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Update on newborn dried bloodspot testing for cerebrotendinous xanthomatosis: An available high-throughput liquid-chromatography tandem mass spectrometry method.

ABSTRACT: BACKGROUND:Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder of bile acid synthesis that can cause progressive neurological damage and premature death. Detection of CTX in the newborn period would be beneficial since an effective treatment is available. We previously described a liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) test with potential to screen newborn dried bloodspots (DBS) for CTX. We report here modifications to the methodology and application of the modified test to analysis of DBS from a CTX-affected and unaffected newborns. METHODS:The testing methodology utilizes keto derivatization to enable sensitive LC-ESI-MS/MS measurement of elevated 7?,12?-dihydroxy-4-cholesten-3-one (7?12?C4) in CTX newborn DBS. We report here method modifications, including use of a DBS extraction procedure used in newborn screening laboratories and a reduced analysis time of 2 min per sample. RESULTS:Rapid isotope-dilution LC-ESI/MS/MS quantification of the ketosterol bile acid precursor 7?12?C4 provides a test that could readily discriminate a CTX positive newborn DBS sample (with a concentration of 104.4 ng/ml) from unaffected newborn samples (with a mean concentration of 4.1 ± 3.4 ng/ml; range 0.2-15.6 ng/ml, n = 39) analyzed in a blinded manner. CONCLUSIONS:We provide additional evidence suggesting 7?12?C4 may be a promising test marker to screen newborn DBS for CTX. Early detection and intervention through newborn screening would greatly benefit those affected with CTX, preventing morbidity and mortality.

SUBMITTER: Bleyle L

PROVIDER: S-EPMC4908045 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Update on newborn dried bloodspot testing for cerebrotendinous xanthomatosis: An available high-throughput liquid-chromatography tandem mass spectrometry method.

Bleyle Lisa L Huidekoper Hidde H HH Vaz Frederic M FM Singh Renu R Steiner Robert D RD DeBarber Andrea E AE

Molecular genetics and metabolism reports 20160312

<h4>Background</h4>Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder of bile acid synthesis that can cause progressive neurological damage and premature death. Detection of CTX in the newborn period would be beneficial since an effective treatment is available. We previously described a liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) test with potential to screen newborn dried bloodspots (DBS) for CTX. We report here modifications to the method ...[more]

PMID: 27331003

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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.

Dataset Information

Update on newborn dried bloodspot testing for cerebrotendinous xanthomatosis: An available high-throughput liquid-chromatography tandem mass spectrometry method.

Publications

Update on newborn dried bloodspot testing for cerebrotendinous xanthomatosis: An available high-throughput liquid-chromatography tandem mass spectrometry method.

Similar Datasets

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