Research, Appendix & References Research Read more Recent progress There have been a number of advances in the last few years in the identification of new genes causing specific ataxias, largely due to recent developments in gene sequencing technologies. Worldwide research using next generation sequencing and whole exome/genome sequencing has led to the identification of many new forms of ataxia and these developments are beginning to be translated into clinical services available to patients34. Research is also progressing in understanding the basic biological mechanisms underlying the ataxias and many therapeutic targets have now been identified. This has then lead to pre-clinical studies of potential disease-modifying drugs in animal and cell models, and encouragingly a number of clinical trials in people with ataxia are ongoing. A summary of recent published trials is found below (Table 14). This is included to illustrate that a number of types of drug trials have taken place. There are also many more trials in the pipeline, either to confirm the results of pilot studies listed or exploring new potential treatments (see www.clinicaltrials.gov). Although there are as yet no approved treatments for the majority of progressive ataxias, it is hopeful that due to this increased activity approved treatments will become available soon. Table 14: List of recent published trials in ataxia Medication Type of ataxia Type of drug/mode of action Idebenone279–286 Friedreich’s ataxia Antioxidant CoQ10/Vitamin E287, 288 Friedreich’s ataxia Antioxidant Carnitine/creatine289 Friedreich’s ataxia Antioxidant Deferiprone290 Friedreich’s ataxia Iron chelator Deferiprine and idebenone291 Friedreich’s ataxia Iron chelator & antioxidant Triple therapy Idebenone, deferiprone and riboflavin292 Friedreich’s ataxia Iron chelator & antioxidants EPO293–295 Friedreich’s ataxia Increases frataxin Carbamylated EPO296 Friedreich’s ataxia Increases frataxin A0001297 Friedreich’s ataxia Antioxidant Nicotinamide298 Friedreich’s ataxia Increases frataxin RG2833299 Friedreich’s ataxia Increases frataxin Interferon gamma300,301 Friedreich’s ataxia Increases frataxin Resveratrol302 Friedreich’s ataxia Antioxidant Riluzole303,304 Mixed ataxias Drug repurposing/unknown mechanism Lithium305,306 SCA2, SCA3 Drug repurposing/ reduces protein aggregates Varenicline307–313 SCA3, SCA14, Friedreich’s ataxia, Fragile X tremor/ataxia Drug repurposing/unknown mechanism Memantine314, 315 Fragile X tremor/ataxia Drug repurposing/unknown mechanism Research has also focused on the development of tools to measure the severity and progression of ataxia for use in trials such as validated ataxia-specific rating scales (detailed in Table 15, below). Table 15: Ataxia rating scales International cooperative ataxia rating scale (ICARS)316 All ataxias Scale for the Assessment and Rating of Ataxia (SARA)148,317 Spinocerebellar ataxias/Friedreich’s ataxia Friedreich’s ataxia rating scale (FARS)318 Friedreich’s ataxia Friedreich’s ataxia impact scale (FAIS)319 Friedreich’s ataxia Inventory of non-ataxia signs (INAS)320 Progressive ataxia disorders Databases and natural history data is being collected by networks of researchers worldwide and this has been of immense use in the design and implementation of clinical trials317,321. Due to all these encouraging developments, and the incentives provided in legislation on research in rare disease generally, pharmaceutical and biotech companies are now engaging more in ataxia research and indeed many research trials are being run by pharmaceutical companies, often in collaboration with university researchers and patient groups, such as Ataxia UK. Participating in research studies It is good clinical practice to offer patients the opportunity to take part in research projects. For information on research studies recruiting participants in the UK contact Ataxia UK, the ataxia charity who supports people with ataxia and works towards developing treatments for the ataxias. Ataxia UK For more information on ataxia research contact Ataxia UK, which provides up-to-date information for patients and healthcare professionals on developments in the ataxia field, including opportunities for patients to take part in research. Healthcare professionals are encouraged to join Ataxia UK’s Medical Registry and/or Researcher’s Registry and receive regular electronic newsletters with information on any trials recruiting participants. Information on ataxia conferences and ataxia training days is also provided. Ataxia UK also provides funding for research projects and facilitates research (eg: by organising ataxia conferences/meetings, helping to recruit participants in research projects and advising on the research landscape) and is willing to work in partnership with interested parties from academia, industry, patient groups and other stakeholders (contact email@example.com). Appendix Read more A list of neurologists at Ataxia UK Accredited Specialist Ataxia Centres and other Centres of expertise*. The following are adult neurologists (and clinical geneticists where indicated). Specialist Ataxia Centres Prof Marios Hadjivassilliou Ataxia UK Accredited Ataxia Centre, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Trust Glossop Road, Sheffield S10 2JF Dr Paola Giunti Ataxia UK Accredited Ataxia Centre, National Hospital for Neurology and Neurosurgery Queen Square, London WC1N 3BG Prof Rita Horvath Ataxia UK Accredited Ataxia Centre,Newcastle upon Tyne Hospitals NHS trust, Royal Victoria Infirmary Queen Victoria Road, Newcastle upon Tyne NE1 4LP Other Centres Dr George Tofaris & Prof Andrea Nemeth (Clinical Geneticist) Ataxia Clinic John Radcliffe Hospital, Oxford OX3 9DU Dr Richard Davenport Western General Hospital Crewe Road South, Edinburgh EH4 2XU Dr Rajith de Silva Queen’s Hospital Rom Valley Way, Romford, Essex RM7 0AG Dr John Ealing Salford Royal NHS Foundation Trust Stott lane, Salford, Greater Manchester M6 8HD Dr Nick Fletcher The Walton Centre for Neurology and Neurosurgery, NHS Trust, Lower Lane, Liverpool L9 7LJ Dr Simon Hammans St Richard’s Hospital Spitalfield Lane, Chichester, West Sussex PO19 6SE Dr Paul Hart St Helier Hospital Wrythe Lane, Carshalton, Surrey SM5 1AA Dr John McKinley & Dr Seamus Kearney Royal Victoria Hospital Grosvenor Road, Belfast BT12 6BA Dr Neil Robertson & Dr Mark Wardle University Hospital Wales Heath Park, Cardiff CF14 4XN Dr Alastair Wilkins Southmead Hospital Bristol BS10 5NB Professor Nicholas Wood Institute of Neurology Queen Square, London WC1N 3BG Dr Paul Worth Cambridge University Hospitals NHS Foundation Trust Hills Road, Cambridge CB2 0QQ Paediatric neurologists & paediatric clinical geneticists Prof Peter Baxter: Sheffield Children’s Hospital, Western Bank, Sheffield, S10 2TH Prof Andrea Nemeth (Clinical geneticist, see details above) Dr V Ramesh: Great Northern Children’s Hospital, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP *Please note that this is a list of specialists known to Ataxia UK and to the Guideline Development Group and is not an exhaustive list. We would welcome contact from other neurologists with expertise in ataxia (email: firstname.lastname@example.org) References Read more 1. Daker-White, G. et al. Trouble with ataxia: A longitudinal qualitative study of the diagnosis and medical management of a group of rare, progressive neurological conditions. SAGE Open Med. 1, Sep 28 (2013). 