% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Schls:139656,
      author       = {Schöls, Ludger and Rattay, Tim W and Martus, Peter and
                      Meisner, Christoph and Baets, Jonathan and Fischer, Imma and
                      Jägle, Christine and Fraidakis, Matthew J and Martinuzzi,
                      Andrea and Saute, Jonas Alex and Scarlato, Marina and
                      Antenora, Antonella and Stendel, Claudia and Höflinger,
                      Philip and Lourenco, Charles Marques and Abreu, Lisa and
                      Smets, Katrien and Paucar, Martin and Deconinck, Tine and
                      Bis, Dana M and Wiethoff, Sarah and Bauer, Peter and
                      Arnoldi, Alessia and Marques, Wilson and Jardim, Laura
                      Bannach and Hauser, Stefan and Criscuolo, Chiara and Filla,
                      Alessandro and Züchner, Stephan and Bassi, Maria Teresa and
                      Klopstock, Thomas and De Jonghe, Peter and Björkhem,
                      Ingemar and Schüle, Rebecca},
      title        = {{H}ereditary spastic paraplegia type 5: natural history,
                      biomarkers and a randomized controlled trial.},
      journal      = {Brain},
      volume       = {140},
      number       = {12},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2020-05978},
      pages        = {3112-3127},
      year         = {2017},
      abstract     = {Spastic paraplegia type 5 (SPG5) is a rare subtype of
                      hereditary spastic paraplegia, a highly heterogeneous group
                      of neurodegenerative disorders defined by progressive
                      neurodegeneration of the corticospinal tract motor neurons.
                      SPG5 is caused by recessive mutations in the gene CYP7B1
                      encoding oxysterol-7α-hydroxylase. This enzyme is involved
                      in the degradation of cholesterol into primary bile acids.
                      CYP7B1 deficiency has been shown to lead to accumulation of
                      neurotoxic oxysterols. In this multicentre study, we have
                      performed detailed clinical and biochemical analysis in 34
                      genetically confirmed SPG5 cases from 28 families, studied
                      dose-dependent neurotoxicity of oxysterols in human cortical
                      neurons and performed a randomized placebo-controlled double
                      blind interventional trial targeting oxysterol accumulation
                      in serum of SPG5 patients. Clinically, SPG5 manifested in
                      childhood or adolescence (median 13 years). Gait ataxia was
                      a common feature. SPG5 patients lost the ability to walk
                      independently after a median disease duration of 23 years
                      and became wheelchair dependent after a median 33 years. The
                      overall cross-sectional progression rate of 0.56 points on
                      the Spastic Paraplegia Rating Scale per year was slightly
                      lower than the longitudinal progression rate of 0.80 points
                      per year. Biochemically, marked accumulation of CYP7B1
                      substrates including 27-hydroxycholesterol was confirmed in
                      serum (n = 19) and cerebrospinal fluid (n = 17) of SPG5
                      patients. Moreover, 27-hydroxycholesterol levels in serum
                      correlated with disease severity and disease duration.
                      Oxysterols were found to impair metabolic activity and
                      viability of human cortical neurons at concentrations found
                      in SPG5 patients, indicating that elevated levels of
                      oxysterols might be key pathogenic factors in SPG5. We thus
                      performed a randomized placebo-controlled trial (EudraCT
                      2015-000978-35) with atorvastatin 40 mg/day for 9 weeks in
                      14 SPG5 patients with 27-hydroxycholesterol levels in serum
                      as the primary outcome measure. Atorvastatin, but not
                      placebo, reduced serum 27-hydroxycholesterol from 853 ng/ml
                      [interquartile range (IQR) 683-1113] to 641 (IQR 507-694)
                      $(-31.5\%,$ P = 0.001, Mann-Whitney U-test). Similarly,
                      25-hydroxycholesterol levels in serum were reduced. In
                      cerebrospinal fluid 27-hydroxycholesterol was reduced by
                      $8.4\%$ but this did not significantly differ from placebo.
                      As expected, no effects were seen on clinical outcome
                      parameters in this short-term trial. In this study, we
                      define the mutational and phenotypic spectrum of SPG5,
                      examine the correlation of disease severity and progression
                      with oxysterol concentrations, and demonstrate in a
                      randomized controlled trial that atorvastatin treatment can
                      effectively lower 27-hydroxycholesterol levels in serum of
                      SPG5 patients. We thus demonstrate the first causal
                      treatment strategy in hereditary spastic paraplegia.},
      keywords     = {Adolescent / Adult / Atorvastatin: therapeutic use /
                      Biomarkers: blood / Biomarkers: cerebrospinal fluid /
                      Case-Control Studies / Cell Proliferation / Cross-Sectional
                      Studies / Cytochrome P450 Family 7: genetics / Disease
                      Progression / Double-Blind Method / Family / Female / Humans
                      / Hydroxycholesterols: metabolism /
                      Hydroxymethylglutaryl-CoA Reductase Inhibitors: therapeutic
                      use / Induced Pluripotent Stem Cells / Male / Middle Aged /
                      Mutation / Neurites / Oxysterols: blood / Oxysterols:
                      cerebrospinal fluid / Pedigree / Severity of Illness Index /
                      Spastic Paraplegia, Hereditary: drug therapy / Spastic
                      Paraplegia, Hereditary: genetics / Spastic Paraplegia,
                      Hereditary: metabolism / Steroid Hydroxylases: genetics /
                      Young Adult / Biomarkers (NLM Chemicals) /
                      Hydroxycholesterols (NLM Chemicals) /
                      Hydroxymethylglutaryl-CoA Reductase Inhibitors (NLM
                      Chemicals) / Oxysterols (NLM Chemicals) /
                      27-hydroxycholesterol (NLM Chemicals) /
                      25-hydroxycholesterol (NLM Chemicals) / Atorvastatin (NLM
                      Chemicals) / Steroid Hydroxylases (NLM Chemicals) /
                      Cytochrome P450 Family 7 (NLM Chemicals) / CYP7B1 protein,
                      human (NLM Chemicals)},
      cin          = {AG Schöls / AG Gasser / AG Höglinger 1 / AG Levin},
      ddc          = {610},
      cid          = {I:(DE-2719)5000005 / I:(DE-2719)1210000 /
                      I:(DE-2719)1110002 / I:(DE-2719)1111016},
      pnm          = {344 - Clinical and Health Care Research (POF3-344) / 345 -
                      Population Studies and Genetics (POF3-345)},
      pid          = {G:(DE-HGF)POF3-344 / G:(DE-HGF)POF3-345},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29126212},
      pmc          = {pmc:PMC5841036},
      doi          = {10.1093/brain/awx273},
      url          = {https://pub.dzne.de/record/139656},
}