TY - JOUR
T1 - Hereditary spastic paraplegia type 5
T2 - Natural history, biomarkers and a randomized controlled trial
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
N1 - Funding Information:
This study was supported by the European Union within the 7th European Community Framework Program through funding for the NEUROMICS network (F5-2012-305121 to L.S., P.B., J.B. and P.D.J.), the E-Rare Network NEUROLIPID (01GM1408B to R.S. and M.T.B.) and a Marie Curie International Outgoing Fellowship (grant PIOF-GA-2012-326681 to R.S. and L.S.). Further support was provided by the US National Institutes of Health (NIH) (grants R01NS075764 and U54NS065712 to S.Z:, grant 5R01NS072248 to R.S. and S.Z., grant U54NS092091 to R.S. and S.Z.), the Association Belge contre les Maladies Neuromusculaire (ABMM) - Aide à la Recherche ASBL, the Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg and the Europäischen Sozialfonds in Baden-Württemberg (grant to S.W.), the Eva-Luise and Horst Köhler foundation (grant to R.S.), the German HSP-Selbsthilfegruppe e.V. (grant to R.S. and L.S.), Swedish Brain Power, Hjärnfonden and the Stockholm County (grants to I.B.), the Italian Ministry of Health (grant RC1016001 to A.M.) and the Brazilian funding agencies MCTI/CNPQ/Universal 14/2014 (460941/2014-3) and FIPE-HCPA (GPPG-HCPA 14-0695). T.R. is supported by the Clinician Scientist Program of the University of Tübingen (#386-0) and J.B. is supported by a Senior Clinical Researcher mandate of the Research Fund - Flanders (FWO).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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-7a-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.
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-7a-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.
KW - SPG5
KW - biomarker
KW - hereditary spastic paraplegia
KW - oxysterol
KW - randomized controlled trial
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U2 - 10.1093/brain/awx273
DO - 10.1093/brain/awx273
M3 - Article
C2 - 29126212
AN - SCOPUS:85038252603
VL - 140
SP - 3112
EP - 3127
JO - Brain
JF - Brain
SN - 0006-8950
IS - 12
ER -