Repeat Expansions in a Chilean Cohort With Adult-Onset Cerebellar Ataxia

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Leonor Bustamante, Marcelo Miranda, David Pellerin, Mariana Barreto, and 30 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7103872/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Dec, 2025 Read the published version in The Cerebellum → Version 1 posted 9 You are reading this latest preprint version Abstract INTRODUCTION: The diagnosis of hereditary ataxias caused by repeat expansions continue to present unique methodological challenges, especially for developing countries where genomic medicine services are not well established. The purpose of this work is to present a cohort of patients who presented with adult-onset ataxia of suspected genetic etiology, but had remained undiagnosed until now. They were analyzed for a set of repeat expansions including the genes causing the more recently identified types, SCA27B and RFC1 -related CANVAS. PATIENTS AND METHODS: We followed an IRB-approved protocol to recruit adult patients with a possible diagnosis of hereditary cerebellar ataxia. All individuals signed an informed consent form, and after a neurological evaluation, DNA samples from blood were obtained. In selected cases, a complete vestibular function evaluation and brain magnetic resonance imaging was acquired. RESULTS: In 17 of the 56 studied cases (including 11 of 43 index cases) we established a genetic diagnosis, which demonstrates that this is a promising approach to adult-onset ataxias in a population that remains underrepresented in worldwide genomic studies. We identified 9 individuals with SCA27B and 7 with CANVAS syndrome, highlighting the epidemiological relevance of these newly recognized etiologies, an information useful for planning the allocation of resources towards improving the access to genomic medicine in in our region. Repeat expansions Latin American population Neurogenetics SCA27B CANVAS syndrome Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Hereditary ataxias are a heterogeneous group of neurodegenerative diseases characterised by progressive gait disorder, incoordination, ocular movement disorders, and dysarthria [ 1 ]. Within the autosomal dominant group, the most commonly recognised genetic causes of ataxia are CAG triplet repeat expansions in the genes ATXN1 (SCA1), ATXN2 (SCA2), ATXN3 (SCA3), CACNA1A (SCA6), and ATXN7 (SCA7). Expansions of GAA triplet repeat also cause Friedreich Ataxia, the most common form of autosomal recessive ataxia. While next-generation sequencing (NGS) has significantly improved the diagnostic yield in many genetic disorders, its utility remains limited when it comes to reliably detecting repeat expansions. Thus, disorders caused by repeat expansions continue to present unique methodological challenges. Interestingly, in the present decade two new causative loci have been identified, and with their discovery the cause of a significant proportion of cases with late-onset ataxia has been established. One of them is the identification of GAA repeat expansions in the Fibroblast Growth Factor 14 ( FGF14 ) gene causing SCA27B, responsible for 10–60% of previously unsolved cases of late-onset cerebellar ataxia [ 2 ]. On the other hand, biallelic expansions in the Replication Factor C, subunit 1 ( RFC1 ) gene cause more than 90% of cases of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) [ 3 ]. In Chile, there is insufficient information about the molecular epidemiology of ataxias, mainly due to the limited access to genetic testing, as previously reported [ 4 ]. Although a formal survey of the Chilean population does not exist, a recent study by the Pan American Hereditary Ataxia Network (PAHAN) estimated that the number of cases of hereditary ataxia in Chile is similar to other Latin American and Caribbean regions [ 5 ]. The purpose of this work is to present a cohort of patients who presented with adult-onset ataxia of suspected genetic etiology, where a set of repeat expansions were analyzed, including the genes causing the more recently identified types, SCA27B and RFC1 -related CANVAS. Although in several of these cases a genetic etiology had been strongly suspected due to a positive family history, they had remained undiagnosed for several years mainly due to lack of access to genetic testing, reflecting their usual trajectory in a country outside the developed world. The findings presented here are in accordance with recent publications from other populations, underscoring the relevance of the newly recognized etiologies. These results are useful in designing a future screening program in an adult population with suspected ataxia of genetic origin. PATIENTS AND METHODS Protocols and recruitment The protocol was approved by the Ethics Committee of the Faculty of Medicine, Universidad de Chile (Protocol 2021 − 192). Adult patients with a possible diagnosis of hereditary cerebellar ataxia were invited to participate by their attending neurologist. Exclusion criteria were cognitive impairment, dementia or inability to provide consent. All individuals signed an informed consent form. The recruitment