Journal of Neurology

, Volume 263, Issue 11, pp 2170–2178 | Cite as

Long-term treatment with thiamine as possible medical therapy for Friedreich ataxia

  • Antonio Costantini
  • Tiziana Laureti
  • Maria Immacolata Pala
  • Marco Colangeli
  • Simona Cavalieri
  • Elisa Pozzi
  • Alfredo Brusco
  • Sandro Salvarani
  • Carlo Serrati
  • Roberto Fancellu
Original Communication

Abstract

Thiamine (vitamin B1) is a cofactor of fundamental enzymes of cell energetic metabolism; its deficiency causes disorders affecting both the peripheral and central nervous system. Previous studies reported low thiamine levels in cerebrospinal fluid and pyruvate dehydrogenase dysfunction in Friedreich ataxia (FRDA). We investigated the effect of long-term treatment with thiamine in FRDA, evaluating changes in neurological symptoms, echocardiographic parameters, and plasma FXN mRNA levels. Thirty-four consecutive FRDA patients have been continuously treated with intramuscular thiamine 100 mg twice a week and have been assessed with the Scale for the Assessment and Rating of Ataxia (SARA) at baseline, after 1 month, and then every 3 months during treatment. Thiamine administration ranged from 80 to 930 days and was effective in improving total SARA scores from 26.6 ± 7.7 to 21.5 ± 6.2 (p < 0.02). Moreover, deep tendon reflexes reappeared in 57 % of patients with areflexia at baseline, and swallowing improved in 63 % of dysphagic patients. Clinical improvement was stable in all patients, who did not show worsening even after 2 years of treatment. In a subgroup of 13 patients who performed echocardiogram before and during treatment, interventricular septum thickness reduced significantly (p < 0.02). Frataxin mRNA blood levels were modestly increased in one-half of treated patients. We suppose that a focal thiamine deficiency may contribute to a selective neuronal damage in the areas involved in FRDA. Further studies are mandatory to evaluate thiamine role on FXN regulation, to exclude placebo effect, to verify our clinical results, and to confirm restorative and neuroprotective action of thiamine in FRDA.

Keywords

Thiamine Spinocerebellar ataxia Triplet expansion diseases Friedreich ataxia 

References

  1. 1.
    Pandolfo M (2012) Friedreich ataxia. Handb Clin Neurol 103:275–294PubMedCrossRefGoogle Scholar
  2. 2.
    Puccio H, Anheim M, Tranchant C (2014) Pathophysiogical and therapeutic progress in Friedreich ataxia. Rev Neurol (Paris) 170(5):355–365CrossRefGoogle Scholar
  3. 3.
    Collins A (2013) Clinical neurogenetics: friedreich ataxia. Neurol Clin 31(4):1095–1120PubMedCrossRefGoogle Scholar
  4. 4.
    Corben LA, Lynch D, Pandolfo M, Schulz JB, Delatycki MB, Clinical Management Guidelines Writing Group (2014) Consensus clinical management guidelines for Friedreich ataxia. Orphanet J Rare Dis 30(9):184. doi:10.1186/s13023-014-0184-7 CrossRefGoogle Scholar
  5. 5.
    Ilg W, Bastian AJ, Boesch S, Burciu RG, Celnik P, Claaßen J, Feil K, Kalla R, Miyai I, Nachbauer W, Schöls L, Strupp M, Synofzik M, Teufel J, Timmann D (2014) Consensus paper: management of degenerative cerebellar disorders. Cerebellum 13(2):248–268. doi:10.1007/s12311-013-0531-6 PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Sechi G, Serra A (2007) Wernicke’s encephalopathy: new clinical settings and recent advances in diagnosis and management. Lancet Neurol 6:442–455PubMedCrossRefGoogle Scholar
  7. 7.
    Mulholland PJ (2006) Susceptibility of the cerebellum to thiamine deficiency. Cerebellum 5(1):55–63PubMedCrossRefGoogle Scholar
  8. 8.
    Alekseeva N, McGee J, Kelley RE, Maghzi AH, Gonzalez-Toledo E, Minagar A (2014) Toxic-metabolic, nutritional, and medicinal-induced disorders of cerebellum. Neurol Clin 32(4):901–911PubMedCrossRefGoogle Scholar
  9. 9.
