Atorvastatin reduces toxic fatty compounds in the brain
This multicentre study has demonstrated the effectiveness of Atorvastatin in reducing toxic levels of oxysterols in the neurons that result from an enzyme deficiency associated with the gene mutation. The study also correlated disease severity and progression with oxysterol concentrations. As expected with a short-term trial (9 weeks) there were no effects on clinical outcome measures.
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.
SOURCE: Brain. 2017 Nov 6. doi: 10.1093/brain/awx273. [Epub ahead of print] PMID: 29126212
Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial.
Schöls L1,2, Rattay TW1,2, Martus P3, Meisner C3, Baets J4,5,6, Fischer I3, Jägle C7, Fraidakis MJ8, Martinuzzi A9, Saute JA10,11,12, Scarlato M13, Antenora A14, Stendel C15,16,17, Höflinger P1,2, Lourenco CM18,19, Abreu L20,21, Smets K4,5,6, Paucar M22, Deconinck T4,6, Bis DM20,21, Wiethoff S1,2,23, Bauer P24,25, Arnoldi A26, Marques W18, Jardim LB10,11,12,19, Hauser S1,2, Criscuolo C14, Filla A14, Züchner S20,21, Bassi MT26, Klopstock T15,16,17, De Jonghe P4,5,6, Björkhem I27, Schüle R1,2.
1 Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, 72076 Tübingen, Germany.
2 German Center of Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.
3 Institute for Clinical Epidemiology and Applied Biostatistics, Eberhard-Karls-University, 72076 Tübingen, Germany.
4 Neurogenetics Group, Center for Molecular Neurology, VIB, 2610 Antwerp, Belgium.
5 Department of Neurology, Antwerp University Hospital, 2610 Antwerp, Belgium.
6 Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium.
7 Center for Rare Diseases and Institute of Human Genetics and Applied Genomics, Eberhard-Karls-University, 72076 Tübingen, Germany.
8 Rare Neurological Diseases Unit, Department of Neurology, University Hospital ‘Attikon’, Medical School of the University of Athens, 12462 Athens, Greece.
9 Scientific Institute IRCCS E. Medea, Conegliano Research Center, 31015 Conegliano, Italy.
10 Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
11 Genetics Identification Laboratory, Hospital de Clínicas de Porto Alegre, 90035 Porto Alegre, Brazil.
12 Postgraduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), 90040 Porto Alegre, Brazil.
13 Neurology Department and INSPE, San Raffaele Hospital, 20132 Milan, Italy.
14 Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University Naples, 80131 Naples, Italy.
15 Department of Neurology, Friedrich Baur Institute, Ludwig-Maximilians-University, 80336 Munich, Germany.
16 Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
17 German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany.
18 Departamento de Neurologia, Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, 14049 Ribeirao Preto, Brazil.
19 Department of Internal Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), 90040 Porto Alegre, Brazil.
20 John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, 33136 Miami, Florida, USA.
21 Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, 33136 Miami, Florida, USA.
22 Department of Neurology, Karolinska University Hospital Huddinge and Department of Clinical Neuroscience, Karolinska Institute, 14152 Huddinge, Sweden.
23 Institute of Neurology, Queen Square, London WC1N 3BG, UK.
24 Institute of Medical Genetics and Applied Genomics, Eberhard-Karls-University, 72076 Tübingen, Germany.
25 CENTOGENE AG, 18057 Rostock, Germany.
26 Laboratory of Molecular Biology, Scientific Institute IRCCS E. Medea, 23842 Bosisio Parini, Italy.
27 Karolinska University Hospital Huddinge, Karolinska Institute, 14152 Stockholm, Sweden.