Evidence and practices of the use of next generation sequencing in patients with undiagnosed autosomal dominant cerebellar ataxias: a review

NOVIS, Luiz Eduardo; SPITZ, Mariana; JARDIM, Marcia; RASKIN, Salmo; TEIVE, Hélio A. G.

doi:10.1590/0004-282X20200017

Luiz Eduardo NOVIS

Universidade do Estado do Rio de Janeiro, Hospital Universitário Pedro Ernesto, Serviço de Neurologia, Rio de Janeiro RJ, Brazil.

https://orcid.org/0000-0003-1479-2953

Mariana SPITZ

Universidade do Estado do Rio de Janeiro, Hospital Universitário Pedro Ernesto, Serviço de Neurologia, Rio de Janeiro RJ, Brazil.

https://orcid.org/0000-0001-7548-2313

Marcia JARDIM

Universidade do Estado do Rio de Janeiro, Hospital Universitário Pedro Ernesto, Serviço de Neurologia, Rio de Janeiro RJ, Brazil.

https://orcid.org/0000-0003-1784-6857

Salmo RASKIN

Laboratório Genetika, Curitiba PR, Brazil.

https://orcid.org/0000-0002-7191-0592

Hélio A. G. TEIVE

Universidade Federal do Paraná, Departamento de Clínica Médica, Serviço de Neurologia, Setor de Distúrbios do Movimento, Hospital das Clínicas, Curitiba PR, Brazil.

https://orcid.org/0000-0002-4045-1178

Correspondence: Luiz Eduardo Novis de Farias; E-mail: luizeduardonovis@hotmail.com

Conflict of interest: There is no conflict of interest to declare.

Figures (3)
Tables (5)

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Figure 1.
Whole exome sequencing³⁴34. Hui P. Next generation sequencing: chemistry, technology and applications. Top Curr Chem. 2014;336:1-18. https://doi.org/10.1007/128_2012_329
https://doi.org/https://doi.org/10.1007/... ^,³⁵35. Galatolo D, Tessa A, Filla A, Santorelli FM. Clinical application of next generation sequencing in hereditary spinocerebellar ataxia: increasing the diagnostic yield and broadening the ataxia-spasticity spectrum. A retrospective analysis. Neurogenetics. 2018 Jan;19(1):1-8. https://doi.org/10.1007/s10048-017-0532-6
https://doi.org/https://doi.org/10.1007/... ^,³⁶36. Xue Y, Ankala A, Wilcox WR, Hegde MR. Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/genome sequencing. Genet Med. 2015;17(6):444-51. https://doi.org/10.1038/gim.2014.122
https://doi.org/https://doi.org/10.1038/... ^,³⁹39. van de Warrenburg B, Schouten M, de Bot S, Vermeer S, Meijer R, Pennings M, et al. Clinical exome sequencing for cerebellar ataxia and spastic paraplegia uncovers novel gene-disease associations and unanticipated rare disorders. Eur J Hum Genet. 2017 Mar;25(3):393-0. https://doi.org/10.1038/ejhg.2016.168
https://doi.org/https://doi.org/10.1038/... ^,⁴²42. Fogel B, Lee H, Deignan J, Strom SP, Kantarci S, Wang X, et al. Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA Neurol. 2014 Oct;71(10):1237-46. https://doi.org/10.1001/jamaneurol.2014.1944
https://doi.org/https://doi.org/10.1001/... ^,⁴⁵45. Coutelier M, Hammer MB, Stevanin G, Monin ML, Davoine C, Mochel F, et al. Efficacy of exome targeted capture sequencing to detect mutations in known cerebellar ataxia genes. JAMA Neurol. 2018 May;75(5):591-9. https://doi.org/10.1001/jamaneurol.2017.5121
https://doi.org/https://doi.org/10.1001/... ^,⁴⁷47. Iqbal Z, Rydning SL, Wedding IM, Koht J, Pihlstrøm L, Rengmark AH, et al. Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia. PLoS One. 2017 Mar;12(3):e0174667. https://doi.org/10.1371/journal.pone.0174667
https://doi.org/https://doi.org/10.1371/... ^,⁵⁰50. Pena L, Jiang YH, Schoch K, Spillmann RC, Walley N, Stong N, et al. Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases. Genet Med. 2018 Apr;20(4):464-9. https://doi.org/10.1038/gim.2017.128
https://doi.org/https://doi.org/10.1038/... ^,⁵¹51. Lelieveld SH, Spielmann M, Mundlos S, Veltman JA, Gilissen C. Comparison of exome and genome sequencing technologies for the complete capture of protein-coding regions. Hum Mutat. 2015 Aug;36(8):815-22. https://doi.org/10.1002/humu.22813
https://doi.org/https://doi.org/10.1002/... .