2. Daker-White, G., Greenfield, J. & Ealing, J. ‘Six sessions is a drop in the ocean’: an exploratory study of neurological physiotherapy in idiopathic and inherited ataxias. Physiotherapy 99, 335–340 (2013). 3. Wardle, M. & Robertson, N. Progressive late-onset cerebellar ataxia. Adv. Clin. Neurosci. Rehabil. 7, 6–12 (2007). 4. Musselman, K. E. et al. Prevalence of ataxia in children. A systematic review. Neurology 82, 80–89 (2014). 5. Morrison, P. J., Johnston, W. P. & Nevin, N. C. The epidemiology of Huntington’s disease in Northern Ireland. J. Med. Genet. 32, 524–530 (1995). 6. MacDonald, et al. The incidence and lifetime prevalence of neurological disorders in a prospective community-based study in the UK. Brain J. Neurol. 123 ( Pt 4), 665–676 (2000). 7. Cossée, M. et al. Evolution of the Friedreich’s ataxia trinucleotide repeat expansion: founder effect and premutations. Proc. Natl. Acad. Sci. U. S. A. 94, 7452–7457 (1997). 8. Vankan, P. Prevalence gradients of Friedreich’s Ataxia and R1b haplotype in Europe co-localize, suggesting a common Palaeolithic origin in the Franco-Cantabrian ice age refuge. J. Neurochem. 126, 11–20 (2013). 9. Muzaimi, M. B. et al. Population based study of late onset cerebellar ataxia in south east Wales. J. Neurol. Neurosurg. Psychiatry 75, 1129–1134 (2004). 10. Qaseem, A. et al. Guidelines International Network: toward international standards for clinical practice guidelines. Ann. Intern. Med. 156, 525–531 (2012). 11. Tom, M. Clinical guidelines using clinical guidelines to improve patient care within the NHS. (1996). 12. National Health and Medical Research Council, A. G. NHMRC additional levels of evidence and grades for recommendations for developers of guidelines. (2009). 13. Schulz, J. B. et al. Diagnosis and treatment of Friedreich ataxia: a European perspective. Nat. Rev. Neurol. 5, 222–234 (2009). 14. Md, K. P et al. Paraneoplastic cerebellar degeneration. I.A clinical analysis of 55 anti‐Yo antibody‐positive patients. Neurology 42, 1931– 1931 (1992). 15. Cooper, S. A.et al. Sporadic Creutzfeldt–Jakob disease with cerebellar ataxia at onset in the UK. J. Neurol. Neurosurg. Psychiatry 77, 1273–1275 (2006). 16. Brownell, B. & Oppenheimer, D. R. An ataxic form of subacute presenile polioencephalopathy (Creutzfeldt-Jakob disease). J. Neurol. Neurosurg. Psychiatry 28, 350–361 (1965). 17. Gilman, S. et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71, 670–676 (2008). 18. Finsterer, J. Mitochondrial Ataxias. Can. J. Neurol. Sci. J. Can. Sci. Neurol. 36, 543–553 (2009). 19. Durr, A. Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond. Lancet Neurol. 9, 885–894 (2010). 20. Hagerman, P. Fragile X-associated tremor/ataxia syndrome (FXTAS): Pathology and mechanisms. Acta Neuropathol. (Berl.) 126, 1–19 (2013). 21. Jayadev, S. & Bird, T. D. Hereditary ataxias: overview. Genet. Med. 15, 673–683 (2013). 22. Greenfield, J., Treacy, C. & Giunti, P. Centres of Excellence for the care of people with progressive ataxias. Br. J. Nurs. Mark Allen Publ. 15, 932–936 (2006). 23. Duncan, A. J. et al. Determination of coenzyme Q10 status in blood mononuclear cells, skeletal muscle, and plasma by HPLC with di-propoxycoenzyme Q10 as an internal standard. Clin. Chem. 51, 2380–2382 (2005). 24. Vedolin, L. et al. Inherited cerebellar ataxia in childhood: a pattern-recognition approach using brain MRI. AJNR Am. J. Neuroradiol. 34, 925– 934, S1-2 (2013). 25. Department of Health. The National Service Framework for Long-term Conditions. (2005). 26. Morrison, P. J. Paediatric and adult autosomal dominant ataxias (update 6). Eur. J. Paediatr. Neurol. JPN Off. J. Eur. Paediatr. Neurol. Soc. 14, 261–263 (2010). 27. Mancuso, M. et al. The genetics of ataxia: through the labyrinth of the Minotaur, looking for Ariadne’s thread. J. Neurol. 261, 528–541 (2014). 28. Johns Hopkins University, M.-N. I. of G. M. & National Centre for Biotechnology Information, N. L. of M. Online Mendelian Inheritance in Man, OMIM (TM) Available at: www.omim.org/. 29. Pfeffer, G. et al. SPG7 mutations are a common cause of undiagnosed ataxia. Neurology 84, 1174–1176 (2015). 30. Delatycki, M. B., Williamson, R. & Forrest, S. M. Friedreich ataxia: an overview. J. Med. Genet. 37, 1–8 (2000). 31. Ruano, L.et al. The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology 42, 174–183 (2014). 32. Shibata-Hamaguchi, A. et al. Prevalence of Spinocerebellar Degenerations in the Hokuriku District in Japan. Neuroepidemiology 32, 176–183 (2009). 33. Wardle, M. et al. Dentatorubral pallidoluysian atrophy in South Wales. J. Neurol. Neurosurg. Psychiatry 79, 804–807 (2008). 34. Nemeth, A. H. et al. Next generation sequencing for molecular diagnosis of neurological disorders using ataxias as a model. Brain 136, 3106–3118 (2013). 35. Dr Talbot (University of Oxford) personal communication (unpublished results). 36. Stevenson, V. L. Rehabilitation in practice: Spasticity management. Clin. Rehabil. 24, 293–304 (2010). 37. Lieber, R. L et al. Structural and functional changes in spastic skeletal muscle. Muscle Nerve 29, 615–627 (2004). 38. Lance, J. W. The control of muscle tone, reflexes, and movement: Robert Wartenberg Lecture. Neurology 30, 1303–1313 (1980). 39. Pandyan, A. D. et al. Spasticity: clinical perceptions, neurological realities and meaningful measurement. Disabil. Rehabil. 27, 2–6 (2005). 40. Bot, S. T. et al. Reviewing the genetic causes of spastic-ataxias. Neurology 79, 1507–1514 (2012). 41. Shakespeare, D. T., Boggild, M. & Young, C. Antispasticity agents for multiple sclerosis. Cochrane Database Syst. Rev. CD001332 (2003). doi:10.1002/14651858.CD001332 42. Amatya, B et al. Non pharmacological interventions for spasticity in multiple sclerosis. Cochrane Database Syst. Rev. 2, CD009974 (2013). 43. Ade-Hall, R. A. & Moore, A. P. Botulinum toxin type A in the treatment of lower limb spasticity in cerebral palsy. Cochrane Database Syst. Rev. CD001408 (2000). 44. Hoare, B. J. et al. Botulinum toxin A as an adjunct to treatment in the management of the upper limb in children with spastic cerebral palsy (UPDATE). Cochrane Database Syst. Rev. CD003469 (2010). 45. Taricco, M et al. Pharmacological interventions for spasticity following spinal cord injury. Cochrane Database Syst. Rev. CD001131 (2000). 