took place from November 2022 to November 2024 in three cities of Chile, namely the capital Santiago de Chile, the northern city La Serena and the southern city Punta Arenas. All patients were evaluated by their attending neurologist, who recorded the symptoms and rated them according to the SARA (Scale for the Assessment and Rating of Ataxia) scale [ 6 ]. For patients with a positive result or expansions in FGF14 or RFC1 genes, a vestibular function evaluation was performed by an ENT specialist using video head impulse test (vHIT) and video oculography. In selected cases, magnetic resonance imaging (MRI) of the brain was acquired with the protocol described below. In other cases, neuroimaging data (either images or radiologist reports) was obtained by accessing previous patients’ records. DNA extraction DNA quantity and purity were determined using spectrophotometry with a NanoDrop™ instrument. DNA integrity was assessed by visual inspection following electrophoresis on 2% agarose gels. DNA sample were stored at − 20°C before being shipped to the labs where analyses were performed. Genotyping The FGF14 repeat locus was genotyped as described previously using long-range PCR and bidirectional repeat-primed PCR (RP-PCR) [ 7 ]. GAA expansions of 250 repeat units or more are considered pathogenic. The RFC1 -repeat locus was genotyped using RP-PCR [ 8 ], and flanking PCR, where samples with no product on this step were subsequently confirmed with southern blotting to carry biallelic expansions of the pentanucleotide AAGGG (11 repeats or larger). The expansions in ATXN1, ATXN2, ATXN3, CACNA1A , and ATXN7 were tested through PCR of the regions of interest using fluorescent labeled primers flanking the CAG repeat sequence. Fragment length analysis was conducted by capillary electrophoresis on an automated genetic analyzer to determine the exact number of CAG repeats in each allele. Alleles were categorized as normal, intermediate, or pathogenic based on established repeat length thresholds for the specific SCA subtype tested. MRI Acquisition MRI was performed with a SIEMENS 3T Lumina scanner. T1-weighted images were acquired using a 3D MP2RAGE sequence with 1 mm isotopic resolution and TR/TE of 5000/2.76 ms. FLAIR T2- weighted images used a 3D 1 mm sequence with 6000/3.56 ms. Multi-shell DWI is obtained with 2 mm isotropic EPI-DWI, including b-values of 0, 300, 1000, and 2000, using an anterior-posterior phase encoding direction and TR/TE of 3000/65 ms. For b = 0 DWI, the same resolution is used with a posterior-anterior phase encoding. GRE is acquired in 2 mm axial slices with TR/TE of 639/20 ms. RESULTS A total of 56 affected patients from 43 families were included in the study. 38 (67.8%) of the patients were females, and the age of onset ranged from 18 to 64 years (See Table 1). As hereditary ataxias are rare diseases with an estimated prevalence of 1 to 9 individuals per 100,000 in the general population [9], gathering this sample in our country with a population of around 18 million represents a collective effort from highly specialized clinicians. Most participants experienced a prolonged diagnostic journey, often marked by years without a definitive diagnosis and inclusion only after the exclusion of other movement disorders. INSERT TABLE 1 HERE Pathogenic repeat expansions in either RFC1 , FGF14 and ATXN2 were detected in 17 out of 56 individuals (Figure 1). A total of 9 patients from 5 families presented a pathogenic (GAA) ≥250 repeat expansion in FGF14 . The expansion sizes ranged widely, with the largest allele being of 483 repeats, and the smallest of 255 repeats (See Table 2, and Supplementary Table 1). Episodic symptoms, not always associated with exercise, were often triggered by heat, or emotional stress. Four individuals reported ethanol intolerance. We observed T2/FLAIR hyperintensity of the superior cerebellar peduncles and cerebellar atrophy in three patients (See Table 2). Overall, the phenotypic variability, particularly in age at onset and symptom triggers, emphasizes the relative heterogeneity associated with SCA27B. INSERT FIGURE 1 HERE Biallelic pathogenic AAGGG repeat expansions in the RFC1 gene were identified in 7 patients, including two siblings and 5 unrelated individuals. Comprehensive genetic testing for multiple genes associated with ataxia revealed a pathogenic expansion in ATXN2 in one patient. In addition, an intermediate expansion in ATXN1 was found in one patient, and two intermediate FGF14 (GAA) 200-249 expansions, considered of uncertain pathogenicity, were also found. These are variants of uncertain pathogenicity, and to date we do not have additional information to allow us to solve these cases. In the following paragraphs we describe in more detail some of the more relevant findings. INSERT FIGURE 2 HERE Family 1 Family 1 comprises 17 individuals with either confirmed or self-reported cerebellar ataxia, with a mean age of onset of 39 years. Figure 2 shows the pedigree, indicating which individuals were included in our study, all of them of Hispanic ancestry. The index case (individual IV-7), a 54 year old woman, reported paroxysmal symptoms from age 