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Figure 2.
Target sequencing panel³⁴34. Hui P. Next generation sequencing: chemistry, technology and applications. Top Curr Chem. 2014;336:1-18. https://doi.org/10.1007/128_2012_329
https://doi.org/https://doi.org/10.1007/... ^,³⁵35. Galatolo D, Tessa A, Filla A, Santorelli FM. Clinical application of next generation sequencing in hereditary spinocerebellar ataxia: increasing the diagnostic yield and broadening the ataxia-spasticity spectrum. A retrospective analysis. Neurogenetics. 2018 Jan;19(1):1-8. https://doi.org/10.1007/s10048-017-0532-6
https://doi.org/https://doi.org/10.1007/... ^,³⁶36. Xue Y, Ankala A, Wilcox WR, Hegde MR. Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/genome sequencing. Genet Med. 2015;17(6):444-51. https://doi.org/10.1038/gim.2014.122
https://doi.org/https://doi.org/10.1038/... ^,³⁹39. van de Warrenburg B, Schouten M, de Bot S, Vermeer S, Meijer R, Pennings M, et al. Clinical exome sequencing for cerebellar ataxia and spastic paraplegia uncovers novel gene-disease associations and unanticipated rare disorders. Eur J Hum Genet. 2017 Mar;25(3):393-0. https://doi.org/10.1038/ejhg.2016.168
https://doi.org/https://doi.org/10.1038/... ^,⁴²42. Fogel B, Lee H, Deignan J, Strom SP, Kantarci S, Wang X, et al. Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA Neurol. 2014 Oct;71(10):1237-46. https://doi.org/10.1001/jamaneurol.2014.1944
https://doi.org/https://doi.org/10.1001/... ^,⁴⁵45. Coutelier M, Hammer MB, Stevanin G, Monin ML, Davoine C, Mochel F, et al. Efficacy of exome targeted capture sequencing to detect mutations in known cerebellar ataxia genes. JAMA Neurol. 2018 May;75(5):591-9. https://doi.org/10.1001/jamaneurol.2017.5121
https://doi.org/https://doi.org/10.1001/... ^,⁴⁷47. Iqbal Z, Rydning SL, Wedding IM, Koht J, Pihlstrøm L, Rengmark AH, et al. Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia. PLoS One. 2017 Mar;12(3):e0174667. https://doi.org/10.1371/journal.pone.0174667
https://doi.org/https://doi.org/10.1371/... ^,⁵⁰50. Pena L, Jiang YH, Schoch K, Spillmann RC, Walley N, Stong N, et al. Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases. Genet Med. 2018 Apr;20(4):464-9. https://doi.org/10.1038/gim.2017.128
https://doi.org/https://doi.org/10.1038/... ^,⁵¹51. Lelieveld SH, Spielmann M, Mundlos S, Veltman JA, Gilissen C. Comparison of exome and genome sequencing technologies for the complete capture of protein-coding regions. Hum Mutat. 2015 Aug;36(8):815-22. https://doi.org/10.1002/humu.22813
https://doi.org/https://doi.org/10.1002/... .