46. Ashworth, N. L., Satkunam, L. E. & Deforge, D. Treatment for spasticity in amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst. Rev. CD004156 (2006). 47. Abbruzzese, G. The medical management of spasticity. Eur. J. Neurol. Off. J. Eur. Fed. Neurol. Soc. 9 Suppl 1, 30-34-61 (2002). 48. Karst, P. D. M., Wippermann, S. & Ahrens, J. Role of Cannabinoids in the Treatment of Pain and (Painful) Spasticity. Drugs 70, 2409–2438 (2012). 49. Zajicek, J. et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. The Lancet 362, 1517– 1526 (2003). 50. Collin, C. et al. & Sativex Spasticity in MS Study Group. Randomized controlled trial of cannabisbased medicine in spasticity caused by multiple sclerosis. Eur. J. Neurol. Off. J. Eur. Fed. Neurol. Soc. 14, 290–296 (2007). 51. Thompson, A. J et al. Clinical management of spasticity. J. Neurol. Neurosurg. Psychiatry 76, 459–463 (2005). 52. Olver, J. et al. Botulinum toxin assessment, intervention and aftercare for lower limb disorders of movement and muscle tone in adults: international consensus statement. Eur. J. Neurol. Off. J. Eur. Fed. Neurol. Soc. 17 Suppl 2, 57–73 (2010). 53. Lazorthes, Y.et al. The surgical management of spasticity. Eur. J. Neurol. Off. J. Eur. Fed. Neurol. Soc. 9 Suppl 1, 35-41-61 (2002). 54. Seeberger, L. C. Cerebellar Tremor - Definiton and Treatment. CNI Online Rev. (2005). 55. Pirker, W. et al. Chronic thalamic stimulation in a patient with spinocerebellar ataxia type 2. Mov. Disord. Off. J. Mov. Disord. Soc. 18, 222–225 (2003). 56. Blomstedt, P., Fytagoridis, A. & Tisch, S. Deep brain stimulation of the posterior subthalamic area in the treatment of tremor. Acta Neurochir. (Wien) 151, 31–36 (2009). 57. Mammis, A et al. Deep brain stimulation for the treatment of tremor and ataxia associated with abetalipoproteinemia. Tremor Hyperkinetic Mov. N. Y. N 2, (2012). 58. van de Warrenburg, B. P. C. et al. The syndrome of (predominantly cervical) dystonia and cerebellar ataxia: new cases indicate a distinct but heterogeneous entity. J. Neurol. Neurosurg. Psychiatry 78, 774–775 (2007). 59. Jankovic, J. Treatment of dystonia. Lancet Neurol. 5, 864–872 (2006). 60. Dystonia - Treatment. NHS Choices. [available at: http://www.nhs.uk/Conditions/Dystonia/Pages/Treatment.aspx] 61. Albanese, A. et al. EFNS guidelines on diagnosis and treatment of primary dystonias. Eur. J. Neurol. 18, 5–18 (2011). 62. Milbrandt, T. A., Kunes, J. R. & Karol, L. A. Friedreich’s ataxia and scoliosis: the experience at two institutions. J. Pediatr. Orthop. 28, 234– 238 (2008). 63. Pandolfo, M. Friedreich ataxia: the clinical picture. J. Neurol. 256 Suppl 1, 3–8 (2009). 64. Cady, R. B. & Bobechko, W. P. Incidence, natural history, and treatment of scoliosis in Friedreich’s ataxia. J. Pediatr. Orthop. 4, 673–676 (1984). 65. Labelle, H. et al. Natural history of scoliosis in Friedreich’s ataxia. J. Bone Joint Surg. Am. 68, 564–572 (1986). 66. Daher, Y. H. et al. Spinal deformities in patients with Friedreich ataxia: a review of 19 patients. J. Pediatr. Orthop. 5, 553–557 (1985). 67. Tsirikos, A. I. & Smith, G. Scoliosis in patients with Friedreich’s ataxia. J. Bone Joint Surg. Br. 94–B, 684–689 (2012). 68. NICE. Neuropathic pain - pharmacological management: The pharmacological management of neuropathic pain in adults in non-specialist settings. (2013). 69. Malo, S. et al. Electrocardiographic and vectocardiographic findings in Friedreich’s ataxia. Can. J. Neurol. Sci. J. Can. Sci. Neurol. 3, 323–328 (1976). 70. Albano, L. M. J. et al. Friedreich’s ataxia: cardiac evaluation of 25 patients with clinical diagnosis and literature review. Arq. Bras. Cardiol. 78, 444–451 (2002). 71. Payne, R. M. & Wagner, G. R. Cardiomyopathy in Friedreich Ataxia: Clinical Findings and Research. J. Child Neurol. 27, 1179–1186 (2012). 72. Schadt, K. A. et al. Cross-Sectional Analysis of Electrocardiograms in a Large Heterogeneous Cohort of Friedreich Ataxia Subjects. J. Child Neurol. 27, 1187–1192 (2012). 73. Frank Weidemann, S. S. Cardiomyopathy of Friedreich Ataxia. J. Neurochem. 126, (2013). 74. Weidemann, F. et al. The Heart in Friedreich Ataxia: Definition of Cardiomyopathy, Disease Severity, and Correlation with Neurological Symptoms. Circulation 125(13):1626-34. (2012). 75. Rajagopalan, B. et al. Analysis of the factors influencing the cardiac phenotype in Friedreich’s ataxia. Mov. Disord. Off. J. Mov. Disord. Soc. 25, 846–852 (2010). 76. Bourke, T. & Keane, D. Friedreich’s Ataxia: a review from a cardiology perspective. Ir. J. Med. Sci. 180, 799–805 (2011). 77. Child, J. S. et al. Cardiac involvement in Friedreich’s ataxia: a clinical study of 75 patients. J. Am. Coll. Cardiol. 7, 1370–1378 (1986). 78. Weidemann, F. et al. The cardiomyopathy in Friedreich’s ataxia - New biomarker for staging cardiac involvement. Int. J. Cardiol. 194, 50–57 (2015). 79. Friedman, L. S. et al. Elevation of serum cardiac troponin I in a cross-sectional cohort of asymptomatic subjects with Friedreich ataxia. Int. J. Cardiol. 167, 1622–1624 (2013). 80. Tsou, A. Y. et al. Mortality in Friedreich Ataxia. J. Neurol. Sci. 307, 46–49 (2011). 81. Kipps, A. et al. The Longitudinal Course of Cardiomyopathy in Friedreich’s Ataxia During Childhood. Pediatr. Cardiol. 30, 306–310 (2008). 82. Cikes, M. et al. The role of echocardiographic deformation imaging in hypertrophic myopathies. Nat. Rev. Cardiol. 7, 384–396 (2010). 83. Regner, S. R. et al. Analysis of Echocardiograms in a Large Heterogeneous Cohort of Patients With Friedreich Ataxia. Am. J. Cardiol. 109, 401–405 (2012). 84. Schöls, L. et al. Friedreich’s ataxia. Revision of the phenotype according to molecular genetics. Brain J. Neurol. 120 ( Pt 12), 2131–2140 (1997). 85. Members, W. C. et al. 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 124, e783–e831 (2011). 86. Yancy, C. W. et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure A Report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. Circulation 128, e240–e327 (2013). 87. Russo, A. M. et al. ACCF/HRS/AHA/ASE/HFSA/ SCAI/SCCT/SCMR 2013 appropriate use criteria for implantable cardioverter-defibrillators and cardiac resynchronization therapy. J. Am. Coll. Cardiol. 61, 1318–1368 (2013). 88. Wenning, G. K. et al. The natural history of multiple system atrophy: a prospective European cohort study. Lancet Neurol. 12, 264–274 (2013). 89. Dürr, A. et al. Clinical and Genetic Abnormalities in Patients with Friedreich’s Ataxia. N. Engl. J. Med. 335, 1169–1175 (1996). 90. Vezina JG et al. Urodynamic evaluation of patients with hereditary ataxias. Can. J. Neurol. Sci. J. Can. Sci. Neurol. 9, 127–129 (1982). 91. Nardulli, R. et al. Urodynamic evaluation of 12 ataxic subjects: neurophysiopathologic considerations. Funct. Neurol. 7, 223–225 (1992). 92. Schmitz-Hübsch, T. et al. Spinocerebellar ataxia types 1, 2, 3, and 6: disease severity and nonataxia symptoms. Neurology 71, 982–989 (2008). 