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Metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis

Metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis

Authors :
Philip Höflinger
Stefan Hauser
Eylan Yutuc
Holger Hengel
Lauren Griffiths
Florentine Radelfahr
Owain W. Howell
Yuqin Wang
Sonja L. Connor
P. Barton Duell
Andrea E. DeBarber
Peter Martus
Dieter Lütjohann
William J. Griffiths
Ludger Schöls
Source :
Journal of Lipid Research, Vol 62, Iss , Pp 100078- (2021)
Publication Year :
2021
Publisher :
Elsevier, 2021.

Abstract

Cerebrotendinous xanthomatosis (CTX) is caused by autosomal recessive loss-of-function mutations in CYP27A1, a gene encoding cytochrome p450 oxidase essential for bile acid synthesis, resulting in altered bile acid and lipid metabolism. Here, we aimed to identify metabolic aberrations that drive ongoing neurodegeneration in some patients with CTX despite chenodeoxycholic acid (CDCA) supplementation, the standard treatment in CTX. Using chromatographic separation techniques coupled to mass spectrometry, we analyzed 26 sterol metabolites in serum and cerebrospinal fluid (CSF) of patients with CTX and in one CTX brain. Comparing samples of drug naive patients to patients treated with CDCA and healthy controls, we identified 7α,12α-dihydroxycholest-4-en-3-one as the most prominently elevated metabolite in serum and CSF of drug naive patients. CDCA treatment substantially reduced or even normalized levels of all metabolites increased in untreated patients with CTX. Independent of CDCA treatment, metabolites of the 27-hydroxylation pathway were nearly absent in all patients with CTX. 27-hydroxylated metabolites accounted for ∼45% of total free sterol content in CSF of healthy controls but

Details

Language :
English
ISSN :
00222275
Volume :
62
Issue :
100078-
Database :
Directory of Open Access Journals
Journal :
Journal of Lipid Research
Publication Type :
Academic Journal
Accession number :
edsdoj.41d7e6fd58f7466ca39ad0e0f6bfc8e4
Document Type :
article
Full Text :
https://doi.org/10.1016/j.jlr.2021.100078