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Figure 3.
Whole genome sequencing³⁴34. Hui P. Next generation sequencing: chemistry, technology and applications. Top Curr Chem. 2014;336:1-18. https://doi.org/10.1007/128_2012_329
https://doi.org/https://doi.org/10.1007/... ^,³⁵35. Galatolo D, Tessa A, Filla A, Santorelli FM. Clinical application of next generation sequencing in hereditary spinocerebellar ataxia: increasing the diagnostic yield and broadening the ataxia-spasticity spectrum. A retrospective analysis. Neurogenetics. 2018 Jan;19(1):1-8. https://doi.org/10.1007/s10048-017-0532-6
https://doi.org/https://doi.org/10.1007/... ^,³⁶36. Xue Y, Ankala A, Wilcox WR, Hegde MR. Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/genome sequencing. Genet Med. 2015;17(6):444-51. https://doi.org/10.1038/gim.2014.122
https://doi.org/https://doi.org/10.1038/... ^,³⁹39. van de Warrenburg B, Schouten M, de Bot S, Vermeer S, Meijer R, Pennings M, et al. Clinical exome sequencing for cerebellar ataxia and spastic paraplegia uncovers novel gene-disease associations and unanticipated rare disorders. Eur J Hum Genet. 2017 Mar;25(3):393-0. https://doi.org/10.1038/ejhg.2016.168
https://doi.org/https://doi.org/10.1038/... ^,⁴²42. Fogel B, Lee H, Deignan J, Strom SP, Kantarci S, Wang X, et al. Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA Neurol. 2014 Oct;71(10):1237-46. https://doi.org/10.1001/jamaneurol.2014.1944
https://doi.org/https://doi.org/10.1001/... ^,⁴⁵45. Coutelier M, Hammer MB, Stevanin G, Monin ML, Davoine C, Mochel F, et al. Efficacy of exome targeted capture sequencing to detect mutations in known cerebellar ataxia genes. JAMA Neurol. 2018 May;75(5):591-9. https://doi.org/10.1001/jamaneurol.2017.5121
https://doi.org/https://doi.org/10.1001/... ^,⁴⁷47. Iqbal Z, Rydning SL, Wedding IM, Koht J, Pihlstrøm L, Rengmark AH, et al. Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia. PLoS One. 2017 Mar;12(3):e0174667. https://doi.org/10.1371/journal.pone.0174667
https://doi.org/https://doi.org/10.1371/... ^,⁵⁰50. Pena L, Jiang YH, Schoch K, Spillmann RC, Walley N, Stong N, et al. Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases. Genet Med. 2018 Apr;20(4):464-9. https://doi.org/10.1038/gim.2017.128
https://doi.org/https://doi.org/10.1038/... ^,⁵¹51. Lelieveld SH, Spielmann M, Mundlos S, Veltman JA, Gilissen C. Comparison of exome and genome sequencing technologies for the complete capture of protein-coding regions. Hum Mutat. 2015 Aug;36(8):815-22. https://doi.org/10.1002/humu.22813
https://doi.org/https://doi.org/10.1002/... .

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Table 1.
Autossomal dominant cerebellar ataxia clinical classification.

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Table 2.
Phenotype characteristics of each spinocerebellar ataxia.

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Table 3.
Prevalence of spinocerebellar ataxias across the world.

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Table 4.
Prevalence of spinocerebellar ataxia in Brazil.

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Table 5.
Main mutations found with next-generation sequencing technology.

Figure 1. Whole exome sequencing³⁴34. Hui P. Next generation sequencing: chemistry, technology and applications. Top Curr Chem. 2014;336:1-18. https://doi.org/10.1007/128_2012_329
https://doi.org/https://doi.org/10.1007/... ^,³⁵35. Galatolo D, Tessa A, Filla A, Santorelli FM. Clinical application of next generation sequencing in hereditary spinocerebellar ataxia: increasing the diagnostic yield and broadening the ataxia-spasticity spectrum. A retrospective analysis. Neurogenetics. 2018 Jan;19(1):1-8. https://doi.org/10.1007/s10048-017-0532-6
https://doi.org/https://doi.org/10.1007/... ^,³⁶36. Xue Y, Ankala A, Wilcox WR, Hegde MR. Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/genome sequencing. Genet Med. 2015;17(6):444-51. https://doi.org/10.1038/gim.2014.122
https://doi.org/https://doi.org/10.1038/... ^,³⁹39. van de Warrenburg B, Schouten M, de Bot S, Vermeer S, Meijer R, Pennings M, et al. Clinical exome sequencing for cerebellar ataxia and spastic paraplegia uncovers novel gene-disease associations and unanticipated rare disorders. Eur J Hum Genet. 2017 Mar;25(3):393-0. https://doi.org/10.1038/ejhg.2016.168
https://doi.org/https://doi.org/10.1038/... ^,⁴²42. Fogel B, Lee H, Deignan J, Strom SP, Kantarci S, Wang X, et al. Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA Neurol. 2014 Oct;71(10):1237-46. https://doi.org/10.1001/jamaneurol.2014.1944
https://doi.org/https://doi.org/10.1001/... ^,⁴⁵45. Coutelier M, Hammer MB, Stevanin G, Monin ML, Davoine C, Mochel F, et al. Efficacy of exome targeted capture sequencing to detect mutations in known cerebellar ataxia genes. JAMA Neurol. 2018 May;75(5):591-9. https://doi.org/10.1001/jamaneurol.2017.5121
https://doi.org/https://doi.org/10.1001/... ^,⁴⁷47. Iqbal Z, Rydning SL, Wedding IM, Koht J, Pihlstrøm L, Rengmark AH, et al. Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia. PLoS One. 2017 Mar;12(3):e0174667. https://doi.org/10.1371/journal.pone.0174667
https://doi.org/https://doi.org/10.1371/... ^,⁵⁰50. Pena L, Jiang YH, Schoch K, Spillmann RC, Walley N, Stong N, et al. Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases. Genet Med. 2018 Apr;20(4):464-9. https://doi.org/10.1038/gim.2017.128
https://doi.org/https://doi.org/10.1038/... ^,⁵¹51. Lelieveld SH, Spielmann M, Mundlos S, Veltman JA, Gilissen C. Comparison of exome and genome sequencing technologies for the complete capture of protein-coding regions. Hum Mutat. 2015 Aug;36(8):815-22. https://doi.org/10.1002/humu.22813
https://doi.org/https://doi.org/10.1002/... .