    Jhala SS, Hazell AS (2011) Modeling neurodegenerative disease pathophysiology in thiamine deficiency: consequences of impaired oxidative metabolism. Neurochem Int 58:248–260PubMedCrossRefGoogle Scholar
  10. 10.
    Mkrtchyan G, Aleshin V, Parkhomenko Y, Kaehne T, Luigi Di Salvo M, Parroni A, Contestabile R, Vovk A, Bettendorff L, Bunik V (2015) Molecular mechanisms of the non-coenzyme action of thiamin in brain: biochemical, structural and pathway analysis. Sci Rep 27:12583CrossRefGoogle Scholar
  11. 11.
    Gibson GE, Blass JP (2007) Thiamine-dependent processes and treatment strategies in neurodegeneration. Antioxid Redox Signal 9(10):1605–1619PubMedCrossRefGoogle Scholar
  12. 12.
    Pfeiffer RF (2014) Neurologic manifestations of malabsorption syndromes. Handb Clin Neurol 120:621–632PubMedCrossRefGoogle Scholar
  13. 13.
    Butterworth RF (2003) Thiamin deficiency and brain disorders. Nutr Res Rev 16:277–284PubMedCrossRefGoogle Scholar
  14. 14.
    Pedraza OL, Botez MI (1992) Thiamine status in inherited degenerative ataxias. J Neurol Neurosurg Psychiatry 55(2):136–137PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Poloni M, Mazzarello P, Laforenza U, Caramella C, Patrini C (1992) Thiamin contents of cerebrospinal fluid, plasma and erythrocytes in cerebellar ataxias. Eur Neurol 32(3):154–158PubMedCrossRefGoogle Scholar
  16. 16.
    Botez MI, Young SN (2001) Biogenic amine metabolites and thiamine in cerebrospinal fluid in heredo-degenerative ataxias. Can J Neurol Sci 28(2):134–140PubMedGoogle Scholar
  17. 17.
    Barbeau A, Butterworth RF, Ngo T, Breton G, Melançon S, Shapcott D, Geoffroy G, Lemieux B (1976) Pyruvate metabolism in Friedreich’s ataxia. Can J Neurol Sci 3(4):379–388PubMedCrossRefGoogle Scholar
  18. 18.
    Kark RA, Rodriguez-Budelli M, Blass JP (1978) Evidence for a primary defect of lipoamide dehydrogenase in Friedreich’s ataxia. Adv Neurol 21:163–180PubMedGoogle Scholar
  19. 19.
    Purkiss P, Baraitser M, Borud O, Chalmers RA (1981) Biochemical and clinical studies in Friedreich’s ataxia. J Neurol Neurosurg Psychiatry 44:574–580PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Gledhill RF, Labadarios D (1984) Biochemical vitamin deficiencies in Friedreich’s ataxia. J Neurol Neurosurg Psychiatry 47(1):111–112PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Costantini A, Giorgi R, D’Agostino S, Pala MI (2013) High dose thiamine improves the symptoms of Friedreich’s ataxia. BMJ Case Rep. doi:10.1136/bcr-2013-009424 (published online first: 22 May) Google Scholar
  22. 22.
    Schmitz-Hübsch T, du Montcel ST, Baliko L, Berciano J, Boesch S, Depondt C, Giunti P, Globas C, Infante J, Kang JS, Kremer B, Mariotti C, Melegh B, Pandolfo M, Rakowicz M, Ribai P, Rola R, Schöls L, Szymanski S, van de Warrenburg BP, Dürr A, Klockgether T, Fancellu R (2006) Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 66(11):1717–1720PubMedCrossRefGoogle Scholar
  23. 23.
    Klockgether T, Lüdtke R, Kramer B, Abele M, Bürk K, Schöls L, Riess O, Laccone F, Boesch S, Lopes-Cendes I, Brice A, Inzelberg R, Zilber N, Dichgans J (1998) The natural history of degenerative ataxia: a retrospective study in 466 patients. Brain 121:589–600PubMedCrossRefGoogle Scholar
  24. 24.