93. Fowler, C. J. et al. A UK consensus on the management of the bladder in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 80, 470–477 (2009). 94. Hadjivassiliou, M. et al. Gluten ataxia. Cerebellum Lond. Engl. 7, 494–498 (2008). 95. Faecal incontinence in adults: management. NICE Guidelines CG49. (June 2007) 96. Kirchhof, K. et al. Erectile and urinary dysfunction may be the presenting features in patients with multiple system atrophy: a retrospective study. Int. J. Impot. Res. 15, 293–298 (2003). 97. Choices, NHS How to have a balanced diet - Live Well - NHS Choices. (2015). 98. Chou, K. L. et al. Sialorrhea in Parkinson’s disease: A review. Mov. Disord. 22, 2306–2313 (2007). 99. Bavikatte, G., Lin Sit, P. & Hassoon, A. Management of Drooling of saliva. 2012, British Journal of Medical Practitioners, 5(1) 100. Rance, G., Corben, L. & Delatycki, M. Auditory processing deficits in children with Friedreich ataxia. J. Child Neurol. 27, 1197–1203 (2012). 101. Starr, A. et al. Auditory neuropathy. Brain J. Neurol. 119 ( Pt 3), 741–753 (1996). 102. Rance, G. & Uus, K. Listening devices for individuals with Friedreichs ataxia and spinocerebellar ataxia (unpublished results). (2015). 103. Anderson, K. L. & Goldstein, H. Speech perception benefits of FM and infrared devices to children with hearing aids in a typical classroom. Lang. Speech Hear. Serv. Sch. 35, 169–184 (2004). 104. Rance, G. et al. Auditory perception in individuals with Friedreich’s ataxia. Audiol. Neurootol. 15, 229–240 (2010). 105. Berlin, C. I., Morlet, T. & Hood, L. J. Auditory neuropathy/dyssynchrony: its diagnosis and management. Pediatr. Clin. North Am. 50, 331–340, vii–viii (2003). 106. Rance, G. et al. Successful treatment of auditory perceptual disorder in individuals with Friedreich ataxia. Neuroscience 171, 552–555 (2010). 107. Shallop, J. K. et al. Cochlear implants in five cases of auditory neuropathy: postoperative findings and progress. The Laryngoscope 111, 555–562 (2001). 108. Bandini, F. et al. Gabapentin but not vigabatrin is effective in the treatment of acquired nystagmus in multiple sclerosis: How valid is the GABAergic hypothesis? J. Neurol. Neurosurg. Psychiatry 71, 107–110 (2001). 109. Averbuch-Heller, L. et al. A double-blind controlled study of gabapentin and baclofen as treatment for acquired nystagmus. Ann. Neurol. 41, 818–825 (1997). 110. Strupp, M. et al. Treatment of downbeat nystagmus with 3,4-diaminopyridine: a placebo-controlled study. Neurology 61, 165–170 (2003). 111. Rucker, J. C. Current Treatment of Nystagmus. Curr. Treat. Options Neurol. 7, 69–77 (2005). 112. Stahl, J. S., Plant, G. T. & Leigh, R. J. Medical treatment of nystagmus and its visual consequences. J. R. Soc. Med. 95, 235–237 (2002). 113. Porter N. et al. Catastrophic visual loss in a patient with Friedreich ataxia. Arch. Ophthalmol. 125, 273–274 (2007). 114. Fortuna, F. et al. Visual system involvement in patients with Friedreich’s ataxia. Brain J. Neurol. 132, 116–123 (2009). 115. Garrard, P. et al. Cognitive and social cognitive functioning in spinocerebellar ataxia. J. Neurol. 255, 398–405 (2008). 116. Sokolovsky, N. et al. A preliminary characterisation of cognition and social cognition in spinocerebellar ataxia types 2, 1, and 7. Behav. Neurol. 23, 17–29 (2010). 117. Klinke, I. et al. Neuropsychological Features of Patients with Spinocerebellar Ataxia (SCA) Types 1, 2, 3, and 6. The Cerebellum 9, 183 (2010). 118. Torrens, L. et al. Spinocerebellar ataxia type 8 in Scotland: frequency, neurological, neuropsychological and neuropsychiatric findings. Acta Neurol. Scand. 117, 41–48 (2008). 119. Suenaga, M. et al. Cognitive impairment in spinocerebellar ataxia type 6. J. Neurol. Neurosurg. Psychiatry 79, 496–499 (2008). 120. Wollmann, T. et al. Neuropsychological Test Performance of Patients With Friedreich’s Ataxia. J. Clin. Exp. Neuropsychol. 24, 677–686 (2002). 121. Le Pira, F. et al. Cognitive findings in spinocerebellar ataxia type 2: relationship to genetic and clinical variables. J. Neurol. Sci. 201, 53–57 (2002). 122. Kawai, Y. et al. Prefrontal hypoperfusion and cognitive dysfunction correlates in spinocerebellar ataxia type 6. J. Neurol. Sci. 271, 68–74 (2008). 123. Bürk, K. et al. Executive dysfunction in spinocerebellar ataxia type 1. Eur. Neurol. 46, 43–48 (2001). 124. Bürk, K. et al. Cognitive deficits in spinocerebellar ataxia type 1, 2, and 3. J. Neurol. 250, 207–211 (2003). 125. Lilja, A., Hämäläinen, P., Kaitaranta, E. & Rinne, R. Cognitive impairment in spinocerebellar ataxia type 8. J. Neurol. Sci. 237, 31–38 (2005). 126. Orsi, L. et al. Neuropsychological picture of 33 spinocerebellar ataxia cases. J. Clin. Exp. Neuropsychol. 33, 315–325 (2011). 127. Mantovan, M. C. et al. Exploring mental status in Friedreich’s ataxia: a combined neuropsychological, behavioral and neuroimaging study. Eur. J. Neurol. Off. J. Eur. Fed. Neurol. Soc. 13, 827–835 (2006). 128. Bürk, K. et al. Cognitive deficits in spinocerebellar ataxia 2. Brain J. Neurol. 122 ( Pt 4), 769–777 (1999). 129. McMurtray, A. M. et al. Depressive and memory symptoms as presenting features of spinocerebellar ataxia. J. Neuropsychiatry Clin. Neurosci. 18, 420–422 (2006). 130. White, M., Lalonde, R. & Botez-Marquard, T. Neuropsychologic and neuropsychiatric characteristics of patients with Friedreich’s ataxia. Acta Neurol. Scand. 102, 222–226 (2000). 131. Hart, R. P. et al. Information processing speed in Friedreich’s ataxia. Ann. Neurol. 17, 612–614 (1985). 132. Ciancarelli, I., Cofini, V. & Carolei, A. Evaluation of neuropsychological functions in patients with Friedreich ataxia before and after cognitive therapy. Funct. Neurol. 25, 81–85 (2010). 133. D’Agata, F. et al. The Recognition of Facial Emotions in Spinocerebellar Ataxia Patients. The Cerebellum 10, 600–610 (2011). 134. Silva, C. B. da et al. Neuroanatomical correlates of depression in Friedreich’s ataxia: a voxelbased morphometry study. Cerebellum Lond. Engl. 12, 429–436 (2013). 135. Schmitz-Hübsch, T. et al. Depression comorbidity in spinocerebellar ataxia. Mov. Disord. Off. J. Mov. Disord. Soc. 26, 870–876 (2011). 136. NICE Guidelines (CG91). Depression in adults with a chronic physical health problem. (2009) 137. D’Adamo, M. C. Episodic ataxia type 1. In GeneReviews 2010 Feb 9 [updated 2015 Jun 25]. 138. Spacey, S. Episodic ataxia type 2. In GeneReviews 2003 Feb 24 [updated 2015 Oct 15] 139. Platt D. & Griggs R. C. USe of acetazolamide in sulfonamide-allergic patients with neurologic channelopathies. Arch. Neurol. 69, 527–529 (2012). 140. Tawil, R. et al. Randomized trials of dichlorphenamide in the periodic paralyses. Working Group on Periodic Paralysis. Ann. Neurol. 47, 46–53 (2000). 141. Strupp, M. et al. A randomized trial of 4-aminopyridine in EA2 and related familial episodic ataxias. Neurology 77, 269–275 (2011). 