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Planning Future Clinical Trials for Machado-Joseph Disease

  • Jonas Alex Morales Saute
  • Laura Bannach Jardim
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1049)

Abstract

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is an autosomal dominant multiple neurological systems degenerative disorder caused by a CAG repeat expansion at ATXN3 gene. Only a few treatments were evaluated in randomized clinical trials (RCT) in SCA3/MJD patients, with a lack of evidence for both disease-modifying and symptomatic therapies. The present chapter discuss in detail major methodological issues for planning future RCT for SCA3/MJD. There are several potential therapies for SCA3/MJD with encouraging preclinical results. Route of treatment, dosage titration and potential therapy biomarkers might differ among candidate drugs; however, the core study design and protocol will be mostly the same. RCT against placebo group is the best study design to test a disease-modifying therapy; the same cannot be stated for some symptomatic treatments. Main outcomes for future RCT are clinical scales: the Scale for the Assessment and Rating of ataxia (SARA) is currently the instrument of choice to prove efficacy of disease-modifying or symptomatic treatments against ataxia, the most important disease feature. Ataxia quantitative scales or its composite scores can be used as primary outcomes to provide preliminary evidence of efficacy in phase 2 RCT, due to a greater sensitivity to change. Details regarding eligibility criteria, randomization, sample size estimation, duration and type of analysis for both disease modifying and symptomatic treatment trials, were also discussed. Finally, a section anticipates the methodological issues for testing novel drugs when an effective treatment is already available. We conclude emphasizing four points, the first being the need of RCT for a number of different aims in the care of SCA3/MJD. Due to large sample sizes needed to warrant power, RCT for disease-modifying therapies should be multicenter enterprises. There is an urge need for surrogate markers validated for several drug classes. Finally, engagement of at risk or presymptomatic individuals in future trials will enable major advances on treatment research for SCA3/MJD.

Keywords

SCA3 Machado-Joseph disease Clinical trials Treatment Study design 

References

  1. 1.
    Costa MC, Paulson HL (2012) Toward understanding Machado-Joseph disease. Prog Neurobiol 97:239–257CrossRefGoogle Scholar
  2. 2.
    Jardim LB, Pereira ML, Silveira I et al (2001) Neurologic findings in Machado-Joseph disease: relation with disease duration, subtypes, and (CAG)n. Arch Neurol 58:899–904CrossRefGoogle Scholar
  3. 3.
    Saute JA, Jardim LB (2015) Machado Joseph disease: clinical and genetic aspects, and current treatment. Expert Opin Orphan Drugs 3:517–535CrossRefGoogle Scholar
  4. 4.
    Kawaguchi Y, Okamoto T, Taniwaki M et al (1994) CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet 8:221–228CrossRefGoogle Scholar
  5. 5.
    Maciel P, Gaspar C, DeStefano AL et al (1995) Correlation between CAG repeat length and clinical features in Machado-Joseph disease. Am J Hum Genet 57:54–61PubMedPubMedCentralGoogle Scholar
  6. 6.
    Correia M, Coutinho P, Silva MC et al (1995) Evaluation of the effect of sulphametoxazole and trimethoprim in patients with Machado-Joseph disease. Rev Neurol 23:632–634PubMedGoogle Scholar
  7. 7.
    Sakai T, Matsuishi T, Yamada S et al (1995) Sulfamethoxazole-trimethoprim doubleblind, placebo-controlled, crossover trial in Machado-Joseph disease: sulfamethoxazole-trimethoprim increases cerebrospinal fluid level of biopterin. J Neural Transm Gen Sect 102:159–172CrossRefGoogle Scholar
  8. 8.
    Schulte T, Mattern R, Berger K et al (2001) Double-blind crossover trial of trimethoprim-sulfamethoxazole in spinocerebellar ataxia type 3/Machado-Joseph disease. Arch Neurol 58:1451–1457CrossRefGoogle Scholar
  9. 9.
