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The Cerebellum

, Volume 11, Issue 1, pp 155–166 | Cite as

Spinocerebellar Ataxia Types 1, 2, 3 and 6: the Clinical Spectrum of Ataxia and Morphometric Brainstem and Cerebellar Findings

  • Heike Jacobi
  • Till-Karsten Hauser
  • Paola Giunti
  • Christoph Globas
  • Peter Bauer
  • Tanja Schmitz-Hübsch
  • László Baliko
  • Alessandro Filla
  • Caterina Mariotti
  • Maria Rakowicz
  • Perine Charles
  • Pascale Ribai
  • Sandra Szymanski
  • Jon Infante
  • Bart P. C. van de Warrenburg
  • Alexandra Dürr
  • Dagmar Timmann
  • Sylvia Boesch
  • Roberto Fancellu
  • Rafal Rola
  • Chantal Depondt
  • Ludger Schöls
  • Elzbieta Zdzienicka
  • Jun-Suk Kang
  • Susanne Ratzka
  • Berry Kremer
  • Dennis A. Stephenson
  • Béla Melegh
  • Massimo Pandolfo
  • Sophie Tezenas du Montcel
  • Johannes Borkert
  • Jörg B. Schulz
  • Thomas Klockgether
Article

Abstract

To assess the clinical spectrum of ataxia and cerebellar oculomotor deficits in the most common spinocerebellar ataxias (SCAs), we analysed the baseline data of the EUROSCA natural history study, a multicentric cohort study of 526 patients with either spinocerebellar ataxia type 1, 2, 3 or 6. To quantify ataxia symptoms, we used the Scale for the Assessment and Rating of Ataxia (SARA). The presence of cerebellar oculomotor signs was assessed using the Inventory of Non-Ataxia Symptoms (INAS). In a subgroup of patients, in which magnetic resonance images (MRIs) were available, we correlated MRI morphometric measures with clinical signs on an exploratory basis. The SARA subscores posture and gait (items 1–3), speech (item 4) and the limb kinetic subscore (items 5–8) did not differ between the genotypes. The scores of SARA item 3 (sitting), 5 (finger chase) and 6 (nose–finger test) differed between the subtypes whereas the scores of the remaining items were not different. In SCA1, ataxia symptoms were correlated with brainstem atrophy and in SCA3 with both brainstem and cerebellar atrophy. Cerebellar oculomotor deficits were most frequent in SCA6 followed by SCA3, whereas these abnormalities were less frequent in SCA1 and SCA2. Our data suggest that vestibulocerebellar, spinocerebellar and pontocerebellar circuits in SCA1, SCA2, SCA3 and SCA6 are functionally impaired to almost the same degree, but at different anatomical levels. The seemingly low prevalence of cerebellar oculomotor deficits in SCA1 and SCA2 is most probably related to the defective saccadic system in these disorders.

Keywords

Ataxia Brainstem Cerebellum Clinical scale Magnetic resonance imaging (MRI) Spinocerebellar ataxia (SCA) 

Notes

Acknowledgments

We are grateful to Drs. Klopstock and Petersen (Department of Neurology, University of Munich, Munich, Germany), Dr. Abdo (Department of Neurology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands) and Dr. Verstappen (Canisius Wilhelina Hospital, Nijmegen, the Netherlands) for contribution of patients and help in patient assessment. We thank all the patients for participating in the study. This study was supported by grant EUROSCA/LSHM-CT-2004-503304 from the European Union, GeneMove/01 GM 0503 from the German Ministry of Education and Research and grant 3 PO5B 019 24 from the Polish Ministry of Scientific Research and Information Technology.

Conflicts of Interest

The authors report no conflicts of interest.

