TY  - JOUR
AU  - Schöls, Ludger
AU  - Rattay, Tim W
AU  - Martus, Peter
AU  - Meisner, Christoph
AU  - Baets, Jonathan
AU  - Fischer, Imma
AU  - Jägle, Christine
AU  - Fraidakis, Matthew J
AU  - Martinuzzi, Andrea
AU  - Saute, Jonas Alex
AU  - Scarlato, Marina
AU  - Antenora, Antonella
AU  - Stendel, Claudia
AU  - Höflinger, Philip
AU  - Lourenco, Charles Marques
AU  - Abreu, Lisa
AU  - Smets, Katrien
AU  - Paucar, Martin
AU  - Deconinck, Tine
AU  - Bis, Dana M
AU  - Wiethoff, Sarah
AU  - Bauer, Peter
AU  - Arnoldi, Alessia
AU  - Marques, Wilson
AU  - Jardim, Laura Bannach
AU  - Hauser, Stefan
AU  - Criscuolo, Chiara
AU  - Filla, Alessandro
AU  - Züchner, Stephan
AU  - Bassi, Maria Teresa
AU  - Klopstock, Thomas
AU  - De Jonghe, Peter
AU  - Björkhem, Ingemar
AU  - Schüle, Rebecca
TI  - Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial.
JO  - Brain
VL  - 140
IS  - 12
SN  - 0006-8950
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2020-05978
SP  - 3112-3127
PY  - 2017
AB  - 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
KW  - Adolescent
KW  - Adult
KW  - Atorvastatin: therapeutic use
KW  - Biomarkers: blood
KW  - Biomarkers: cerebrospinal fluid
KW  - Case-Control Studies
KW  - Cell Proliferation
KW  - Cross-Sectional Studies
KW  - Cytochrome P450 Family 7: genetics
KW  - Disease Progression
KW  - Double-Blind Method
KW  - Family
KW  - Female
KW  - Humans
KW  - Hydroxycholesterols: metabolism
KW  - Hydroxymethylglutaryl-CoA Reductase Inhibitors: therapeutic use
KW  - Induced Pluripotent Stem Cells
KW  - Male
KW  - Middle Aged
KW  - Mutation
KW  - Neurites
KW  - Oxysterols: blood
KW  - Oxysterols: cerebrospinal fluid
KW  - Pedigree
KW  - Severity of Illness Index
KW  - Spastic Paraplegia, Hereditary: drug therapy
KW  - Spastic Paraplegia, Hereditary: genetics
KW  - Spastic Paraplegia, Hereditary: metabolism
KW  - Steroid Hydroxylases: genetics
KW  - Young Adult
KW  - Biomarkers (NLM Chemicals)
KW  - Hydroxycholesterols (NLM Chemicals)
KW  - Hydroxymethylglutaryl-CoA Reductase Inhibitors (NLM Chemicals)
KW  - Oxysterols (NLM Chemicals)
KW  - 27-hydroxycholesterol (NLM Chemicals)
KW  - 25-hydroxycholesterol (NLM Chemicals)
KW  - Atorvastatin (NLM Chemicals)
KW  - Steroid Hydroxylases (NLM Chemicals)
KW  - Cytochrome P450 Family 7 (NLM Chemicals)
KW  - CYP7B1 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:29126212
C2  - pmc:PMC5841036
DO  - DOI:10.1093/brain/awx273
UR  - https://pub.dzne.de/record/139656
ER  -