43. These episodes were triggered by tobacco use, alcohol consumption, physical exertion, and emotional stress. The episodes were characterized by slurred speech, gait unsteadiness, confusion, and slow reactivity. Neurological examination revealed mild limb and gait ataxia without other major systemic neurological deficits. Oculomotor testing showed prominent abnormalities, with disruption of ocular fixation with abundant square wave jerks, alterations of ocular alignment with esophoria associated with diplopia, reduced saccade velocity (greater in the vertical plane), and hypometric saccades in all directions. She had no downbeat nystagmus (DBN). At time of last examination, she had a SARA score of 7, indicating mild ataxia. Genetic testing identified a pathogenic FGF14 (GAA) 483 repeat expansion in the FGF14 gene, supporting the diagnosis of SCA27B (Table 2). The index’s brother, individual IV-9, described paroxysmal symptoms beginning at age 18. These episodes typically occur minutes after exposure to tobacco smoke, alcohol consumption, physical exercise, emotional stress, or high temperatures, such as on a hot day or after a warm shower. During these episodes, he experiences slurred speech, loss of balance, gait instability, drowsiness, and decreased alertness. At time of last examination, his SARA score was 5. He showed saccadic pursuit and no DBN. He had previously undergone genetic testing at a clinically-accredited laboratory, which returned negative results for expansions in ATXN1, ATXN2, ATXN3 , and ATXN7 . Subsequent genetic analysis identified a pathogenic FGF14 (GAA) 450 repeat expansion (see Patient 12, Table 2). Their mother is also affected by late-onset, slowly progressing ataxia. Whereas no genetic result is available from her, her previous brain MRI showed hyperintensity of the superior cerebellar peduncles (SCP), which has been previously reported in SCA27B by Chen et al [10] . Furthermore, a maternal aunt and a first-degree cousin of the proband (both affected, see III-4 and IV-13 on Figure 2) also have pathogenic FGF14 expansions of 350 and 433 GAA triplets, respectively (see Table 2). INSERT FIGURE 3 HERE Family 2 Family 2 corresponds to a family of 11 individuals with either self-reported or confirmed ataxia, most of them located in Punta Arenas, in the Chilean Patagonia. Figure 3 shows part of this family including the two individuals with ataxia who were genetically tested, both of them of Hispanic ancestry. The index case (II-3) is a female (see Figure 3 and Table 2) who at time of the study reported 8 years of progressive ataxia. She described gait instability, whose severity did not prevent her from carrying her daily activities, but worsened under stressful situations. She complained of diplopia and oscillopsia and her oto-neurological examination showed slow horizontal and vertical saccades, and no DBN. At last examination, her SARA score was 6, consistent with mild ataxia. The genetic test for this patient showed a pathogenic FGF14 (GAA) 301 repeat expansion. The patient's mother (individual I-1 in Figure 3 and Table 2) began exhibiting symptoms of ataxia at the age of 51. Clinical examination revealed impaired balance and gait, and vertical gaze paresis without DBN. Genetic analysis identified an expansion of 255 GAA triplet repeats in the FGF14 gene. Table 2 presents a summary of the relevant findings of the individuals where FGF14 mutations were identified. INSERT TABLE 2 HERE Family 3 Previously, we reported the case of a male with ataxia and cough, where biallelic pathogenic AAGGG expansions in RFC1 were identified [11] . Now, we have confirmed that his two sisters exhibiting chronic cough and sensory neuropathy also carry biallelic RFC1 expansions. MRI Findings The brain MRI performed on six patients with SCA27B revealed hyperintensity of the midbrain and superior cerebellar peduncles bilaterally, in addition to cerebellar atrophy. Figure 4 shows representative images of the individual IV-9 from Family 1 (see Figure 2), highlighting cerebellar atrophy and the SCP sign. INSERT FIGURE 4. HERE DISCUSSION This manuscript presents the largest genetic study of Chilean individuals with ataxia to date. Interestingly, this survey was only answered by specialists from the Chilean capital city of Santiago, but our study recruited individuals currently being attended in the Northern and Southern regions of the country as well. Our study reflects that, while ataxia is a well-known syndrome and several molecular tests are available, even in a country of middle income like Chile, many patients continue to undergo a diagnostic odyssey, with many years and several referrals before obtaining a diagnosis. In the present work, a research collaboration has made possible to complete the genetic study for this cohort and reach a diagnosis in a significant proportion of cases. Our results point to relevant issues in planning the future implementation of genomic services in patients and families with ataxia in Chile. Namely, newly recognized expansions in the RFC1 and FGF14 genes account for a relevant proportion of the cases, and they have recognizable clinical features that