000139656 001__ 139656
000139656 005__ 20240321220647.0
000139656 0247_ $$2doi$$a10.1093/brain/awx273
000139656 0247_ $$2pmid$$apmid:29126212
000139656 0247_ $$2pmc$$apmc:PMC5841036
000139656 0247_ $$2ISSN$$a0006-8950
000139656 0247_ $$2ISSN$$a1460-2156
000139656 0247_ $$2altmetric$$aaltmetric:28649259
000139656 037__ $$aDZNE-2020-05978
000139656 041__ $$aEnglish
000139656 082__ $$a610
000139656 1001_ $$0P:(DE-2719)2810795$$aSchöls, Ludger$$b0$$eFirst author$$udzne
000139656 245__ $$aHereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial.
000139656 260__ $$aOxford$$bOxford Univ. Press$$c2017
000139656 264_1 $$2Crossref$$3online$$bOxford University Press (OUP)$$c2017-11-06
000139656 264_1 $$2Crossref$$3print$$bOxford University Press (OUP)$$c2017-12-01
000139656 3367_ $$2DRIVER$$aarticle
000139656 3367_ $$2DataCite$$aOutput Types/Journal article
000139656 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1706013927_18611
000139656 3367_ $$2BibTeX$$aARTICLE
000139656 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000139656 3367_ $$00$$2EndNote$$aJournal Article
000139656 520__ $$aSpastic 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.
000139656 536__ $$0G:(DE-HGF)POF3-344$$a344 - Clinical and Health Care Research (POF3-344)$$cPOF3-344$$fPOF III$$x0
000139656 536__ $$0G:(DE-HGF)POF3-345$$a345 - Population Studies and Genetics (POF3-345)$$cPOF3-345$$fPOF III$$x1
000139656 588__ $$aDataset connected to CrossRef, PubMed,
000139656 650_7 $$2NLM Chemicals$$aBiomarkers
000139656 650_7 $$2NLM Chemicals$$aHydroxycholesterols
000139656 650_7 $$2NLM Chemicals$$aHydroxymethylglutaryl-CoA Reductase Inhibitors
000139656 650_7 $$2NLM Chemicals$$aOxysterols
000139656 650_7 $$06T2NA6P5SQ$$2NLM Chemicals$$a27-hydroxycholesterol
000139656 650_7 $$0767JTD2N31$$2NLM Chemicals$$a25-hydroxycholesterol
000139656 650_7 $$0A0JWA85V8F$$2NLM Chemicals$$aAtorvastatin
000139656 650_7 $$0EC 1.14.-$$2NLM Chemicals$$aSteroid Hydroxylases
000139656 650_7 $$0EC 1.14.14.23$$2NLM Chemicals$$aCytochrome P450 Family 7
000139656 650_7 $$0EC 1.14.14.29$$2NLM Chemicals$$aCYP7B1 protein, human
000139656 650_2 $$2MeSH$$aAdolescent
000139656 650_2 $$2MeSH$$aAdult
000139656 650_2 $$2MeSH$$aAtorvastatin: therapeutic use
000139656 650_2 $$2MeSH$$aBiomarkers: blood
000139656 650_2 $$2MeSH$$aBiomarkers: cerebrospinal fluid
000139656 650_2 $$2MeSH$$aCase-Control Studies
000139656 650_2 $$2MeSH$$aCell Proliferation
000139656 650_2 $$2MeSH$$aCross-Sectional Studies
000139656 650_2 $$2MeSH$$aCytochrome P450 Family 7: genetics
000139656 650_2 $$2MeSH$$aDisease Progression
000139656 650_2 $$2MeSH$$aDouble-Blind Method
000139656 650_2 $$2MeSH$$aFamily
000139656 650_2 $$2MeSH$$aFemale
000139656 650_2 $$2MeSH$$aHumans
000139656 650_2 $$2MeSH$$aHydroxycholesterols: metabolism
000139656 650_2 $$2MeSH$$aHydroxymethylglutaryl-CoA Reductase Inhibitors: therapeutic use
000139656 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells
000139656 650_2 $$2MeSH$$aMale
000139656 650_2 $$2MeSH$$aMiddle Aged
000139656 650_2 $$2MeSH$$aMutation
000139656 650_2 $$2MeSH$$aNeurites
000139656 650_2 $$2MeSH$$aOxysterols: blood
000139656 650_2 $$2MeSH$$aOxysterols: cerebrospinal fluid
000139656 650_2 $$2MeSH$$aPedigree
000139656 650_2 $$2MeSH$$aSeverity of Illness Index
000139656 650_2 $$2MeSH$$aSpastic Paraplegia, Hereditary: drug therapy