Full Financial Disclosures

H. Jacobi, T.-K. Hauser, P. Giunti, C. Globas, T. Schmitz-Hübsch, L. Baliko, A. Filla, C. Mariotti, P. Charles, P. Ribai, S. Szymanski, J. Infante, A. Dürr, D. Timmann, R. Fancellu, R. Rola, E. Zdzienicka, J.-S. Kang, S. Ratzka, D.A. Stephenson, S. Tezenas du Montcel and J. Borkert have declared no financial disclosure in stock ownership in medically related fields, consultancies, advisory boards, partnerships, honoraria, intellectual property rights, expert testimony, contracts, royalties and others. H. Jacobi, T.-K. Hauser, C. Globas, L. Baliko, P. Charles, S. Szymanski, R. Fancellu, R. Rola, J.-S. Kang, S. Ratzka, D.A. Stephenson and J. Borkert have declared no grants. P. Giunti was supported by grants from EUROSCA FP7 and Ataxia UK; T. Schmitz-Hübsch by grants from EUROSCA; A. Filla by grants from Ministry of Health: RF-SDN-2007-666932 and MIUR (Ministry of Research): E61J10000020001; C. Mariotti by grants from E-Rare; EFACTS, FP7 no: 242193; Study No.: 12631A; EudraCT No.: 2008-003662-25; Sponsor: International Clinical Research; H. Lundbeck A/S 2500 Valby (Copenhagen), Denmark; P. Ribai by grants from Société Française de Neurologie (SFN) and Association Française contre l’ataxie de Friedreich (AFAF); J. Infante by grants from Fondo de Investigación Sanitaria (PI 070014); A. Dürr by grants from PHRC National 2003 (agency: Assistance Publique-Hôpitaux de Paris (2005–2012)), Eurosca (agency: European Union (2004–2009)) and Spax (agency: French Agency for Research (2010–2012)); D. Timmann by grants from German Research Foundation (DFG TI 239/9-1), EU (Partner Marie Curie Initial Training Network) and Bernd Fink Foundation; E. Zdzienicka by grants from EUROSCA grant LSHM-CT-2004-503304 PO5E 019 29-Myotonic Dystrophy type 1 and 2 by the Polish State Committee of Scientific Research and RISCA 511-006-10001 from the Polish Ministry of Science and Higher Education and S. Tezenas du Montcel by grants from the European Union (grant EUROSCA (LSHM-CT-2004-503304)), the Assistance Publique-Hôpitaux de Paris (grant PHRC AOM 03059) and from the European Union C08A043 (funded by the French National Agency for Research). H. Jacobi is employed by the University of Bonn while T.-K. Hauser is by the University of Tübingen; P. Giunti by the UCL/UCLH; T. Schmitz-Hübsch by the University of Bonn; L. Baliko by the County Hospital, Veszprém, Hungary; A. Filla by the Federico II University, Napoli, Italy; C. Mariotti by the Fondazione IRCCS Neurological Institute Carlo Besta, Milan; P. Charles by the Hôpital de la Salpêtrière, Département de Génétique, Paris, France; P. Ribai by the Hôpital de la Salpêtrière, Département de Génétique, Paris, France; S. Szymanski by the St. Josef Hospital, University Hospital of Bochum; J. Infante by the University of Cantabria, Santander, Spain; A. Dürr by the Hôpital de la Salpêtrière, Département de Génétique, Paris, France; D. Timmann by the University of Duisburg-Essen; R. Fancellu by the Ospedale Villa Scassi, ASL3 Genovese, Genoa, Italy; R. Rola by the Institute of Psychiatry and Neurology and The Medical University of Warsaw, Poland; E. Zdzienicka by the Institute of Psychiatry and Neurology, Warsaw, Poland; J.-S. Kang by the University of Frankfurt, Frankfurt am Main, Germany; S. Ratzka by the Klinikum Augsburg, Department of Neurology, Germany; D.A. Stephenson by the UCL Medical Institute, USA; S. Tezenas du Montcel by the Department of Biostatistics and Medical Informatics and by the University Pierre et Marie Curie, Paris, France and J. Borkert by the University of Göttingen. C. Globas was employed by the Clinic of Psychiatry, University Tübingen from April 2009 to March 2010 and is currently employed by the Clinic of Neurology, University, Zürich since May 2010.

P. Bauer has declared no financial disclosure in stock ownership in medically related fields, advisory boards, partnerships, intellectual property rights, expert testimony, contracts, royalties and other; is a consultant at CENTOGENE (Rostock, Germany) and was supported by grants from Research Council (BMBF) to GeNeMove (01GM0603), EUROSPA (01GM0807) and RISCA (09GM0820) as well as from the EU for EUROSCA (LSHM-CT-2004-503304), MarkMD (FP7-People PIAP-2008-230596) and TECHGENE (FP7-Health 2007-B 223143). A further project received funding from the HSP-Selbsthilfegruppe Deutschland e.V. Honoraria was received from Roche Diagnostics (Mannheim, Germany) and Actelion Pharmaceuticals (Basel, Switzerland). He is employed by the University of Tübingen.

M. Rakowicz has declared no financial disclosure in stock ownership in medically related fields, advisory boards, honoraria, intellectual property rights, expert testimony, contracts, royalties and other; is a consultant at the Private Neurological Office, Warsaw, Poland; is partner of Ma-Je-R Ltd, Warsaw, Poland; was supported by grants from EUROSCA grant LSHM-CT-2004-503304, PO5E 019 29 by the Polish State Committee of Scientific Research and RISCA 511-006-10001 from the Polish Ministry of Science and Higher Education and is employed by the Institute of Psychiatry and Neurology, Warsaw.