    Brusse E, Brusse-Keizer MG, Duivenvoorden HJ, van Swieten JC (2011) Fatigue in spinocerebellar ataxia: patient self-assessment of an early and disabling symptom. Neurology 76(11):953–959PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Trouillas P, Takayanagi T, Hallett M, Currier RD, Subramony SH, Wessel K, Bryer A, Diener HC, Massaquoi S, Gomez CM, Coutinho P, Ben Hamida M, Campanella G, Filla A, Schut L, Timann D, Honnorat J, Nighoghossian N, Manyam B (1997) International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. J Neurol Sci 145(2):205–211PubMedCrossRefGoogle Scholar
  26. 26.
    Lu J, Frank EL (2008) Rapid HPLC measurement of thiamine and its phosphate esters in whole blood. Clin Chem 54(5):901–906PubMedCrossRefGoogle Scholar
  27. 27.
    Reetz K, Dogan I, Costa AS, Dafotakis M, Fedosov K, Giunti P, Parkinson MH, Sweeney MG, Mariotti C, Panzeri M, Nanetti L, Arpa J, Sanz-Gallego I, Durr A, Charles P, Boesch S, Nachbauer W, Klopstock T, Karin I, Depondt C, vom Hagen JM, Schöls L, Giordano IA, Klockgether T, Bürk K, Pandolfo M, Schulz JB (2015) Biological and clinical characteristics of the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS) cohort: a cross-sectional analysis of baseline data. Lancet Neurol 14(2):174–182PubMedCrossRefGoogle Scholar
  28. 28.
    Strawser CJ, Schadt KA, Lynch DR (2014) Therapeutic approaches for the treatment of Friedreich’s ataxia. Expert Rev Neurother 14(8):949–957PubMedCrossRefGoogle Scholar
  29. 29.
    Di Prospero NA, Baker A, Jeffries N, Fischbeck KH (2007) Neurological effects of high-dose idebenone in patients with Friedreich’s ataxia: a randomised, placebo-controlled trial. Lancet Neurol 6(10):878–886PubMedCrossRefGoogle Scholar
  30. 30.
    Lynch DR, Perlman SL, Meier T (2010) A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia. Arch Neurol 67(8):941–947PubMedCrossRefGoogle Scholar
  31. 31.
    Mariotti C, Nachbauer W, Panzeri M, Poewe W, Taroni F, Boesch S (2013) Erythropoietin in Friedreich ataxia. J Neurochem 126(Suppl 1):80–87PubMedCrossRefGoogle Scholar
  32. 32.
    Boesch S, Nachbauer W, Mariotti C, Sacca F, Filla A, Klockgether T, Klopstock T, Schöls L, Jacobi H, Büchner B, vom Hagen JM, Nanetti L, Manicom K (2014) Safety and tolerability of carbamylated erythropoietin in Friedreich’s ataxia. Mov Disord 29(7):935–939PubMedCrossRefGoogle Scholar
  33. 33.
    Pandolfo M, Arpa J, Delatycki MB, Le Quan Sang KH, Mariotti C, Munnich A, Sanz-Gallego I, Tai G, Tarnopolsky MA, Taroni F, Spino M, Tricta F (2014) Deferiprone in Friedreich ataxia: a 6-month randomized controlled trial. Ann Neurol 76(4):509–521PubMedCrossRefGoogle Scholar
  34. 34.
    Gottesfeld JM, Rusche JR, Pandolfo M (2013) Increasing frataxin gene expression with histone deacetylase inhibitors as a therapeutic approach for Friedreich’s ataxia. J Neurochem 126(Suppl 1):147–154PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Soragni E, Miao W, Iudicello M, Jacoby D, De Mercanti S, Clerico M, Longo F, Piga A, Ku S, Campau E, Du J, Penalver P, Rai M, Madara JC, Nazor K, O’Connor M, Maximov A, Loring JF, Pandolfo M, Durelli L, Gottesfeld JM, Rusche JR (2014) Epigenetic therapy for Friedreich ataxia. Ann Neurol 76(4):489–508PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Libri V, Yandim C, Athanasopoulos S, Loyse N, Natisvili T, Law PP, Chan PK, Mohammad T, Mauri M, Tam KT, Leiper J, Piper S, Ramesh A, Parkinson MH, Huson L, Giunti P, Festenstein R (2014) Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich’s ataxia: an exploratory, open-label, dose-escalation study. Lancet 384(9942):504–513PubMedCrossRefGoogle Scholar
  37. 37.
