Skip to main content
Top
Published in:

16-01-2025 | Spinocerebellar Ataxia | Genetics (E.M. Valente, Section Editor) Free for a limited time

Recent Advances in the Genetics of Ataxias: An Update on Novel Autosomal Dominant Repeat Expansions

Authors: David Pellerin, Pablo Iruzubieta, Isaac R. L. Xu, Matt C. Danzi, Andrea Cortese, Matthis Synofzik, Henry Houlden, Stephan Zuchner, Bernard Brais

Published in: Current Neurology and Neuroscience Reports | Issue 1/2025

Login to get access

Abstract

Purpose of Review

Autosomal dominant cerebellar ataxias, also known as spinocerebellar ataxias (SCAs), are genetically and clinically diverse neurodegenerative disorders characterized by progressive cerebellar dysfunction. Despite advances in sequencing technologies, a large proportion of patients with SCA still lack a definitive genetic diagnosis. The advent of advanced bioinformatic tools and emerging genomics technologies, such as long-read sequencing, offers an unparalleled opportunity to close the diagnostic gap for hereditary ataxias. This article reviews the recently identified repeat expansion SCAs and describes their molecular basis, epidemiology, and clinical features.

Recent Findings

Leveraging advanced bioinformatic tools and long-read sequencing, recent studies have identified novel pathogenic short tandem repeat expansions in FGF14, ZFHX3, and THAP11, associated with SCA27B, SCA4, and SCA51, respectively. SCA27B, caused by an intronic (GAA)•(TTC) repeat expansion, has emerged as one of the most common forms of adult-onset hereditary ataxias, especially in European populations. The coding GGC repeat expansion in ZFHX3 causing SCA4 was identified more than 25 years after the disorder’s initial clinical description and appears to be a rare cause of ataxia outside northern Europe. SCA51, caused by a coding CAG repeat expansion, is overall rare and has been described in a small number of patients.