may guide the diagnostic process, in terms of age of onset and temporal pattern of symptoms. These genotype-phenotype correlations are especially relevant because testing for gene expansions is labor intensive and can be expensive, therefore justifying the use of a multi-tiered workup, and also because they may provide guidelines regarding outcome and treatment response. In our sample, among those individuals who had a SCA27B the median AAO was over 30 years of age. Furthermore, we have preliminary observations that all three of these individuals who have received 4-amynopiridine have benefited from it. This is in line with previous reports that show that there is a reduction of symptoms with its use, surpassing that of acetazolamide, considered the first-line treatment for episodic ataxia [ 12 ]. A longer follow-up will be required to show whether this effect is sustained over time. We performed an MRI on three confirmed cases of SCA27B. Cerebellar atrophy was identified in all patients, which has been usually described in patients with genetic ataxias, as well as hyperintensity in the midbrain and superior cerebellar peduncles. The last was recently reported as the Superior Cerebellar Peduncle Sign, which has been recognized as a potentially characteristic finding of patients with SCA27B by Chen et al., [ 10 ], being present in up to 60% of patients. The pathophysiology of this sign is not been completely understood, but theory points to potential vasogenic edema. This highlights the potential role of MRI as a complementary tool to guide genetics testing if signs, such as the SCP sign, are proven to be specific. However, larger cohort studies determining the sensitivity and specificity of the SCP sign are needed before establishing the diagnostic value of this sign. An important point to notice is that the SCP sign can be missed on T2w axial images and may only be observed on high-resolution T2/FLAIR 3D sequences, which points to the need for acquiring appropriate MRI sequences. Nevertheless, this sequence can be acquired on clinical MRI equipment. In this cohort, out of 56 patients, only one individual was found to carry an ATXN2 expansion, and one carried an intermediate expansion in ATXN1. As our project was set up following the model of the “Undiagnosed diseases” unit, our cohort received the more challenging cases. For instance, previously we had published a series of 10 unrelated individuals with confirmed SCA3 [ 12 ]. In total,, we were able to solve 17/56 cases, or 30.3%. Considering only index cases, our genetic study solved 26% of cases (11/43). As hereditary ataxias display significant genetic heterogeneity, we expect that as a follow up step to this study we can increase this yield using a more individualized approach, like the one proposed by Pérez-Maturo et al [ 13 ]. CONCLUSIONS Establishing the molecular cause of cerebellar ataxia is a necessary step toward providing adequate genetic counseling, and helping to predict a patient’s clinical course and establish necessary follow ups. As Latin American countries advance toward better healthcare services, these results should be taken into account when designing programs for molecular diagnosis of ataxia and related neurological conditions across the continent. Declarations FUNDING DECLARATION This work was funded by Foundation Diagnosis, a nonprofit organization based in Providencia, Santiago, Chile (RPJ N°294390); by Hospital Clínico-Faculty of Medicine, Universidad de Chile (OAIC FGF 14 Project IE 62/24); by Clinica MEDS (Fondo Semilla 2024, PI MMC); by Canadian Institutes of Health Research (Grant 189963 to BB), and by UCL Queen Square Institute of Neurology in the University College London. D.P. holds a fellowship award from the Canadian Institutes of Health Research. B.P.G holds a fellowship from Agencia Nacional de Investigación y Desarrollo, ANID, Chile. N.D. holds a fellowship award from the NIHR UCLH BRC. ACKNOWLEDGEMENTS The authors are grateful to Dr. Roberta La Piana for her insightful comments regarding the neuroimages, as well as to all the patients that participated in the study. COMPLIANCE WITH ETHICAL STANDARDS AND CONSENT TO PARTICIPATE All procedures performed in this study were in accordance with the ethical standards of the institutional review board of Universidad de Chile, where the study was carried out, with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study protocol, "Creación de una Unidad de Enfermedades sin Diagnóstico en la Universidad de Chile” was reviewed and approved by the Comité de Ética de la Investigación en Seres Humanos (CEISH) de la Facultad de Medicina de la Universidad de Chile N° 092-2021, on October 12 th , 2021, and renewed on April 11 th 2023. Prior to participation, all individuals provided written informed consent after receiving a comprehensive explanation of the study's purpose, procedures, potential risks, and benefits. Participant confidentiality and privacy were rigorously maintained throughout the study, with all data being anonymized to protect personal identities. CLINICAL TRIAL NUMBER: Not applicable References Jayadev S, Bird TD. Hereditary ataxias: Overview. Genetics in Medicine. 