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| 001 | 139656 | ||
| 005 | 20240321220647.0 | ||
| 024 | 7 | _ | |a 10.1093/brain/awx273 |2 doi |
| 024 | 7 | _ | |a pmid:29126212 |2 pmid |
| 024 | 7 | _ | |a pmc:PMC5841036 |2 pmc |
| 024 | 7 | _ | |a 0006-8950 |2 ISSN |
| 024 | 7 | _ | |a 1460-2156 |2 ISSN |
| 024 | 7 | _ | |a altmetric:28649259 |2 altmetric |
| 037 | _ | _ | |a DZNE-2020-05978 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 610 |
| 100 | 1 | _ | |a Schöls, Ludger |0 P:(DE-2719)2810795 |b 0 |e First author |u dzne |
| 245 | _ | _ | |a Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial. |
| 260 | _ | _ | |a Oxford |c 2017 |b Oxford Univ. Press |
| 264 | _ | 1 | |3 online |2 Crossref |b Oxford University Press (OUP) |c 2017-11-06 |
| 264 | _ | 1 | |3 print |2 Crossref |b Oxford University Press (OUP) |c 2017-12-01 |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1706013927_18611 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 520 | _ | _ | |a 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. |
| 536 | _ | _ | |a 344 - Clinical and Health Care Research (POF3-344) |0 G:(DE-HGF)POF3-344 |c POF3-344 |f POF III |x 0 |
| 536 | _ | _ | |a 345 - Population Studies and Genetics (POF3-345) |0 G:(DE-HGF)POF3-345 |c POF3-345 |f POF III |x 1 |
| 588 | _ | _ | |a Dataset connected to CrossRef, PubMed, |
| 650 | _ | 7 | |a Biomarkers |2 NLM Chemicals |
| 650 | _ | 7 | |a Hydroxycholesterols |2 NLM Chemicals |
| 650 | _ | 7 | |a Hydroxymethylglutaryl-CoA Reductase Inhibitors |2 NLM Chemicals |
| 650 | _ | 7 | |a Oxysterols |2 NLM Chemicals |
| 650 | _ | 7 | |a 27-hydroxycholesterol |0 6T2NA6P5SQ |2 NLM Chemicals |
| 650 | _ | 7 | |a 25-hydroxycholesterol |0 767JTD2N31 |2 NLM Chemicals |
| 650 | _ | 7 | |a Atorvastatin |0 A0JWA85V8F |2 NLM Chemicals |
| 650 | _ | 7 | |a Steroid Hydroxylases |0 EC 1.14.- |2 NLM Chemicals |
| 650 | _ | 7 | |a Cytochrome P450 Family 7 |0 EC 1.14.14.23 |2 NLM Chemicals |
| 650 | _ | 7 | |a CYP7B1 protein, human |0 EC 1.14.14.29 |2 NLM Chemicals |
| 650 | _ | 2 | |a Adolescent |2 MeSH |
| 650 | _ | 2 | |a Adult |2 MeSH |
| 650 | _ | 2 | |a Atorvastatin: therapeutic use |2 MeSH |
| 650 | _ | 2 | |a Biomarkers: blood |2 MeSH |
| 650 | _ | 2 | |a Biomarkers: cerebrospinal fluid |2 MeSH |
| 650 | _ | 2 | |a Case-Control Studies |2 MeSH |
| 650 | _ | 2 | |a Cell Proliferation |2 MeSH |
| 650 | _ | 2 | |a Cross-Sectional Studies |2 MeSH |
| 650 | _ | 2 | |a Cytochrome P450 Family 7: genetics |2 MeSH |
| 650 | _ | 2 | |a Disease Progression |2 MeSH |
| 650 | _ | 2 | |a Double-Blind Method |2 MeSH |
| 650 | _ | 2 | |a Family |2 MeSH |
| 650 | _ | 2 | |a Female |2 MeSH |
| 650 | _ | 2 | |a Humans |2 MeSH |
| 650 | _ | 2 | |a Hydroxycholesterols: metabolism |2 MeSH |
| 650 | _ | 2 | |a Hydroxymethylglutaryl-CoA Reductase Inhibitors: therapeutic use |2 MeSH |
| 650 | _ | 2 | |a Induced Pluripotent Stem Cells |2 MeSH |