142. Graves, T. D. et al. Episodic ataxia type 1: clinical characterization, quality of life and genotype– phenotype correlation. Brain 137, 1009–1018 (2014). 143. Hadjivassiliou, M. ,et al. A. Dietary treatment of gluten ataxia. J. Neurol. Neurosurg. Psychiatry 74, 1221–1224 (2003). 144. Sapone, A. et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med. 10, 13 (2012). 145. Hadjivassiliou, M. et al. Gluten ataxia in perspective: epidemiology, genetic susceptibility and clinical characteristics. Brain J. Neurol. 126, 685–691 (2003). 146. Hadjivassiliou, M. et al. Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase. Ann. Neurol. 64, 332–343 (2008). 147. Hadjivassiliou, M. et al. Transglutaminase 6 antibodies in the diagnosis of gluten ataxia. Neurology 80, 1740–1745 (2013). 148. Schmitz-Hübsch, T. et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 66, 1717–1720 (2006). 149. Nanri, K. et al. Intravenous immunoglobulin therapy for autoantibody-positive cerebellar ataxia. Intern. Med. Tokyo Jpn. 48, 783–790 (2009). 150. Schuelke, M. Ataxia with vitamin E deficiency. In GeneReviews 2013. 151. Baumgartner, M. R. Vitamin-responsive disorders: cobalamin, folate, biotin, vitamins B1 and E. Handb. Clin. Neurol. 113, 1799–1810 (2013). 152. Klockgether, T. Handbook of Ataxia Disorders. (CRC Press, 2000). 153. Lagier-Tourenne, C. et al. ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency. Am. J. Hum. Genet. 2008 Mar; 82(3):661-72. 154. Mollet, J. et al. CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures. - Am. J. Hum. Genet. 2008 Mar; 82(3):623-30. 155. Rahman, S. et al. 176th ENMC International Workshop: Diagnosis and treatment of Coenzyme Q10 deficiency. Neuromuscul Disord. 2012 Jan; 22(1): 76–86. 156. Emmanuele, V. et al. Heterogeneity of coenzyme Q10 deficiency: patient study and literature review. Arch. Neurol. 69, 978–983 (2012). 157. Horvath R. Update on clinical aspects and treatment of selected vitamin-responsive disorders II (riboflavin and CoQ 10). - J Inherit Metab Dis. 4:679-87 (2012). 158. Balreira, A. et al. ANO10 mutations cause ataxia and coenzyme Q10 deficiency. J. Neurol. 261, 2192–2198 (2014). 159. Quinzii, CM. et al. Coenzyme Q deficiency and cerebellar ataxia associated with an aprataxin mutation. Neurology. 8;64(3):539-41 (2005). 160. Federico, A., Dotti, M. T. & Gallus, G. N. Cerebrotendinous xanthomatosis. In GeneReviews. 2003. [last update April 2016] 161. Rafiq, M. et al. A neurological rarity not to be missed: cerebrotendinous xanthomatosis. Pract. Neurol. 11, 296–300 (2011). 162. Patterson, M. C. et al. Recommendations for the diagnosis and management of Niemann-Pick disease type C: an update. Mol. Genet. Metab. 106, 330–344 (2012). 163. Porter, F. D. et al. Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease. Sci. Transl. Med. 2, 56ra81 (2010). 164. Patterson, M. C. et al. Stable or improved neurological manifestations during miglustat therapy in patients from the international disease registry for Niemann-Pick disease type C: an observational cohort study. Orphanet J. Rare Dis. 10, 65 (2015). 165. Wraith, J. E. et al. Miglustat in adult and juvenile patients with Niemann–Pick disease type C: long-term data from a clinical trial. Mol. Genet. Metab. 99, 351–357 (2010). 166. Patterson, M. C. et al. Long-Term Miglustat Therapy in Children With Niemann-Pick Disease Type C. J. Child Neurol. 25, 300–305 (2010). 167. Pineda, M. et al. Miglustat in patients with Niemann-Pick disease Type C (NP-C): a multicenter observational retrospective cohort study. Mol. Genet. Metab. 98, 243–249 (2009). 168. Patterson, M. C. et al. Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol. 6, 765–772 (2007). 169. Leen, W. G. et al. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain J. Neurol. 133, 655–670 (2010). 170. Pons, R. et al. The spectrum of movement disorders in Glut-1 deficiency. Mov. Disord. Off. J. Mov. Disord. Soc. 25, 275–281 (2010). 171. Wang, D. et al. Glut-1 deficiency syndrome: clinical, genetic, and therapeutic aspects. Ann. Neurol. 57, 111–118 (2005). 172. Peretti, N. et al. Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers. Orphanet J. Rare Dis. 5, 24 (2010). 173. Benlian, P. Orphanet: Familial hypobetalipoproteinemia (last update May 2009). 174. Wendel, U. Hartnup disease. In: Orphanet (last update April 2014) 175. Kniffin, C. Biotinidase deficiency. OMIM Entry - # 253260, 2009 176. Suormala, T. M., Baumgartner, E. R., Wick, H., Scheibenreiter, S. & Schweitzer, S. Comparison of patients with complete and partial biotinidase deficiency: biochemical studies. J. Inherit. Metab. Dis. 13, 76–92 (1990). 177. Brown G. Pyruvate dehydrogenase deficiency. Orphanet (last update April 2012) 178. Baxter, P. in Cerebellar disorders in children Chapter 39, (MacKeith Press, 2012). 179. Poll-The, B.T., Wanders, R.J.A., Refsum disease. Orphanet (last update July 2015) 180. World Health Organisation. International Classification of Functioning, Disability & Health. (2001). 181. Schalling, E., Hammarberg, B. & Hartelius, L. A longitudinal study of dysarthria in spinocerebellar ataxia (SCA): aspects of articulation, prosody, and voice. J. Med. Speech-Lang. Pathol. 16, 103–17 (31 ref) (2008). 182. Duffy, J. R. Motor Speech Disorders: Substrates, Differential Diagnosis, and Management. (Elsevier Mosby, 2005). 183. Weismer, G. in Motor Speech Disorders (Plural Publishing, 2006). 184. Sapir, S. et al. Effects of intensive voice treatment (the Lee Silverman Voice Treatment [LSVT]) on ataxic dysarthria: a case study. Am. J. Speech- Lang. Pathol. Am. Speech-Lang.-Hear. Assoc. 12, 387–399 (2003). 185. Kent, R. D. et al. Ataxic dysarthria. J. Speech Lang. Hear. Res. JSLHR 43, 1275–1289 (2000). 186. Sidtis, J. J., Ahn, J. S., Gomez, C. & Sidtis, D. Speech characteristics associated with three genotypes of ataxia. J. Commun. Disord. 44, 478–492 (2011). 187. Joanette, Y. & Dudley, J. G. Dysarthric symptomatology of Friedreich’s ataxia. Brain Lang. 10, 39–50 (1980). 188. Blaney, B. & Hewlett, N. Dysarthria and Friedreich’s ataxia: what can intelligibility assessment tell us? Int. J. Lang. Commun. Disord. R. Coll. Speech Lang. Ther. 42, 19–37 (2007). 189. Miller, N. et al. Changing perceptions of self as a communicator in Parkinson’s disease: a longitudinal follow-up study. Disabil. Rehabil. 33, 204–210 (2011). 190. Vogel, A. P., Folker, J. & Poole, M. L. in Cochrane Database of Systematic Reviews (John Wiley & Sons, Ltd, 2014). 191. Yorkston, K. M. et al. The effect of rate control on the intelligibility and naturalness of dysarthric speech. J. Speech Hear. Disord. 55, 550–560 (1990). 192. McMicken, B. L., Ostergren, J. A. & Vento-Wilson, M. Therapeutic Intervention in a Case of Ataxic Dysarthria Associated With a History of Amateur Boxing. Commun. Disord. 33(1) 55-64 (2011). 