    Schulz KF, Altman DG, Moher D (2010) For the CONSORT group. Ann Intern Med 152Google Scholar
  10. 10.
    Ristori G, Romano S, Visconti A, Cannoni S, Spadaro M, Frontali M, Pontieri FE, Vanacore N, Salvetti M (2010) Riluzole in cerebellar ataxia: a randomized, double-blind, placebo-controlled pilot trial. Neurology 74:839–845CrossRefGoogle Scholar
  11. 11.
    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 14:985–991CrossRefGoogle Scholar
  12. 12.
    Saute JA, de Castilhos RM, Monte TL et al (2014) A randomized, phase 2 clinical trial of lithium carbonate in Machado-Joseph disease. Mov Disord 29:568–573CrossRefGoogle Scholar
  13. 13.
    Zesiewicz TA, Greenstein PE, Sullivan KL, Wecker L, Miller A, Jahan I, Chen R, Perlman SL (2012) A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3. Neurology 78:545–550CrossRefGoogle Scholar
  14. 14.
    Saccà F, Puorro G, Brunetti A, Capasso G, Cervo A, Cocozza S, de Leva M, Marsili A, Pane C, Quarantelli M, Russo CV, Trepiccione F, De Michele G, Filla A, Brescia Morra V (2015) A randomized controlled pilot trial of lithium in spinocerebellar ataxia type 2. J Neurol 262(1):149–153CrossRefGoogle Scholar
  15. 15.
    Olanow CW, Rascol O, Hauser R, Feigin PD, Jankovic J, Lang A, Langston W, Melamed E, Poewe W, Stocchi F, Tolosa E (2009) ADAGIO study investigators. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med 361(13):1268–1278CrossRefGoogle Scholar
  16. 16.
    Katz R (2004) Biomarkers and surrogate markers: an FDA perspective. NeuroRx 1(2):189–195CrossRefGoogle Scholar
  17. 17.
    Trouillas P, Takayanagi T, Hallett M et al (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 145:205–211CrossRefGoogle Scholar
  18. 18.
    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):1717–1720CrossRefGoogle Scholar
  19. 19.
    Kieling C, Rieder CRM, Silva ACF et al (2008) A neurological examination score for the assessment of spinocerebellar ataxia 3 (SCA3). Eur J Neurol 15:371–376CrossRefGoogle Scholar
  20. 20.
    Schmitz-Hübsch T, Coudert M, Bauer P, Giunti P, Globas C, Baliko L, Filla A, Mariotti C, Rakowicz M, Charles P, Ribai P, Szymanski S, Infante J, van de Warrenburg BP, Dürr A, Timmann D, Boesch S, Fancellu R, Rola R, Depondt C, Schöls L, Zdienicka E, Kang JS, Döhlinger S, Kremer B, Stephenson DA, Melegh B, Pandolfo M, di Donato S, du Montcel ST, Klockgether T (2008) Spinocerebellar ataxia types 1, 2, 3, and 6: disease severity and nonataxia symptoms. Neurology 71:982–989CrossRefGoogle Scholar
  21. 21.
    du Montcel ST, Charles P, Ribai P et al (2008) Composite cerebellar functional severity score: validation of a quantitative score of cerebellar impairment. Brain 131:1352–1361CrossRefGoogle Scholar
  22. 22.
    Schmitz-Hübsch T, Giunti P, Stephenson DA et al (2008) SCA Functional Index: a useful compound performance measure for spinocerebellar ataxia. Neurology 71:486–492CrossRefGoogle Scholar
  23. 23.
    Saute JA, Donis KC, Serrano-Munuera C et al (2012) Ataxia rating scales–psychometric profiles, natural history and their application in clinical trials. Cerebellum 11:488–504CrossRefGoogle Scholar
  24. 24.
    França MC, D’Abreu A, Nucci A et al (2009) Progression of ataxia in patients with Machado-Joseph disease. Mov Disord 24:1387–1390CrossRefGoogle Scholar
  25. 25.
