Keywords
SCA1
SCA2
SCA3
SCA4
diagnosis
treatment
epidemiology
How to Cite
Abstract
Spinocerebellar ataxias (SCAs) are genetically acquired dominant diseases that cause neurodegeneration. Although they mainly affect the cerebellum and spinal cord, other areas of the nervous system, such as the basal ganglia and the cerebral cortex, are also impacted, compromising the precise execution of movements. Symptoms include postural hypotonia, oculomotor disturbances, ataxic gait, cerebellar atrophy, and respiratory and speech dysfunctions. Since 2006, the Ataxia Rating and Assessment Scale (SARA) has been used to diagnose and determine the severity of ataxia. There is no cure or approved pharmacological therapy for SCAs; Current treatment is based on physical therapy, occupational therapy and speech therapy to improve gait, coordination and posture. Research in mice aims to suppress the mutant ataxin that causes SCAs. This work reviewed the literature from the last five years on the epidemiology, pathogenesis, diagnosis and treatment of SCAs. The data reveal that people with SCA2 and SCA6 present a reduction in brain volumes before clinical symptoms, with faster progression in men. Extracerebellar degeneration in SCA6 is less pronounced than in SCA1, SCA2, and SCA3. Sequencing studies indicate underestimation of CAG repeats in SCA6. Combination therapies and transcranial direct current stimulation (tDCS) have shown significant improvements in motor symptoms and quality of life for all subtypes, with magnetic resonance imaging (MRI) measurements being highly sensitive. It is concluded that studies on SCAs are essential to understand their characteristics, diagnoses and treatments, improving therapeutic approaches and patients' quality of life. Early interventions, such as occupational therapies and the use of MRI, hold promise for effective management of these diseases.
References
Bear MF. Neurociências. 4a.ed. Local:Porto Alegre. Local de Publicação: Artmed; 2017.
Bhandari J, Thada PK, Samanta D. Spinocerebellar Ataxia. [Atualizado em 10 ago. 2022; citado em 2022 dez. 27]. In: StatPearls [Internet]. Ilha do Tesouro (FL): StatPearls Publishing; 2022 jan. Disponível em: https://www.ncbi.nlm.nih.gov/books/NBK557816/
Sullivan R, Yau WY, O'Connor E, Houlden H. Spinocerebellar ataxia: an update. J Neurol. 2019 fev [citado em 2022 dez. 27];266(2):533-44. doi: 10.1007/s00415-018-9076-4
Coarelli G, Brice A, Durr A. Recent advances in understanding dominant spinocerebellar ataxias from clinical and genetic points of view. F1000Res. 2018 nov 12 [citado em 2022 dez. 27];7:F1000 Faculty Rev-1781. doi: 10.12688/f1000research.15788.1
Müller U. Spinocerebellar ataxias (SCAs) caused by common mutations. Neurogenetics [Internet]. 16 ago 2021 [citado em 2023 jan. 13];22(4):235-50. Disponível em: https://doi.org/10.1007/s10048-021-00662-5
Moulaire P, Poulet P. E, Petit E, Klockgether T, Durr A, Ashisawa T. Temporal dynamics of the scale for the assessment and rating of ataxia in spinocerebellar ataxias. Movement Disorders [Internet]. 23 out 2022 [citado em 2023 jan. 13]. Disponível em: https://doi.org/10.1002/mds.29255
Ashizawa T, Öz G, Paulson HL. Spinocerebellar ataxias: prospects and challenges for therapy development. Nature Reviews Neurology [Internet]. 21 ago 2018 [citado em 2023 jan. 13];14(10):590-605. Disponível em: https://doi.org/10.1038/s41582-018-0051-6
Klockgether T, Mariotti C, Paulson HL. Spinocerebellar ataxia. Nat Rev Dis Primers. 2019 abr 11 [citado em 2023 jan. 13];5(1):24. doi: 10.1038/s41572-019-0074-3
Elsaey MA, Namikawa K, Köster RW. Genetic Modeling of the Neurodegenerative Disease Spinocerebellar Ataxia Type 1 in Zebrafish. Int J Mol Sci. 2021 jul 8 [citado em 2023 jan 13];22(14):7351. doi: 10.3390/ijms22147351
Chen JM, Chen SK, Jin PP, Sun SC. Identification of the ataxin-1 interaction network and its impact on spinocerebellar ataxia type 1. Hum Genomics. 2022 jul 29 [citado em 2023 jan. 13];16(1):29. doi: 10.1186/s40246-022-00404-0
