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Section for Clinical Neurogenetics

Neurogenetic diseases like cerebellar ataxia, hereditary spastic paraplegia and leukodystrophy are rare disorders. For many of them the causative gene is still not known. We aim to discover the genetic cause as this offers not only a definite diagnosis for our patients but also opens a window into pathogenesis and potential interventions in early stages of the disease process. To this end we are modelling neurogenetic diseases using induced pluripotent stem cells and its differentiation into neurons which are genetically identical to our patients.

In 2010 we founded the first Center for Rare Diseases (ZSE) in Germany with support from the former first lady Eva Luise Köhler. The ZSE is dedicated to translational research. Many patients with rare movement disorders are seen in the specialized outpatient clinics. Clinical research builds up representative cohorts ready for trials with comprehensive phenotyping and longitudinal data on the natural course of disease as well as biobanking for biomarker development.

Clinical studies
Experimental Research


We provide specialized outpatient clinics for diagnostic and therapy of rare movement disorders at the Department of Neurology:


Our clinical research aims to prepare the way towards new therapies. For this purpose several steps are required:

  1. Representative cohorts are a basic requirement for the development of new therapiesespecially in rare diseases. Funded by the German-HSP-patient-support group we establish a web-based registry for hereditary spastic paraplegia including a standardised recording of clinical and genetic data. Data of the baseline analysis is now available (Schüle et al., 2016). Follow-up examinations will provide prospective data about the progress of the disease in its natural course. Such data is essential in the planning of interventional trials which aim to slow down the course of the disease. Similar studies are carried out for Friedreich’s ataxia and other early onset ataxias, spinocerebellar ataxias, multiple system atrophy as well as adult forms of leukodystrophy.                                                                                                                                                                                                                                                                                            
  2. As clinical progression is rather slow and depends on many external factors, biomarkers that reflect disease activity are urgently needed. For hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) we are assessing cytokine profiles in blood and CSF reflecting abnormal processes in HDLS pathogenesis. Similarly, biomarkers are also developed to measure progression in ataxias and HSP.                                                                                                                                                                                                                                                    
  3. Ideally, therapeutical approaches should start before the onset of symptoms and postpone or prevent disease manifestation. In autosomal dominantly inherited diseases like HDLS, SPG4 and spinocerebellar ataxias (SCA) first degree relatives of patients have a 50% risk to carry the disease causing mutation. In depth examinations of such individuals at risk can help to identify markers that indicate disease activity in presymptomatic stages of the disease before the patients experience any impairment. We set up studies to define presymptomatic biomarkers in healthy mutation carriers of HDLS as well as SPG4 (preSPG4 study) and spinocerebellar ataxias (RISCA study; Jacobi et al., 2015) by combining computerized movement recording, elaborated MRI techniques and analyses of disease proteins (Lindig et al., 2015).                                                                                                                                                                                                                                             
  4. The major goal of this research to establish trial ready cohorts that are suitable for interventional trials with promising compound identified in experimental approaches performed in parallel in our lab. Following this line, we recently performed the first randomized placebo-controlled trial in hereditary spastic paraplegia type 5 (SPG5) (Schöls et al., 2017).                                                                                                                                                                                                                         


The Schöls lab takes advantage of the broad access to patient-derived biomaterials and focusses on the identification of new disease genes and disease modelling by using induced pluripotent stem cells (iPSCs).

  • Fibroblasts are reprogrammed into induced pluripotent stem cells (iPSC) by nucleofection of episomal plasmids carrying classic reprogramming factors (Fig. 1; Hauser et al., 2016). These stem cells can be re-differentiated into neurons or other tissue relevant for pathogenesis (e.g. hepatocytes). This approach allows to analyze neurons or other cell types in the culture dish that are genetically identical to our patients.

  • iPSC-derived neurons are used to model the respective disease. E.g. hereditary spastic paraplegia preferentially affects the long axons of the cortico-spinal tract. Using live cell imaging and high content imaging we could demonstrate impaired axonal outgrowth in SPG4 neurons, the most common form of hereditary spastic paraplegia (in cooperation with Prof. Dr. Oliver Brüstle, Bonn). Furthermore, SPG4 axons present with largely increased numbers of axonal swellings compared to control neurons.