Figure 2. Target sequencing panel³⁴34. Hui P. Next generation sequencing: chemistry, technology and applications. Top Curr Chem. 2014;336:1-18. https://doi.org/10.1007/128_2012_329
https://doi.org/https://doi.org/10.1007/... ^,³⁵35. Galatolo D, Tessa A, Filla A, Santorelli FM. Clinical application of next generation sequencing in hereditary spinocerebellar ataxia: increasing the diagnostic yield and broadening the ataxia-spasticity spectrum. A retrospective analysis. Neurogenetics. 2018 Jan;19(1):1-8. https://doi.org/10.1007/s10048-017-0532-6
https://doi.org/https://doi.org/10.1007/... ^,³⁶36. Xue Y, Ankala A, Wilcox WR, Hegde MR. Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/genome sequencing. Genet Med. 2015;17(6):444-51. https://doi.org/10.1038/gim.2014.122
https://doi.org/https://doi.org/10.1038/... ^,³⁹39. van de Warrenburg B, Schouten M, de Bot S, Vermeer S, Meijer R, Pennings M, et al. Clinical exome sequencing for cerebellar ataxia and spastic paraplegia uncovers novel gene-disease associations and unanticipated rare disorders. Eur J Hum Genet. 2017 Mar;25(3):393-0. https://doi.org/10.1038/ejhg.2016.168
https://doi.org/https://doi.org/10.1038/... ^,⁴²42. Fogel B, Lee H, Deignan J, Strom SP, Kantarci S, Wang X, et al. Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA Neurol. 2014 Oct;71(10):1237-46. https://doi.org/10.1001/jamaneurol.2014.1944
https://doi.org/https://doi.org/10.1001/... ^,⁴⁵45. Coutelier M, Hammer MB, Stevanin G, Monin ML, Davoine C, Mochel F, et al. Efficacy of exome targeted capture sequencing to detect mutations in known cerebellar ataxia genes. JAMA Neurol. 2018 May;75(5):591-9. https://doi.org/10.1001/jamaneurol.2017.5121
https://doi.org/https://doi.org/10.1001/... ^,⁴⁷47. Iqbal Z, Rydning SL, Wedding IM, Koht J, Pihlstrøm L, Rengmark AH, et al. Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia. PLoS One. 2017 Mar;12(3):e0174667. https://doi.org/10.1371/journal.pone.0174667
https://doi.org/https://doi.org/10.1371/... ^,⁵⁰50. Pena L, Jiang YH, Schoch K, Spillmann RC, Walley N, Stong N, et al. Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases. Genet Med. 2018 Apr;20(4):464-9. https://doi.org/10.1038/gim.2017.128
https://doi.org/https://doi.org/10.1038/... ^,⁵¹51. Lelieveld SH, Spielmann M, Mundlos S, Veltman JA, Gilissen C. Comparison of exome and genome sequencing technologies for the complete capture of protein-coding regions. Hum Mutat. 2015 Aug;36(8):815-22. https://doi.org/10.1002/humu.22813
https://doi.org/https://doi.org/10.1002/... .