    Torman VL, de Vries J, Verbeek D, Brunt E, Kampinga H, Jardim LB (2016) Interrelation between size of CAG-expansion and progression of ICARS scores in a Dutch Cohort of SCA3/MJD patients. International Meeting on Spastic Paraparesis and Ataxias 2016, Abstract 55, page 55, bookletGoogle Scholar
  26. 26.
    Ashizawa T, Figueroa KP, Perlman SL, Gomez CM, Wilmot GR, Schmahmann JD, Ying SH, Zesiewicz TA, Paulson HL, Shakkottai VG, Bushara KO, Kuo SH, Geschwind MD, Xia G, Mazzoni P, Krischer JP, Cuthbertson D, Holbert A, Ferguson JH, Pulst SM, Subramony SH (2013) Clinical characteristics of patients with spinocerebellar ataxias 1, 2, 3 and 6 in the US; a prospective observational study. Orphanet J Rare Dis 8(1):177CrossRefGoogle Scholar
  27. 27.
    Jacobi H, Bauer P, Giunti P et al (2011) The natural history of spinocerebellar ataxia type 1, 2, 3, and 6: a 2-year follow-up study. Neurology 77:1035–1041CrossRefGoogle Scholar
  28. 28.
    Tezenas du Montcel S, Charles P, Goizet C, Marelli C, Ribai P, Vincitorio C, Anheim M, Guyant-Maréchal L, Le Bayon A, Vandenberghe N, Tchikviladzé M, Devos D, Le Ber I, N’Guyen K, Cazeneuve C, Tallaksen C, Brice A, Durr A (2012) Factors influencing disease progression in autosomal dominant cerebellar ataxia and spastic paraplegia. Arch Neurol 69(4):500–508Google Scholar
  29. 29.
    Jacobi H, du Montcel ST, Bauer P, Giunti P, Cook A, Labrum R, Parkinson MH, Durr A, Brice A, Charles P, Marelli C, Mariotti C, Nanetti L, Panzeri M, Rakowicz M, Sulek A, Sobanska A, Schmitz-Hübsch T, Schöls L, Hengel H, Baliko L, Melegh B, Filla A, Antenora A, Infante J, Berciano J, van de Warrenburg BP, Timmann D, Szymanski S, Boesch S, Kang JS, Pandolfo M, Schulz JB, Molho S, Diallo A, Klockgether T (2015) Long-term disease progression in spinocerebellar ataxia types 1, 2, 3, and 6: a longitudinal cohort study. Lancet Neurol 14(11):1101–1108 CrossRefGoogle Scholar
  30. 30.
    Lee YC, Liao YC, Wang PS, Lee IH, Lin KP, Soong BW (2011) Comparison of cerebellar ataxias: A three-year prospective longitudinal assessment. Mov Disord 26(11):2081–2087CrossRefGoogle Scholar
  31. 31.
    Aggarwal SP, Zinman L, Simpson E, McKinley J, Jackson KE, Pinto H, Kaufman P, Conwit RA, Schoenfeld D, Shefner J, Cudkowicz M (2010) Northeast and Canadian amyotrophic lateral sclerosis consortia. Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 9:481–488CrossRefGoogle Scholar
  32. 32.
    Saute JA, Rieder CR, Castilhos RM, Monte TL, Schumacher-Schuh AF, Donis KC, D’Ávila R, Souza GN, Russo AD, Furtado GV, Gheno TC, Souza DO, Saraiva-Pereira ML, Portela LV, Camey S, Torman VB, Jardim LB (2015) Planning future clinical trials in Machado Joseph disease: lessons from a phase 2 trial. J Neurol Sci 358(1–2):72–76CrossRefGoogle Scholar
  33. 33.
    Jardim LB, Hauser L, Kieling C et al (2010) Progression rate of neurological deficits in a 10-year cohort of SCA3 patients. Cerebellum 9:419–428CrossRefGoogle Scholar
  34. 34.
    Schmitz- Hübsch T, Fimmers R, Rakowicz M et al (2010) Responsiveness of different rating instruments in spinocerebellar ataxia patients. Neurology 74:678–684CrossRefGoogle Scholar
  35. 35.