Summary

The recent identification of three novel pathogenic repeat expansions underscores the importance of this class of genomic variation in the pathogenesis of SCAs. Progress in sequencing technologies holds promise for closing the diagnostic gap in SCAs and guiding the development of therapeutic strategies for ataxia.
Literature
1.
2.
go back to reference Sullivan R, Yau WY, O’Connor E, Houlden H. Spinocerebellar ataxia: an update. J Neurol. 2019;266(2):533–44.CrossRefPubMed Sullivan R, Yau WY, O’Connor E, Houlden H. Spinocerebellar ataxia: an update. J Neurol. 2019;266(2):533–44.CrossRefPubMed
3.
go back to reference Coarelli G, Coutelier M, Durr A. Autosomal dominant cerebellar ataxias: new genes and progress towards treatments. Lancet Neurol. 2023;22(8):735–49.PubMedCrossRef Coarelli G, Coutelier M, Durr A. Autosomal dominant cerebellar ataxias: new genes and progress towards treatments. Lancet Neurol. 2023;22(8):735–49.PubMedCrossRef
4.
go back to reference Ruano L, Melo C, Silva MC, Coutinho P. The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology. 2014;42(3):174–83.PubMedCrossRef Ruano L, Melo C, Silva MC, Coutinho P. The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology. 2014;42(3):174–83.PubMedCrossRef
5.
go back to reference Rudaks LI, Yeow D, Ng K, Deveson IW, Kennerson ML, Kumar KR. An Update on the Adult-Onset Hereditary Cerebellar Ataxias: Novel Genetic Causes and New Diagnostic Approaches. Cerebellum. 2024;23(5):2152–68.PubMedPubMedCentralCrossRef Rudaks LI, Yeow D, Ng K, Deveson IW, Kennerson ML, Kumar KR. An Update on the Adult-Onset Hereditary Cerebellar Ataxias: Novel Genetic Causes and New Diagnostic Approaches. Cerebellum. 2024;23(5):2152–68.PubMedPubMedCentralCrossRef
6.
go back to reference Hengel H, Pellerin D, Wilke C, Fleszar Z, Brais B, Haack T, et al. As Frequent as Polyglutamine Spinocerebellar Ataxias: SCA27B in a Large German Autosomal Dominant Ataxia Cohort. Mov Disord. 2023;38(8):1557–8.PubMedCrossRef Hengel H, Pellerin D, Wilke C, Fleszar Z, Brais B, Haack T, et al. As Frequent as Polyglutamine Spinocerebellar Ataxias: SCA27B in a Large German Autosomal Dominant Ataxia Cohort. Mov Disord. 2023;38(8):1557–8.PubMedCrossRef
7.
go back to reference Durr A. Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond. Lancet Neurol. 2010;9(9):885–94.PubMedCrossRef Durr A. Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond. Lancet Neurol. 2010;9(9):885–94.PubMedCrossRef
8.
go back to reference Chen Z, Wang P, Wang C, Peng Y, Hou X, Zhou X, et al. Updated frequency analysis of spinocerebellar ataxia in China. Brain. 2018;141(4):e22.PubMedCrossRef Chen Z, Wang P, Wang C, Peng Y, Hou X, Zhou X, et al. Updated frequency analysis of spinocerebellar ataxia in China. Brain. 2018;141(4):e22.PubMedCrossRef
9.
go back to reference Alshimemeri S, Abo Alsamh D, Zhou L, Furtado S, Kraft S, Bruno V, et al. Demographics and Clinical Characteristics of Autosomal Dominant Spinocerebellar Ataxia in Canada. Mov Disord Clin Pract. 2023;10(3):440–51.PubMedPubMedCentralCrossRef Alshimemeri S, Abo Alsamh D, Zhou L, Furtado S, Kraft S, Bruno V, et al. Demographics and Clinical Characteristics of Autosomal Dominant Spinocerebellar Ataxia in Canada. Mov Disord Clin Pract. 2023;10(3):440–51.PubMedPubMedCentralCrossRef
10.
go back to reference Perlman S. Hereditary Ataxia Overview. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews(®). Seattle (WA): University of Washington, Seattle Copyright © 1993–2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved 1993 Perlman S. Hereditary Ataxia Overview. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews(®). Seattle (WA): University of Washington, Seattle Copyright © 1993–2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved 1993
11.
go back to reference 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;70(6):746–55.PubMedCrossRef 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;70(6):746–55.PubMedCrossRef
12.
go back to reference Barbier M, Bahlo M, Pennisi A, Jacoupy M, Tankard RM, Ewenczyk C, et al. Heterozygous PNPT1 Variants Cause Spinocerebellar Ataxia Type 25. Ann Neurol. 2022;92(1):122–37.PubMedCrossRef Barbier M, Bahlo M, Pennisi A, Jacoupy M, Tankard RM, Ewenczyk C, et al. Heterozygous PNPT1 Variants Cause Spinocerebellar Ataxia Type 25. Ann Neurol. 2022;92(1):122–37.PubMedCrossRef
13.
go back to reference Coutelier M, Jacoupy M, Janer A, Renaud F, Auger N, Saripella GV, et al. NPTX1 mutations trigger endoplasmic reticulum stress and cause autosomal dominant cerebellar ataxia. Brain. 2022;145(4):1519–34.PubMedCrossRef Coutelier M, Jacoupy M, Janer A, Renaud F, Auger N, Saripella GV, et al. NPTX1 mutations trigger endoplasmic reticulum stress and cause autosomal dominant cerebellar ataxia. Brain. 2022;145(4):1519–34.PubMedCrossRef
14.
go back to reference Corral-Juan M, Casquero P, Giraldo-Restrepo N, Laurie S, Martinez-Piñeiro A, Mateo-Montero RC, et al. New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49). Brain Commun. 2022;4(2):fcac030.PubMedPubMedCentralCrossRef Corral-Juan M, Casquero P, Giraldo-Restrepo N, Laurie S, Martinez-Piñeiro A, Mateo-Montero RC, et al. New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49). Brain Commun. 2022;4(2):fcac030.PubMedPubMedCentralCrossRef
16.
go back to reference Kernohan KD, Boycott KM. The expanding diagnostic toolbox for rare genetic diseases. Nat Rev Genet. 2024;25(6):401–15.PubMedCrossRef Kernohan KD, Boycott KM. The expanding diagnostic toolbox for rare genetic diseases. Nat Rev Genet. 2024;25(6):401–15.PubMedCrossRef
17.
go back to reference Tanudisastro HA, Deveson IW, Dashnow H, MacArthur DG. Sequencing and characterizing short tandem repeats in the human genome. Nat Rev Genet. 2024;25(7):460–75.PubMedCrossRef Tanudisastro HA, Deveson IW, Dashnow H, MacArthur DG. Sequencing and characterizing short tandem repeats in the human genome. Nat Rev Genet. 2024;25(7):460–75.PubMedCrossRef
18.
go back to reference Dolzhenko E, English A, Dashnow H, De Sena Brandine G, Mokveld T, Rowell WJ, Karniski C, Kronenberg Z, Danzi MC, Cheung WA, Bi C, Farrow E, Wenger A, Chua KP, Martínez-Cerdeño V, Bartley TD, Jin P, Nelson DL, Zuchner S, Pastinen T, ... Eberle MA. Characterization and visualization of tandem repeats at genome scale. Nat Biotechnol. 2024;42(10):1606–14. https://doi.org/10.1038/s41587-023-02057-3.CrossRefPubMed Dolzhenko E, English A, Dashnow H, De Sena Brandine G, Mokveld T, Rowell WJ, Karniski C, Kronenberg Z, Danzi MC, Cheung WA, Bi C, Farrow E, Wenger A, Chua KP, Martínez-Cerdeño V, Bartley TD, Jin P, Nelson DL, Zuchner S, Pastinen T, ... Eberle MA. Characterization and visualization of tandem repeats at genome scale. Nat Biotechnol. 2024;42(10):1606–14. https://​doi.​org/​10.​1038/​s41587-023-02057-3.CrossRefPubMed
19.
go back to reference Dolzhenko E, Bennett MF, Richmond PA, Trost B, Chen S, van Vugt J, et al. ExpansionHunter Denovo: a computational method for locating known and novel repeat expansions in short-read sequencing data. Genome Biol. 2020;21(1):102.PubMedPubMedCentralCrossRef Dolzhenko E, Bennett MF, Richmond PA, Trost B, Chen S, van Vugt J, et al. ExpansionHunter Denovo: a computational method for locating known and novel repeat expansions in short-read sequencing data. Genome Biol. 2020;21(1):102.PubMedPubMedCentralCrossRef
20.
go back to reference Danzi MC, Dohrn MF, Fazal S, Beijer D, Rebelo AP, Cintra V, et al. Deep structured learning for variant prioritization in Mendelian diseases. Nat Commun. 2023;14(1):4167.PubMedPubMedCentralCrossRef Danzi MC, Dohrn MF, Fazal S, Beijer D, Rebelo AP, Cintra V, et al. Deep structured learning for variant prioritization in Mendelian diseases. Nat Commun. 2023;14(1):4167.PubMedPubMedCentralCrossRef
21.