Figure 3. Whole genome sequencing³⁴34. Hui P. Next generation sequencing: chemistry, technology and applications. Top Curr Chem. 2014;336:1-18. https://doi.org/10.1007/128_2012_329
https://doi.org/https://doi.org/10.1007/... ^,³⁵35. Galatolo D, Tessa A, Filla A, Santorelli FM. Clinical application of next generation sequencing in hereditary spinocerebellar ataxia: increasing the diagnostic yield and broadening the ataxia-spasticity spectrum. A retrospective analysis. Neurogenetics. 2018 Jan;19(1):1-8. https://doi.org/10.1007/s10048-017-0532-6
https://doi.org/https://doi.org/10.1007/... ^,³⁶36. Xue Y, Ankala A, Wilcox WR, Hegde MR. Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/genome sequencing. Genet Med. 2015;17(6):444-51. https://doi.org/10.1038/gim.2014.122
https://doi.org/https://doi.org/10.1038/... ^,³⁹39. van de Warrenburg B, Schouten M, de Bot S, Vermeer S, Meijer R, Pennings M, et al. Clinical exome sequencing for cerebellar ataxia and spastic paraplegia uncovers novel gene-disease associations and unanticipated rare disorders. Eur J Hum Genet. 2017 Mar;25(3):393-0. https://doi.org/10.1038/ejhg.2016.168
https://doi.org/https://doi.org/10.1038/... ^,⁴²42. Fogel B, Lee H, Deignan J, Strom SP, Kantarci S, Wang X, et al. Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA Neurol. 2014 Oct;71(10):1237-46. https://doi.org/10.1001/jamaneurol.2014.1944
https://doi.org/https://doi.org/10.1001/... ^,⁴⁵45. Coutelier M, Hammer MB, Stevanin G, Monin ML, Davoine C, Mochel F, et al. Efficacy of exome targeted capture sequencing to detect mutations in known cerebellar ataxia genes. JAMA Neurol. 2018 May;75(5):591-9. https://doi.org/10.1001/jamaneurol.2017.5121
https://doi.org/https://doi.org/10.1001/... ^,⁴⁷47. Iqbal Z, Rydning SL, Wedding IM, Koht J, Pihlstrøm L, Rengmark AH, et al. Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia. PLoS One. 2017 Mar;12(3):e0174667. https://doi.org/10.1371/journal.pone.0174667
https://doi.org/https://doi.org/10.1371/... ^,⁵⁰50. Pena L, Jiang YH, Schoch K, Spillmann RC, Walley N, Stong N, et al. Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases. Genet Med. 2018 Apr;20(4):464-9. https://doi.org/10.1038/gim.2017.128
https://doi.org/https://doi.org/10.1038/... ^,⁵¹51. Lelieveld SH, Spielmann M, Mundlos S, Veltman JA, Gilissen C. Comparison of exome and genome sequencing technologies for the complete capture of protein-coding regions. Hum Mutat. 2015 Aug;36(8):815-22. https://doi.org/10.1002/humu.22813
https://doi.org/https://doi.org/10.1002/... .

Associated clinical features	Genetic subtypes
Peripheral neuropathy	1, 2, 3, 4, 18, 25, 38, 43, 46
Pyramidal signs	1, 3, 7, 8, 10, 14, 15, 17, 35, 40, 43
Dystonia	3, 14, 17, 20, 35
Myoclonus	14
Parkinsonism	2, 3, 10, 14, 17, 19/22, 21
Tremor	12, 15, 27
Chorea	17, 27, DRPLA*
Cognitive impairment	2, 8, 13, 17, 19/22, 21, 36, 44, 48, DRPLA
Psychiatric symptoms	2, 17, 48
Ophthalmoplegia	2, 3, 28, 40
Visual impairment	7
Face/tongue fasciculation	36
Ichthyosiform plaques	34
Seizures	10, 19/22, ATN 1**
Narcolepsy	DNMT1***
Hearing loss	31, 36, DNMT1