    Chan E, Charles P, Ribai P et al (2011) Quantitative assessment of the evolution of cerebellar signs in spinocerebellar ataxias. Mov Disord 26:534–538CrossRefGoogle Scholar
  36. 36.
    Giordano I, Bogdanow M, Jacobi H et al (2013) Experience in a short-term trial with 4-aminopyridine in cerebellar ataxia. J Neurol 260:2175–2176CrossRefGoogle Scholar
  37. 37.
    Streiner DL, Norman GR (2008) Health measurement scales: a practical guide to their development and use. Oxford University Press, OxfordCrossRefGoogle Scholar
  38. 38.
    Molnar FJ, Man-Son-Hing M, Fergusson D (2009) Systematic review of measures of clinical significance employed in randomized controlled trials of drugs for dementia. J Am Geriatr Soc 57(3):536–546CrossRefGoogle Scholar
  39. 39.
    Fahey MC, Corben L, Collins V, Churchyard AJ, Delatycki MB (2007) How is disease progress in Friedreich’s ataxia best measured? A study of four rating scales. J Neurol Neurosurg Psychiatry 78:411CrossRefGoogle Scholar
  40. 40.
    Guy W (1976) National Institute of Mental Health. ECDEU Assessment manual for psychopharmacology, revised edition. National Institute of Mental Health, Rockville, MDGoogle Scholar
  41. 41.
    Matilla-Dueñas A, Ashizawa T, Brice A et al (2014) Consensus paper: pathological mechanisms underlying neurodegeneration in spinocerebellar ataxias. Cerebellum 13:269–302CrossRefGoogle Scholar
  42. 42.
    Coelho T, Maia LF, Martins da Silva A, Waddington Cruz M, Planté-Bordeneuve V, Lozeron P, Suhr OB, Campistol JM, Conceição IM, Schmidt HH, Trigo P, Kelly JW, Labaudinière R, Chan J, Packman J, Wilson A, Grogan DR (2012) Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology 79(8):785–792CrossRefGoogle Scholar
  43. 43.
    Rosas HD, Doros G, Gevorkian S, Malarick K, Reuter M, Coutu JP, Triggs TD, Wilkens PJ, Matson W, Salat DH, Hersch SM (2014) PRECREST: a phase II prevention and biomarker trial of creatine in at-risk Huntington disease. Neurology 82:850–857CrossRefGoogle Scholar
  44. 44.
    Jacobi H, Reetz K, du Montcel ST, Bauer P, Mariotti C, Nanetti L, Rakowicz M, Sulek A, Durr A, Charles P, Filla A, Antenora A, Schöls L, Schicks J, Infante J, Kang JS, Timmann D, Di Fabio R, Masciullo M, Baliko L, Melegh B, Boesch S, Bürk K, Peltz A, Schulz JB, Dufaure-Garé I, Klockgether T (2013) 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 12:650–658CrossRefGoogle Scholar
  45. 45.
    Suresh K (2011) An overview of randomization techniques: an unbiased assessment of outcome in clinical research. J Hum Reprod Sci 4(1):8–11CrossRefGoogle Scholar
  46. 46.
    Coutinho P, Silva MC, Gonçalves AF et al (1994) Epidemiologia da doença de Machado-Joseph em Portugal. Rev Port Neurol 3:69–76Google Scholar
  47. 47.
    Souza GN, Kersting N, Krum‐Santos AC, Santos ASP, Furtado GV, Pacheco D, Gonçalves TA, Saute JA, Schuler-Faccini L, Mattos EP, Saraiva-Pereira ML, Jardim LB (2016) Spinocerebellar ataxia type 3/Machado-Joseph disease: segregation patterns and factors influencing instability of expanded CAG transmissions. Clin Genet 90(2):134–140CrossRefGoogle Scholar
  48. 48.