go back to reference Fazal S, Danzi MC, Xu I, Kobren SN, Sunyaev S, Reuter C, et al. RExPRT: a machine learning tool to predict pathogenicity of tandem repeat loci. Genome Biol. 2024;25(1):39.PubMedPubMedCentralCrossRef Fazal S, Danzi MC, Xu I, Kobren SN, Sunyaev S, Reuter C, et al. RExPRT: a machine learning tool to predict pathogenicity of tandem repeat loci. Genome Biol. 2024;25(1):39.PubMedPubMedCentralCrossRef
22.
go back to reference Vegezzi E, Ishiura H, Bragg DC, Pellerin D, Magrinelli F, Currò R, et al. Neurological disorders caused by novel non-coding repeat expansions: clinical features and differential diagnosis. Lancet Neurol. 2024;23(7):725–39.PubMedCrossRef Vegezzi E, Ishiura H, Bragg DC, Pellerin D, Magrinelli F, Currò R, et al. Neurological disorders caused by novel non-coding repeat expansions: clinical features and differential diagnosis. Lancet Neurol. 2024;23(7):725–39.PubMedCrossRef
23.
go back to reference Cortese A, Simone R, Sullivan R, Vandrovcova J, Tariq H, Yau WY, et al. Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nat Genet. 2019;51(4):649–58.PubMedPubMedCentralCrossRef Cortese A, Simone R, Sullivan R, Vandrovcova J, Tariq H, Yau WY, et al. Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nat Genet. 2019;51(4):649–58.PubMedPubMedCentralCrossRef
24.
go back to reference Rafehi H, Szmulewicz DJ, Bennett MF, Sobreira NLM, Pope K, Smith KR, et al. Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS. Am J Hum Genet. 2019;105(1):151–65.PubMedPubMedCentralCrossRef Rafehi H, Szmulewicz DJ, Bennett MF, Sobreira NLM, Pope K, Smith KR, et al. Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS. Am J Hum Genet. 2019;105(1):151–65.PubMedPubMedCentralCrossRef
25.
go back to reference Jadhav B, Garg P, van Vugt J, Ibanez K, Gagliardi D, Lee W, et al. A phenome-wide association study of methylated GC-rich repeats identifies a GCC repeat expansion in AFF3 associated with intellectual disability. Nat Genet. 2024;56(11):2322–32.PubMedCrossRef Jadhav B, Garg P, van Vugt J, Ibanez K, Gagliardi D, Lee W, et al. A phenome-wide association study of methylated GC-rich repeats identifies a GCC repeat expansion in AFF3 associated with intellectual disability. Nat Genet. 2024;56(11):2322–32.PubMedCrossRef
26.
go back to reference Pellerin D, Danzi MC, Wilke C, Renaud M, Fazal S, Dicaire MJ, et al. Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia. N Engl J Med. 2023;388(2):128–41.PubMedCrossRef Pellerin D, Danzi MC, Wilke C, Renaud M, Fazal S, Dicaire MJ, et al. Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia. N Engl J Med. 2023;388(2):128–41.PubMedCrossRef
27.
go back to reference Rafehi H, Read J, Szmulewicz DJ, Davies KC, Snell P, Fearnley LG, et al. An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA27B/ATX-FGF14. Am J Hum Genet. 2023;110(6):1018.PubMedPubMedCentralCrossRef Rafehi H, Read J, Szmulewicz DJ, Davies KC, Snell P, Fearnley LG, et al. An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA27B/ATX-FGF14. Am J Hum Genet. 2023;110(6):1018.PubMedPubMedCentralCrossRef
28.
go back to reference Chen Z, Gustavsson EK, Macpherson H, Anderson C, Clarkson C, Rocca C, et al. Adaptive Long-Read Sequencing Reveals GGC Repeat Expansion in ZFHX3 Associated with Spinocerebellar Ataxia Type 4. Mov Disord. 2024;39(3):486–97.PubMedCrossRef Chen Z, Gustavsson EK, Macpherson H, Anderson C, Clarkson C, Rocca C, et al. Adaptive Long-Read Sequencing Reveals GGC Repeat Expansion in ZFHX3 Associated with Spinocerebellar Ataxia Type 4. Mov Disord. 2024;39(3):486–97.PubMedCrossRef
29.
go back to reference Figueroa KP, Gross C, Buena-Atienza E, Paul S, Gandelman M, Kakar N, et al. A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy. Nat Genet. 2024;56(6):1080–9.PubMedCrossRef Figueroa KP, Gross C, Buena-Atienza E, Paul S, Gandelman M, Kakar N, et al. A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy. Nat Genet. 2024;56(6):1080–9.PubMedCrossRef
30.
go back to reference Wallenius J, Kafantari E, Jhaveri E, Gorcenco S, Ameur A, Karremo C, et al. Exonic trinucleotide repeat expansions in ZFHX3 cause spinocerebellar ataxia type 4: A poly-glycine disease. Am J Hum Genet. 2024;111(1):82–95.PubMedCrossRef Wallenius J, Kafantari E, Jhaveri E, Gorcenco S, Ameur A, Karremo C, et al. Exonic trinucleotide repeat expansions in ZFHX3 cause spinocerebellar ataxia type 4: A poly-glycine disease. Am J Hum Genet. 2024;111(1):82–95.PubMedCrossRef
31.
go back to reference Paucar M, Nilsson D, Engvall M, Laffita-Mesa J, Söderhäll C, Skorpil M, Halldin C, Fazio P, Lagerstedt-Robinson K, Solders G, Angeria M, Varrone A, Risling M, Jiao H, Nennesmo I, Wedell A, Svenningsson P. Spinocerebellar ataxia type 4 is caused by a GGC expansion in the ZFHX3 gene and is associated with prominent dysautonomia and motor neuron signs. J Intern Med. 2024;296(3):234–48. https://doi.org/10.1111/joim.13815.CrossRefPubMed Paucar M, Nilsson D, Engvall M, Laffita-Mesa J, Söderhäll C, Skorpil M, Halldin C, Fazio P, Lagerstedt-Robinson K, Solders G, Angeria M, Varrone A, Risling M, Jiao H, Nennesmo I, Wedell A, Svenningsson P. Spinocerebellar ataxia type 4 is caused by a GGC expansion in the ZFHX3 gene and is associated with prominent dysautonomia and motor neuron signs. J Intern Med. 2024;296(3):234–48. https://​doi.​org/​10.​1111/​joim.​13815.CrossRefPubMed
32.
go back to reference Tan D, Wei C, Chen Z, Huang Y, Deng J, Li J, et al. CAG Repeat Expansion in THAP11 Is Associated with a Novel Spinocerebellar Ataxia. Mov Disord. 2023;38(7):1282–93.PubMedCrossRef Tan D, Wei C, Chen Z, Huang Y, Deng J, Li J, et al. CAG Repeat Expansion in THAP11 Is Associated with a Novel Spinocerebellar Ataxia. Mov Disord. 2023;38(7):1282–93.PubMedCrossRef
33.
go back to reference Wang Q, McEwen DG, Ornitz DM. Subcellular and developmental expression of alternatively spliced forms of fibroblast growth factor 14. Mech Dev. 2000;90(2):283–7.PubMedCrossRef Wang Q, McEwen DG, Ornitz DM. Subcellular and developmental expression of alternatively spliced forms of fibroblast growth factor 14. Mech Dev. 2000;90(2):283–7.PubMedCrossRef
34.
go back to reference Ceroni F, Osborne D, Clokie S, Bax DA, Cassidy EJ, Dunn MJ, et al. Analysis of Fibroblast Growth Factor 14 (FGF14) structural variants reveals the genetic basis of the early onset nystagmus locus NYS4 and variable ataxia. Eur J Hum Genet. 2023;31(3):353–9.PubMedCrossRef Ceroni F, Osborne D, Clokie S, Bax DA, Cassidy EJ, Dunn MJ, et al. Analysis of Fibroblast Growth Factor 14 (FGF14) structural variants reveals the genetic basis of the early onset nystagmus locus NYS4 and variable ataxia. Eur J Hum Genet. 2023;31(3):353–9.PubMedCrossRef
35.
go back to reference Piarroux J, Riant F, Humbertclaude V, Remerand G, Hadjadj J, Rejou F, et al. FGF14-related episodic ataxia: delineating the phenotype of Episodic Ataxia type 9. Ann Clin Transl Neurol. 2020;7(4):565–72.PubMedPubMedCentralCrossRef Piarroux J, Riant F, Humbertclaude V, Remerand G, Hadjadj J, Rejou F, et al. FGF14-related episodic ataxia: delineating the phenotype of Episodic Ataxia type 9. Ann Clin Transl Neurol. 2020;7(4):565–72.PubMedPubMedCentralCrossRef
36.
go back to reference van Swieten JC, Brusse E, de Graaf BM, Krieger E, van de Graaf R, de Koning I, et al. A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia [corrected]. Am J Hum Genet. 2003;72(1):191–9.PubMedCrossRef van Swieten JC, Brusse E, de Graaf BM, Krieger E, van de Graaf R, de Koning I, et al. A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia [corrected]. Am J Hum Genet. 2003;72(1):191–9.PubMedCrossRef
37.
go back to reference Groth CL, Berman BD. Spinocerebellar Ataxia 27: A Review and Characterization of an Evolving Phenotype. Tremor Other Hyperkinet Mov (N Y). 2018;8:534.PubMedCrossRef Groth CL, Berman BD. Spinocerebellar Ataxia 27: A Review and Characterization of an Evolving Phenotype. Tremor Other Hyperkinet Mov (N Y). 2018;8:534.PubMedCrossRef
38.
go back to reference Stevanin G, Durr A, Dussert C, Penet C, Brice A. Mutations in the FGF14 gene are not a major cause of spinocerebellar ataxia in Caucasians. Neurology. 2004;63(5):936.PubMedCrossRef Stevanin G, Durr A, Dussert C, Penet C, Brice A. Mutations in the FGF14 gene are not a major cause of spinocerebellar ataxia in Caucasians. Neurology. 2004;63(5):936.PubMedCrossRef