Srinivasan SR, Shakkottai VG. Moving Towards Therapy in SCA1: Insights from Molecular Mechanisms, Identification of Novel Targets, and Planning for Human Trials. Neurotherapeutics. 2019 out [citado em 2023 jan. 10];16(4):999-08. doi: 10.1007/s13311-019-00763-y
Velázquez-Pérez L, Rodríguez-Labrada R, González-Garcés Y, Vázquez-Mojena Y, Pérez-Rodríguez R, Ziemann U. Neurophysiological features in spinocerebellar ataxia type 2: prospects for novel biomarkers. Clin Neurophysiol. 2022 mar [citado em 2023 jan. 13];135:1-12. doi: 10.1016/j.clinph.2021.12.005
Pelosi L, Iodice R, Antenora A, Kilfoyle D, Mulroy E, Rodrigues M, et al. Spinocerebellar ataxia type 2-neuronopathy or neuropathy? Muscle Nerve. 2019 set [citado em 2023 jan. 13];60(3):271-78. doi: 10.1002/mus.26613
Egorova PA, Bezprozvanny IB. Molecular mechanisms and therapeutics for spinocerebellar ataxia type 2. Neurotherapeutics. 2019 ago 21 [citado em 2023 jan. 13];16(4):1050-73. Disponível em: https://doi.org/10.1007/s13311-019-00777-6
Velázquez-Pérez L, Rodríguez-Diaz JC, Rodríguez-Labrada R, Medrano-Montero J, Aguilera Cruz AB, Reynaldo-Cejas L, et al. Neurorehabilitation improves the motor features in prodromal SCA2: a randomized, controlled trial. Mov Disord. 2019 jul [citado em 2023 jan. 13];34(7):1060-68. doi: 10.1002/mds.27676.
Afonso IT, Lima P, Conceição A, Matos CA, Nóbrega C. Mutant ataxin-2 expression in aged animals aggravates neuropathological features associated with spinocerebellar ataxia type 2. Int. J. Mol. Ciência. 2022 [citado em 2023 jan. 13];23(19):11896. doi: https://doi.org/10.3390/ijms231911896
Marcelo A, Afonso IT, Afonso-Reis R, Brito DV, Costa RG, Rosa A, et al. Autophagy in Spinocerebellar ataxia type 2, a dysregulated pathway, and a target for therapy. Cell Death Dis. 2021 nov 29 [citado em 2023 jan. 13];12(1117). doi: https://doi.org/10.1038/s41419-021-04404-1
Paulson H. Machado-Joseph disease/spinocerebellar ataxia type 3. Handb Clin Neurol. 2012 [citado em 2023 jan. 13];103:437-49. doi: 10.1016/B978-0-444-51892-7.00027-9
McLoughlin HS, Moore LR, Paulson HL. Pathogenesis of SCA3 and implications for other polyglutamine diseases. Neurobiol Dis. 2020 fev [citado em 2023 Jan. 13];134:104635. doi: 10.1016/j.nbd.2019.104635
Paulson H, Shakkottai V. Ataxia espinocerebelar tipo 3. 1998 out 10 [atualizado em 2020 jun 4; citado em: 13 jan. 2023]. In: Adam MP, Everman DB, Mirzaa GM, et al. GeneReviews® [Internet]. Seattle (WA): Universidade de Washington, Seattle; 1993-2023. Disponível em: https://www.ncbi.nlm.nih.gov/books/NBK1196/
Casey HL, Gomez CM. Ataxia espinocerebelar tipo 6. 23 out 1998 [Atualizado em 21 nov 2019; citado em: 21 dez. 2022]. In: Adam MP, Everman DB, Mirzaa GM, et al. GeneReviews® [Internet]. Seattle (WA): Universidade de Washington, Seattle; 1993-23. Disponível em: https://www.ncbi.nlm.nih.gov/books/NBK1140/
Bohne P, Rybarski M, Mourabit DB, Krause F, Mark MD. Cerebellar contribution to threat probability in a SCA6 mouse model. Hum Mol Genet. 2022 Nov 10 [citado em 2022 dez. 21];31(22):3807-28. doi: 10.1093/hmg/ddac135
Reetz K, Rodríguez‐Labrada R, Dogan I, Mirzazade S, Romanzetti S, Schulz JB, et al. Brain atrophy measures in preclinical and manifest spinocerebellar ataxia type 2. Ann Clin Transl Neurol. fevereiro de 2018;5(2):128–37.
Maas RP, Teerenstra S, Lima M, Pires P, Pereira de Almeida L, van Gaalen J, Timmann D, Infante J, Onyike C, Bushara K, Jacobi H, Reetz K, Santana MM, Afonso Ribeiro J, Hübener‐Schmid J, de Vries JJ, Synofzik M, Schöls L, Garcia‐Moreno H, Giunti P, Faber J, Klockgether T, van de Warrenburg BP. Differential temporal dynamics of axial and appendicular ataxia in SCA3. Mov Disord [Internet]. 8 jul 2022 [citado 15 jan 2024]. Disponível em: https://doi.org/10.1002/mds.29135
Wiethoff S, O’Connor E, Haridy NA, Nethisinghe S, Wood N, Giunti P, et al. Sequencing analysis of the SCA6 CAG expansion excludes an influence of repeat interruptions on disease onset. J Neurol Neurosurg Psychiatry. novembro de 2018;89(11):1226–7.