    Lei LF, Yang GP, Wang JL, Chuang DM, Song WH, Tang BS, Jiang H (2016) Safety and efficacy of valproic acid treatment in SCA3/MJD patients. Parkinsonism Relat Disord 26:55–61CrossRefGoogle Scholar
  49. 49.
    Temple R (1999) Are surrogate markers adequate to assess cardiovascular disease drugs? JAMA 282:790–795CrossRefGoogle Scholar
  50. 50.
    Fleming TR, DeMets DL (1996) Surrogate endpoints in clinical trials: are we being misled? Ann Intern Med 125:605–613CrossRefGoogle Scholar
  51. 51.
    Fleming TR, Powers JH (2012) Biomarkers and surrogate endpoints in clinical trials. Stat Med 31(25):2973–2984CrossRefGoogle Scholar
  52. 52.
    Tort ABL, Portela LV, Rockenbach IC et al (2005) S100B and NSE serum concentrations in Machado Joseph disease. Clin Chim Acta 351:143–148CrossRefGoogle Scholar
  53. 53.
    Zhou J, Lei L, Shi Y et al (2011) Serum concentrations of NSE and S100B in spinocerebellar ataxia type 3/Machado-Joseph disease. Zhong Nan Da Xue Xue Bao Yi Xue Ban 36:504–510PubMedGoogle Scholar
  54. 54.
    Schulz JB, Borkert J, Wolf S et al (2010) Visualization, quantification and correlation of brain atrophy with clinical symptoms in spinocerebellar ataxia types 1, 3 and 6. Neuroimage 49:158–168CrossRefGoogle Scholar
  55. 55.
    Guimarães RP, D’Abreu A, Yasuda CL et al (2013) A multimodal evaluation of microstructural white matter damage in spinocerebellar ataxia type 3. Mov Disord 28:1125–1132CrossRefGoogle Scholar
  56. 56.
    Reetz K, Costa AS, Mirzazade S et al (2013) Genotype-specific patterns of atrophy progression are more sensitive than clinical decline in SCA1, SCA3 and SCA6. Brain 136:905–917CrossRefGoogle Scholar
  57. 57.
    de Rezende TJ, D’Abreu A, Guimarães RP, Lopes TM, Lopes-Cendes I, Cendes F, Castellano G, França MC Jr (2015) Cerebral cortex involvement in Machado-Joseph disease. Eur J Neurol 22(2):277–283, e23–e24Google Scholar
  58. 58.
    Saute JA, da Silva ACF, Muller AP et al (2011) Serum insulin-like system alterations in patients with spinocerebellar ataxia type 3. Mov Disord 26:731–735CrossRefGoogle Scholar
  59. 59.
    Saute JA, Souza GN, Haas CB et al (2016) Peripheral insulin sensitivity and body composition alterations in early stage Machado Joseph disease [abstract]. Mov Disord 31 (suppl 2)Google Scholar
  60. 60.
    de Assis AM, Saute JAM, Longoni A, Haas CB, Torrez VR, Brochier AW, Souza GN, Furtado GV, Gheno TC, Russo A, Monte TL, Castilhos RM, Schumacher-Schuh A, D’Avila R, Donis KC, de Mello Rieder CR, Souza DO, Camey S, Leotti VB, Jardim LB, Portela LV (2017) Peripheral Oxidative Stress Biomarkers in Spinocerebellar Ataxia Type 3/Machado-Joseph Disease. Front Neurol 8:485Google Scholar
  61. 61.
    da Silva Carvalho G, Saute JA, Haas CB, Torrez VR, Brochier AW, Souza GN, Furtado GV, Gheno T, Russo A, Monte TL, Schumacher-Schuh A, D’Avila R, Donis KC, Castilhos RM, Souza DO, Saraiva-Pereira ML, Torman VL, Camey S, Portela LV, Jardim LB (2016) Cytokines in Machado Joseph disease/spinocerebellar ataxia 3. Cerebellum 15:518–525Google Scholar
  62. 62.