2013. 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. 2023;95. Davies K, Szmulewicz DJ, Corben LA, Delatycki M, Lockhart PJ. RFC1 -Related Disease. Neurol Genet. 2022;8. Saffie Awad P, Vial Undurraga F, Chaná-Cuevas P. Clinical features of 63 patients with ataxia. Rev Med Chil. 2018;146. Jardim LB, Hasan A, Kuo S, han, Magaña JJ, França M, Marques W et al. An Exploratory Survey on the Care for Ataxic Patients in the American Continents and the Caribbean. Cerebellum. 2023;22. Schmitz-Hübsch T, Du Montcel ST, Baliko L, Berciano J, Boesch S, Depondt C et al. Scale for the assessment and rating of ataxia: Development of a new clinical scale. Neurology. 2006;66. 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. Cortese A, Reilly M, Houlden H. RFC1 CANVAS / Spectrum Disorder. Gene Reviews (R) Internet. 1993rd–2025th ed. Seattle, WA: University of Washington; 2020. Sandford E, Burmeister M. Genes and genetic testing in hereditary ataxias. Genes (Basel). 2014. Chen S, Ashton C, Sakalla R, Clement G, Planel S, Bonnet C et al. Involvement of the Superior Cerebellar Peduncles in GAA- FGF14 Ataxia. Neurol Genet. 2025;11. Miranda MC, Diaz M, Hughes RG, Barreto MY, Nakousi NC, Campero MS et al. CANVAS: una nueva etiología de la ataxia del adulto. La asociación con tos orienta al diagnóstico. Comunicación de 2 pacientes Late-Onset Cerebellar Ataxia with Neuropathy: Uncovering the Role of RFC1 Gene Mutations. Rev Med Chil [Internet]. 2023 [cited 2025 Jul 2];151:524–9. Available from: https://www.scielo.cl/pdf/rmc/v151n4/0717-6163-rmc-151-04-0524.pdf Miranda M. Diagnóstico de Ataxia espino-cerebelosa tipo 3 (Enfermedad de Machado-Joseph) en Chile. Rev Med Chil [Internet]. 2015 [cited 2025 Jul 2];143:126–7. Available from: https://www.scielo.cl/pdf/rmc/v143n1/art19.pdf Perez Maturo J, Zavala L, Vega P, González-Morón D, Medina N, Salinas V et al. Overwhelming genetic heterogeneity and exhausting molecular diagnostic process in chronic and progressive ataxias: facing it up with an algorithm, a gene, a panel at a time. J Hum Genet. 2020;65. Tables Table 1. Summary of the sample characteristics Female sex n(%) 38(67.8%) Age at Onset (range) 18-64 yo Ancestry European n=2 Hispanic n= 54 Had previous negative genetic tests n = 6 Familial cases 19 individuals from 6 families Table 2. Clinical features of 8 patients with SCA27B Patient 7 Patient 12 Patient 10 Patient 13 Patient 11 Patient 8 Patient 9 Patient 16 Pedigree N/A IV-9 IV-7 III-4 IV-13 II-3 I-1 N/A Family N/A Family 1 Family 1 Family 1 Family 1 Family 2 Family 2 N/A Sex Male Male Female Female Female Female Female Male FGF14 GAA alleles expansion repeats 10/331 47/450 41/483 11/350 22/433 10/301 8/255 250/260 Age at onset of episodic symptom(s) (if episodic) 64 18 43 40 N/A 33 - - Potential triggers of episodic symptoms Sensory overload Hot weather, smokin, alcohol No Yes - Yes/Stress No Anesthesia, vaccines, heat Exercise-induced perception of imbalance No Yes Yes Yes - No Yes Yes Ethanol intolerance No Yes Yes N/A - Yes Not assessed (does not drink alcohole) Yes Superior Cerebellar Peduncle Sign on MRI Present Present Present (Faint) N/A N/A Present N/A Present Additional Declarations No competing interests reported. Supplementary Files 2025ATAXIACHILESUPPL.docx Cite Share Download PDF Status: Published Journal Publication published 22 Dec, 2025 Read the published version in The Cerebellum → Version 1 posted Editorial decision: Revision requested 26 Aug, 2025 Reviews received at journal 14 Aug, 2025 Reviews received at journal 14 Aug, 2025 Reviewers agreed at journal 24 Jul, 2025 Reviewers agreed at journal 23 Jul, 2025 Reviewers invited by journal 22 Jul, 2025 Editor assigned by journal 15 Jul, 2025 Submission checks completed at journal 15 Jul, 2025 First submitted to journal 11 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Macdonald Foundation, University of Miami Miller School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Stephan","middleName":"","lastName":"Zuchner","suffix":""},{"id":489856574,"identity":"705b0c99-7cec-437c-9b1a-0c241376151a","order_by":16,"name":"Henry Houlden","email":"","orcid":"","institution":"University College London","correspondingAuthor":false,"prefix":"","firstName":"Henry","middleName":"","lastName":"Houlden","suffix":""},{"id":489856575,"identity":"e78d69eb-a780-40de-825e-69979f5bbc3e","order_by":17,"name":"Bernard Brais","email":"","orcid":"","institution":"McGill University","correspondingAuthor":false,"prefix":"","firstName":"Bernard","middleName":"","lastName":"Brais","suffix":""},{"id":489856576,"identity":"61ff8c40-d924-44e9-80ec-b48ceb23bdb9","order_by":18,"name":"Ramiro Fernández","email":"","orcid":"","institution":"Hospital Clínico de Magallanes","correspondingAuthor":false,"prefix":"","firstName":"Ramiro","middleName":"","lastName":"Fernández","suffix":""},{"id":489856577,"identity":"61016ccc-6fcc-4b72-b761-28bd1c68ff74","order_by":19,"name":"José Fuentes Manríquez","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"José","middleName":"Fuentes","lastName":"Manríquez","suffix":""},{"id":489856578,"identity":"205cf80d-e9ca-4f0a-8cb7-53185e8e3508","order_by":20,"name":"Javiera