| 650 | _ | 2 | |a Male |2 MeSH |
| 650 | _ | 2 | |a Middle Aged |2 MeSH |
| 650 | _ | 2 | |a Mutation |2 MeSH |
| 650 | _ | 2 | |a Neurites |2 MeSH |
| 650 | _ | 2 | |a Oxysterols: blood |2 MeSH |
| 650 | _ | 2 | |a Oxysterols: cerebrospinal fluid |2 MeSH |
| 650 | _ | 2 | |a Pedigree |2 MeSH |
| 650 | _ | 2 | |a Severity of Illness Index |2 MeSH |
| 650 | _ | 2 | |a Spastic Paraplegia, Hereditary: drug therapy |2 MeSH |
| 650 | _ | 2 | |a Spastic Paraplegia, Hereditary: genetics |2 MeSH |
| 650 | _ | 2 | |a Spastic Paraplegia, Hereditary: metabolism |2 MeSH |
| 650 | _ | 2 | |a Steroid Hydroxylases: genetics |2 MeSH |
| 650 | _ | 2 | |a Young Adult |2 MeSH |
| 700 | 1 | _ | |a Rattay, Tim W |0 P:(DE-2719)2811827 |b 1 |u dzne |
| 700 | 1 | _ | |a Martus, Peter |b 2 |
| 700 | 1 | _ | |a Meisner, Christoph |b 3 |
| 700 | 1 | _ | |a Baets, Jonathan |b 4 |
| 700 | 1 | _ | |a Fischer, Imma |b 5 |
| 700 | 1 | _ | |a Jägle, Christine |b 6 |
| 700 | 1 | _ | |a Fraidakis, Matthew J |b 7 |
| 700 | 1 | _ | |a Martinuzzi, Andrea |b 8 |
| 700 | 1 | _ | |a Saute, Jonas Alex |b 9 |
| 700 | 1 | _ | |a Scarlato, Marina |b 10 |
| 700 | 1 | _ | |a Antenora, Antonella |b 11 |
| 700 | 1 | _ | |a Stendel, Claudia |0 P:(DE-2719)2812141 |b 12 |u dzne |
| 700 | 1 | _ | |a Höflinger, Philip |0 P:(DE-2719)2813301 |b 13 |u dzne |
| 700 | 1 | _ | |a Lourenco, Charles Marques |b 14 |
| 700 | 1 | _ | |a Abreu, Lisa |b 15 |
| 700 | 1 | _ | |a Smets, Katrien |b 16 |
| 700 | 1 | _ | |a Paucar, Martin |b 17 |
| 700 | 1 | _ | |a Deconinck, Tine |b 18 |
| 700 | 1 | _ | |a Bis, Dana M |b 19 |
| 700 | 1 | _ | |a Wiethoff, Sarah |0 P:(DE-2719)2814026 |b 20 |u dzne |
| 700 | 1 | _ | |a Bauer, Peter |b 21 |
| 700 | 1 | _ | |a Arnoldi, Alessia |b 22 |
| 700 | 1 | _ | |a Marques, Wilson |b 23 |
| 700 | 1 | _ | |a Jardim, Laura Bannach |b 24 |
| 700 | 1 | _ | |a Hauser, Stefan |0 P:(DE-2719)2810998 |b 25 |u dzne |
| 700 | 1 | _ | |a Criscuolo, Chiara |b 26 |
| 700 | 1 | _ | |a Filla, Alessandro |b 27 |
| 700 | 1 | _ | |a Züchner, Stephan |b 28 |
| 700 | 1 | _ | |a Bassi, Maria Teresa |b 29 |
| 700 | 1 | _ | |a Klopstock, Thomas |0 P:(DE-2719)2810704 |b 30 |u dzne |
| 700 | 1 | _ | |a De Jonghe, Peter |b 31 |
| 700 | 1 | _ | |a Björkhem, Ingemar |b 32 |
| 700 | 1 | _ | |a Schüle, Rebecca |0 P:(DE-HGF)0 |b 33 |
| 773 | 1 | 8 | |a 10.1093/brain/awx273 |b : Oxford University Press (OUP), 2017-11-06 |n 12 |p 3112-3127 |3 journal-article |2 Crossref |t Brain |v 140 |y 2017 |x 0006-8950 |
| 773 | _ | _ | |a 10.1093/brain/awx273 |g Vol. 140, no. 12, p. 3112 - 3127 |0 PERI:(DE-600)1474117-9 |n 12 |q 140:12<3112 - 3127 |p 3112-3127 |t Brain |v 140 |y 2017 |x 0006-8950 |
| 856 | 7 | _ | |2 Pubmed Central |u http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841036 |
| 856 | 4 | _ | |u https://pub.dzne.de/record/139656/files/DZNE-2020-05978_Restricted.pdf |
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