    Shi Y, Huang F, Tang B et al (2014) MicroRNA profiling in the serums of SCA3/MJD patients. Int J Neurosci 124:97–101CrossRefGoogle Scholar
  63. 63.
    Raposo M, Bettencourt C, Maciel P et al (2015) Novel candidate blood-based transcriptional biomarkers of Machado-Joseph disease. Mov Disord 30:968–975CrossRefGoogle Scholar
  64. 64.
    Zijlstra MP, Rujano MA, Van Waarde MA et al (2010) Levels of DNAJB family members (HSP40) correlate with disease onset in patients with spinocerebellar ataxia type 3. Eur J Neurosci 32:760–770CrossRefGoogle Scholar
  65. 65.
    Miyai I, Ito M, Hattori N et al (2012) Cerebellar ataxia rehabilitation trial in degenerative cerebellar diseases. Neurorehabil Neural Repair 26:515–522CrossRefGoogle Scholar
  66. 66.
    Pedroso JL, França MC, Braga-Neto P et al (2013) Nonmotor and extracerebellar features in Machado-Joseph disease: a review. Mov Disord 28:1200–1208CrossRefGoogle Scholar
  67. 67.
    Jin J-L, Liu Z, Lu Z-J et al (2013) Safety and efficacy of umbilical cord mesenchymal stem cell therapy in hereditary spinocerebellar ataxia. Curr Neurovasc Res 10:11–20CrossRefGoogle Scholar
  68. 68.
    Ilg W, Synofzik M, Br€otz D et al (2009) Intensive coordinative training improves motor performance in degenerative cerebellar disease. Neurology 73:1823–1830CrossRefGoogle Scholar
  69. 69.
    Fonteyn EMR, Heeren A, Engels J-JC, Den Boer JJ, van de Warrenburg BPC, Weerdesteyn V (2014) Gait adaptability training improves obstacle avoidance and dynamic stability in patients with cerebellar degeneration. Gait Posture 40(1):247–251CrossRefGoogle Scholar
  70. 70.
    Freeman W, Wszolek Z (2005) Botulinum toxin type A for treatment of spasticity in spinocerebellar ataxia type 3 (Machado-Joseph disease). Mov Disord 20:644CrossRefGoogle Scholar
  71. 71.
    Tuite PJ, Lang AE (1996) Severe and prolonged dysphagia complicating botulinum toxin A injections for dystonia in Machado-Joseph disease. Neurology 46:846PubMedGoogle Scholar
  72. 72.
    Cardoso F, de Oliveira JT, Puccioni-Sohler M et al (2000) Eyelid dystonia in Machad Joseph disease. Mov Disord 15:1028–1030CrossRefGoogle Scholar
  73. 73.
    Nunes MB, Martinez AR, Rezende TJ, Friedman JH, Lopes-Cendes I, D’Abreu A, França MC Jr (2015) Dystonia in Machado-Joseph disease: clinical profile, therapy and anatomical basis. Parkinsonism Relat Disord 21:1441–1447CrossRefGoogle Scholar
  74. 74.
    Nandagopal R, Moorthy SGK (2004) Dramatic levodopa responsiveness of dystonia in a sporadic case of spinocerebellar ataxia type 3. Postgrad Med J 80:363–365CrossRefGoogle Scholar
  75. 75.
    Wilder-Smith E, Tan EK, Law HY et al (2003) Spinocerebellar ataxia type 3 presenting as an L-DOPA responsive dystonia phenotype in a Chinese family. J Neurol Sci 213:25–28CrossRefGoogle Scholar
  76. 76.
    Buhmann C, Bussopulos A, Oechsner M (2003) Dopaminergic response in parkinsonian phenotype of Machado-Joseph disease. Mov Disord 18:219–221CrossRefGoogle Scholar
  77. 77.
    Lu CS, Chang HC, Kuo PC et al (2004) The parkinsonian phenotype of spinocerebellar ataxia type 3 in a Taiwanese family. Parkinsonism Relat Disord 10:369–373CrossRefGoogle Scholar
  78. 78.