39.
go back to reference Wilke C, Pellerin D, Mengel D, Traschütz A, Danzi MC, Dicaire MJ, et al. GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response. Brain. 2023;146(10):4144–57.PubMedCrossRef Wilke C, Pellerin D, Mengel D, Traschütz A, Danzi MC, Dicaire MJ, et al. GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response. Brain. 2023;146(10):4144–57.PubMedCrossRef
40.
go back to reference Wirth T, Clément G, Delvallée C, Bonnet C, Bogdan T, Iosif A, et al. Natural History and Phenotypic Spectrum of GAA-FGF14 Sporadic Late-Onset Cerebellar Ataxia (SCA27B). Mov Disord. 2023;38(10):1950–6.PubMedCrossRef Wirth T, Clément G, Delvallée C, Bonnet C, Bogdan T, Iosif A, et al. Natural History and Phenotypic Spectrum of GAA-FGF14 Sporadic Late-Onset Cerebellar Ataxia (SCA27B). Mov Disord. 2023;38(10):1950–6.PubMedCrossRef
41.
go back to reference Méreaux JL, Davoine CS, Pellerin D, Coarelli G, Coutelier M, Ewenczyk C, et al. Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions. EBioMedicine. 2024;99:104931.PubMedCrossRef Méreaux JL, Davoine CS, Pellerin D, Coarelli G, Coutelier M, Ewenczyk C, et al. Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions. EBioMedicine. 2024;99:104931.PubMedCrossRef
42.
go back to reference Satolli S, Rossi S, Vegezzi E, Pellerin D, Manca ML, Barghigiani M, Battisti C, Bilancieri G, Bruno G, Capacci E, Casali C, Ceravolo R, Cocozza S, Cotti Piccinelli S, Criscuolo C, Danzi MC, De Micco R, De Michele G, Dicaire MJ, Falcone GMI, ... Santorelli FM. Spinocerebellar ataxia 27B: a frequent and slowly progressive autosomal-dominant cerebellar ataxia-experience from an Italian cohort. J Neurol. 2024;271(8):5478–88. https://doi.org/10.1007/s00415-024-12506-x.CrossRefPubMed Satolli S, Rossi S, Vegezzi E, Pellerin D, Manca ML, Barghigiani M, Battisti C, Bilancieri G, Bruno G, Capacci E, Casali C, Ceravolo R, Cocozza S, Cotti Piccinelli S, Criscuolo C, Danzi MC, De Micco R, De Michele G, Dicaire MJ, Falcone GMI, ... Santorelli FM. Spinocerebellar ataxia 27B: a frequent and slowly progressive autosomal-dominant cerebellar ataxia-experience from an Italian cohort. J Neurol. 2024;271(8):5478–88. https://​doi.​org/​10.​1007/​s00415-024-12506-x.CrossRefPubMed
43.
go back to reference Pellerin D, Heindl F, Wilke C, Danzi MC, Traschütz A, Ashton C, et al. GAA-FGF14 disease: defining its frequency, molecular basis, and 4-aminopyridine response in a large downbeat nystagmus cohort. EBioMedicine. 2024;102:105076.PubMedPubMedCentralCrossRef Pellerin D, Heindl F, Wilke C, Danzi MC, Traschütz A, Ashton C, et al. GAA-FGF14 disease: defining its frequency, molecular basis, and 4-aminopyridine response in a large downbeat nystagmus cohort. EBioMedicine. 2024;102:105076.PubMedPubMedCentralCrossRef
44.
go back to reference Ouyang R, Wan L, Pellerin D, Long Z, Hu J, Jiang Q, et al. The genetic landscape and phenotypic spectrum of GAA-FGF14 ataxia in China: a large cohort study. EBioMedicine. 2024;102:105077.PubMedPubMedCentralCrossRef Ouyang R, Wan L, Pellerin D, Long Z, Hu J, Jiang Q, et al. The genetic landscape and phenotypic spectrum of GAA-FGF14 ataxia in China: a large cohort study. EBioMedicine. 2024;102:105077.PubMedPubMedCentralCrossRef
45.
go back to reference Kartanou C, Mitrousias A, Pellerin D, Kontogeorgiou Z, Iruzubieta P, Dicaire MJ, et al. The FGF14 GAA repeat expansion in Greek patients with late-onset cerebellar ataxia and an overview of the SCA27B phenotype across populations. Clin Genet. 2024;105(4):446–52.PubMedCrossRef Kartanou C, Mitrousias A, Pellerin D, Kontogeorgiou Z, Iruzubieta P, Dicaire MJ, et al. The FGF14 GAA repeat expansion in Greek patients with late-onset cerebellar ataxia and an overview of the SCA27B phenotype across populations. Clin Genet. 2024;105(4):446–52.PubMedCrossRef
46.
go back to reference Iruzubieta P, Pellerin D, Bergareche A, Albajar I, Mondragón E, Vinagre A, et al. Frequency and phenotypic spectrum of spinocerebellar ataxia 27B and other genetic ataxias in a Spanish cohort of late-onset cerebellar ataxia. Eur J Neurol Off J Eur Fed Neurol Soc. 2023;30(12):3828–33. Iruzubieta P, Pellerin D, Bergareche A, Albajar I, Mondragón E, Vinagre A, et al. Frequency and phenotypic spectrum of spinocerebellar ataxia 27B and other genetic ataxias in a Spanish cohort of late-onset cerebellar ataxia. Eur J Neurol Off J Eur Fed Neurol Soc. 2023;30(12):3828–33.
47.
go back to reference Ando M, Higuchi Y, Yuan J, Yoshimura A, Kojima F, Yamanishi Y, et al. Clinical variability associated with intronic FGF14 GAA repeat expansion in Japan. Ann Clin Transl Neurol. 2024;11(1):96–104.PubMedCrossRef Ando M, Higuchi Y, Yuan J, Yoshimura A, Kojima F, Yamanishi Y, et al. Clinical variability associated with intronic FGF14 GAA repeat expansion in Japan. Ann Clin Transl Neurol. 2024;11(1):96–104.PubMedCrossRef
48.
go back to reference Abou Chaar W, Eranki AN, Stevens HA, Watson SL, Wong DY, Avila VS, et al. Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B). Ann Neurol. 2024;96(6):1092–103.PubMedCrossRef Abou Chaar W, Eranki AN, Stevens HA, Watson SL, Wong DY, Avila VS, et al. Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B). Ann Neurol. 2024;96(6):1092–103.PubMedCrossRef
49.
go back to reference Pellerin D, Danzi MC, Renaud M, Houlden H, Synofzik M, Zuchner S, et al. Spinocerebellar ataxia 27B: A novel, frequent and potentially treatable ataxia. Clin Transl Med. 2024;14(1):e1504.PubMedPubMedCentralCrossRef Pellerin D, Danzi MC, Renaud M, Houlden H, Synofzik M, Zuchner S, et al. Spinocerebellar ataxia 27B: A novel, frequent and potentially treatable ataxia. Clin Transl Med. 2024;14(1):e1504.PubMedPubMedCentralCrossRef
50.
go back to reference Pellerin D, Danzi M, Renaud M, Houlden H, Synofzik M, Zuchner S, et al. GAA-FGF14-Related Ataxia. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews(®). Seattle (WA): University of Washington, Seattle Copyright © 1993–2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved. 1993 Pellerin D, Danzi M, Renaud M, Houlden H, Synofzik M, Zuchner S, et al. GAA-FGF14-Related Ataxia. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews(®). Seattle (WA): University of Washington, Seattle Copyright © 1993–2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved. 1993
51.
go back to reference Ashton C, Indelicato E, Pellerin D, Clément G, Danzi MC, Dicaire MJ, et al. Spinocerebellar ataxia 27B: episodic symptoms and acetazolamide response in 34 patients. Brain Commun. 2023;5(5):fcad239.PubMedPubMedCentralCrossRef Ashton C, Indelicato E, Pellerin D, Clément G, Danzi MC, Dicaire MJ, et al. Spinocerebellar ataxia 27B: episodic symptoms and acetazolamide response in 34 patients. Brain Commun. 2023;5(5):fcad239.PubMedPubMedCentralCrossRef
52.
go back to reference Borsche M, Thomsen M, Szmulewicz DJ, Lübbers B, Hinrichs F, Lockhart PJ, et al. Bilateral vestibulopathy in RFC1-positive CANVAS is distinctly different compared to FGF14-linked spinocerebellar ataxia 27B. J Neurol. 2024;271(2):1023–7.PubMedCrossRef Borsche M, Thomsen M, Szmulewicz DJ, Lübbers B, Hinrichs F, Lockhart PJ, et al. Bilateral vestibulopathy in RFC1-positive CANVAS is distinctly different compared to FGF14-linked spinocerebellar ataxia 27B. J Neurol. 2024;271(2):1023–7.PubMedCrossRef
53.
go back to reference Chen S, Ashton C, Sakalla R, Clement G, Planel S, Bonnet C, Lamont P, Kulanthaivelu K, Nalini A, Houlden H, Duquette A, Dicaire MJ, Agudo PI, Martinez JR, de Lucas EM, Berjon RS, Ceberio JI, Indelicato E, Boesch S, Synofzik M, … La Piana R. Neuroradiological findings in GAA-FGF14 ataxia (SCA27B): more than cerebellar atrophy. medRxiv : the preprint server for health sciences. 2024. 2024.02.16.24302945. https://doi.org/10.1101/2024.02.16.24302945. Chen S, Ashton C, Sakalla R, Clement G, Planel S, Bonnet C, Lamont P, Kulanthaivelu K, Nalini A, Houlden H, Duquette A, Dicaire MJ, Agudo PI, Martinez JR, de Lucas EM, Berjon RS, Ceberio JI, Indelicato E, Boesch S, Synofzik M, … La Piana R. Neuroradiological findings in GAA-FGF14 ataxia (SCA27B): more than cerebellar atrophy. medRxiv : the preprint server for health sciences. 2024. 2024.02.16.24302945. https://​doi.​org/​10.​1101/​2024.​02.​16.​24302945.
