Current concepts in the treatment of hereditary ataxias

ABSTRACT

Hereditary ataxias (HA) represents an extensive group of clinically and genetically heterogeneous neurodegenerative diseases, characterized by progressive ataxia combined with extra-cerebellar and multi-systemic involvements, including peripheral neuropathy, pyramidal signs, movement disorders, seizures, and cognitive dysfunction. There is no effective treatment for HA, and management remains supportive and symptomatic. In this review, we will focus on the symptomatic treatment of the main autosomal recessive ataxias, autosomal dominant ataxias, X-linked cerebellar ataxias and mitochondrial ataxias. We describe management for different clinical symptoms, mechanism-based approaches, rehabilitation therapy, disease modifying therapy, future clinical trials and perspectives, genetic counseling and preimplantation genetic diagnosis.

RESUMO

As ataxias hereditárias representam um grupo complexo de doenças neurodegenerativas, e se caracterizam por ataxia cerebelar progressiva, associada a sinais e sintomas extra-cerebelares e sistêmicos, os quais incluem: neuropatia periférica, sinais piramidais, distúrbios do movimento, convulsões e disfunção cognitiva. Não existe um tratamento efetivo para a cura das ataxias hereditárias. Até o momento os tratamentos disponíveis são apenas sintomáticos. Nesta revisão vamos abordar tratamento sintomático das principais ataxias autossçmicas recessivas, ataxias autossçmicas dominantes, ataxias ligadas ao X e ataxias mitocondriais. Descrevemos os diferentes sintomas, abordagens terapêuticas baseadas no mecanismo fisiopatológico, terapia de reabilitação, terapia modificadora da doença, futuros ensaios clínicos, perspectivas, níveis de evidência, aconselhamento genético e diagnóstico genético pré-implantacional.

hereditary ataxias - treatment - rehabilitation therapy - disease modifying therapy

ataxias hereditárias - tratamento - terapia de reabilitação - terapia modificadora da doença

