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A useful multi-analyte blood test for cerebrotendinous xanthomatosis.

ABSTRACT: 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 5?-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 5?-cholestanol that, although elevated, was below the cut-off used for diagnosis of CTX (10 ?g/mL or 1.0 mg/dL).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.Quantification of plasma ketosterol BA precursors (7?-hydroxy-4-cholesten-3-one, 7?,12?-dihydroxy-4-cholesten-3-one and 7?,12?-dihydroxy-5?-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 5?-cholestanol alone.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.

SUBMITTER: DeBarber AE

PROVIDER: S-EPMC4175980 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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A useful multi-analyte blood test for cerebrotendinous xanthomatosis.

DeBarber Andrea E AE Luo Jenny J Giugliani Roberto R Souza Carolina F M CF Chiang John Pei-Wen JP Merkens Louise S LS Pappu Anuradha S AS Steiner Robert D RD

Clinical biochemistry 20140421 9

<h4>Objectives</h4>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 CT ...[more]

PMID: 24769274

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Project description:BackgroundClassic cerebrotendinous xanthomatosis (CTX; OMIM #213700) manifests with chronic diarrhea, juvenile cataracts, tendon xanthomas and neurological symptoms. It is due to biallelic inactivation of CYP27A1 wich leads to cholestanol accumulation in the central nervous system, eyes and tendons. Less commonly, the disease can present in young adults as spastic paraparesis in the absence of xanthomas.Case presentationWe report a 38-year old woman who presented with chronic diarrhea and progressive spastic paraparesis in her twenties. Brain magnetic resonance imaging (MRI) showed cerebral atrophy with diffuse periventricular white matter hyperintensities. Spinal MRI was normal. CYP27A1 gene sequencing confirmed the diagnosis of CTX. Chenodeoxycholic acid (CDCA) treatment was introduced with remission of diarrhea. Unfortunately, the treatment had to be discontinued several times and the patient developed psychosis and an severe ataxospastic gait. Spinal MRI revealed new linear hyperintensities of the corticospinal and gracile tracts. Thirty-three spinal CTX patients were identified by searching in Pubmed, EMBASE™ and Web of Science databases. All patients presented pyramidal signs and 48% had dorsal column signs. Juvenile cataracts were described in 78% of patients, chronic diarrhea in 65%, and tendon xanthomas in 31%. Disease improvement or stabilization with chenodeoxycholic acid was observed in 69% of patients. A higher prevalence of the Arg395Cys allele was observed in patients with spinal CTX as compared to CTX in general (ᵡ2; p < 0.00001).ConclusionsThe diagnosis of spinal CTX can be easily missed or delayed in absence of xanthomas. There is a higher prevalence of the Arg395Cys allele in spinal CTX as compared to classic childhood-onset CTX. CDCA treatment seems to stabilize or improve clinical symptoms in most patients. However, as seen in our patient and in two previously reported cases, sudden interruption of CDCA may lead to irreversible neurological complications.

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A useful multi-analyte blood test for cerebrotendinous xanthomatosis.

Publications

A useful multi-analyte blood test for cerebrotendinous xanthomatosis.

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