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@ARTICLE{Hflinger:155559,
      author       = {Höflinger, Philip and Hauser, Stefan and Yutuc, Eylan and
                      Hengel, Holger and Griffiths, Lauren and Radelfahr,
                      Florentine and Howell, Owain W and Wang, Yuqin and Connor,
                      Sonja L and Duell, P Barton and DeBarber, Andrea E and
                      Martus, Peter and Lütjohann, Dieter and Griffiths, William
                      J and Schöls, Ludger},
      title        = {{M}etabolic profiling in serum, cerebrospinal fluid, and
                      brain of patients with cerebrotendinous xanthomatosis.},
      journal      = {Journal of lipid research},
      volume       = {62},
      issn         = {0022-2275},
      address      = {Bethesda, Md.},
      publisher    = {ASBMB},
      reportid     = {DZNE-2021-00737},
      pages        = {100078},
      year         = {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 $<2\%$ in patients with CTX. Metabolic changes
                      in brain tissue corresponded well with findings in CSF.
                      Interestingly, 7α,12α-dihydroxycholest-4-en-3-one and
                      5α-cholestanol did not exert toxicity in neuronal cell
                      culture. In conclusion, we propose that increased
                      7α,12α-dihydroxycholest-4-en-3-one and lack of
                      27-hydroxycholesterol may be highly sensitive metabolic
                      biomarkers of CTX. As CDCA cannot reliably prevent disease
                      progression despite reduction of most accumulated
                      metabolites, supplementation of 27-hydroxylated bile acid
                      intermediates or replacement of CYP27A1 might be required to
                      counter neurodegeneration in patients with progressive
                      disease despite CDCA treatment.},
      keywords     = {Xanthomatosis, Cerebrotendinous / bile acid metabolism
                      (Other) / cerebrospinal fluid (Other) / cholesterol
                      metabolism (Other) / cytochrome P450 (Other) / inborn errors
                      of metabolism (Other) / lipodystrophies (Other) / mass spec
                      (Other) / oxysterols, cerebrotendinous xanthomathosis
                      (Other)},
      cin          = {AG Gasser / U Clinical Researchers - München},
      ddc          = {540},
      cid          = {I:(DE-2719)1210000 / I:(DE-2719)7000003},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33891937},
      pmc          = {pmc:PMC8135047},
      doi          = {10.1016/j.jlr.2021.100078},
      url          = {https://pub.dzne.de/record/155559},
}