000139656 650_2 $$2MeSH$$aSpastic Paraplegia, Hereditary: genetics
000139656 650_2 $$2MeSH$$aSpastic Paraplegia, Hereditary: metabolism
000139656 650_2 $$2MeSH$$aSteroid Hydroxylases: genetics
000139656 650_2 $$2MeSH$$aYoung Adult
000139656 7001_ $$0P:(DE-2719)2811827$$aRattay, Tim W$$b1$$udzne
000139656 7001_ $$aMartus, Peter$$b2
000139656 7001_ $$aMeisner, Christoph$$b3
000139656 7001_ $$aBaets, Jonathan$$b4
000139656 7001_ $$aFischer, Imma$$b5
000139656 7001_ $$aJägle, Christine$$b6
000139656 7001_ $$aFraidakis, Matthew J$$b7
000139656 7001_ $$aMartinuzzi, Andrea$$b8
000139656 7001_ $$aSaute, Jonas Alex$$b9
000139656 7001_ $$aScarlato, Marina$$b10
000139656 7001_ $$aAntenora, Antonella$$b11
000139656 7001_ $$0P:(DE-2719)2812141$$aStendel, Claudia$$b12$$udzne
000139656 7001_ $$0P:(DE-2719)2813301$$aHöflinger, Philip$$b13$$udzne
000139656 7001_ $$aLourenco, Charles Marques$$b14
000139656 7001_ $$aAbreu, Lisa$$b15
000139656 7001_ $$aSmets, Katrien$$b16
000139656 7001_ $$aPaucar, Martin$$b17
000139656 7001_ $$aDeconinck, Tine$$b18
000139656 7001_ $$aBis, Dana M$$b19
000139656 7001_ $$0P:(DE-2719)2814026$$aWiethoff, Sarah$$b20$$udzne
000139656 7001_ $$aBauer, Peter$$b21
000139656 7001_ $$aArnoldi, Alessia$$b22
000139656 7001_ $$aMarques, Wilson$$b23
000139656 7001_ $$aJardim, Laura Bannach$$b24
000139656 7001_ $$0P:(DE-2719)2810998$$aHauser, Stefan$$b25$$udzne
000139656 7001_ $$aCriscuolo, Chiara$$b26
000139656 7001_ $$aFilla, Alessandro$$b27
000139656 7001_ $$aZüchner, Stephan$$b28
000139656 7001_ $$aBassi, Maria Teresa$$b29
000139656 7001_ $$0P:(DE-2719)2810704$$aKlopstock, Thomas$$b30$$udzne
000139656 7001_ $$aDe Jonghe, Peter$$b31
000139656 7001_ $$aBjörkhem, Ingemar$$b32
000139656 7001_ $$0P:(DE-HGF)0$$aSchüle, Rebecca$$b33
000139656 77318 $$2Crossref$$3journal-article$$a10.1093/brain/awx273$$b : Oxford University Press (OUP), 2017-11-06$$n12$$p3112-3127$$tBrain$$v140$$x0006-8950$$y2017
000139656 773__ $$0PERI:(DE-600)1474117-9$$a10.1093/brain/awx273$$gVol. 140, no. 12, p. 3112 - 3127$$n12$$p3112-3127$$q140:12<3112 - 3127$$tBrain$$v140$$x0006-8950$$y2017
000139656 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841036
000139656 8564_ $$uhttps://pub.dzne.de/record/139656/files/DZNE-2020-05978_Restricted.pdf
000139656 8564_ $$uhttps://pub.dzne.de/record/139656/files/DZNE-2020-05978_Restricted.pdf?subformat=pdfa$$xpdfa
000139656 909CO $$ooai:pub.dzne.de:139656$$pVDB
000139656 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2810795$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b0$$kDZNE
000139656 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2811827$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b1$$kDZNE
000139656 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2812141$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b12$$kDZNE
000139656 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2813301$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b13$$kDZNE
000139656 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2814026$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b20$$kDZNE
000139656 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2810998$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b25$$kDZNE
000139656 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2810704$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b30$$kDZNE