    Romano S, Coarelli G, Marcotulli C, Leonardi L, Piccolo F, Spadaro M, Frontali M, Ferraldeschi M, Vulpiani MC, Ponzelli F, Salvetti M, Orzi F, Petrucci A, Vanacore N, Casali C, Ristori G (2015) Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 14(10):985–991PubMedCrossRefGoogle Scholar
  38. 38.
    Zesiewicz TA, Sullivan KL, Gooch CL, Lynch DR (2009) Subjective improvement in proprioception in 2 patients with atypical Friedreich ataxia treated with varenicline (Chantix). J Clin Neuromuscul Dis 10(4):191–193PubMedCrossRefGoogle Scholar
  39. 39.
    Yiu EM, Tai G, Peverill RE, Lee KJ, Croft KD, Mori TA, Scheiber-Mojdehkar B, Sturm B, Praschberger M, Vogel AP, Rance G, Stephenson SE, Sarsero JP, Stockley C, Lee CY, Churchyard A, Evans-Galea MV, Ryan MM, Lockhart PJ, Corben LA, Delatycki MB (2015) An open-label trial in Friedreich ataxia suggests clinical benefit with high-dose resveratrol, without effect on frataxin levels. J Neurol 262(5):1344–1353PubMedCrossRefGoogle Scholar
  40. 40.
    Marelli C, Figoni J, Charles P, Anheim M, Tchikviladze M, Vincitorio CM, du Montcel ST, Brice A, Golmard JL, Dürr A (2012) Annual change in Friedreich’s ataxia evaluated by the Scale for the Assessment and Rating of Ataxia (SARA) is independent of disease severity. Mov Disord 27(1):135–138PubMedCrossRefGoogle Scholar
  41. 41.
    Bürk K, Mälzig U, Wolf S, Heck S, Dimitriadis K, Schmitz-Hübsch T, Hering S, Lindig TM, Haug V, Timmann D, Degen I, Kruse B, Dörr JM, Ratzka S, Ivo A, Schöls L, Boesch S, Klockgether T, Klopstock T, Schulz JB (2009) Comparison of three clinical rating scales in Friedreich ataxia (FRDA). Mov Disord 24(12):1779–1784PubMedCrossRefGoogle Scholar
  42. 42.
    Bürk K, Schulz SR, Schulz JB (2013) Monitoring progression in Friedreich ataxia (FRDA): the use of clinical scales. J Neurochem 126(Suppl 1):118–124PubMedCrossRefGoogle Scholar
  43. 43.
    Arpa J, Sanz-Gallego I, Rodríguez-de-Rivera FJ, Domínguez-Melcón FJ, Prefasi D, Oliva-Navarro J, Moreno-Yangüela M (2014) Triple therapy with deferiprone, idebenone and riboflavin in Friedreich’s ataxia—open-label trial. Acta Neurol Scand 129(1):32–40PubMedCrossRefGoogle Scholar
  44. 44.
    Arpa J, Sanz-Gallego I, Rodríguez-de-Rivera FJ, Domínguez-Melcón FJ, Prefasi D, Oliva-Navarro J, Moreno-Yangüela M, Pascual-Pascual SI (2013) Triple therapy with darbepoetin alfa, idebenone, and riboflavin in Friedreich’s ataxia: an open-label trial. Cerebellum 12(5):713–720PubMedCrossRefGoogle Scholar
  45. 45.
    Seyer L, Greeley N, Foerster D, Strawser C, Gelbard S, Dong Y, Schadt K, Cotticelli MG, Brocht A, Farmer J, Wilson RB, Lynch DR (2015) Open-label pilot study of interferon gamma-1b in Friedreich ataxia. Acta Neurol Scand 132(1):7–15PubMedCrossRefGoogle Scholar
  46. 46.