Country	n	SCA1	SCA2	SCA3	SCA6	SCA7	SCA8	SCA 10	SCA 12	SCA14	SCA 17	DRPLA	und.	References
Mexico	108	ND	45,4	12	ND	7,4	ND	13,9	ND	NR	2,8	ND	18	Alonso et al.¹⁵15. Alonso E, Martínez-Ruano L, De Biase I, Mader C, Ochoa A, Yescas P, et al. Distinct distribution of autosomal dominant spinocerebellar ataxia in the Mexican population. Mov Disord. 2007 May;22(7):1050-3. http://dx.doi.org/10.1002/mds.21470 https://doi.org/http://dx.doi.org/10.100...
Portugal	199	ND	2,5	80,5	<1	1,25	1	ND	ND	<1	<1	8,5	26,5*	Coutinho et al.¹²12. Coutinho P, Ruano L, Loureiro JL, Cruz VT, Barros J, Tuna A, et al. Hereditary ataxia and spastic paraplegia in Portugal: a population-based prevalence study. JAMA Neurol. 2013 Jun;70(6):746-55. https://doi.org/10.1001/jamaneurol.2013.1707 https://doi.org/https://doi.org/10.1001/...
Cuba	177	ND	86,8	1,2	ND	ND	NP	NP	NR	NP	ND	ND	12	Velázquez et al. 2009 ¹⁶16. Velázquez-Pérez L, Santos FN, García R, Paneque HM, Hechavarría PR. Epidemiology of Cuban hereditary ataxia. Rev Neurol. 2001 Apr;32(7):606-11.
Italy	225	21	24	<1	<1	<1	<1	ND	ND	NP	<1	<1	41	Brusco et al.¹⁴14. Brusco A, Gellera C, Cagnoli C, Saluto A, Castucci A, Michielotto C, et al. Molecular genetics of hereditary spinocerebellar ataxia: mutation analysis of spinocerebellar ataxia genes and CAG/CTG repeat expansion detection in 225 Italian families. Arch Neurol. 2004 May;61(5):727-33. https://doi.org/10.1001/archneur.61.5.727 https://doi.org/https://doi.org/10.1001/...
Australia	88	16	6	12	17	2	NP	NP	NR	NP	NP	ND	41	Storey et al.¹³13. Storey E, du Sart D, Shaw J, Lorentzos P, Kelly L, McKinley Gardner R, et al. Frequency of spinocerebellar ataxia types 1, 2, 3, 6, and 7 in Australian patients with spinocerebellar ataxia. Am J Med Genet. 2000 Dec;95(4):351-7. https://doi.org/10.1002/1096-8628(20001211)95:4%3C351::aid-ajmg10%3E3.0.co;2-r https://doi.org/https://doi.org/10.1002/...
China	85	4,7	5,9	48,2	ND	ND	NP	NP	NR	NP	NP	ND	41,2	Tang et al.¹⁷17. Tang B, Liu C, Shen L, Dai H, Pan Q, Jing L, et al. Frequency of SCA1, SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA CAG trinucleotide repeat expansion in patients with hereditary spinocerebellar ataxia from Chinese kindreds. Arch Neurol. 2000 Apr;57(4):540-4. https://doi.org/10.1001/archneur.57.4.540 https://doi.org/https://doi.org/10.1001/...
Japan (Honshu)	101	ND	5,9	33,7	5,9	NP	NP	NP	NR	NP	NP	19,8	?	Watanabe et al.¹⁸18. Watanabe H, Tanaka F, Matsumoto M, Doyu M, Ando T, Mitsuma T, et al. Frequency analysis of autosomal dominant cerebellar ataxias in Japanese patients and clinical characterization of spinocerebellar ataxia type 6. Clin Genet. 1998 Jan;53(1):13-9. https://doi.org/10.1034/j.1399-0004.1998.531530104.x https://doi.org/https://doi.org/10.1034/...
Finland	49	4	2	ND	2	12	18	ND	ND	NP	2	ND	61	Juvonen et al. ¹⁹19. Juvonen V, Hietala M, Kairisto V, Savontaus ML. The occurrence of dominant spinocerebellar ataxias among 251 Finnish ataxia patients and the role of predisposing large normal alleles in a genetically isolated population. Acta Neurol Scand. 2005 Mar;111(3):154-62. https://doi.org/10.1111/j.1600-0404.2005.00349.x https://doi.org/https://doi.org/10.1111/...
Germany	77	9	10%	42	22	NP	NP	NP	NR	NP	NP	NP	17	Schöls et al.²2. Schöls L, Amoiridis G, Büttner T, Przuntek H, Epplen JT, Riess O. Autosomal dominant cerebellar ataxia: Phenotype differences in genetically defined subtypes? Ann Neurol. 1997 Dec;42(6):924-32. https://doi.org/10.1002/ana.410420615 https://doi.org/https://doi.org/10.1002/...
Norway	48	<1	<1	<1	ND	NP	NP	NP	NR	NP	NP	NP	92	Erichsen et al.¹¹11. Erichsen AK, Koht J, Stray-Pedersen A, Abdelnoor M, Tallaksen CM. Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway: a population-based study. Brain. 2009 Jun;132(Pt 6):1577-88. https://doi.org/10.1093/brain/awp056 https://doi.org/https://doi.org/10.1093/...
India	77	15,6	24,7	2,6	ND	2,6	ND	NP	6,5	NP	NP	ND	48	Srivastava et al.²⁰20. Srivastava AK, Choudhry S, Gopinath MS, Roy S, Tripathi M, Brahmachari SK, et al. Molecular and clinical correlation in five Indian families with spinocerebellar ataxia 12. Ann Neurol. 2001 Dec;50(6):796-800. https://doi.org/10.1002/ana.10048 https://doi.org/https://doi.org/10.1002/...