54.
go back to reference Pellerin D, Wilke C, Traschütz A, Nagy S, Currò R, Dicaire MJ, et al. Intronic FGF14 GAA repeat expansions are a common cause of ataxia syndromes with neuropathy and bilateral vestibulopathy. J Neurol Neurosurg Psychiatry. 2024;95(2):175–9.PubMedCrossRef Pellerin D, Wilke C, Traschütz A, Nagy S, Currò R, Dicaire MJ, et al. Intronic FGF14 GAA repeat expansions are a common cause of ataxia syndromes with neuropathy and bilateral vestibulopathy. J Neurol Neurosurg Psychiatry. 2024;95(2):175–9.PubMedCrossRef
55.
go back to reference Pellerin D, Heindl F, Traschütz A, Rujescu D, Hartmann AM, Brais B, et al. RFC1 repeat expansions in downbeat nystagmus syndromes: frequency and phenotypic profile. J Neurol. 2024;271(5):2886–92.PubMedPubMedCentralCrossRef Pellerin D, Heindl F, Traschütz A, Rujescu D, Hartmann AM, Brais B, et al. RFC1 repeat expansions in downbeat nystagmus syndromes: frequency and phenotypic profile. J Neurol. 2024;271(5):2886–92.PubMedPubMedCentralCrossRef
56.
go back to reference Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008;71(9):670–6.PubMedPubMedCentralCrossRef Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008;71(9):670–6.PubMedPubMedCentralCrossRef
57.
go back to reference Wenning GK, Stankovic I, Vignatelli L, Fanciulli A, Calandra-Buonaura G, Seppi K, et al. The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy. Mov Disord. 2022;37(6):1131–48.PubMedPubMedCentralCrossRef Wenning GK, Stankovic I, Vignatelli L, Fanciulli A, Calandra-Buonaura G, Seppi K, et al. The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy. Mov Disord. 2022;37(6):1131–48.PubMedPubMedCentralCrossRef
58.
go back to reference Wirth T, Bonnet C, Delvallée C, Pellerin D, Bogdan T, Clément G, et al. Does Spinocerebellar ataxia 27B mimic cerebellar multiple system atrophy? J Neurol. 2024;271(4):2078–85.PubMedCrossRef Wirth T, Bonnet C, Delvallée C, Pellerin D, Bogdan T, Clément G, et al. Does Spinocerebellar ataxia 27B mimic cerebellar multiple system atrophy? J Neurol. 2024;271(4):2078–85.PubMedCrossRef
59.
go back to reference Matsushima M, Yaguchi H, Koshimizu E, Kudo A, Shirai S, Matsuoka T, et al. FGF14 GAA repeat expansion and ZFHX3 GGC repeat expansion in clinically diagnosed multiple system atrophy patients. J Neurol. 2024;271(6):3643–7.PubMedCrossRef Matsushima M, Yaguchi H, Koshimizu E, Kudo A, Shirai S, Matsuoka T, et al. FGF14 GAA repeat expansion and ZFHX3 GGC repeat expansion in clinically diagnosed multiple system atrophy patients. J Neurol. 2024;271(6):3643–7.PubMedCrossRef
60.
go back to reference Brais B, Pellerin D, Danzi MC. Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia. Reply N Engl J Med. 2023;388(21):e70.PubMed Brais B, Pellerin D, Danzi MC. Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia. Reply N Engl J Med. 2023;388(21):e70.PubMed
61.
go back to reference Bonnet C, Pellerin D, Roth V, Clément G, Wandzel M, Lambert L, et al. Optimized testing strategy for the diagnosis of GAA-FGF14 ataxia/spinocerebellar ataxia 27B. Sci Rep. 2023;13(1):9737.PubMedPubMedCentralCrossRef Bonnet C, Pellerin D, Roth V, Clément G, Wandzel M, Lambert L, et al. Optimized testing strategy for the diagnosis of GAA-FGF14 ataxia/spinocerebellar ataxia 27B. Sci Rep. 2023;13(1):9737.PubMedPubMedCentralCrossRef
62.
go back to reference Zeng YH, Gan SR, Chen WJ. Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia. N Engl J Med. 2023;388(21):e70.PubMed Zeng YH, Gan SR, Chen WJ. Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia. N Engl J Med. 2023;388(21):e70.PubMed
63.
go back to reference Novis LE, Frezatti RS, Pellerin D, Tomaselli PJ, Alavi S, Della Coleta MV, et al. Frequency of GAA-FGF14 Ataxia in a Large Cohort of Brazilian Patients With Unsolved Adult-Onset Cerebellar Ataxia. Neurol Genet. 2023;9(5):e200094.PubMedPubMedCentralCrossRef Novis LE, Frezatti RS, Pellerin D, Tomaselli PJ, Alavi S, Della Coleta MV, et al. Frequency of GAA-FGF14 Ataxia in a Large Cohort of Brazilian Patients With Unsolved Adult-Onset Cerebellar Ataxia. Neurol Genet. 2023;9(5):e200094.PubMedPubMedCentralCrossRef
64.
go back to reference Seemann J, Traschütz A, Ilg W, Synofzik M. 4-Aminopyridine improves real-life gait performance in SCA27B on a single-subject level: a prospective n-of-1 treatment experience. J Neurol. 2023;270(11):5629–34.PubMedPubMedCentralCrossRef Seemann J, Traschütz A, Ilg W, Synofzik M. 4-Aminopyridine improves real-life gait performance in SCA27B on a single-subject level: a prospective n-of-1 treatment experience. J Neurol. 2023;270(11):5629–34.PubMedPubMedCentralCrossRef
65.
go back to reference Milovanović A, Dragaševic-Mišković N, Thomsen M, Borsche M, Hinrichs F, Westenberger A, et al. RFC1 and FGF14 Repeat Expansions in Serbian Patients with Cerebellar Ataxia. Mov Disord Clin Pract. 2024;11(6):626–33.PubMedPubMedCentralCrossRef Milovanović A, Dragaševic-Mišković N, Thomsen M, Borsche M, Hinrichs F, Westenberger A, et al. RFC1 and FGF14 Repeat Expansions in Serbian Patients with Cerebellar Ataxia. Mov Disord Clin Pract. 2024;11(6):626–33.PubMedPubMedCentralCrossRef
66.
go back to reference Mohren L, Erdlenbruch F, Leitão E, Kilpert F, Hönes GS, Kaya S, et al. Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions. Nat Commun. 2024;15(1):7665.PubMedPubMedCentralCrossRef Mohren L, Erdlenbruch F, Leitão E, Kilpert F, Hönes GS, Kaya S, et al. Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions. Nat Commun. 2024;15(1):7665.PubMedPubMedCentralCrossRef
67.
go back to reference Scriver CR. Human genetics: lessons from Quebec populations. Annu Rev Genomics Hum Genet. 2001;2:69–101.PubMedCrossRef Scriver CR. Human genetics: lessons from Quebec populations. Annu Rev Genomics Hum Genet. 2001;2:69–101.PubMedCrossRef
68.
go back to reference Zheng ZH, Cao CY, Cheng B, Yuan RY, Zeng YH, Guo ZB, Qiu YS, Lv WQ, Liang H, Li JL, Zhang WX, Fang MK, Sun YH, Lin W, Hong JM, Gan SR, Wang N, Chen WJ, Du GQ, Fang L. Characteristics of tandem repeat inheritance and sympathetic nerve involvement in GAA-FGF14 ataxia. J Hum Genet. 2024;69(9):433–40. https://doi.org/10.1038/s10038-024-01262-5.CrossRefPubMed Zheng ZH, Cao CY, Cheng B, Yuan RY, Zeng YH, Guo ZB, Qiu YS, Lv WQ, Liang H, Li JL, Zhang WX, Fang MK, Sun YH, Lin W, Hong JM, Gan SR, Wang N, Chen WJ, Du GQ, Fang L. Characteristics of tandem repeat inheritance and sympathetic nerve involvement in GAA-FGF14 ataxia. J Hum Genet. 2024;69(9):433–40. https://​doi.​org/​10.​1038/​s10038-024-01262-5.CrossRefPubMed
69.
go back to reference Miyatake S, Doi H, Yaguchi H, Koshimizu E, Kihara N, Matsubara T, Mori Y, Kunieda K, Shimizu Y, Toyota T, Shirai S, Matsushima M, Okubo M, Wada T, Kunii M, Johkura K, Miyamoto R, Osaki Y, Miyama T, Satoh M, ... Matsumoto N. Complete nanopore repeat sequencing of SCA27B (GAA-FGF14 ataxia) in Japanese. J Neurol Neurosurg Psychiatry. 2024;95(12):1187–95. https://doi.org/10.1136/jnnp-2024-333541.CrossRefPubMed Miyatake S, Doi H, Yaguchi H, Koshimizu E, Kihara N, Matsubara T, Mori Y, Kunieda K, Shimizu Y, Toyota T, Shirai S, Matsushima M, Okubo M, Wada T, Kunii M, Johkura K, Miyamoto R, Osaki Y, Miyama T, Satoh M, ... Matsumoto N. Complete nanopore repeat sequencing of SCA27B (GAA-FGF14 ataxia) in Japanese. J Neurol Neurosurg Psychiatry. 2024;95(12):1187–95. https://​doi.​org/​10.​1136/​jnnp-2024-333541.CrossRefPubMed
70.