Gajardo","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Javiera","middleName":"","lastName":"Gajardo","suffix":""},{"id":489856579,"identity":"fce991dc-80b0-4900-8d8c-39856058b44b","order_by":21,"name":"Javiera León","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Javiera","middleName":"","lastName":"León","suffix":""},{"id":489856580,"identity":"f7e49cfb-3b0b-47a9-9a1b-c79c468fff2f","order_by":22,"name":"Camila Melo","email":"","orcid":"","institution":"Clínica MEDS","correspondingAuthor":false,"prefix":"","firstName":"Camila","middleName":"","lastName":"Melo","suffix":""},{"id":489856581,"identity":"1b4cea26-cd37-4194-89cc-28fd0299ac09","order_by":23,"name":"Daniela Muñoz","email":"","orcid":"","institution":"Instituto Nacional de Movimientos Anormales (INMOV)","correspondingAuthor":false,"prefix":"","firstName":"Daniela","middleName":"","lastName":"Muñoz","suffix":""},{"id":489856582,"identity":"96e9c7ba-a752-4a5c-b28c-a9244ad89ae3","order_by":24,"name":"Ximena Pizarro","email":"","orcid":"","institution":"Instituto Nacional de Movimientos Anormales (INMOV)","correspondingAuthor":false,"prefix":"","firstName":"Ximena","middleName":"","lastName":"Pizarro","suffix":""},{"id":489856583,"identity":"03141bbb-b293-4a7b-9867-49c131677565","order_by":25,"name":"Pablo Rodríguez","email":"","orcid":"","institution":"Hospital Clínico de Magallanes","correspondingAuthor":false,"prefix":"","firstName":"Pablo","middleName":"","lastName":"Rodríguez","suffix":""},{"id":489856584,"identity":"66509a9b-5bbf-41bf-b6d9-7b1a2b2726d1","order_by":26,"name":"Philippe Salles","email":"","orcid":"","institution":"CETRAM","correspondingAuthor":false,"prefix":"","firstName":"Philippe","middleName":"","lastName":"Salles","suffix":""},{"id":489856585,"identity":"f4929e8f-2946-4f8c-a327-4a34d7c34dad","order_by":27,"name":"Camilo Sepúlveda","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Camilo","middleName":"","lastName":"Sepúlveda","suffix":""},{"id":489856586,"identity":"991820c0-8852-40f1-aeb1-edb4f24d6e5a","order_by":28,"name":"José Miguel Tirapegui","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"José","middleName":"Miguel","lastName":"Tirapegui","suffix":""},{"id":489856587,"identity":"a2e8b456-3470-4b48-ba80-7c84b4bb81ee","order_by":29,"name":"Daniel Valenzuela","email":"","orcid":"","institution":"Hospital Barros Luco Trudeau","correspondingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"","lastName":"Valenzuela","suffix":""},{"id":489856588,"identity":"925247ee-7951-486b-85fc-486f2db31411","order_by":30,"name":"Felipe Vial","email":"","orcid":"","institution":"Instituto Nacional de Movimientos Anormales (INMOV)","correspondingAuthor":false,"prefix":"","firstName":"Felipe","middleName":"","lastName":"Vial","suffix":""},{"id":489856589,"identity":"0d9840e1-8adf-4552-831f-4aae5e68f898","order_by":31,"name":"Patricia Orellana Pineda","email":"","orcid":"","institution":"University of Chile Clinical Hospital","correspondingAuthor":false,"prefix":"","firstName":"Patricia","middleName":"Orellana","lastName":"Pineda","suffix":""},{"id":489856590,"identity":"505f5a7e-df73-4f3e-93c0-8e343888895d","order_by":32,"name":"Cristian Garrido","email":"","orcid":"","institution":"University of Chile Clinical Hospital","correspondingAuthor":false,"prefix":"","firstName":"Cristian","middleName":"","lastName":"Garrido","suffix":""},{"id":489856591,"identity":"8ea2a549-fd99-449e-b97e-34db9db4b827","order_by":33,"name":"Gonzalo Miranda","email":"","orcid":"","institution":"University of Chile Clinical Hospital","correspondingAuthor":false,"prefix":"","firstName":"Gonzalo","middleName":"","lastName":"Miranda","suffix":""}],"badges":[],"createdAt":"2025-07-11 18:08:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7103872/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7103872/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12311-025-01937-5","type":"published","date":"2025-12-22T15:58:32+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":87554605,"identity":"2e595580-b9ed-4726-905f-1e48a9c1c6f1","added_by":"auto","created_at":"2025-07-25 06:45:47","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":21937,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSummary of genetic results. \u003c/strong\u003eFor each group, the percentage of the total is shown\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7103872/v1/7379e59fcd259ea0f78fdef7.png"},{"id":87555151,"identity":"2a0e1a5b-5d5e-4ab5-b50f-95ee77d03db9","added_by":"auto","created_at":"2025-07-25 06:53:47","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":230823,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePedigree (Family 1)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7103872/v1/5a1ace9d55214535f662e78a.jpeg"},{"id":87555147,"identity":"034cb5b8-496e-4625-b275-4ee1346df4ea","added_by":"auto","created_at":"2025-07-25 06:53:47","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":58436,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePedigree (Family 2)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7103872/v1/92beb5734650c5f100fe6562.jpeg"},{"id":87554609,"identity":"c8e49065-0c03-4d17-b9c9-2a499055b2b0","added_by":"auto","created_at":"2025-07-25 06:45:47","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1255356,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImaging findings in a Chilean patient with a confirmed pathogenic expansion in \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eFGF14\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e. \u003c/strong\u003eCoronal (a, b), sagittal (c), and axial (d) images of 3D T2-FLAIR sequence, showing mesencephalic hyperintensity extending to the superior peduncles (arrow) denominated the Superior Peduncle Sign. Axial section (e) of T2 sequence showing atrophy of the cerebellar vermis (arrow).