Reference	n	SCA1	SCA2	SCA3	SCA6	SCA7	SCA 8	SCA10	SCA12	SCA17	DRPLA	und.
Silveira²⁸28. Silveira I, Lopes-Cendes I, Kish S, Maciel P, Gaspar C, Coutinho P, et al. Frequency of spinocerebellar ataxia type 1, dentatorubropallidoluysian atrophy, and Machado-Joseph disease mutations in a large group of spinocerebellar ataxia patients. Neurology. 1996 Jan;46(1):214-8.	67	5%	NP	55%	NP	NP	NP	NP	NP	NP	2%	61,20%
Lopes-Cendes²⁹29. Lopes-Cendes I , Teive HG , Calcagnotto ME , Da Costa JC , Cardoso F , Viana E, et al. Frequência das diferentes mutações causadoras de ataxia espinocerebelar (SCA1, SCA2, MJD / SCA3 e DRPLA) em um grande grupo de pacientes brasileiros. Arq Neuropsiquiatr. 1997 Sep;55(3B):519-29.	54	6%	9%	44%	NP	NP	NP	NP	NP	NP	NP	40%
Jardim²¹21. Jardim LB, Pereira ML, Silveira I, Ferro A, Sequeiros J, Giugliani R. Neurologic findings in Machado-Joseph disease. Relation with disease duration, subtypes, and (CAG). Arch Neurol. 2001 Jun;58(6):899-904. https://doi.org/10.1001/archneur.58.6.899 https://doi.org/https://doi.org/10.1001/...	52	ND	ND	92%	ND	2%	*	NP	NP	NP	ND	6%
Trott³⁰30. A Trott, LB Jardima, HT Ludwiga, JAM Sautea, O Artigala’s, et al. Letter to the editor: Spinocerebellar ataxias in 114 Brazilian families: clinical and molecular findings. Clin Genet. 2006;70:173-6. https://doi.org10.1111/j.1399-0004.2006.00656.x https://doi.org/https://doi.org10.1111/j...	114	ND	4,40%	84,20%	1,80%	ND	NP	1,80%	NP	ND	ND	6%
Freund³¹31. Freund AA, Scola RH, Teive HA, Arndt RC, Costa-Ribeiro MC, Alle LF, Werneck LC. Microsatellite and allele frequency in unaffected and affected individuals. Arq Neuropsiquiatr. 2009;67(4):1124-32.	115	ND	5,20%	21,70%	0,80%	2,60%	NP	NP	NP	NP	NP	69,50%
Teive²³23. Teive HAG, Munhoz RP, Arruda WO, Lopes-Cendes I, Raskin S, Werneck LC, et al. Spinocerebellar ataxias: genotype-phenotype correlations in 104 Brazilian families. Clinics. 2012;67(5):443-9. https://doi.org/10.6061/clinics/2012(05)07 https://doi.org/https://doi.org/10.6061/...	104	2,90%	7,20%	72,50%	ND	4,30%	NP	11,60%	NP	NP	NP	33,70%
Cintra²²22. Cintra VP, Lourenço CM, Marques SE, Oliveira LM, Tumas V, Marques Junior W. Mutational screening of 320 Brazilian patients with autosomal dominant spinocerebellar ataxia. J Neurol Sci. 2014 Oct;347(1-2):375-9. https://doi.org/10.1016/j.jns.2014.10.036 https://doi.org/https://doi.org/10.1016/...	150	6%	3%	81%	1,50%	7%	0,80%	0,80%	NP	NP	NP	12,70%
Castilhos²⁵25. de Castilhos RM, Furtado GV, Gheno TC, Schaeffer P, Russo A, Barsottini O, et al. Spinocerebellar ataxias in Brazil - frequencies and modulating effects of related genes. Cerebellum. 2014 Feb;13(1):17-28. https://doi.org/10.1007/s12311-013-0510-y https://doi.org/https://doi.org/10.1007/...	359	5,20%	7,80%	59,60%	1,40%	5,60%	NP	3,30%	ND	ND	ND	18,10%
Teive²⁶26. Nascimento FA, Rodrigues VOR, Pelloso FC, Camargo CHF, Moro A, Raskin S, et al. Spinocerebellar ataxias in Southern Brazil: Genotypic and phenotypic evaluation of 213 families. Clin Neurol Neurosurg 2019; Sep; 184: 105427. https://doi.org/10.1016/j.clineuro.2019.105427 https://doi.org/https://doi.org/10.1016/...	460	4.3%	6.5%	45.7%	0.6%	1.8%	NP	18.3%	NP	NP	NP	22.8%
Braga-Neto²⁷27. Braga-Neto P, Pedroso JL, Furtado GV, Gheno TC, Saraiva-Pereira ML, Jardim LB, et al. Dentatorubro-Pallidoluysian Atrophy (DRPLA) among 700 families with ataxia in Brazil. Cerebellum. 2017 Aug;16(4):812-6. https://doi.org/10.1007/s12311-017-0862-9 https://doi.org/https://doi.org/10.1007/...	487	4,30%	11,50%	53,60%	1,20%	4,50%	NP	2,20%	0,20%	ND	0,20%	22.3%