go back to reference Mizushima K, Shibata Y, Shirai S, Matsushima M, Miyatake S, Iwata I, et al. Prevalence of repeat expansions causing autosomal dominant spinocerebellar ataxias in Hokkaido, the northernmost island of Japan. J Hum Genet. 2024;69(1):27–31.PubMedCrossRef Mizushima K, Shibata Y, Shirai S, Matsushima M, Miyatake S, Iwata I, et al. Prevalence of repeat expansions causing autosomal dominant spinocerebellar ataxias in Hokkaido, the northernmost island of Japan. J Hum Genet. 2024;69(1):27–31.PubMedCrossRef
71.
go back to reference De T, Sharma P, Upilli B, Vivekanand A, Bari S, Sonakar AK, et al. Spinocerebellar ataxia type 27B (SCA27B) in India: insights from a large cohort study suggest ancient origin. Neurogenetics. 2024;25(4):393–403.PubMedCrossRef De T, Sharma P, Upilli B, Vivekanand A, Bari S, Sonakar AK, et al. Spinocerebellar ataxia type 27B (SCA27B) in India: insights from a large cohort study suggest ancient origin. Neurogenetics. 2024;25(4):393–403.PubMedCrossRef
72.
go back to reference Pellerin D, Del Gobbo GF, Couse M, Dolzhenko E, Nageshwaran SK, Cheung WA, et al. A common flanking variant is associated with enhanced stability of the FGF14-SCA27B repeat locus. Nat Genet. 2024;56(7):1366–70.PubMedPubMedCentralCrossRef Pellerin D, Del Gobbo GF, Couse M, Dolzhenko E, Nageshwaran SK, Cheung WA, et al. A common flanking variant is associated with enhanced stability of the FGF14-SCA27B repeat locus. Nat Genet. 2024;56(7):1366–70.PubMedPubMedCentralCrossRef
73.
go back to reference Pellerin D, Iruzubieta P, Tekgül Ş, Danzi MC, Ashton C, Dicaire MJ, et al. Non-GAA Repeat Expansions in FGF14 Are Likely Not Pathogenic-Reply to: “Shaking Up Ataxia: FGF14 and RFC1 Repeat Expansions in Affected and Unaffected Members of a Chilean Family.” Mov Disord. 2023;38(8):1575–7.PubMedCrossRef Pellerin D, Iruzubieta P, Tekgül Ş, Danzi MC, Ashton C, Dicaire MJ, et al. Non-GAA Repeat Expansions in FGF14 Are Likely Not Pathogenic-Reply to: “Shaking Up Ataxia: FGF14 and RFC1 Repeat Expansions in Affected and Unaffected Members of a Chilean Family.” Mov Disord. 2023;38(8):1575–7.PubMedCrossRef
74.
go back to reference Pellerin D, Seemann J, Traschütz A, Brais B, Ilg W, Synofzik M. Reduced Age-Dependent Penetrance of a Large FGF14 GAA Repeat Expansion in a 74-Year-Old Woman from a German Family with SCA27B. Movement Disorders : Official Journal of the Movement Disorder Society. 2024;39(10):1892–4. https://doi.org/10.1002/mds.29915.CrossRefPubMed Pellerin D, Seemann J, Traschütz A, Brais B, Ilg W, Synofzik M. Reduced Age-Dependent Penetrance of a Large FGF14 GAA Repeat Expansion in a 74-Year-Old Woman from a German Family with SCA27B. Movement Disorders : Official Journal of the Movement Disorder Society. 2024;39(10):1892–4. https://​doi.​org/​10.​1002/​mds.​29915.CrossRefPubMed
75.
go back to reference Zheng H, Xie W. The role of 3D genome organization in development and cell differentiation. Nat Rev Mol Cell Biol. 2019;20(9):535–50.PubMedCrossRef Zheng H, Xie W. The role of 3D genome organization in development and cell differentiation. Nat Rev Mol Cell Biol. 2019;20(9):535–50.PubMedCrossRef
76.
go back to reference Duffy MF, Ding J, Langston RG, Shah SI, Nalls MA, Scholz SW, Whitaker DT, Auluck PK, Marenco S, Gibbs JR, Cookson MR. Divergent patterns of healthy aging across human brain regions at single-cell resolution reveal links to neurodegenerative disease. bioRxiv : the preprint server for biology. 2023. 2023.07.31.551097. https://doi.org/10.1101/2023.07.31.551097. Duffy MF, Ding J, Langston RG, Shah SI, Nalls MA, Scholz SW, Whitaker DT, Auluck PK, Marenco S, Gibbs JR, Cookson MR. Divergent patterns of healthy aging across human brain regions at single-cell resolution reveal links to neurodegenerative disease. bioRxiv : the preprint server for biology. 2023. 2023.07.31.551097. https://​doi.​org/​10.​1101/​2023.​07.​31.​551097.
77.
go back to reference Shakkottai VG, Xiao M, Xu L, Wong M, Nerbonne JM, Ornitz DM, et al. FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons. Neurobiol Dis. 2009;33(1):81–8.PubMedCrossRef Shakkottai VG, Xiao M, Xu L, Wong M, Nerbonne JM, Ornitz DM, et al. FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons. Neurobiol Dis. 2009;33(1):81–8.PubMedCrossRef
78.
go back to reference Lou JY, Laezza F, Gerber BR, Xiao M, Yamada KA, Hartmann H, et al. Fibroblast growth factor 14 is an intracellular modulator of voltage-gated sodium channels. J Physiol. 2005;569(Pt 1):179–93.PubMedPubMedCentralCrossRef Lou JY, Laezza F, Gerber BR, Xiao M, Yamada KA, Hartmann H, et al. Fibroblast growth factor 14 is an intracellular modulator of voltage-gated sodium channels. J Physiol. 2005;569(Pt 1):179–93.PubMedPubMedCentralCrossRef
79.
go back to reference Xiao M, Bosch MK, Nerbonne JM, Ornitz DM. FGF14 localization and organization of the axon initial segment. Mol Cell Neurosci. 2013;56:393–403.PubMedCrossRef Xiao M, Bosch MK, Nerbonne JM, Ornitz DM. FGF14 localization and organization of the axon initial segment. Mol Cell Neurosci. 2013;56:393–403.PubMedCrossRef
80.
go back to reference Di Re J, Wadsworth PA, Laezza F. Intracellular Fibroblast Growth Factor 14: Emerging Risk Factor for Brain Disorders. Front Cell Neurosci. 2017;11:103.PubMedPubMedCentralCrossRef Di Re J, Wadsworth PA, Laezza F. Intracellular Fibroblast Growth Factor 14: Emerging Risk Factor for Brain Disorders. Front Cell Neurosci. 2017;11:103.PubMedPubMedCentralCrossRef
81.
go back to reference Bosch MK, Carrasquillo Y, Ransdell JL, Kanakamedala A, Ornitz DM, Nerbonne JM. Intracellular FGF14 (iFGF14) Is Required for Spontaneous and Evoked Firing in Cerebellar Purkinje Neurons and for Motor Coordination and Balance. J Neurosci. 2015;35(17):6752–69.PubMedPubMedCentralCrossRef Bosch MK, Carrasquillo Y, Ransdell JL, Kanakamedala A, Ornitz DM, Nerbonne JM. Intracellular FGF14 (iFGF14) Is Required for Spontaneous and Evoked Firing in Cerebellar Purkinje Neurons and for Motor Coordination and Balance. J Neurosci. 2015;35(17):6752–69.PubMedPubMedCentralCrossRef
83.
go back to reference Goldfarb M, Schoorlemmer J, Williams A, Diwakar S, Wang Q, Huang X, et al. Fibroblast growth factor homologous factors control neuronal excitability through modulation of voltage-gated sodium channels. Neuron. 2007;55(3):449–63.PubMedPubMedCentralCrossRef Goldfarb M, Schoorlemmer J, Williams A, Diwakar S, Wang Q, Huang X, et al. Fibroblast growth factor homologous factors control neuronal excitability through modulation of voltage-gated sodium channels. Neuron. 2007;55(3):449–63.PubMedPubMedCentralCrossRef
84.
go back to reference Campuzano V, Montermini L, Moltò MD, Pianese L, Cossée M, Cavalcanti F, et al. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996;271(5254):1423–7.PubMedCrossRef Campuzano V, Montermini L, Moltò MD, Pianese L, Cossée M, Cavalcanti F, et al. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996;271(5254):1423–7.PubMedCrossRef
85.
go back to reference Matos-Rodrigues G, van Wietmarschen N, Wu W, Tripathi V, Koussa NC, Pavani R, et al. S1-END-seq reveals DNA secondary structures in human cells. Mol Cell. 2022;82(19):3538-52.e5.PubMedPubMedCentralCrossRef Matos-Rodrigues G, van Wietmarschen N, Wu W, Tripathi V, Koussa NC, Pavani R, et al. S1-END-seq reveals DNA secondary structures in human cells. Mol Cell. 2022;82(19):3538-52.e5.PubMedPubMedCentralCrossRef
86.
go back to reference Sakamoto N, Chastain PD, Parniewski P, Ohshima K, Pandolfo M, Griffith JD, et al. Sticky DNA: self-association properties of long GAA.TTC repeats in R.R.Y triplex structures from Friedreich’s ataxia. Molecular Cell. 1999;3(4):465–75.PubMedCrossRef Sakamoto N, Chastain PD, Parniewski P, Ohshima K, Pandolfo M, Griffith JD, et al. Sticky DNA: self-association properties of long GAA.TTC repeats in R.R.Y triplex structures from Friedreich’s ataxia. Molecular Cell. 1999;3(4):465–75.PubMedCrossRef
87.
go back to reference Ohshima K, Montermini L, Wells RD, Pandolfo M. Inhibitory effects of expanded GAA.TTC triplet repeats from intron I of the Friedreich ataxia gene on transcription and replication in vivo. J Biol Chem. 1998;273(23):14588–95.PubMedCrossRef Ohshima K, Montermini L, Wells RD, Pandolfo M. Inhibitory effects of expanded GAA.TTC triplet repeats from intron I of the Friedreich ataxia gene on transcription and replication in vivo. J Biol Chem. 1998;273(23):14588–95.PubMedCrossRef