193. Ramig, L. O. et al. Changes in vocal loudness following intensive voice treatment (LSVT) in individuals with Parkinson’s disease: a comparison with untreated patients and normal age-matched controls. Mov. Disord. Off. J. Mov. Disord. Soc. 16, 79–83 (2001). 194. Yorkston, K. M. et al. Management of Motor Speech Disorders in Children and Adults. (Pro- Ed, 1999). 195. Rapoport, M., van Reekum, R. & Mayberg, H. The role of the cerebellum in cognition and behavior: a selective review. J. Neuropsychiatry Clin. Neurosci. 12, 193–198 (2000). 196. Ponsford, J., Sloan, S. & Snow, P. Traumatic Brain Injury: Rehabilitation for Everyday Adaptive Living. (Psychology Press, 1995). 197. Murdoch, B. & Theodoros, D. Speech and Language Disorders in Multiple Sclerosis. (Whurr, 2001). 198. Logemann, J. Evaluation and Treatment of Swallowing Disorders. (College Hill Press, 1998). 199. Nilsson, H. et al. Swallowing in hereditary sensory ataxia. Dysphagia 11, 140–143 (1996). 200. Ekberg, O. et al. Social and psychological burden of dysphagia: its impact on diagnosis and treatment. Dysphagia 17, 139–146 (2002). 201. Health, D. of. The expert patient: a new approach to chronic disease management for the 21st century. Department of Health, National Archives (2001). 202. Cassidy, E. et al. Using interpretative phenomenological analysis to inform physiotherapy practice: An introduction with reference to the lived experience of cerebellar ataxia. Physiother. Theory Pract. 27, 263–277 (2011). 203. Armutlu, K., Karabudak, R. & Nurlu, G. Physiotherapy approaches in the treatment of ataxic multiple sclerosis: a pilot study. Neurorehabil. Neural Repair 15, 203–211 (2001). 204. Balliet, R. et al. Retraining of functional gait through the reduction of upper extremity weightbearing in chronic cerebellar ataxia. Int. Rehabil. Med. 8, 148–153 (1987). 205. Brown, K. E. et al. Physical therapy for central vestibular dysfunction. Arch. Phys. Med. Rehabil. 87, 76–81 (2006). 206. Brown, T. H. et al. Body weight-supported treadmill training versus conventional gait training for people with chronic traumatic brain injury. J. Head Trauma Rehabil. 20, 402–415 (2005). 207. Cakrt, O. et al. Balance rehabilitation therapy by tongue electrotactile biofeedback in patients with degenerative cerebellar disease. NeuroRehabilitation 31, 429–434 (2012). 208. Cernak, K. et al. Locomotor training using bodyweight support on a treadmill in conjunction with ongoing physical therapy in a child with severe cerebellar ataxia. Phys. Ther. 88, 88–97 (2008). 209. Gialanella, B. et al. Walking and disability after rehabilitation in patients with cerebellar stroke. Minerva Med. 96, 373–378 (2005). 210. Gill-Body, K. M. et al. Rehabilitation of balance in two patients with cerebellar dysfunction. Phys. Ther. 77, 534–552 (1997). 211. Ilg, W. et al. Intensive coordinative training improves motor performance in degenerative cerebellar disease. Neurology 73, 1823–1830 (2009). 212. Miyai, I. et al. Cerebellar Ataxia Rehabilitation Trial in Degenerative Cerebellar Diseases. Neurorehabil. Neural Repair 26, 515–522 (2012). 213. Smedal, T. et al. Balance and gait improved in patients with MS after physiotherapy based on the Bobath concept. Physiother. Res. Int. J. Res. Clin. Phys. Ther. 11, 104–116 (2006). 214. Vaz, D. V. et al. Treadmill training for ataxic patients: a single-subject experimental design. Clin. Rehabil. 22, 234–241 (2008). 215. Stoykov, M. E. P., Stojakovich, M. & Stevens, J. A. Beneficial effects of postural intervention on prehensile action for an individual with ataxia resulting from brainstem stroke. NeuroRehabilitation 20, 85–89 (2005). 216. Ilg, W. et al. Long-term effects of coordinative training in degenerative cerebellar disease. Mov. Disord. Off. J. Mov. Disord. Soc. 25, 2239–2246 (2010). 217. Fonteyn, E. M. R. et al. Falls in Spinocerebellar Ataxias: Results of the EuroSCA Fall Study. The Cerebellum 9, 232–239 (2010). 218. Fonteyn, E. M. R. et al. Prospective Analysis of Falls in Dominant Ataxias. Eur. Neurol. 69, 53–57 (2013). 219. Jan, H. Intensive mobility training as a means of late rehabilitation after brain injury. Adapt. Phys. Act. Q. 6, 176–187 (1989). 220. Gillen, G. Improving activities of daily living performance in an adult with ataxia. Am. J. Occup. Ther. Off. Publ. Am. Occup. Ther. Assoc. 54, 89–96 (2000). 221. Harris-Love, M. O. et al. Rehabilitation management of Friedreich ataxia: lower extremity force-control variability and gait performance. Neurorehabil. Neural Repair 18, 117–124 (2004). 222. Jones, L. et al. The effectiveness of occupational therapy and physiotherapy in multiple sclerosis patients with ataxia of the upper limb and trunk. Clin. Rehabil. 10, 277–282 (1996). 223. Karakaya, M. et al. Investigation and comparison of the effects of rehabilitation on balance and coordination problems in patients with posterior fossa and cerebellopontine angle tumours. J. Neurosurg. Sci. 44, 220–225 (2000). 224. Perlmutter, E. & Gregory, P. C. Rehabilitation treatment options for a patient with paraneoplastic cerebellar degeneration. Am. J. Phys. Med. Rehabil. Assoc. Acad. Physiatr. 82, 158–162 (2003). 225. Hatakenaka, M. et al. Impaired motor learning by a pursuit rotor test reduces functional outcomes during rehabilitation of poststroke ataxia. Neurorehabil. Neural Repair 26, 293–300 (2012). 226. Hatakenaka, M. et al. Finger tapping variability as a marker for cerebellar ataxia and response to rehabilitation. Arch. Phys. Med. Rehabil. 93, E51– E2 (2012). 227. Bunn, L. M. et al. Training balance with optokinetic stimuli in the home: a randomized controlled feasibility study in people with pure cerebellar disease. Clin. Rehabil. 29, 143–153 (2015). 228. Ilg, W. et al. Video game–based coordinative training improves ataxia in children with degenerative ataxia. Neurology 79, 2056–2060 (2012). 229. Crowdy, K. A. et al. Evidence for interactive locomotor and oculomotor deficits in cerebellar patients during visually guided stepping. Exp. Brain Res. Exp. Hirnforsch. Expérimentation Cérébrale 135, 437–454 (2000). 230. Crowdy, K. A. et al. Rehearsal by eye movement improves visuomotor performance in cerebellar patients. Exp. Brain Res. Exp. Hirnforsch. Expérimentation Cérébrale 146, 244–247 (2002). 231. Jeka, J. J. Light touch contact as a balance aid. Phys. Ther. 77, 476–487 (1997). 232. Bateni, H. et al. Can use of walkers or canes impede lateral compensatory stepping movements? Gait Posture 20, 74–83 (2004). 233. Richardson, D. Physical therapy in spasticity. Eur. J. Neurol. Off. J. Eur. Fed. Neurol. Soc. 9 Suppl 1, 17-22-61 (2002). 234. Katalinic, O. M. et al. Stretch for the treatment and prevention of contractures. Cochrane Database Syst. Rev. CD007455 (2010). 235. Deuschl, G. Bain, P. & Brin, M. Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee. Mov. Disord. Off. J. Mov. Disord. Soc. 13 Suppl 3, 2–23 (1998). 