Authors	Genes mutations
Coutelier et al.⁴⁴44. Coutelier M, Coarelli G, Monin ML, Konop J, Davoine CS, Tesson C, et al. A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies. Brain. 2017 Jun;140(6):1579-94. https://doi.org/10.1093/brain/awx081 https://doi.org/https://doi.org/10.1093/...	CACNA1A (16 cases); Del. ITPR1(11 cases); SPG 7 (9 cases), AFG3L2 (7 cases)
Hadjivassiliou et al.⁴³43. Hadjivassiliou M, Martindale J, Shanmugarajah P, Grünewald RA, Sarrigiannis PG, Beauchamp N, et al. Causes of progressive cerebellar ataxia: prospective evaluation of 1500 patients. J Neurol Neurosurg Psychiatry. 2017 Apr;88(4):301-9. https://doi.org/10.1136/jnnp-2016-314863 https://doi.org/https://doi.org/10.1136/...	CACNA1A (11 cases), PRKCG (5 cases), SPTBN2 (4 cases), SPG 7 (4 cases)
Coutelier et al.⁴⁵45. Coutelier M, Hammer MB, Stevanin G, Monin ML, Davoine C, Mochel F, et al. Efficacy of exome targeted capture sequencing to detect mutations in known cerebellar ataxia genes. JAMA Neurol. 2018 May;75(5):591-9. https://doi.org/10.1001/jamaneurol.2017.5121 https://doi.org/https://doi.org/10.1001/...	SPG 7 (14 cases); SACS (8 cases); SEXT (7 cases), SYNE 1 (6 cases), CACNA1A (6 cases)
Németh et al.⁴¹41. Németh AH, Kwasniewska AC, Lise S, Parolin Schnekenberg R, Becker EB, Bera KD, et al. Next generation sequencing for molecular diagnosis of neurological disorders using ataxias as a model. Brain. 2013 Oct;136(Pt 10):3106-18. https://doi.org/10.1093/brain/awt236 https://doi.org/https://doi.org/10.1093/...	SEXT (2 cases), TTBK2 (1 case), PRKCG (1 case), MRE11A (1 case), SACS (1 case)
Fogel et al.⁴²42. Fogel B, Lee H, Deignan J, Strom SP, Kantarci S, Wang X, et al. Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA Neurol. 2014 Oct;71(10):1237-46. https://doi.org/10.1001/jamaneurol.2014.1944 https://doi.org/https://doi.org/10.1001/...	SYNE 1 (3 cases), SPG 7 (2 cases)
Pyle et al.⁴⁰40. Pyle A, Smertenko T, Bargiela D, Helen Griffin, Jennifer Duff, Marie Appleton, et al. Exome sequencing in undiagnosed inherited and sporadic ataxias. Brain. 2015 Feb;138(2):276-83. https:// doi.org/10.1093/brain/awu348 https://doi.org/https:// doi.org/10.1093...	SPG 7 (3 cases), SACS (3 cases), NPC1 (2 cases), TUBB4A (2 cases)

[1] Correspondence: Luiz Eduardo Novis de Farias; E-mail: luizeduardonovis@hotmail.com

ADCA 1	SCA 1-4, 8, 12-14, 15, 17-22, 25, 27, 28, 31, 32, 34-37, 38, 42-44, 46-48, DRPLA, DNMT1
ADCA 2	SCA 7
ADCA 3	SCA 5, 6, 10, 11, 23, 26, 30, 37, 41, 45

Brasil

Brasil

Evidence and practices of the use of next generation sequencing in patients with undiagnosed autosomal dominant cerebellar ataxias: a review

Evidências e práticas do uso do sequenciamento de nova geração em pacientes com ataxias cerebelares autossômicas dominantes não diagnosticadas: uma revisão

ABSTRACT