88.
go back to reference Soragni E, Herman D, Dent SY, Gottesfeld JM, Wells RD, Napierala M. Long intronic GAA*TTC repeats induce epigenetic changes and reporter gene silencing in a molecular model of Friedreich ataxia. Nucleic Acids Res. 2008;36(19):6056–65.PubMedPubMedCentralCrossRef Soragni E, Herman D, Dent SY, Gottesfeld JM, Wells RD, Napierala M. Long intronic GAA*TTC repeats induce epigenetic changes and reporter gene silencing in a molecular model of Friedreich ataxia. Nucleic Acids Res. 2008;36(19):6056–65.PubMedPubMedCentralCrossRef
89.
go back to reference Greene E, Mahishi L, Entezam A, Kumari D, Usdin K. Repeat-induced epigenetic changes in intron 1 of the frataxin gene and its consequences in Friedreich ataxia. Nucleic Acids Res. 2007;35(10):3383–90.PubMedPubMedCentralCrossRef Greene E, Mahishi L, Entezam A, Kumari D, Usdin K. Repeat-induced epigenetic changes in intron 1 of the frataxin gene and its consequences in Friedreich ataxia. Nucleic Acids Res. 2007;35(10):3383–90.PubMedPubMedCentralCrossRef
90.
go back to reference Saveliev A, Everett C, Sharpe T, Webster Z, Festenstein R. DNA triplet repeats mediate heterochromatin-protein-1-sensitive variegated gene silencing. Nature. 2003;422(6934):909–13.PubMedCrossRef Saveliev A, Everett C, Sharpe T, Webster Z, Festenstein R. DNA triplet repeats mediate heterochromatin-protein-1-sensitive variegated gene silencing. Nature. 2003;422(6934):909–13.PubMedCrossRef
91.
go back to reference Delatycki MB, Bidichandani SI. Friedreich ataxia- pathogenesis and implications for therapies. Neurobiol Dis. 2019;132:104606.PubMedCrossRef Delatycki MB, Bidichandani SI. Friedreich ataxia- pathogenesis and implications for therapies. Neurobiol Dis. 2019;132:104606.PubMedCrossRef
92.
go back to reference Li Y, Lu Y, Polak U, Lin K, Shen J, Farmer J, et al. Expanded GAA repeats impede transcription elongation through the FXN gene and induce transcriptional silencing that is restricted to the FXN locus. Hum Mol Genet. 2015;24(24):6932–43.PubMedPubMedCentral Li Y, Lu Y, Polak U, Lin K, Shen J, Farmer J, et al. Expanded GAA repeats impede transcription elongation through the FXN gene and induce transcriptional silencing that is restricted to the FXN locus. Hum Mol Genet. 2015;24(24):6932–43.PubMedPubMedCentral
93.
go back to reference Groh M, Lufino MM, Wade-Martins R, Gromak N. R-loops associated with triplet repeat expansions promote gene silencing in Friedreich ataxia and fragile X syndrome. PLoS Genet. 2014;10(5):e1004318.PubMedPubMedCentralCrossRef Groh M, Lufino MM, Wade-Martins R, Gromak N. R-loops associated with triplet repeat expansions promote gene silencing in Friedreich ataxia and fragile X syndrome. PLoS Genet. 2014;10(5):e1004318.PubMedPubMedCentralCrossRef
94.
go back to reference Pellerin D, Méreaux JL, Boluda S, Danzi MC, Dicaire MJ, Davoine CS, et al. Somatic instability of the FGF14-SCA27B GAA•TTC repeat reveals a marked expansion bias in the cerebellum. Brain. 2024;388(5):128. Pellerin D, Méreaux JL, Boluda S, Danzi MC, Dicaire MJ, Davoine CS, et al. Somatic instability of the FGF14-SCA27B GAA•TTC repeat reveals a marked expansion bias in the cerebellum. Brain. 2024;388(5):128.
95.
97.
go back to reference Handsaker RE, Kashin S, Reed NM, Tan S, Lee W-S, McDonald TM, Morris K, Kamitaki N, Mullally CD, Morakabati N, Goldman M, Lind G, Kohli R, Lawton E, Hogan M, Ichihara K, Berretta S, McCarroll SA. Long somatic DNA-repeat expansion drives neurodegeneration in Huntington disease. bioRxiv 2024.05.17.592722. https://doi.org/10.1101/2024.05.17.592722. Handsaker RE, Kashin S, Reed NM, Tan S, Lee W-S, McDonald TM, Morris K, Kamitaki N, Mullally CD, Morakabati N, Goldman M, Lind G, Kohli R, Lawton E, Hogan M, Ichihara K, Berretta S, McCarroll SA. Long somatic DNA-repeat expansion drives neurodegeneration in Huntington disease. bioRxiv 2024.05.17.592722. https://​doi.​org/​10.​1101/​2024.​05.​17.​592722.
98.
go back to reference Flanigan K, Gardner K, Alderson K, Galster B, Otterud B, Leppert MF, et al. Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1. Am J Human Genet. 1996;59(2):392–9. Flanigan K, Gardner K, Alderson K, Galster B, Otterud B, Leppert MF, et al. Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1. Am J Human Genet. 1996;59(2):392–9.
100.
go back to reference Chen Z, Tucci A, Ryten M. Deep intronic FGF14 GAA repeat expansion in late-onset cerebellar ataxia. N Engl J Med. 2023;388(21):e70.PubMed Chen Z, Tucci A, Ryten M. Deep intronic FGF14 GAA repeat expansion in late-onset cerebellar ataxia. N Engl J Med. 2023;388(21):e70.PubMed
101.
go back to reference Chen Z, Tucci A, Cipriani V, Gustavsson EK, Ibañez K, Reynolds RH, et al. Functional genomics provide key insights to improve the diagnostic yield of hereditary ataxia. Brain. 2023;146(7):2869–84.PubMedPubMedCentralCrossRef Chen Z, Tucci A, Cipriani V, Gustavsson EK, Ibañez K, Reynolds RH, et al. Functional genomics provide key insights to improve the diagnostic yield of hereditary ataxia. Brain. 2023;146(7):2869–84.PubMedPubMedCentralCrossRef
102.
go back to reference Sato N, Amino T, Kobayashi K, Asakawa S, Ishiguro T, Tsunemi T, et al. Spinocerebellar ataxia type 31 is associated with “inserted” penta-nucleotide repeats containing (TGGAA)n. Am J Hum Genet. 2009;85(5):544–57.PubMedPubMedCentralCrossRef Sato N, Amino T, Kobayashi K, Asakawa S, Ishiguro T, Tsunemi T, et al. Spinocerebellar ataxia type 31 is associated with “inserted” penta-nucleotide repeats containing (TGGAA)n. Am J Hum Genet. 2009;85(5):544–57.PubMedPubMedCentralCrossRef
103.
go back to reference Shirai S, Mizushima K, Shibata Y, Matsushima M, Iwata I, Yaguchi H, et al. Spinocerebellar ataxia type 4 is not detected in a cohort from Hokkaido, the northernmost island of Japan. J Neurol Sci. 2024;460:122974.PubMedCrossRef Shirai S, Mizushima K, Shibata Y, Matsushima M, Iwata I, Yaguchi H, et al. Spinocerebellar ataxia type 4 is not detected in a cohort from Hokkaido, the northernmost island of Japan. J Neurol Sci. 2024;460:122974.PubMedCrossRef
104.
go back to reference Novis LE, Alavi S, Pellerin D, Della Coleta MV, Raskin S, Spitz M, et al. Unraveling the genetic landscape of undiagnosed cerebellar ataxia in Brazilian patients. Parkinsonism Relat Disord. 2024;119:105961.PubMedCrossRef Novis LE, Alavi S, Pellerin D, Della Coleta MV, Raskin S, Spitz M, et al. Unraveling the genetic landscape of undiagnosed cerebellar ataxia in Brazilian patients. Parkinsonism Relat Disord. 2024;119:105961.PubMedCrossRef
105.
go back to reference Rudaks LI, Yeow D, Kumar KR. SCA4 Unravelled After More than 25 Years Using Advanced Genomic Technologies. Mov Disord. 2024;39(3):457–61.PubMedCrossRef Rudaks LI, Yeow D, Kumar KR. SCA4 Unravelled After More than 25 Years Using Advanced Genomic Technologies. Mov Disord. 2024;39(3):457–61.PubMedCrossRef
106.
go back to reference Ma L, Herren AW, Espinal G, Randol J, McLaughlin B, Martinez-Cerdeño V, et al. Composition of the Intranuclear Inclusions of Fragile X-associated Tremor/Ataxia Syndrome. Acta Neuropathol Commun. 2019;7(1):143.PubMedPubMedCentralCrossRef Ma L, Herren AW, Espinal G, Randol J, McLaughlin B, Martinez-Cerdeño V, et al. Composition of the Intranuclear Inclusions of Fragile X-associated Tremor/Ataxia Syndrome. Acta Neuropathol Commun. 2019;7(1):143.PubMedPubMedCentralCrossRef
107.
go back to reference Sellier C, Buijsen RAM, He F, Natla S, Jung L, Tropel P, et al. Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome. Neuron. 2017;93(2):331–47.PubMedPubMedCentralCrossRef Sellier C, Buijsen RAM, He F, Natla S, Jung L, Tropel P, et al. Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome. Neuron. 2017;93(2):331–47.PubMedPubMedCentralCrossRef