Jäschke D, Steiner KM, Chang DI, Claaßen J, Uslar E, Thieme A, et al. Age-related differences of cerebellar cortex and nuclei: MRI findings in healthy controls and its application to spinocerebellar ataxia (SCA6) patients. NeuroImage. abril de 2023;270:119950.
Jacobi H, Schaprian T, Schmitz‐Hübsch T, Schmid M, Klockgether T. Disease progression of spinocerebellar ataxia types 1, 2, 3 and 6 before and after ataxia onset. Ann Clin Transl Neurol [Internet]. 17 ago 2023 [citado 24 out 2023]. Disponível em: https://doi.org/10.1002/acn3.51875
Oliveira CM, Leotti VB, Polita S, Anes M, Cappelli AH, Rocha AG, Ecco G, Bolzan G, Kersting N, Duarte JA, Saraiva-Pereira ML, Junior MC, Rezende TJ, Jardim LB. The longitudinal progression of MRI changes in pre-ataxic carriers of SCA3/MJD. J Neurol [Internet]. 16 maio 2023 [citado 15 jan 2024]. Disponível em: https://doi.org/10.1007/s00415-023-11763-6
Giovana Diaféria, Bommarito S, Henrique P, Sung Woo Park, Padovani M, Louise F, et al. Effect of speech therapy on quality of life in patients with spinocerebelar ataxia type 3. Arquivos De Neuro-psiquiatria. 2022 Oct 1;80(10):1017–25.
Carrell EM, Keiser MS, Robbins AB, Davidson BL. Combined overexpression of ATXN1L and mutant ATXN1 knockdown by AAV rescue motor phenotypes and gene signatures in SCA1 mice. Molecular Therapy Methods & Clinical Development [Internet]. 2022 Jun 9 [cited 2023 Jul 24];25:333–43. Available from: https://pubmed.ncbi.nlm.nih.gov/35573049/
Tezenas Du Montcel S, Petit E, Olubajo T, Faber J, Lallemant-Dudek P, Bushara K, et al. Baseline Clinical and Blood Biomarkers in Patients With Preataxic and Early-Stage Disease Spinocerebellar Ataxia 1 and 3. Neurology. 25 de abril de 2023;100(17):e1836–48.
Osório C, White JJ, Lu H, Beekhof GC, Fiocchi FR, Andriessen CA, Dijkhuizen S, Post L, Schonewille M. Pre-ataxic loss of intrinsic plasticity and motor learning in a mouse model of SCA1. Brain [Internet]. 10 nov 2022 [citado 15 jan 2024]. Disponível em: https://doi.org/10.1093/brain/awac422
Nigri A, Sarro L, Mongelli A, Pinardi C, Porcu L, Castaldo A, et al. Progression of Cerebellar Atrophy in Spinocerebellar Ataxia Type 2 Gene Carriers: A Longitudinal MRI Study in Preclinical and Early Disease Stages. Front Neurol. 15 de dezembro de 2020;11:616419.
Benussi A, Cantoni V, Manes M, Libri I, Dell’Era V, Datta A, et al. Motor and cognitive outcomes of cerebello-spinal stimulation in neurodegenerative ataxia. Brain. 2021 May 5;144(8):2310–21.
Aprigliano F, Martelli D, Kang J, Kuo SH, Kang UJ, Monaco V, et al. Effects of repeated waist-pull perturbations on gait stability in subjects with cerebellar ataxia. Journal of NeuroEngineering and Rehabilitation. 2019 Apr 11;16(1).
Friedrich J, Kordasiewicz H, O’Callaghan BL, Handler HP, Wagener C, Duvick LA, et al. Antisense oligonucleotide–mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles. 2018 Nov 2;3(21).
Chandrasekaran J, Petit E, Park YW, Du Montcel ST, Joers JM, Deelchand DK, et al. Clinically Meaningful MAGNETIC RESONANCE Endpoints Sensitive to Preataxic Spinocerebellar Ataxia Types 1 and 3. Ann Neurol. abril de 2023;93(4):686–701.
This work is licensed under a Creative Commons Attribution 4.0 International License.
Copyright (c) 2024 Julia Moreira Lemos, Jonathan Jordão De Mello Fernandes, Giovanna Cristina Dourado Faria, Ana Luíza Quevedo, Luiz Antonio Lupi Junior