000139656 9131_ $$0G:(DE-HGF)POF3-344$$1G:(DE-HGF)POF3-340$$2G:(DE-HGF)POF3-300$$3G:(DE-HGF)POF3$$4G:(DE-HGF)POF$$aDE-HGF$$bGesundheit$$lErkrankungen des Nervensystems$$vClinical and Health Care Research$$x0
000139656 9131_ $$0G:(DE-HGF)POF3-345$$1G:(DE-HGF)POF3-340$$2G:(DE-HGF)POF3-300$$3G:(DE-HGF)POF3$$4G:(DE-HGF)POF$$aDE-HGF$$bGesundheit$$lErkrankungen des Nervensystems$$vPopulation Studies and Genetics$$x1
000139656 9141_ $$y2017
000139656 915__ $$0StatID:(DE-HGF)0420$$2StatID$$aNationallizenz$$d2022-11-09$$wger
000139656 915__ $$0StatID:(DE-HGF)0200$$2StatID$$aDBCoverage$$bSCOPUS$$d2022-11-09
000139656 915__ $$0StatID:(DE-HGF)0300$$2StatID$$aDBCoverage$$bMedline$$d2022-11-09
000139656 915__ $$0StatID:(DE-HGF)0199$$2StatID$$aDBCoverage$$bClarivate Analytics Master Journal List$$d2022-11-09
000139656 915__ $$0StatID:(DE-HGF)0150$$2StatID$$aDBCoverage$$bWeb of Science Core Collection$$d2022-11-09
000139656 915__ $$0StatID:(DE-HGF)1050$$2StatID$$aDBCoverage$$bBIOSIS Previews$$d2022-11-09
000139656 915__ $$0StatID:(DE-HGF)1110$$2StatID$$aDBCoverage$$bCurrent Contents - Clinical Medicine$$d2022-11-09
000139656 915__ $$0StatID:(DE-HGF)1030$$2StatID$$aDBCoverage$$bCurrent Contents - Life Sciences$$d2022-11-09
000139656 915__ $$0StatID:(DE-HGF)0100$$2StatID$$aJCR$$bBRAIN : 2021$$d2022-11-09
000139656 915__ $$0StatID:(DE-HGF)0600$$2StatID$$aDBCoverage$$bEbsco Academic Search$$d2022-11-09
000139656 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bASC$$d2022-11-09
000139656 915__ $$0StatID:(DE-HGF)9915$$2StatID$$aIF >= 15$$bBRAIN : 2021$$d2022-11-09
000139656 9201_ $$0I:(DE-2719)5000005$$kAG Schöls$$lClinical Neurogenetics$$x0
000139656 9201_ $$0I:(DE-2719)1210000$$kAG Gasser$$lParkinson Genetics$$x1
000139656 9201_ $$0I:(DE-2719)1110002$$kAG Höglinger 1$$lTranslational Neurodegeneration$$x2
000139656 9201_ $$0I:(DE-2719)1111016$$kAG Levin$$lClinical Neurodegeneration$$x3
000139656 980__ $$ajournal
000139656 980__ $$aVDB
000139656 980__ $$aI:(DE-2719)5000005
000139656 980__ $$aI:(DE-2719)1210000
000139656 980__ $$aI:(DE-2719)1110002
000139656 980__ $$aI:(DE-2719)1111016
000139656 980__ $$aUNRESTRICTED
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1111/j.1399-0004.2011.01624.x$$o10.1111/j.1399-0004.2011.01624.x
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1080/00365510510025746$$o10.1080/00365510510025746
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.nmd.2008.10.009$$o10.1016/j.nmd.2008.10.009
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1080/00365518309168239$$o10.1080/00365518309168239
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1194/jlr.R006338$$o10.1194/jlr.R006338
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1164/rccm.19310erratum$$o10.1164/rccm.19310erratum
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1002/mds.23466$$o10.1002/mds.23466
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1002/j.1552-4604.1996.tb04224.x$$o10.1002/j.1552-4604.1996.tb04224.x
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1164/ajrccm.166.1.at1102$$o10.1164/ajrccm.166.1.at1102
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1007/s00415-009-5109-3$$o10.1007/s00415-009-5109-3
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1002/chem.201202627$$o10.1002/chem.201202627
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1007/s00415-014-7247-5$$o10.1007/s00415-014-7247-5