Publikationsverlauf

Eingereicht: 15. Dezember 2015

Angenommen: 04. Januar 2016

Artikel online veröffentlicht:
06. September 2023

• REFERENCES

• 1 Teive HA, Ashizawa T. Primary and secondary ataxias. Curr Opin Neurol. 2015;28:413-22. doi:10.1097/WCO.20160038201600380227
• 2 Anheim M, Tranchant C, Koenig M. The autosomal recessive cerebellar ataxias. N Engl J Med. 2012;366(7):636-46. doi:10.1056/NEJMra1006610
• 3 Fogel BL, Perlman S. Clinical features and molecular genetics of autosomal recessive cerebellar ataxias. Lancet Neurol. 2007;6(3):245-57. doi:10.1016/S1474-4422(07)70054-6
• 4 Abrahão A, Pedroso JL, Braga-Neto P, Bor-Seng-Shu E, Carvalho Aguiar P, Barsottini OG. Milestones in Friedreich ataxia: more than a century and still learning. Neurogenetics. 2015;16(3):151-60. doi: 10.1007/s10048-015-0439-z
• 5 Hentati F, El-Euch G, Bouhlal Y, Amouri R. Ataxia with vitamin E deficiency and abetalipoproteinemia. Handb Clin Neurol. 2012;103:295-305. doi:10.1016/B978-0-444-51892-7.00018-8
• 6 Weinstein R. Phytanic acid storage disease (Refsum’s disease): clinical characteristics, pathophysiology and the role of therapeutic apheresis in its management. J Clin Apher. 1999;14(4):181-4. doi:10.1002/(SICI)1098-1101(1999)14:4<181::AID-JCA5>3.0.CO;2-Z
• 7 Mengel E, Klünemann HH, Lourenço CM, Hendriksz CJ, Sedel F, Walterfang M, et al. Niemann-Pick disease type C symptomatology: an expert-based clinical description. Orphanet J Rare Dis. 2013;8(1):166. doi:10.1186/1750-1172-8-166
• 8 Björkhem I. Cerebrotendinous xanthomatosis. Curr Opin Lipidol. 2013;24(4):283-7. doi:10.1097/MOL.0b013e328362df13
• 9 Emmanuele V, López LC, Berardo A, Naini A, Tadesse S, Wen B et al. Heterogeneity of coenzyme Q10 deficiency: patient study and literature review. Arch Neurol. 2012;69(8):978-83. doi:10.1001/archneurol.2012.206
• 10 Leen WG, Klepper J, Verbeek MM, Leferink M, Hofste T, Engelen BG et al. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain. 2010;133(3):655-70. doi:10.1093/brain/awp336
• 11 Gabsi S, Gouider-Khouja N, Belal S, Fki M, Kefi M, Turki I et al. Effect of vitamin E supplementation in patients with ataxia with vitamin E deficiency. Eur J Neurol. 2001;8(5):477-81. doi:10.1046/j.1468-1331.2001.00273.x
• 12 Jansen GA, Waterham HR, Wanders RJA. Molecular basis of Refsum disease: sequence variations in phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7). Hum Mutat. 2004;23(3):209-18. doi:10.1002/humu.10315
• 13 Verrips A, Hoefsloot LH, Steenbergen GC, Theelen JP, Wevers RA, Gabreëls FJ et al. Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis. Brain. 2000;123(5):908-19. doi:10.1093/brain/123.5.908
• 14 Patterson MC, Hendriksz CJ, Walterfang M, Sedel F, Vanier MT, Wijburg F et al. Recommendations for the diagnosis and management of Niemann-Pick disease type C: an update. Mol Genet Metab. 2012;106(3):330-44. doi:10.1016/j.ymgme.2012.03.012
• 15 Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE. Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol. 2007;6(9):765-72. doi:10.1016/S1474-4422(07)70194-1
• 16 Verrips A, Wevers RA, Van Engelen BG, Keyser A, Wolthers BG, Barkhof F et al. Effect of simvastatin in addition to chenodeoxycholic acid in patients with cerebrotendinous xanthomatosis. Metabolism Clin Exp. 1999;48(2):233-8. doi:10.1016/S0026-0495(99)90040-9
• 17 Quinzii CM, Hirano M. Primary and secondary CoQ(10) deficiencies in humans. Biofactors. 2011;37(5):361-5. doi:10.1002/biof.155
• 18 Pineda M, Montero R, Aracil A, O’Callaghan MM, Mas A, Espinos C et al. Coenzyme Q(10)-responsive ataxia: 2-year-treatment follow-up. Mov Disord. 2010;25(9):1262-8. doi:10.1002/mds.23129
• 19 Pascual JM, Wang D, Lecumberri B, Yang H, Mao X, Yang R et al. GLUT1 deficiency and other glucose transporter diseases. Eur J Endocrinol. 2004;150(5):627-33. doi:10.1530/eje.0.1500627
• 20 Fecarotta S, Amitrano M, Romano A, Della Casa R, Bruschini D, Astarita L et al. The videofluoroscopic swallowing study shows a sustained improvement of dysphagia in children with Niemann-Pick disease type C after therapy with miglustat. Am J Med Genet A. 2011;155A(3):540-7. doi:10.1002/ajmg.a.33847
• 21 Ilg W, Bastian AJ, Boesch S, Burciu RG, Celnik P, Claaßen J et al. Consensus paper: management of degenerative cerebellar disorders. Cerebellum. 2014;13(2):248-68. doi:10.1007/s12311-013-0531-6