    Velasco-Sánchez D, Aracil A, Montero R, Mas A, Jiménez L, O’Callaghan M, Tondo M, Capdevila A, Blanch J, Artuch R, Pineda M (2011) Combined therapy with idebenone and deferiprone in patients with Friedreich’s ataxia. Cerebellum 10(1):1–8PubMedCrossRefGoogle Scholar
  47. 47.
    Sanz-Gallego I, Torres-Aleman I, Arpa J (2014) IGF-1 in Friedreich’s Ataxia—proof-of-concept trial. Cerebellum Ataxias 1:10PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Strupp M, Teufel J, Habs M, Feuerecker R, Muth C, van de Warrenburg BP, Klopstock T, Feil K (2013) Effects of acetyl-DL-leucine in patients with cerebellar ataxia: a case series. J Neurol 260(10):2556–2561PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Takei A, Hamada S, Homma S, Hamada K, Tashiro K, Hamada T (2010) Difference in the effects of tandospirone on ataxia in various types of spinocerebellar degeneration: an open-label study. Cerebellum 9(4):567–570PubMedCrossRefGoogle Scholar
  50. 50.
    Tan S, Wang RH, Niu HX, Shi CH, Mao CY, Zhang R, Song B, Sun SL, Liu XJ, Hou HM, Liu YT, Gao Y, Fang H, Kong XD, Xu YM (2015) Nerve growth factor for the treatment of spinocerebellar ataxia type 3: an open-label study. Chin Med J (Engl) 128(3):291–294CrossRefGoogle Scholar
  51. 51.
    Arpa J, Sanz-Gallego I, Medina-Báez J, Portela LV, Jardim LB, Torres-Aleman I, Saute JA (2011) Subcutaneous insulin-like growth factor-1 treatment in spinocerebellar ataxias: an open label clinical trial. Mov Disord 26(2):358–359PubMedCrossRefGoogle Scholar
  52. 52.
    Coppola G, Burnett R, Perlman S, Versano R, Gao F, Plasterer H, Rai M, Saccá F, Filla A, Lynch DR, Rusche JR, Gottesfeld JM, Pandolfo M, Geschwind DH (2011) A gene expression phenotype in lymphocytes from Friedrich Ataxia patients. Ann Neurol 70:790–804PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Smithline HA, Donnino M, Greenblatt DJ (2012) Pharmacokinetics of high-dose oral thiamine hydrochloride in healthy subjects. BMC Clin Pharmacol 12:4PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Shi Q, Karuppagounder SS, Xu H, Pechman D, Chen H, Gibson GE (2007) Responses of the mitochondrial alpha-Ketoglutarate dehydrogenase complex to thiamine deficiency may contribute to regional selective vulnerability. Neurochem Int 50:921–931PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Uziel G, Bottacchi E, Moschen G, Giovanardi-Rossi P, Cardace G, Di Donato S (1982) Pyruvate-dehydrogenase complex in ataxic patients: enzyme deficiency in ataxic encephalopathy plus lactic acidosis and normal activity in Friedreich ataxia. Ital J Neurol Sci 3(4):317–321PubMedCrossRefGoogle Scholar
  56. 56.
    Stumpf DA, Parks JK (1979) Friedreich ataxia. II. Normal kinetics of lipoamide dehydrogenase. Neurology 29(6):820–826PubMedCrossRefGoogle Scholar
  57. 57.
    Mastrogiacomo F, LaMarche J, Dozić S, Lindsay G, Bettendorff L, Robitaille Y, Schut L, Kish SJ (1996) Immunoreactive levels of alpha-ketoglutarate dehydrogenase subunits in Friedreich’s ataxia and spinocerebellar ataxia type 1. Neurodegeneration 5(1):27–33PubMedCrossRefGoogle Scholar
  58. 58.
    Bettendorff L, Mastrogiacomo F, LaMarche J, Dozic S, Kish SJ (1996) Brain levels of thiamine and its phosphate esters in Friedreich’s ataxia and spinocerebellar ataxia type 1. Mov Disord 11(4):437–439PubMedCrossRefGoogle Scholar
  59. 59.