    Siebert M, Donis KC, Socal M et al (2012) Glucocerebrosidase gene variants in parkinsonian patients with Machado Joseph/spinocerebellar ataxia 3. Parkinsonism Related Disord 18:185–190CrossRefGoogle Scholar
  79. 79.
    Russo AD, Reckziegel ER, Krum-Santos AC et al (2015) clinical scales predict significant videofluoroscopic dysphagia in Machado Joseph disease patients. Mov Disord Clin Pract 2:260–266CrossRefGoogle Scholar
  80. 80.
    Monte TL, Rieder CRM, Tort AB et al (2003) Use of fluoxetine for treatment of Machado-Joseph disease: an open-label study. Acta Neurol Scand 107:207–210CrossRefGoogle Scholar
  81. 81.
    Silva RCR, Saute JA, Silva ACF et al (2010) Occupational therapy in spinocerebellar ataxia type 3: an open-label trial. Brazilian J Med Biol Res 43:537–542CrossRefGoogle Scholar
  82. 82.
    França MC, D’Abreu A, Nucci A, Lopes-Cendes I (2008) Muscle excitability abnormalities in Machado-Joseph disease. Arch Neurol 65:525–529CrossRefGoogle Scholar
  83. 83.
    Kanai K, Kuwabara S, Arai K et al (2003) Muscle cramp in Machado-Joseph disease: altered motor axonal excitability properties and mexiletine treatment. Brain 126:965–973CrossRefGoogle Scholar
  84. 84.
    França MC, D’Abreu A, Friedman JH et al (2007) Chronic pain in Machado-Joseph disease: a frequent and disabling symptom. Arch Neurol 64:1767–1770CrossRefGoogle Scholar
  85. 85.
    Brusse E, Brusse-Keizer MGJ, Duivenvoorden HJ, van Swieten JC (2011) Fatigue in spinocerebellar ataxia: patient self-assessment of an early and disabling symptom. Neurology 76:953–959CrossRefGoogle Scholar
  86. 86.
    Saute JAM, Jardim LB (2016) Riluzole in patients with hereditary cerebellar ataxia. Lancet Neurol 15(8):788–789CrossRefGoogle Scholar
  87. 87.
    Haffner ME (2006) Adopting orphan drugs–two dozen years of treating rare diseases. N Engl J Med 354:445–447CrossRefGoogle Scholar
  88. 88.
    Schumi J, Wittes JT (2011) Through the looking glass: understanding non-inferiority. Trials 12 (1)Google Scholar
  89. 89.
    Piaggio G, Elbourne DR, Pocock SJ, Evans SJW, Altman DG, for the CONSORT Group (2012) Reporting of Noninferiority and Equivalence Randomized Trials. JAMA 308(24):2594–2604 CrossRefGoogle Scholar
  90. 90.
    Snapinn SM, Current Controlled Trials in Cardiovascular Medicine 1(1):19–21Google Scholar
  91. 91.
    Alves S, Nascimento-Ferreira I, Auregan G et al (2008) Allele-specific RNA silencing of mutant ataxin-3 mediates neuroprotection in a rat model of Machado-Joseph disease. PLoS One 3:e3341CrossRefGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  • Jonas Alex Morales Saute
    • 1
    • 2
    • 3
    • 4
  • Laura Bannach Jardim
    • 1
    • 2
    • 3
    • 4
    • 5
  1. 1.Serviço de Genética MédicaHospital de Clínicas de Porto Alegre (HCPA)Porto AlegreBrazil
  2. 2.Laboratório de Identificação GenéticaCentro de Pesquisa Experimental, HCPAPorto AlegreBrazil
  3. 3.Programa de Pós-Gradução em MedicinaCiências Médicas Universidade Federal do Rio Grande do SulPorto AlegreBrazil
  4. 4.Departamento de Medicina InternaUFRGSPorto AlegreBrazil
  5. 5.Instituto Nacional de Genética Médica Populacional (INAGEMP)Rio de JaneiroBrazil

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