\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7103872/v1/a7781781ff93fff26c149ffc.png"},{"id":99172420,"identity":"a80408a0-67a2-4693-b4e9-079ae9ae7291","added_by":"auto","created_at":"2025-12-29 16:09:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2642182,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7103872/v1/1a037ecf-fb3b-44f4-82ff-57a2d611b6bf.pdf"},{"id":87554616,"identity":"c2a123cc-37b5-41d3-8d74-5c134d95fef2","added_by":"auto","created_at":"2025-07-25 06:45:47","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":220652,"visible":true,"origin":"","legend":"","description":"","filename":"2025ATAXIACHILESUPPL.docx","url":"https://assets-eu.researchsquare.com/files/rs-7103872/v1/e91013b5894712cf4ad16a46.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eRepeat Expansions in a Chilean Cohort With Adult-Onset Cerebellar Ataxia\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eHereditary ataxias are a heterogeneous group of neurodegenerative diseases characterised by progressive gait disorder, incoordination, ocular movement disorders, and dysarthria [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Within the autosomal dominant group, the most commonly recognised genetic causes of ataxia are CAG triplet repeat expansions in the genes \u003cem\u003eATXN1\u003c/em\u003e (SCA1), \u003cem\u003eATXN2\u003c/em\u003e (SCA2), \u003cem\u003eATXN3\u003c/em\u003e (SCA3), \u003cem\u003eCACNA1A\u003c/em\u003e (SCA6), and \u003cem\u003eATXN7\u003c/em\u003e (SCA7). Expansions of GAA triplet repeat also cause Friedreich Ataxia, the most common form of autosomal recessive ataxia. While next-generation sequencing (NGS) has significantly improved the diagnostic yield in many genetic disorders, its utility remains limited when it comes to reliably detecting repeat expansions. Thus, disorders caused by repeat expansions continue to present unique methodological challenges. Interestingly, in the present decade two new causative loci have been identified, and with their discovery the cause of a significant proportion of cases with late-onset ataxia has been established. One of them is the identification of GAA repeat expansions in the Fibroblast Growth Factor 14 (\u003cem\u003eFGF14\u003c/em\u003e) gene causing SCA27B, responsible for 10–60% of previously unsolved cases of late-onset cerebellar ataxia [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. On the other hand, biallelic expansions in the Replication Factor C, subunit 1 (\u003cem\u003eRFC1\u003c/em\u003e) gene cause more than 90% of cases of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn Chile, there is insufficient information about the molecular epidemiology of ataxias, mainly due to the limited access to genetic testing, as previously reported [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Although a formal survey of the Chilean population does not exist, a recent study by the Pan American Hereditary Ataxia Network (PAHAN) estimated that the number of cases of hereditary ataxia in Chile is similar to other Latin American and Caribbean regions [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The purpose of this work is to present a cohort of patients who presented with adult-onset ataxia of suspected genetic etiology, where a set of repeat expansions were analyzed, including the genes causing the more recently identified types, SCA27B and \u003cem\u003eRFC1\u003c/em\u003e-related CANVAS. Although in several of these cases a genetic etiology had been strongly suspected due to a positive family history, they had remained undiagnosed for several years mainly due to lack of access to genetic testing, reflecting their usual trajectory in a country outside the developed world. The findings presented here are in accordance with recent publications from other populations, underscoring the relevance of the newly recognized etiologies. These results are useful in designing a future screening program in an adult population with suspected ataxia of genetic origin.