    Sutak R, Xu X, Whitnall M, Kashem MA, Vyoral D, Richardson DR (2008) Proteomic analysis of hearts from frataxin knockout mice: marked rearrangement of energy metabolism, a response to cellular stress and altered expression of proteins involved in cell structure, motility and metabolism. Proteomics 8(8):1731–1741PubMedCrossRefGoogle Scholar
  60. 60.
    Shi R, Proteau A, Villarroya M, Moukadiri I, Zhang L, Trempe JF, Matte A, Armengod ME, Cygler M (2010) Structural basis for Fe-S cluster assembly and tRNA thiolation mediated by IscS protein-protein interactions. PLoS Biol 8(4):e1000354. doi:10.1371/journal.pbio.1000354 PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Alfadhel M, Almuntashri M, Jadah RH, Bashiri FA, Al Rifai MT, Al Shalaan H, Al Balwi M, Al Rumayan A, Eyaid W, Al-Twaijri W (2013) Biotin-responsive basal ganglia disease should be renamed biotin-thiamine-responsive basal ganglia disease: a retrospective review of the clinical, radiological and molecular findings of 18 new cases. Orphanet J Rare Dis 8:83. doi:10.1186/1750-1172-8-83 PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Kono S, Miyajima H, Yoshida K, Togawa A, Shirakawa K, Suzuki H (2009) Mutations in a thiamine-transporter gene and Wernicke’s-like encephalopathy. N Engl J Med 360:1792–1794PubMedCrossRefGoogle Scholar
  63. 63.
    Lonsdale D (2006) A review of the biochemistry, metabolism and clinical benefits of thiamin(e) and its derivatives. Evid Based Complement Altern Med 3(1):49–59CrossRefGoogle Scholar
  64. 64.
    Sedel F, Challe G, Mayer JM, Boutron A, Fontaine B, Saudubray JM, Brivet M (2008) Thiamine responsive pyruvate dehydrogenase deficiency in an adult with peripheral neuropathy and optic neuropathy. J Neurol Neurosurg Psychiatry 79(7):846–847PubMedCrossRefGoogle Scholar
  65. 65.
    Brown G (2014) Defects of thiamine transport and metabolism. J Inherit Metab Dis 37(4):577–585. doi:10.1007/s10545-014-9712-9 PubMedCrossRefGoogle Scholar
  66. 66.
    Botez MI, Botez-Marquard T, Mayer P, Marchand L, Lalonde R, Reader TA (1998) The treatment of spinocerebellar ataxias: facts and hypotheses. Med Hypotheses 51:381–384PubMedCrossRefGoogle Scholar
  67. 67.
    Reddy PH, Reddy TP (2011) Mitochondria as a therapeutic target for aging and neurodegenerative diseases. Curr Alzheimer Res 8:393–409PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Meador K, Loring D, Nichols M, Zamrini E, Rivner M, Posas H, Thompson E, Moore E (1993) Preliminary findings of high-dose thiamine in dementia of Alzheimer’s type. J Geriatr Psychiatry Neurol 6:222–229PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Antonio Costantini
    • 1
  • Tiziana Laureti
    • 2
  • Maria Immacolata Pala
    • 1
  • Marco Colangeli
    • 3
  • Simona Cavalieri
    • 4
  • Elisa Pozzi
    • 4
  • Alfredo Brusco
    • 4
    • 5
  • Sandro Salvarani
    • 6
  • Carlo Serrati
    • 7
  • Roberto Fancellu
    • 6
    • 7
  1. 1.Department of Neurological Rehabilitation“Villa Immacolata” ClinicViterboItaly
  2. 2.Department of Economics and ManagementUniversity of TusciaViterboItaly
  3. 3.University Studies Abroad ConsortiumUniversity of TusciaViterboItaly
  4. 4.Department of Medical SciencesUniversity of TurinTurinItaly
  5. 5.Medical Genetics UnitCittà della Salute e della Scienza University HospitalTurinItaly
  6. 6.Unit of NeurologyASL3 Villa Scassi HospitalGenoaItaly
  7. 7.Unit of NeurologyIRCCS San Martino University Hospital ISTGenoaItaly

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