  • SPG5 is a subtype of hereditary spastic paraplegia caused by mutations in the cytochrome CYP7B1. Lack of CYP7B1 in the liver leads to metabolic abnormalities with extensive increase of oxysterols in blood but also in CSF. Treating iPSC-derived neurons with oxysterols in concentrations that are found in our patients impairs axonal growth as well as cell viability. Currently we are characterizing metabolic abnormalities in iPSC-derived hepatocytes of SPG5 patients using mass spectrometry in cooperation with Prof. Ingemar Björkhem (Karolinska Institute, Stockholm) and Prof. William Griffiths (Swansea, UK).
  • Genetic studies aim to disclose the genetic cause in patients with ultra-rare diseases. With funding from the DFG we run a trilateral project connecting Israeli, Palestinian and German scientists to discover new genes in so far undefined disorders . Genetic diseases are frequent in Israel and the Palestinian authorities due to numerous consanguineous marriages. Whole exome sequencing allowed us to identify several new genes like AP4B1, WWOX and DNAJC3 (Bauer et al. 2012; Mallaret et al. 2014; Synofzik et al. 2014). Genomic approaches are performed in collaborative European projects like NEUROMICS in close cooperation with Prof. Peter Bauer and Prof. Olaf Rieß (Institute of Medical Genetics, Tübingen), Prof. Michel Koenig (Montpellier), Dr. Holger Prokisch (Helmholtz Centre, Munich) and Prof. Stephan Züchner (Hussman Institute, Miami).

 Carina Arnold
Carina Arnold Master Student
Research Division Clinical Neurogenetics
 Friedemann Bender
Friedemann Bender Medical Doctor
Research Division Clinical Neurogenetics
07071 29-85247 
Dr. Jutta Eymann
Dr. Jutta Eymann Scientific and ZSE Coordinator
Research Division Clinical Neurogenetics
07071 29-85170 
 Elke Feil
Elke Feil Study Assistant
Research Division Clinical Neurogenetics
07071 29-85376 
Dr. Stefan Hauser
Dr. Stefan Hauser Postdoctoral Researcher
Research Division Clinical Neurogenetics
07071 9254-402 
Dr. Stefanie Hayer
Dr. Stefanie Hayer Medical Doctor
Research Division Clinical Neurogenetics
07071 9254-301 
Dr. Holger Hengel
Dr. Holger Hengel Medical Doctor
Research Division Clinical Neurogenetics
07071 29-87609 
 Elena Heuten
Elena Heuten Master Student
Research Division Clinical Neurogenetics
 Philip Hoeflinger
Philip Hoeflinger PhD Student
Research Division Clinical Neurogenetics
07071 9254-402 
Dr. Jennifer Just
Dr. Jennifer Just Medical Doctor
Research Division Clinical Neurogenetics
07071 29-85247 
Dr. Roman Praschberger
Dr. Roman Praschberger Medical Doctor
Research Division Clinical Neurogenetics
07071 29-85247 
Dr. Tim W. Rattay
Dr. Tim W. Rattay Medical Doctor
Research Division Clinical Neurogenetics
07071 29-85247 or 07071 29-61889 
 Yvonne Schelling
Yvonne Schelling Technician
Research Division Clinical Neurogenetics
07071 29-87609 
Prof. Dr. Ludger Schoels
Prof. Dr. Ludger Schoels Research Group Leader
Research Division Clinical Neurogenetics
07071 29-82057 
 Stefanie Schuster
Stefanie Schuster PhD Student
Research Division Clinical Neurogenetics
07071 9254-355 
 Susanne Stimmler
Susanne Stimmler Secretary
Research Division Clinical Neurogenetics
07071 29-82057 
Prof. Dr. Matthis Synofzik
Prof. Dr. Matthis Synofzik Research Group Leader
07071 29-82060 
Dr. Sarah Wiethoff
Dr. Sarah Wiethoff Medical Doctor
Research Division Clinical Neurogenetics
07071 29-85247 
Dr. Carlo Wilke
Dr. Carlo Wilke Medical Doctor
Research Division Clinical Neurogenetics
07071 29-82060 
Dr. Lena Zeltner
Dr. Lena Zeltner Medical Doctor
Research Division Clinical Neurogenetics
07071 29-85247 