• 22 Ristori G, Romano S, Visconti A, Cannoni S, Spadaro M, Frontali M et al. Riluzole in cerebellar ataxia: a randomized, double-blind, placebo-controlled pilot trial. Neurology. 2010;74(10):839-45. doi:10.1212/WNL.0b013e3181d31e23
• 23 Romano S, Coarelli G, Marcotulli C, Leonardi L, Piccolo F, Spadaro M et al. Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2015;14(10):985-91. doi:10.1016/S1474-4422(15)00201-X
• 24 Saute JA, Castilhos RM, Monte TL, Schumacher-Schuh AF, Donis KC, D’Ávila R et al. A randomized, phase 2 clinical trial of lithium carbonate in Machado-Joseph disease. Mov Disord. 2014;29(4):568-73. doi:10.1002/mds.25803
• 25 Velázquez-Pérez L, Rodríguez-Chanfrau J, García-Rodríguez JC, Sánchez-Cruz G, Aguilera-Rodríguez R, Rodríguez-Labrada R et al. Oral zinc sulphate supplementation for six months in SCA2 patients: a randomized, double-blind, placebo-controlled trial. Neurochem Res. 2011;36(10):1793-800. doi:10.1007/s11064-011-0496-0
• 26 Zesiewicz TA, Greenstein PE, Sullivan KL, Wecker L, Miller A, Jahan I et al. A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3. Neurology. 2012;78(8):545-50. doi:10.1212/WNL.0b013e318247cc7a
• 27 Assadi M, Campellone JV, Janson CG, Veloski JJ, Schwartzman RJ, Leone P. Treatment of spinocerebellar ataxia with buspirone. J Neurol Sci. 2007;260(1-2):143-6. doi:10.1016/j.jns.2007.04.019
• 28 Arpa J, Sanz-Gallego I, Medina-Báez J, Portela LV, Jardim LB, Torres-Aleman I et al. Subcutaneous insulin-like growth factor-1 treatment in spinocerebellar ataxias: an open label clinical trial. Mov Disord. 2011;26(2):358-9. doi:10.1002/mds.23423
• 29 Ramirez-Zamora A, Zeigler W, Desai N, Biller J. Treatable causes of cerebellar ataxia. Mov Disord. 2015;30(5):614-23. doi:10.1002/mds.26158
• 30 Strupp M, Kalla R, Claassen J, Adrion C, Mansmann U, Klopstock T et al. A randomized trial of 4-aminopyridine in EA2 and related familial episodic ataxias. Neurology. 2011;77(3):269-75. doi:10.1212/WNL.0b013e318225ab07
• 31 D’Abreu A, França Junior MC, Paulson HL, Lopes-Cendes I. Caring for Machado-Joseph disease: current understanding and how to help patients. Parkinsonism Relat Disord. 2010;16(1):2-7. doi:10.1016/j.parkreldis.2009.08.012
• 32 Shan DE, Soong BW, Sun CM, Lee SJ, Liao KK, Liu RS. Spinocerebellar ataxia type 2 presenting as familial levodopa-responsive parkinsonism. Ann Neurol. 2001;50(6):812-5. doi:10.1002/ana.10055
• 33 Pedroso JL, Braga-Neto P, Felício AC, Aquino CC, Prado LB, Prado GF et al. Sleep disorders in cerebellar ataxias. Arq Neuropsiquiatr. 2011;69(2A):253-7. doi:10.1590/S0004-282X2011000200021
• 34 Kanai K, Kuwabara S, Arai K, Sung JY, Ogawara K, Hattori T. Muscle cramp in Machado-Joseph disease: altered motor axonal excitability properties and mexiletine treatment. Brain. 2003;126(4):965-73. doi:10.1093/brain/awg073
• 35 Schulte T, Mattern R, Berger K, Szymanski S, Klotz P, Kraus PH et al. Double-blind crossover trial of trimethoprim-sulfamethoxazole in spinocerebellar ataxia type 3/Machado-Joseph disease. Arch Neurol. 2001;58(9):1451-7. doi:10.1001/archneur.58.9.1451
• 36 Zanni G, Bertini ES. X-linked disorders with cerebellar dysgenesis. Orphanet J Rare Dis. 2011;6(1):24. doi:10.1186/1750-1172-6-24
• 37 Muzar Z, Lozano R. Current research, diagnosis, and treatment of fragile X-associated tremor/ataxia syndrome. Intractable Rare Dis Res. 2014;3(4):101-9. doi:10.5582/irdr.2014.01029
• 38 Yang JC, Niu YQ, Simon C, Seritan AL, Chen L, Schneider A et al. Memantine effects on verbal memory in fragile X-associated tremor/ataxia syndrome (FXTAS): a double-blind brain potential study. Neuropsychopharmacology. 2014;39(12):2760-8. doi:10.1038/npp.2014.12
• 39 Hagerman J, Jamie SP, Ortigas M, Olichney J, Frysinger R, Harrison M et al. Case Series: Deep brain stimulation in patients with FXTAS. Brain Disord Ther. 2012;1:2. doi:10.4172/2168-975X.1000104
• 40 Santos Ghilardi MG, Cury RG, Ângelos JS, Barbosa DC, Barbosa ER, Teixeira MJ, et al. Long-term improvement of tremor and ataxia after bilateral DBS of VoP/zona incerta in FXTAS. Neurology. 2015;84(18):1904-6. doi:10.1212/WNL.20160038201600381553