108.
go back to reference Boivin M, Deng J, Pfister V, Grandgirard E, Oulad-Abdelghani M, Morlet B, et al. Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases. Neuron. 2021;109(11):1825-35.e5.PubMedPubMedCentralCrossRef Boivin M, Deng J, Pfister V, Grandgirard E, Oulad-Abdelghani M, Morlet B, et al. Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases. Neuron. 2021;109(11):1825-35.e5.PubMedPubMedCentralCrossRef
109.
go back to reference Sone J, Mitsuhashi S, Fujita A, Mizuguchi T, Hamanaka K, Mori K, et al. Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease. Nat Genet. 2019;51(8):1215–21.PubMedCrossRef Sone J, Mitsuhashi S, Fujita A, Mizuguchi T, Hamanaka K, Mori K, et al. Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease. Nat Genet. 2019;51(8):1215–21.PubMedCrossRef
110.
go back to reference Jung CG, Kim HJ, Kawaguchi M, Khanna KK, Hida H, Asai K, et al. Homeotic factor ATBF1 induces the cell cycle arrest associated with neuronal differentiation. Development. 2005;132(23):5137–45.PubMedCrossRef Jung CG, Kim HJ, Kawaguchi M, Khanna KK, Hida H, Asai K, et al. Homeotic factor ATBF1 induces the cell cycle arrest associated with neuronal differentiation. Development. 2005;132(23):5137–45.PubMedCrossRef
111.
go back to reference Kim TS, Kawaguchi M, Suzuki M, Jung CG, Asai K, Shibamoto Y, et al. The ZFHX3 (ATBF1) transcription factor induces PDGFRB, which activates ATM in the cytoplasm to protect cerebellar neurons from oxidative stress. Dis Model Mech. 2010;3(11–12):752–62.PubMedCrossRef Kim TS, Kawaguchi M, Suzuki M, Jung CG, Asai K, Shibamoto Y, et al. The ZFHX3 (ATBF1) transcription factor induces PDGFRB, which activates ATM in the cytoplasm to protect cerebellar neurons from oxidative stress. Dis Model Mech. 2010;3(11–12):752–62.PubMedCrossRef
112.
go back to reference Zhang Z, Wei S, Du H, Su Z, Wen Y, Shang Z, et al. Zfhx3 is required for the differentiation of late born D1-type medium spiny neurons. Exp Neurol. 2019;322:113055.PubMedCrossRef Zhang Z, Wei S, Du H, Su Z, Wen Y, Shang Z, et al. Zfhx3 is required for the differentiation of late born D1-type medium spiny neurons. Exp Neurol. 2019;322:113055.PubMedCrossRef
113.
go back to reference Pérez Baca MDR, Jacobs EZ, Vantomme L, Leblanc P, Bogaert E, Dheedene A, et al. Haploinsufficiency of ZFHX3, encoding a key player in neuronal development, causes syndromic intellectual disability. Am J Hum Genet. 2024;111(3):509–28.PubMedPubMedCentralCrossRef Pérez Baca MDR, Jacobs EZ, Vantomme L, Leblanc P, Bogaert E, Dheedene A, et al. Haploinsufficiency of ZFHX3, encoding a key player in neuronal development, causes syndromic intellectual disability. Am J Hum Genet. 2024;111(3):509–28.PubMedPubMedCentralCrossRef
114.
go back to reference He MF, Liu LH, Luo S, Wang J, Guo JJ, Wang PY, et al. ZFHX3 variants cause childhood partial epilepsy and infantile spasms with favourable outcomes. J Med Genet. 2024;61(7):652–60.PubMedCrossRef He MF, Liu LH, Luo S, Wang J, Guo JJ, Wang PY, et al. ZFHX3 variants cause childhood partial epilepsy and infantile spasms with favourable outcomes. J Med Genet. 2024;61(7):652–60.PubMedCrossRef
115.
go back to reference Pandey N, Mittal U, Srivastava AK, Mukerji M. SMARCA2 and THAP11: potential candidates for polyglutamine disorders as evidenced from polymorphism and protein-folding simulation studies. J Hum Genet. 2004;49(11):596–602.PubMedCrossRef Pandey N, Mittal U, Srivastava AK, Mukerji M. SMARCA2 and THAP11: potential candidates for polyglutamine disorders as evidenced from polymorphism and protein-folding simulation studies. J Hum Genet. 2004;49(11):596–602.PubMedCrossRef
116.
go back to reference Hellenbroich Y, Bubel S, Pawlack H, Opitz S, Vieregge P, Schwinger E, et al. Refinement of the spinocerebellar ataxia type 4 locus in a large German family and exclusion of CAG repeat expansions in this region. J Neurol. 2003;250(6):668–71.PubMedCrossRef Hellenbroich Y, Bubel S, Pawlack H, Opitz S, Vieregge P, Schwinger E, et al. Refinement of the spinocerebellar ataxia type 4 locus in a large German family and exclusion of CAG repeat expansions in this region. J Neurol. 2003;250(6):668–71.PubMedCrossRef
117.
go back to reference Hellenbroich Y, Pawlack H, Rüb U, Schwinger E, Zühlke C. Spinocerebellar ataxia type 4. Investigation of 34 candidate genes. J Neurol. 2005;252(12):1472–5.PubMedCrossRef Hellenbroich Y, Pawlack H, Rüb U, Schwinger E, Zühlke C. Spinocerebellar ataxia type 4. Investigation of 34 candidate genes. J Neurol. 2005;252(12):1472–5.PubMedCrossRef
119.
go back to reference Hsiao CT, Liao NY, Liao YC, Lee YC. THAP11 CAG Repeat Expansion Is Rare or Absent in the Taiwanese Cohort with Cerebellar Ataxia. Mov Disord. 2024;39(5):924–5.PubMedCrossRef Hsiao CT, Liao NY, Liao YC, Lee YC. THAP11 CAG Repeat Expansion Is Rare or Absent in the Taiwanese Cohort with Cerebellar Ataxia. Mov Disord. 2024;39(5):924–5.PubMedCrossRef
120.
go back to reference Fearnley LG, Rafehi H, Bennett MF, Bahlo M. Exploring THAP11 Repeat Expansion beyond Chinese-Ancestry Cohorts: An Examination of 1000 Genomes and UK Biobank Data. Mov Disord. 2023;38(12):2320–2.PubMedPubMedCentralCrossRef Fearnley LG, Rafehi H, Bennett MF, Bahlo M. Exploring THAP11 Repeat Expansion beyond Chinese-Ancestry Cohorts: An Examination of 1000 Genomes and UK Biobank Data. Mov Disord. 2023;38(12):2320–2.PubMedPubMedCentralCrossRef
121.
go back to reference Dejosez M, Krumenacker JS, Zitur LJ, Passeri M, Chu LF, Songyang Z, et al. Ronin is essential for embryogenesis and the pluripotency of mouse embryonic stem cells. Cell. 2008;133(7):1162–74.PubMedPubMedCentralCrossRef Dejosez M, Krumenacker JS, Zitur LJ, Passeri M, Chu LF, Songyang Z, et al. Ronin is essential for embryogenesis and the pluripotency of mouse embryonic stem cells. Cell. 2008;133(7):1162–74.PubMedPubMedCentralCrossRef
122.
go back to reference Fujita J, Freire P, Coarfa C, Benham AL, Gunaratne P, Schneider MD, et al. Ronin Governs Early Heart Development by Controlling Core Gene Expression Programs. Cell Rep. 2017;21(6):1562–73.PubMedPubMedCentralCrossRef Fujita J, Freire P, Coarfa C, Benham AL, Gunaratne P, Schneider MD, et al. Ronin Governs Early Heart Development by Controlling Core Gene Expression Programs. Cell Rep. 2017;21(6):1562–73.PubMedPubMedCentralCrossRef
123.
go back to reference Yin RH, Li Y, Yang F, Zhan YQ, Yu M, Ge CH, et al. Expansion of the polyQ repeats in THAP11 forms intranuclear aggregation and causes cell G0/G1 arrest. Cell Biol Int. 2014;38(6):757–67.PubMedCrossRef Yin RH, Li Y, Yang F, Zhan YQ, Yu M, Ge CH, et al. Expansion of the polyQ repeats in THAP11 forms intranuclear aggregation and causes cell G0/G1 arrest. Cell Biol Int. 2014;38(6):757–67.PubMedCrossRef
Metadata
Title
Recent Advances in the Genetics of Ataxias: An Update on Novel Autosomal Dominant Repeat Expansions
Authors
David Pellerin
Pablo Iruzubieta
Isaac R. L. Xu
Matt C. Danzi
Andrea Cortese
Matthis Synofzik
Henry Houlden
Stephan Zuchner
Bernard Brais
Publication date
16-01-2025
Publisher
Springer US
Published in
Current Neurology and Neuroscience Reports / Issue 1/2025
Print ISSN: 1528-4042
Electronic ISSN: 1534-6293
DOI
https://doi.org/10.1007/s11910-024-01400-8

Keynote series | Spotlight on menopause

Menopause can have a significant impact on the body, with effects ranging beyond the endocrine and reproductive systems. Learn about the systemic effects of menopause, so you can help patients in your clinics through the transition.   

Prof. Martha Hickey
Dr. Claudia Barth
Dr. Samar El Khoudary
Developed by: Springer Medicine
Watch now

Advances in Alzheimer's

Alzheimer's research and care is changing rapidly. Keep up with the latest developments from key international conferences, together with expert insights on how to integrate these advances into practice.

This content is intended for healthcare professionals outside of the UK.

Supported by:
  • Lilly
Developed by: Springer Healthcare IME
Learn more