B.P.C. van de Warrenburg has declared no financial disclosure in stock ownership in medically related fields, consultancies, partnerships, intellectual property rights, expert testimony, contracts, royalties and other; is a medical advisor for the Dutch patient organizations for ADCA, dystonia and hereditary spastic paraplegia; was supported by grants from Prinses Beatrix Fonds, the Brain Foundation, Department of Neurology of the Radboud University Nijmegen Medical Centre, Ipsen Pharmaceuticals (all in the Netherlands) and from the European Union (EUROSCA/LSHM-CT-2004-503304); has received honoraria from editorial work for the Dutch Health Direct Neurology journal (Reed Elsevier) and is employed by the Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.

S. Boesch has declared no financial disclosure in stock ownership in medically related fields, partnerships, grants, intellectual property rights, expert testimony, contracts, royalties and other; is a consultant at Lundbeck; has been a member of the advisory board of Takeda, Novartis and Glaxo; has received honoraria from Takeda, Glaxo and Novartis and is employed by the University of Innsbruck, Austria.

C. Depondt has declared no financial disclosure in stock ownership in medically related fields, consultancies, advisory boards, partnerships, honoraria, grants, intellectual property rights, expert testimony, contracts and royalties but with financial disclosure in payment of congress expenses by UCB Pharma and is employed by the Université Libre de Bruxelles, Belgium.

L. Schöls has declared no financial disclosure in stock ownership in medically related fields, consultancies, advisory boards, partnerships, intellectual property rights, expert testimony, contracts and royalties; has received support from the HSP-Selbsthilfegruppe Deutschland e.V. for research in spastic paraplegia; has received study fees for the MICONOS trial from Santhera Pharmaceuticals; was supported by grants of the German Research Council (BMBF) to Leukonet (01GM0644) and mitoNET (01GM0864) and E-RARE grants of the EU to EUROSPA (01GM0807) and RISCA (01GM0820) and is employed by the University of Tübingen.

B. Kremer has declared no financial disclosure in stock ownership in medically related fields, consultancies, partnerships, intellectual property rights, contracts, royalties and other; has been a member of the advisory board of Hersenstichting Nederland, Prinses Beatrix Foundation and Nederlandse Transplantatiestichting; has received honoraria from the Netherlands and Actelion, the Netherlands; was supported by grants from UMC Nijmegen, UMC Groningen and MS Anders; has various testimonies in legal cases and medical insurance cases and is employed by the University Medical Centre Groningen, Groningen, the Netherlands.

B. Melegh has declared no financial disclosure in stock ownership in medically related fields, honoraria, intellectual property rights, expert testimony, contracts, royalties and other; has been a consultant for national grant funding opportunities; has been a member of the advisory board of Biobanking and Biomolecular Resources (BBMRI); is partner of the WestTeam Biotech Ltd; was supported by grants from ETT (Grant from Ministry of Health) and OTKA (Hungarian Science Foundation) E-Rare-2, EU7 supported project and is employed by the University of Pécs.

M. Pandolfo has declared no financial disclosure in stock ownership in medically related fields, consultancies, partnerships, expert testimony, contracts and other; has been a member of the advisory board for Apopharma; has received honoraria from Santhera AG; was supported by grants from Repligen Corporation; has intellectual property rights: “Direct molecular diagnosis of Friedreich ataxia” M. Pandolfo, L. Montermini, M.D. Molto’, M. Koenig, V. Campuzano, M. Cossee’. US patent (2000) 6,150,091, WO patent (1997) 9705234; is employed by the University of Brussles and receives royalties from Athena Diagnostics.

J. Schulz has declared no financial disclosure in stock ownership in medically related fields, partnerships, intellectual property rights, expert testimony, contracts, royalties and other; acted as a consultant of Santhera; has been a member of the advisory board of Santhera; has received honoraria from Merz, Pfizer and GSK; was supported by grants from BMBF, EU and is employed by the University of Aachen.

T. Klockgether has declared no financial disclosure in stock ownership in medically related fields, consultancies, partnerships, intellectual property rights, expert testimony, contracts, royalties and other; has been a member of the advisory board of the The Cerebellum, Parkinsonism & Related Disorder, ataxia lay organizations; has received lecture honorarium from Lundbeck; was supported by grants from Deutsche Forschungsgemeinschaft (DFG), KFO177 Clinical Research Group (Innate Immunity in Chronic Neurodegeneration) and from the German Ministry of Education and Research (BMBF), E-Rare 01GM0819 RISCA and is employed by the University of Bonn.