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1006/abio.1995.1110$$o10.1006/abio.1995.1110
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.bbrc.2007.05.033$$o10.1016/j.bbrc.2007.05.033
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1093/brain/awp073$$o10.1093/brain/awp073
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/S0140-6736(83)92879-9$$o10.1016/S0140-6736(83)92879-9
000139656 999C5 $$2Crossref$$oHauser 2016$$y2016
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1194/jlr.M500024-JLR200$$o10.1194/jlr.M500024-JLR200
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1053/rmed.2002.1363$$o10.1053/rmed.2002.1363
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1007/s00415-013-7008-x$$o10.1007/s00415-013-7008-x
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1111/ene.12407$$o10.1111/ene.12407
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1194/jlr.M200434-JLR200$$o10.1194/jlr.M200434-JLR200
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.jgg.2014.04.003$$o10.1016/j.jgg.2014.04.003
000139656 999C5 $$2Crossref$$oMacGregor 1981$$y1981
000139656 999C5 $$2Crossref$$oMeaney 2001$$y2001
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1194/jlr.M600529-JLR200$$o10.1194/jlr.M600529-JLR200
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1007/s00415-015-7971-5$$o10.1007/s00415-015-7971-5
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1111/j.1752-8062.2010.00211.x$$o10.1111/j.1752-8062.2010.00211.x
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.amjcard.2009.08.651$$o10.1016/j.amjcard.2009.08.651
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1017/S0317167100012774$$o10.1017/S0317167100012774
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1074/jbc.M002663200$$o10.1074/jbc.M002663200
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1074/jbc.273.29.18153$$o10.1074/jbc.273.29.18153
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1186/1750-1326-4-1$$o10.1186/1750-1326-4-1
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1111/j.1471-4159.2008.05736.x$$o10.1111/j.1471-4159.2008.05736.x
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1080/10715760903040610$$o10.1080/10715760903040610
000139656 999C5 $$2Crossref$$oRoos 2013$$y2013
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1111/j.1399-0004.2011.01715.x$$o10.1111/j.1399-0004.2011.01715.x
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1007/s10048-008-0158-9$$o10.1007/s10048-008-0158-9
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1212/01.wnl.0000228242.53336.90$$o10.1212/01.wnl.0000228242.53336.90
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1194/jlr.M002543$$o10.1194/jlr.M002543
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1002/ana.24611$$o10.1002/ana.24611
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/nprot.2012.116$$o10.1038/nprot.2012.116
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.clinthera.2007.02.008$$o10.1016/j.clinthera.2007.02.008
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1074/jbc.270.50.29739$$o10.1074/jbc.270.50.29739
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1177/0091270006289851$$o10.1177/0091270006289851
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1172/JCI68506$$o10.1172/JCI68506
000139656 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.ajhg.2007.10.001$$o10.1016/j.ajhg.2007.10.001