236. McGruder, J. et al. Weighted wrist cuffs for tremor reduction during eating in adults with static brain lesions. Am. J. Occup. Ther. Off. Publ. Am. Occup. Ther. Assoc. 57, 507–516 (2003). 237. Feys, P. et al. Intention tremor during manual aiming: a study of eye and hand movements. Mult. Scler. Houndmills Basingstoke Engl. 9, 44–54 (2003). 238. Sanes, J. N. et al. Visual and mechanical control of postural and kinetic tremor in cerebellar system disorders. J. Neurol. Neurosurg. Psychiatry 51, 934–943 (1988). 239. Feys, P. et al. Effects of peripheral cooling on intention tremor in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 76, 373–379 (2005). 240. Quintern, J. et al. Influence of visual and proprioceptive afferences on upper limb ataxia in patients with multiple sclerosis. J. Neurol. Sci. 163, 61–69 (1999). 241. Manto, M. Godaux, E. & Jacquy, J. Cerebellar hypermetria is larger when the inertial load is artificially increased. Ann. Neurol. 35, 45–52 (1994). 242. Morgan, M. H. Hewer, R. L. & Cooper, R. Application of an objective method of assessing intention tremor - a further study on the use of weights to reduce intention tremor. J. Neurol. Neurosurg. Psychiatry 38, 259–264 (1975). 243. Aisen, M. L. et al. The effect of mechanical damping loads on disabling action tremor. Neurology 43, 1346–1350 (1993). 244. Vergaro, E. et al. Adaptive robot training for the treatment of incoordination in Multiple Sclerosis. J. NeuroEngineering Rehabil. 7, 37 (2010). 245. Carpinella, I. et al. Robot training of upper limb in multiple sclerosis: comparing protocols with or without manipulative task components. IEEE Trans. Neural Syst. Rehabil. Eng. Publ. IEEE Eng. Med. Biol. Soc. 20, 351–360 (2012). 246. Huhn, K. Guarrera-Bowlby, P. & Deutsch, J. E. The clinical decision-making process of prescribing power mobility for a child with cerebral palsy. Pediatr. Phys. Ther. Off. Publ. Sect. Pediatr. Am. Phys. Ther. Assoc. 19, 254– 260 (2007). 247. Dean, E. Physical therapy in the 21st century (Part II): evidence-based practice within the context of evidence-informed practice. Physiother. Theory Pract. 25, 354–368 (2009). 248. Rhodes, R. E. & Fiala, B. Building motivation and sustainability into the prescription and recommendations for physical activity and exercise therapy: the evidence. Physiother. Theory Pract. 25, 424–441 (2009). 249. Cook, B. in Severe and Complex Neurological Disability. Management of the Physical Condition 216–230 (Butterworth Heinemann Elsevier, 2007). 250. Marianne Anke, S. et al. Effect of Long-Term Climbing Training on Cerebellar Ataxia: A Case Series, Effect of Long-Term Climbing Training on Cerebellar Ataxia: A Case Series. Rehabil. Res. Pract. 2011, e525879 (2011). 251. Fillyaw, M. J. & Ades, P. A. Endurance exercise training in Friedreich ataxia. Arch. Phys. Med. Rehabil. 70, 786–788 (1989). 252. Cassidy, K. N. & Reynolds. Contemporary physiotherapy practice for people with ataxia: the perspectives of clients and physiotherapists. Unpublished (2007). 253. Multiple Sclerosis Society. Translating the NICE and NSF guidance into practice: A guide for physiotherapists. (2008). 254. Hanks, S. B. The role of therapy in Rett syndrome. Am. J. Med. Genet. Suppl. 1, 247–252 (1986). 255. Fogel, B. L. & Perlman, S. An approach to the patient with late-onset cerebellar ataxia. Nat. Clin. Pract. Neurol. 2, 629–635 (2006). 256. Silva, R. C. R. et al. Occupational therapy in spinocerebellar ataxia type 3: an open-label trial. Braz. J. Med. Biol. Res. 43, 537–542 (2010). 257. Gillen, G. Improving mobility and community access in an adult with ataxia. Am. J. Occup. Ther. Off. Publ. Am. Occup. Ther. Assoc. 56, 462–466 (2002). 258. Jain, S. Kings, J. & Playford, E. D. Occupational Therapy for People with Progressive Neurological Disorders: Unpacking the Black Box. Br. J. Occup. Ther. 68, 125–130 (2005). 259. Steultjens, E. M. J. et al. Occupational therapy for multiple sclerosis. Cochrane Database Syst. Rev. CD003608 (2003). 260. Dixon et al. Occupational therapy for patients with Parkinson’s disease. 2 (2010). 261. Fisher, A. G. Assessment of Motor and Process Skills: Volume 1 - Development, Standardisation, and Administration Manual. (Three Star Press, Inc. Fort Collins, 2006). 262. Law, M. et al. Canadian Occupational Performance Measure. (CAOT Publications ACE, 1998). 263. Jain, S., Kings, J. & Playford, E. D. Occupational Therapy for People with Progressive Neurological Disorders: Unpacking the Black Box. Br. J. Occup. Ther. 68, 125–130 (2005). 264. Clark, J., Morrow, M. & Michael, S. Wheelchair postural support for young people with progressive neuromuscular disorders. Int. J. Ther. Rehabil. 11, 365–373 (2004). 265. Creek. Occupational Therapy Defined as a Complex Intervention. (College of Occupational Therapists, 2003). 266. Wilson, C. L. et al. Quality of life in Friedreich ataxia: what clinical, social and demographic factors are important? Eur. J. Neurol. Off. J. Eur. Fed. Neurol. Soc. 14, 1040–1047 (2007). 267. Clark, J., Morrow, M. & Michael, S. Wheelchair postural support for young people with progressive neuromuscular disorders. Int. J. Ther. Rehabil. 11, 365–373 (2004). 268. Jacobs, A. Splinting the Hand and Upper Extremity: Principles and Process. (Lippincott Williams & Wilkins, 2003). 269. Voltz, R. Palliative Care in Neurology. (Oxford University Press, 2004). 270. Saleem, T., Leigh, N. & Higginson, I. Symptom Prevalence Among People Affected by Advanced and Progressive Neurological Conditions-a Systematic Review. J. Palliat. Care 23, 291–299 (2007). 271. WHO Definition of Palliative Care. (World Health Organisation) 272. Neurological Alliance & The National Council for Palliative Care. End of life care in long term neurological conditions: a framework for implementation. (2011). 273. Royal College of Physicians. Concise guidelines- Long-term neurological conditions: management at the interface between neurology, rehabilitation and palliative care. (2008). 274. NHS. Advance Care Planning: A Guide for Health and Social Care Staff. (2007). 275. NHS. Capacity, care planning and advance care planning in life limiting illness: A Guide for Health and Social Care Staff. (2011). 276. Department of Health. End of Life Care Strategy: Promoting high quality care for all adults at the end of life. (2008). 277. Ellershaw, J., Neuberger, R. J. & Ward, C. Care of the dying patient: the last hours or days of life Commentary: a ‘good death’ is possible in the NHS. BMJ 326, 30–34 (2003). 278. Leadership Alliance for the Care of Dying People. One Chance To Get It Right. (2014). 279. Meier, T. et al. Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich’s ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study. J. Neurol. 259, 284–291 (2012). 280. Lagedrost, S. J. et al. Idebenone in Friedreich ataxia cardiomyopathy-results from a 6-month phase III study (IONIA). Am. Heart J. 161, 639–645.e1 (2011). 