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Heike Jacobi
    • 1
  • Till-Karsten Hauser
    • 2
  • Paola Giunti
    • 3
  • Christoph Globas
    • 4
  • Peter Bauer
    • 5
  • Tanja Schmitz-Hübsch
    • 1
  • László Baliko
    • 6
  • Alessandro Filla
    • 7
  • Caterina Mariotti
    • 8
  • Maria Rakowicz
    • 9
  • Perine Charles
    • 10
  • Pascale Ribai
    • 10
    • 11
  • Sandra Szymanski
    • 12
  • Jon Infante
    • 13
  • Bart P. C. van de Warrenburg
    • 14
  • Alexandra Dürr
    • 10
    • 11
    • 15
  • Dagmar Timmann
    • 16
  • Sylvia Boesch
    • 17
  • Roberto Fancellu
    • 8
  • Rafal Rola
    • 18
  • Chantal Depondt
    • 19
  • Ludger Schöls
    • 4
    • 20
  • Elzbieta Zdzienicka
    • 21
  • Jun-Suk Kang
    • 22
  • Susanne Ratzka
    • 23
  • Berry Kremer
    • 24
  • Dennis A. Stephenson
    • 3
  • Béla Melegh
    • 25
  • Massimo Pandolfo
    • 19
  • Sophie Tezenas du Montcel
    • 26
    • 27
  • Johannes Borkert
    • 23
  • Jörg B. Schulz
    • 23
    • 28
  • Thomas Klockgether
    • 1
    • 29
  1. 1.Department of NeurologyUniversity Hospital of BonnBonnGermany
  2. 2.Department of NeuroradiologyUniversity of TübingenTübingenGermany
  3. 3.Department of Molecular NeuroscienceInstitute of Neurology UCLLondonUK
  4. 4.Department of Neurology and Hertie-Institute for Clinical Brain ResearchUniversity of TübingenTübingenGermany
  5. 5.Department of Human GeneticsUniversity of TübingenTübingenGermany
  6. 6.Department of Neurology and StrokeCounty HospitalVeszprémHungary
  7. 7.Department of Neurological SciencesFederico II UniversityNaplesItaly
  8. 8.SOSD Unit of Genetics of Neurodegenerative and Metabolic DiseasesFondazione IRCCS Istituto Neurologico “Carlo Besta”MilanItaly
  9. 9.Department of Clinical NeurophysiologyInstitute of Psychiatry and NeurologyWarsawPoland
  10. 10.Département de GénétiqueAP-HP, Hôpital de la SalpêtrièreParisFrance
  11. 11.NSERM, UMR_S679 Neurologie & Thérapeutique ExpérimentaleParisFrance
  12. 12.Department of Neurology, St. Josef HospitalUniversity Hospital of BochumBochumGermany
  13. 13.Service of Neurology, University Hospital “Marqués de Valdecilla (IFIMAV)”University of Cantabria and “Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)”SantanderSpain
  14. 14.Department of Neurology, Donders Centre for NeuroscienceRadboud University Nijmegen Medical CentreNijmegenthe Netherlands
  15. 15.Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, UMR-S975ParisFrance
  16. 16.Department of NeurologyUniversity Hospital of EssenEssenGermany
  17. 17.Department of NeurologyMedical University InnsbruckInnsbruckAustria
  18. 18.First Department of NeurologyInstitute of Psychiatry and NeurologyWarsawPoland
  19. 19.Department of Neurology, Hôpital ErasmeUniversité Libre de BruxellesBrusselsBelgium
  20. 20.German Center of Neurodegenerative DiseasesUniversity of TübingenTübingenGermany
  21. 21.Department of GeneticsInstitute of Psychiatry and NeurologyWarsawPoland
  22. 22.Department of NeurologyUniversity of FrankfurtFrankfurt am MainGermany
  23. 23.Department of Neurodegeneration and Restorative Research, Centers of Molecular Physiology of the Brain and Neurological MedicineUniversity Hospital of GöttingenGöttingenGermany
  24. 24.Department of NeurologyUniversity Medical Centre GroningenGroningenthe Netherlands
  25. 25.Department of Medical Genetics and Child DevelopmentUniversity of PécsPécsHungary
  26. 26.Department of Biostatistics and Medical InformaticsAP-HPParisFrance
  27. 27.Modelling in Clinical ResearchUniversity Pierre et Marie Curie, ER4ParisFrance
  28. 28.Department of NeurologyUniversity Hospital AachenAachenGermany
  29. 29.German Center for Neurodegenerative Disorders (DZNE)BonnGermany

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