molekuláris genetikai vizsgálat igazolja. A korai felismerés és a kenodezoxikólsav-, valamint a hidroximetil-glutaril-koenzim-A-reduktáz-gátló kezelés megkezdése alapvető jelentőségű az irreverzíbilis neurológiai károsodások és a tartós munkaképtelenség kialakulásának megelőzésében. A szerzők összefoglalják a cerebrotendinosus xanthomatosis patomechanizmusával, laboratóriumi diagnosztikájával és kezelési lehetőségeivel kapcsolatos tudnivalókat. Orv. Hetil., 2014, 155(21), 811-816.

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“…Diagnostic confirmation is routinely performed using fast atom bombardment (FAB)-MS measurement of more specific markers for CTX, bile alcohol glucuronides in urine [6]. We have utilized keto- moiety derivatization to enable sensitive liquid chromatography-electrospray ionization-tandem MS (LC-ESI-MS/MS) measurement of ketosterol BA precursors that accumulate in CTX [7-9]. Free (non-hydrolyzed) plasma 7α-hydroxy-4-cholesten-3-one (7αC4) possessed improved utility over 5α-cholestanol as a marker for CTX [7].…”

Section: Introductionmentioning

confidence: 99%

A useful multi-analyte blood test for cerebrotendinous xanthomatosis

DeBarber¹,

Luo²,

Giugliani³

et al. 2014

Clinical Biochemistry

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Objectives Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder of bile acid (BA) synthesis that can cause progressive neurological damage and premature death. Blood (normally serum or plasma) testing for CTX is performed by a small number of specialized laboratories, routinely by gas chromatography-mass spectrometry (GC-MS) measurement of elevated 5α- cholestanol. We report here on a more sensitive biochemical approach to test for CTX particularly useful for confirmation of CTX in the case of a challenging diagnostic sample with 5α-cholestanol that, although elevated, was below the cut-off used for diagnosis of CTX (10 μg/ml or 1.0 mg/dL). Design and Methods We have previously described liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) methodology utilizing keto derivatization to enable the sensitive quantification of plasma ketosterol BA precursors that accumulate in CTX. We have expanded this methodology to perform isotope dilution LC-ESI-MS/MS quantification of a panel of plasma ketosterol BA precursors, with internal standards readily generated using isotopically-enriched derivatization reagent. Results Quantification of plasma ketosterol BA precursors (7α-hydroxy-4-cholesten-3-one, 7α,12α-dihydroxy-4-cholesten-3-one and 7α,12α-dihydroxy-5β-cholestan-3-one) in a single LC- ESI/MS/MS test provided better discrimination between a CTX-positive and negative samples analyzed (n=20) than measurement of 5α-cholestanol alone. Conclusions Quantification of plasma ketosterol BA precursors provides a more sensitive biochemical approach to discriminate between CTX negative and positive samples. A multiplexed LC-ESI-MS/MS test quantifying a panel of plasma ketosterols, with simple sample preparation, rapid analysis time and readily available internal standards, can be performed by most clinical laboratories. Wider availability of testing will benefit those affected with CTX.

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A blood test for cerebrotendinous xanthomatosis with potential for disease detection in newborns

Cited by 41 publications

References 41 publications

Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX)

Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX)

Laboratory diagnosis of a rare congenital neurodegenerative disease: cerebrotendinous xanthomatosis

A useful multi-analyte blood test for cerebrotendinous xanthomatosis

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