• 41 Chinnery PF. Mithocondrial disorders overview. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH et al., editors. GeneReviews®. Seattle: University of Washington, Seattle; 1993-2015 [cited 2015 Nov 17]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1224/
• 42 Pfeffer G, Majamaa K, Turnbull DM, Thorburn D, Chinnery PF. Treatment for mitochondrial disorders. Cochrane Database Syst Rev. 2012;4:CD004426. doi:10.1002/14651858.CD004426.pub3
• 43 Aizawa CY, Pedroso JL, Braga-Neto P, Callegari MR, Barsottini OG. Patients with autosomal dominant spinocerebellar ataxia have more risk of falls, important balance impairment, and decreased ability to function. Arq Neuropsiquiatr. 2013;71(8):508-11. doi:10.1590/0004-282X20130094
• 44 Fonteyn EM, Keus SH, Verstappen CC, Schöls L, Groot IJ, Warrenburg BP. The effectiveness of allied health care in patients with ataxia: a systematic review. J Neurol. 2014;261:251-8. doi:10.1007/s00415-013-6910-6
• 45 Ilg W, Synofzik M, Brötz D, Burkard S, Giese MA, Schöls L. Intensive coordinative training improves motor performance in degenerative cerebellar disease. Neurology. 2009;73(22):1823-30. doi:10.1212/WNL.0b013e3181c33adf
• 46 Synofzik M, Ilg W. Motor training in degenerative spinocerebellar disease: ataxia-specific improvements by intensive physiotherapy and exergames. Biomed Res Int. 2014;2014:ID583507. doi:10.1155/2014/583507
• 47 Chang YJ, Chou CC, Huang WT, Lu CS, Wong AM, Hsu MJ. Cycling regimen induces spinal circuitry plasticity and improves leg muscle coordination in individuals with spinocerebellar ataxia. Arch Phys Med Rehabil. 2015;96(6):1006-13. doi:10.1016/j.apmr.2015.01.021
• 48 Milne SC, Campagna EJ, Corben LA, Delatycki MB, Teo K, Churchyard AJ et al. Retrospective study of the effects of inpatient rehabilitation on improving and maintaining functional independence in people with Friedreich ataxia. Arch Phys Med Rehabil. 2012;93(10):1860-3. doi:10.1016/j.apmr.2012.03.026
• 49 Schalling E, Hartelius L. Speech in spinocerebellar ataxia. Brain Lang. 2013;127(3):317-22. doi:10.1016/j.bandl.2013.10.002
• 50 Chan PK, Torres R, Yandim C, Law PP, Khadayate S, Mauri M et al. Heterochromatinization induced by GAA-repeat hyperexpansion in Friedreich’s ataxia can be reduced upon HDAC inhibition by vitamin B3. Hum Mol Genet. 2013;22(13):2662–75. doi:10.1093/hmg/ddt115
• 51 Libri V, Yandim C, Athanasopoulos S, Loyse N, Natisvili T, Law PP 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. Lancet. 2014;384(9942):504-13. doi:10.1016/S0140-6736(14)60382-2
• 52 Soragni E, Miao W, Iudicello M, Jacoby D, De Mercanti S, Clerico M et al. Epigenetic therapy for Friedreich ataxia. Ann Neurol. 2014;76(4):489-508. doi:10.1002/ana.24260
• 53 Underwood BR, Rubinsztein DC. Spinocerebellar ataxias caused by polyglutamine expansions: a review of therapeutic strategies. Cerebellum. 2008;7(2):215-21. doi:10.1007/s12311-008-0026-z
• 54 Nóbrega C, Nascimento-Ferreira I, Onofre I, Albuquerque D, Hirai H, Déglon N et al. Silencing mutant ataxin-3 rescues motor deficits and neuropathology in Machado-Joseph disease transgenic mice. PLoS One. 2013;8(1):e52396. doi:10.1371/journal.pone.0052396
• 55 Scoles D, Hung G, Pflieger L, Thai K, Bennett F, Pulst S. Treatment Of Spinocerebellar Ataxia Type 2 (SCA2) with MOE Antisense Oligonucleotides. Neurology. 2015;82(10 Suppl):S47.006.
• 56 Saute JA, Rieder CR, Castilhos RM, Monte TL, Schumacher-Schuh AF, Donis KC et al. Planning future clinical trials in Machado Joseph disease: lessons from a phase 2 trial. J Neurol Sci. 2015;358(1-2):72-6. doi:10.1016/j.jns.2015.08.019
• 57 Amariglio N, Hirshberg A, Scheithauer BW, Cohen Y, Loewenthal R, Trakhtenbrot L et al. Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med. 2009;6(2):e1000029. doi:10.1371/journal.pmed.1000029
• 58 Tur-Kaspa I, Jeelani R, Doraiswamy PM. Preimplantation genetic diagnosis for inherited neurological disorders. Nat Rev Neurol. 2014;10(7):417-24. doi:10.1038/nrneurol.2014.84
• 59 Bushara K. We cannot cure ataxia,we can only eradicate it. JAMA Neurol. 2013;70(9):1099. doi:10.1001/jamaneurol.2013.3026
• 60 Drüsedau M, Dreesen JC, De Die-Smulders C, Hardy K, Bras M, Dumoulin JC et al. Preimplantation genetic diagnosis of spinocerebellar ataxia 3 by (CAG)(n) repeat detection. Mol Hum Reprod. 2004;10(1):71-5. doi:10.1093/molehr/gah008