Selected publications

  • Schöls L, Rattay TW, Martus P, Meisner C, ... Höflinger P, ... Wiethoff S, ... Hauser S, Schüle R. Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial, Brain 2017
  • Pelzl L, Hauser S, Elsir B, Sukkar B, ... Höflinger P, ... Schöls L, Lang F. Lithium Sensitive ORAI1 Expression, Store Operated Ca2+ Entry and Suicidal Death of Neurons in Chorea-Acanthocytosis. Scientific Reports 2017;7:6457
  • Estrada-Cuzcano A, Martin S, Chamova T, … Schöls L … Schüle R. Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78). Brain 2017;140:287-305
  • Schüle R, Wiethoff S, Martus P, … Schöls L. Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients. Annals of Neurology 2016;79:646-658
  • Bonifert T, Gonzalez Menendez I, Battke F, Theurer Y, Synofzik M, Schöls L, Wissinger B. Antisense Oligonucleotide Mediated Splice Correction of a Deep Intronic Mutation in OPA1. Molecular therapy Nucleic acids 2016;5:e390
  • Hauser S, Höflinger P, Theurer Y, Rattay TW, Schöls L. Generation of induced pluripotent stem cells (iPSCs) from a hereditary spastic paraplegia patient carrying a homozygous Y275X mutation in CYP7B1 (SPG5). Stem Cell Research 2016:17:437-440
  • Reetz K, Dogan I, Hilgers RD, … Schöls L, Klockgether T, Burk K, Rai M, Pandolfo M, Schulz JB, Group ES. Progression characteristics of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS): a 2 year cohort study. The Lancet Neurology 2016;15:1346-1354
  • Schöls L, Reimold M, Seidel K, et al. No parkinsonism in SCA2 and SCA3 despite severe neurodegeneration of the dopaminergic substantia nigra. Brain 2015;138:3316-3326
  • Syrbe S, Hedrich UB, Riesch E, … Schöls L, … Lerche H, Lemke JR. De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nature Genetics 2015;47:393-399
  • Lindig T, Bender B, Hauser TK, Mang S, Schweikardt D, Klose U, Karle KN, Schule R, Schöls L, Rattay TW. Gray and white matter alterations in hereditary spastic paraplegia type SPG4 and clinical correlations. J Neurol 2015;262:1961-1971
  • Jacobi H, du Montcel ST, Bauer P, … Schöls L, Hengel H, … Klockgether T. Long-term disease progression in spinocerebellar ataxia types 1, 2, 3, and 6: a longitudinal cohort study. The Lancet Neurology 2015;14:1101-1108
  • Mallaret M, Synofzik M, Lee J, …, Schüle R, Schöls L, Aldaz M, Koenig M. The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation. Brain 2014;137:411-419
  • Synofzik M, Haack TB, Kopajtich R, …, Züchner S, Schüle R, Schöls L, Prokisch H. Absence of BiP Co-chaperone DNAJC3 Causes Diabetes Mellitus and Multisystemic Neurodegeneration. Am J Hum Genet 2014;95:689-97
  • Theofilopoulos S, Griffiths WJ, …, Schüle R, Schöls L, Sailer AW, Kuhle J, Fraidakis MJ, Gustafsson JA, Steffensen KR, Björkhem I, Ernfors P, Sjovall J, Arenas E, Wang Y. Cholestenoic acids regulate motor neuron survival via liver X receptors. J Clin Invest 2014;124: 4829-4842
  • Bonifert T, Karle KN, Tonagel F, … Schöls L, Wissinger B, Synofzik M. Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier. Brain 2014;137:2164-2177
  • Jacobi H, Reetz K, du Montcel ST, … Schöls L, …, Klockgether T. Biological and clinical characteristics of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 in the longitudinal RISCA study: analysis of baseline data. Lancet Neurol 2013;12:650-658
  • Karle KN, Biskup S, Schüle R, Schweitzer KJ, Krüger R, Bauer P, Bender B, Nägele T, Schöls L. De novo mutations in hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS). Neurology 2013;81:2039-2044
  • Martin E, …, Schöls L, Mhiri C, Lamari F, Zuchner S, De Jonghe P, Kabashi E, Brice A, Stevanin G. Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia. Am J Hum Genet 2013;92:238-244
  • Füger P, Sreekumar V, Schule R, Kern JV, Stanchev DT, Schneider CD, Karle KN, Daub KJ, Siegert VK, Flotenmeyer M, Schwarz H, Schöls L, Rasse TM. Spastic Paraplegia Mutation N256s in the Neuronal Microtubule Motor Kif5a Disrupts Axonal Transport in a Drosophila Hsp Model." PLoS Genet 2012;8: e1003066
  • Karle KN, Möckel D, Reid E, Schöls L. "Axonal Transport Deficit in a Kif5a( -/- ) Mouse Model." Neurogenetics 2012;13:169-179
  • Schüle R, Siddique T, Deng HX, Yang Y, Donkervoort S, Hansson M, Madrid RE, Siddique N, Schöls L, Björkhem I. Marked accumulation of 27-hydroxycholesterol in SPG5 patients with hereditary spastic paresis. J Lipid Res 2010:51:819-823
  • Ilg W, Synofzik M, Brotz D, Burkard S, Giese MA, Schöls L. Intensive coordinative training improves motor performance in degenerative cerebellar disease. Neurology 2009;73:1823-1830
  • Schüle R, Holland-Letz T, Klimpe S, Kassubek J, Klopstock T, Mall V, Otto S, Winner B, Schöls L. The Spastic Paraplegia Rating Scale (SPRS): a reliable and valid measure of disease severity. Neurology 2006;67:430-434
  • Schöls L, Bauer P, Schmidt T, Schulte T, Riess O. Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol. 2004;3:291-304



Research Group Leader
Prof. Ludger Schöls Address

Center of Neurology
Hertie Institute for Clinical Brain Research
Department Neurodegenerative Diseases

Hoppe-Seyler-Straße 3
72076 Tübingen

Phone: +49 (0)7071 29-82057
Fax: +49 (0)7071 29-4254