NeurOmics website

NeurOmics website

Integrated European Project on Omics Research of
Rare Neuromuscular and Neurodegenerative Diseases
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      • 1 – Deep phenotype analysis in pre-symptomatic and symptomatic NDD/NMD patients
      • 2 – Identification of novel disease genes in NDD/NMD patients
      • 3 – Identification of modifying factors in cohorts enriched by deep phenotyping
      • 4 – Identification of hypothesis-driven biomarkers for disease progression
      • 5 – Development and implementation of disease group overlapping NGS-based diagnostic panels
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      • 11 – Modifier gene identification, prioritization and study
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      • Agilent Technologies
      • Ariadne Diagnostics, LLC
      • Bio-Prodict
      • Cambridge University
      • deCODE genetics
      • German Center for Neurodegenerative Diseases (DZNE)
      • Institut National de la Santé et de la Recherche Médicale
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      • Leiden University Medical Center – LUMC
      • Newcastle University
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  • Publication highlights
    • Publication highlights
      • 229th ENMC international workshop: Limb girdle muscular dystrophies – nomenclature and reformed classification, 17-19 March 2017, Naarden, The Netherlands

        Volker Straub, Alexander Murphy, Bjarne Udd


        Tracking disease progression non‐invasively in Duchenne and Becker muscular dystrophies

        Pietro Spitali, Kristina Hettne, Roula Tsonaka, Mohammed Charrout, Janneke van den Bergen, Zaïda Koeks, Hermien E. Kan, Melissa T. Hooijmans, Andreas Roos, Volker Straub, Francesco Muntoni,
        Cristina Al‐Khalili‐Szigyarto, Marleen J.A. Koel‐Simmelink, Charlotte E. Teunissen, Hanns Lochmüller, Erik H. Niks, Annemieke Aartsma‐Rus


        Survival in patients with spinocerebellar ataxia types 1, 2, 3, and 6 (EUROSCA): a longitudinal cohort study

        Alhassane Diallo, Heike Jacobi, Arron Cook, Robyn Labrum, Prof Alexandra Durr, Prof Alexis Brice, Perrine Charles, Cecilia Marelli, Caterina Mariotti, Lorenzo Nanetti, Marta Panzeri, Maria Rakowicz, Anna Sobanska, Anna Sulek, Tanja Schmitz-Hübsch, Ludger Schöls, Holger Hengel, Prof Bela Melegh, Prof Alessandro Filla, Antonella Antenora, Jon Infante, Prof José Berciano, Bart P van de Warrenburg, Dagmar Timmann, Sylvia Boesch, Prof Massimo Pandolfo, Prof Jörg B Schulz, Peter Bauer, Paola Giunti, Jun-Suk Kang, Prof Thomas Klockgether, Sophie Tezenas du Montcel


        Recessive variants of MuSK are associated with late onset CMS and predominant limb girdle weakness

        David Owen, Ana Töpf, Veeramani Preethish‐Kumar, Paolo José Lorenzoni, Bas Vroling, Rosana Herminia Scola, Elza Dias‐Tosta, Argemiro Geraldo, Kiran Polavarapu, Saraswati Nashi, Daniel Cox, Teresinha Evangelista, John Dawson, Rachel Thompson, Jan Senderek, Steven Laurie, Sergi Beltran, Marta Gut, Ivo Gut, Atchayaram Nalini, Hanns Lochmüller


        RD-Connect, NeurOmics and EURenOmics: collaborative European initiative for rare diseases

        Hanns Lochmüller, Dorota M. Badowska, Rachel Thompson, Nine V. Knoers, Annemieke Aartsma-Rus, Ivo Gut, Libby Wood, Tina Harmuth, Andre Durudas, Holm Graessner, Franz Schaefer, Olaf Riess, RD-Connect consortium, NeurOmics consortium & EURenOmics consortium


        The Beta-Adrenergic Agonist Salbutamol Modulates Neuromuscular Junction Formation in Zebrafish Models of Human Myasthenic Syndromes

        Grace McMacken, Dan Cox, Andreas Roos, Juliane Müller, Roger Whittaker, Hanns Lochmüller


        Rare non-synonymous variants in SORT1 are associated with increased risk for frontotemporal dementia

        Stéphanie Philtjens, Sara Van Mossevelde, Julie van der Zee, Eline Wauters, Lubina Dillen, Mathieu Vandenbulcke, Rik Vandenberghe, Adrian Ivanoiu, Anne Sieben, Christiana Willems, Luisa Benussi, Roberta Ghidoni, Giuliano Binetti, Barbara Borroni, Alessandro Padovani, Pau Pastor, Monica Diez-Fairen, Miquel Aguilar, Alexandre de Mendonça, Gabriel Miltenberger-Miltényi, Isabel Hernández, Merce Boada, Agustín Ruiz, Benedetta Nacmiass, Sandro Sorbi, Maria Rosário Almeida, Isabel Santana, Jordi Clarimón, Alberto Lleó, Giovanni B. Frisoni, Raquel Sanchez-Valle, Albert Lladó, Estrella Gómez-Tortosa, Ellen Gelpi, Marleen Van den Broeck, Karin Peeters, Patrick Cras, Peter P. De Deyn, Sebastiaan Engelborghs, Marc Cruts, Christine Van


        PFN2 and GAMT as common molecular determinants of axonal Charcot-Marie-Tooth disease

        Manisha Juneja, Abdelkrim Azmi, Jonathan Baets, Andreas Roos, Matthew J Jennings, Paola Saveri, Chiara Pisciotta, Nathalie Bernard-Marissal, Bernard L Schneider, Catherine Verfaillie, Roman Chrast, Pavel Seeman, Angelika F Hahn, Peter de Jonghe, Stuart Maudsley, Rita Horvath, Davide Pareyson, Vincent Timmerman


        Cross-sectional serum metabolomic study of multiple forms of muscular dystrophy

        Pietro Spitali, Kristina Hettne, Roula Tsonaka, Ekrem Sabir, Alexandre Seyer, Jesse B.A. Hemerik, Jelle J. Goeman, Esther Picillo, Manuela Ergoli, Luisa Politano, Annemieke Aartsma-Rus


        Harmonising phenomics information for a better interoperability in the rare disease field

        Sylvie Maiellaa, Annie Olrya, Marc Hanauera, Valérie Lanneaua, Halima Lourghia, Bruno Donadillea, Charlotte Rodwella, Sebastian Köhlerc, Dominik Seelowc, Simon Juppe, Helen Parkinsone, Tudor Grozaf, Michael Brudnod, Peter N. Robinsonb, Ana Ratha


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Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial

Authors

Ludger Schöls, Tim W Rattay, Peter Martus, Christoph Meisner, Jonathan Baets, Imma Fischer, Christine Jägle, Matthew J Fraidakis, Andrea Martinuzzi, Jonas Alex Saute, Marina Scarlato, Antonella Antenora, Claudia Stendel, Philip Höflinger, Charles Marques Lourenco, Lisa Abreu, Katrien Smets, Martin Paucar, Tine Deconinck, Dana M Bis, Sarah Wiethoff, Peter Bauer, Alessia Arnoldi, Wilson Marques, Laura Bannach Jardim, Stefan Hauser, Chiara Criscuolo, Alessandro Filla, Stephan Züchner, Maria Teresa Bassi, Thomas Klopstock, Peter De Jonghe, Ingemar Björkhem, Rebecca Schüle

Journal

Brain,

Publication date

November 2017

Abstract

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.

DOI link

10.1093/brain/awx273

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The NeurOmics project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no 2012-305121.

 
   

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