281. Lynch, D. R., Perlman, S. L. & Meier, T. A phase 3, double-blind, placebo-controlled trial of idebenone in Friedreich ataxia. Arch. Neurol. 67, 941–947 (2010). 282. Brandsema, J. F. et al. Intermediate-dose idebenone and quality of life in Friedreich ataxia. Pediatr. Neurol. 42, 338–342 (2010). 283. Rinaldi, C. et al. Low-dose idebenone treatment in Friedreich’s ataxia with and without cardiac hypertrophy. J. Neurol. 256, 1434–1437 (2009). 284. Pineda, M. et al. Idebenone treatment in paediatric and adult patients with Friedreich ataxia: long-term follow-up. Eur. J. Paediatr. Neurol. EJPN Off. J. Eur. Paediatr. Neurol. Soc. 12, 470–475 (2008). 285. Di Prospero, N. A. et al. Neurological effects of high-dose idebenone in patients with Friedreich’s ataxia: a randomised, placebo-controlled trial. Lancet Neurol. 6, 878–886 (2007). 286. Rustin, P. et al. Idebenone treatment in Friedreich patients: One-year-long randomized placebo-controlled trial. Neurology 62, 524–525 (2004). 287. Cooper, J. M. et al. Coenzyme Q10 and vitamin E deficiency in Friedreich’s ataxia: predictor of efficacy of vitamin E and coenzyme Q10 therapy. Eur. J. Neurol. Off. J. Eur. Fed. Neurol. Soc. 15, 1371–1379 (2008). 288. Hart, P.E. et al. Antioxidant treatment of patients with Friedreich ataxia: Four-year follow-up. Arch. Neurol. 62, 621–626 (2005). 289. Schöls, L. et al. L-carnitine and creatine in Friedreich’s ataxia. A randomized, placebo-controlled crossover trial. J. Neural Transm. Vienna Austria 1996 112, 789–796 (2005). 290. Pandolfo, M. et al. Deferiprone in Friedreich ataxia: a 6-month randomized controlled trial. Ann. Neurol. 76, 509–521 (2014). 291. Velasco-Sánchez, D. et al. Combined therapy with idebenone and deferiprone in patients with Friedreich’s ataxia. Cerebellum Lond. Engl. 10, 1–8 (2011). 292. Arpa, J. et al. Triple therapy with deferiprone, idebenone and riboflavin in Friedreich’s ataxia - open-label trial. Acta Neurol. Scand. 129, 32–40 (2014). 293. Boesch, S. et al. Neurological effects of recombinant human erythropoietin in Friedreich’s ataxia: a clinical pilot trial. Mov. Disord. Off. J. Mov. Disord. Soc. 23, 1940–1944 (2008). 294. Nachbauer, W. et al. Effects of erythropoietin on frataxin levels and mitochondrial function in Friedreich ataxia - a dose-response trial. Cerebellum Lond. Engl. 10, 763–769 (2011). 295. Mariotti, C. et al. Erythropoietin in Friedreich ataxia: no effect on frataxin in a randomized controlled trial. Mov. Disord. Off. J. Mov. Disord. Soc. 27, 446–449 (2012). 296. Boesch, S. et al. Safety and tolerability of carbamylated erythropoietin in Friedreich’s ataxia. Mov. Disord. Off. J. Mov. Disord. Soc. 29, 935– 939 (2014). 297. Lynch, D. R. et al. A0001 in Friedreich ataxia: biochemical characterization and effects in a clinical trial. Mov. Disord. Off. J. Mov. Disord. Soc. 27, 1026–1033 (2012). 298. Libri, V. et al. Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich’s ataxia: an exploratory, open-label, dose-escalation study. The Lancet 384, 504–513 (2014). 299. Soragni, E. et al. Epigenetic therapy for Friedreich ataxia. Ann. Neurol. 76, 489–508 (2014). 300. Marcotulli, C .et al. GIFT 1 - a phase IIa clinical trial to test the safety and efficacy of IFNγ administration in FRDA patients. Neurol Sci.; 37(3):361-4 (2016). 301. Seyer, L. et al. Open-label pilot study of interferon gamma-1b in Friedreich ataxia. Acta Neurol. Scand. 132, 7–15 (2015). 302. Yiu, E. M. et al. An open-label trial in Friedreich ataxia suggests clinical benefit with high-dose resveratrol, without effect on frataxin levels. J. Neurol. 262, 1344–1353 (2015). 303. Romano, S. et al. Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 14, 985–991 (2015). 304. Ristori, G. et al. Riluzole in cerebellar ataxia: a randomized, double-blind, placebo-controlled pilot trial. Neurology 74, 839–845 (2010). 305. Saccà, F. et al. A randomized controlled pilot trial of lithium in spinocerebellar ataxia type 2. J. Neurol. 262, 149–153 (2015). 306. Saute, J. A. M. et al. A randomized, phase 2 clinical trial of lithium carbonate in Machado- Joseph disease. Mov. Disord. Off. J. Mov. Disord. Soc. 29, 568–573 (2014). 307. Young, P. et al. Spinocerebellar ataxia type 3 (Machado-Joseph disease) and varenicline. Rev. Médica Chile 143, 1221–1222 (2015). 308. Connolly, B. S. et al. A randomized trial of varenicline (chantix) for the treatment of spinocerebellar ataxia type 3. Neurology 79, 2218–2218 (2012). 309. Filla, A., Sacca, F. & De Michele, G. A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3. Neurology 78, 1538 (2012). 310. Zesiewicz, T. A. et al. A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3. Neurology 78, 545–550 (2012). 311. Zesiewicz, T. A. et al. Subjective improvement in proprioception in 2 patients with atypical Friedreich ataxia treated with varenicline (Chantix). J. Clin. Neuromuscul. Dis. 10, 191–193 (2009). 312. Zesiewicz, T. A. & Sullivan, K. L. Treatment of ataxia and imbalance with varenicline (chantix): report of 2 patients with spinocerebellar ataxia (types 3 and 14). Clin. Neuropharmacol. 31, 363–365 (2008). 313. Zesiewicz, T. A. et al. Treatment of imbalance with varenicline Chantix(R): report of a patient with fragile X tremor/ataxia syndrome. Acta Neurol. Scand. 119, 135–138 (2009). 314. Seritan, A. L. et al. Memantine for fragile X-associated tremor/ataxia syndrome: a randomized, double-blind, placebo-controlled trial. J. Clin. Psychiatry 75, 264–271 (2014). 315. Yang, J.-C. et al. Memantine effects on verbal memory in fragile X-associated tremor/ataxia syndrome (FXTAS): a double-blind brain potential study. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 39, 2760–2768 (2014). 316. Trouillas, P. et al. 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, 205–211 (1997). 317. Reetz, K. et al. 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, 174–182 (2015). 318. Subramony, S. H. et al. Measuring Friedreich ataxia: Interrater reliability of a neurologic rating scale. Neurology 64, 1261–1262 (2005). 319. Cano, S. J. et al. Friedreich’s ataxia impact scale: a new measure striving to provide the flexibility required by today’s studies. Mov. Disord. Off. J. Mov. Disord. Soc. 24, 984–992 (2009). 320. Jacobi, H. et al. Inventory of Non-Ataxia Signs (INAS): validation of a new clinical assessment instrument. Cerebellum Lond. Engl. 12, 418–428 (2013). 321. Jacobi, H. et al. Long-term disease progression in spinocerebellar ataxia types 1, 2, 3, and 6: a longitudinal cohort study. Lancet Neurol. 14, 1101–1108 (2015). This information is taken from Management of the ataxias - towards best clinical practice third edition, July 2016. This document aims to provide recommendations for healthcare professionals on the diagnosis and management of people with progressive ataxia. To view the full document, including references, click here.