\u003c/p\u003e"},{"header":"PATIENTS AND METHODS","content":"\u003cp\u003e\u003cb\u003eProtocols and recruitment\u003c/b\u003e\u003c/p\u003e\u003cp\u003e The protocol was approved by the Ethics Committee of the Faculty of Medicine, Universidad de Chile (Protocol 2021 − 192). Adult patients with a possible diagnosis of hereditary cerebellar ataxia were invited to participate by their attending neurologist. Exclusion criteria were cognitive impairment, dementia or inability to provide consent. All individuals signed an informed consent form. The recruitment took place from November 2022 to November 2024 in three cities of Chile, namely the capital Santiago de Chile, the northern city La Serena and the southern city Punta Arenas. All patients were evaluated by their attending neurologist, who recorded the symptoms and rated them according to the SARA (Scale for the Assessment and Rating of Ataxia) scale [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. For patients with a positive result or expansions in \u003cem\u003eFGF14\u003c/em\u003e or \u003cem\u003eRFC1\u003c/em\u003e genes, a vestibular function evaluation was performed by an ENT specialist using video head impulse test (vHIT) and video oculography. In selected cases, magnetic resonance imaging (MRI) of the brain was acquired with the protocol described below. In other cases, neuroimaging data (either images or radiologist reports) was obtained by accessing previous patients’ records.\u003c/p\u003e\u003cp\u003e\u003cb\u003eDNA extraction\u003c/b\u003e\u003c/p\u003e\u003cp\u003eDNA quantity and purity were determined using spectrophotometry with a NanoDrop™ instrument. DNA integrity was assessed by visual inspection following electrophoresis on 2% agarose gels. DNA sample were stored at − 20°C before being shipped to the labs where analyses were performed.\u003c/p\u003e\u003cp\u003e\u003cb\u003eGenotyping\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe \u003cem\u003eFGF14\u003c/em\u003e repeat locus was genotyped as described previously using long-range PCR and bidirectional repeat-primed PCR (RP-PCR) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. GAA expansions of 250 repeat units or more are considered pathogenic. The \u003cem\u003eRFC1\u003c/em\u003e-repeat locus was genotyped using RP-PCR [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], and flanking PCR, where samples with no product on this step were subsequently confirmed with southern blotting to carry biallelic expansions of the pentanucleotide AAGGG (11 repeats or larger).\u003c/p\u003e\u003cp\u003eThe expansions in \u003cem\u003eATXN1, ATXN2, ATXN3, CACNA1A\u003c/em\u003e, and \u003cem\u003eATXN7\u003c/em\u003e were tested through PCR of the regions of interest using fluorescent labeled primers flanking the CAG repeat sequence. Fragment length analysis was conducted by capillary electrophoresis on an automated genetic analyzer to determine the exact number of CAG repeats in each allele. Alleles were categorized as normal, intermediate, or pathogenic based on established repeat length thresholds for the specific SCA subtype tested.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMRI Acquisition\u003c/b\u003e\u003c/p\u003e\u003cp\u003eMRI was performed with a SIEMENS 3T Lumina scanner. T1-weighted images were acquired using a 3D MP2RAGE sequence with 1 mm isotopic resolution and TR/TE of 5000/2.76 ms. FLAIR T2- weighted images used a 3D 1 mm sequence with 6000/3.56 ms. Multi-shell DWI is obtained with 2 mm isotropic EPI-DWI, including b-values of 0, 300, 1000, and 2000, using an anterior-posterior phase encoding direction and TR/TE of 3000/65 ms. For b = 0 DWI, the same resolution is used with a posterior-anterior phase encoding. GRE is acquired in 2 mm axial slices with TR/TE of 639/20 ms.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA total of 56 affected patients from 43 families were included in the study. 38 (67.8%) of the patients were females, and the age of onset ranged from 18 to 64 years (See Table 1). As hereditary ataxias are rare diseases with an estimated prevalence of 1 to 9 individuals per 100,000 in the general population [9], gathering this sample in our country with a population of around 18 million represents a collective effort from highly specialized clinicians. Most participants experienced a prolonged diagnostic journey, often marked by years without a definitive diagnosis and inclusion only after the exclusion of other movement disorders.\u003c/p\u003e\n\u003cp\u003eINSERT TABLE 1 HERE\u003c/p\u003e\n\u003cp\u003ePathogenic repeat expansions in either \u003cem\u003eRFC1\u003c/em\u003e, \u003cem\u003eFGF14\u0026nbsp;\u003c/em\u003eand \u003cem\u003eATXN2\u003c/em\u003e were detected in 17 out of 56 individuals (Figure 1). A total of 9 patients from 5 families presented a pathogenic (GAA)\u003csub\u003e\u0026ge;250\u003c/sub\u003e repeat expansion in \u003cem\u003eFGF14\u003c/em\u003e. The expansion sizes ranged widely, with the largest allele being of 483 repeats, and the smallest of 255 repeats (See Table 2, and Supplementary Table 1). Episodic symptoms, not always associated with exercise, were often triggered by heat, or emotional stress. Four individuals reported ethanol intolerance. We observed T2/FLAIR hyperintensity of the superior cerebellar peduncles and cerebellar atrophy in three patients (See Table 2). Overall, the phenotypic variability, particularly in age at onset and symptom triggers, emphasizes the relative heterogeneity associated with SCA27B.\u003c/p\u003e\n\u003cp\u003eINSERT FIGURE 1 HERE\u003c/p\u003e\n\u003cp\u003eBiallelic pathogenic AAGGG repeat expansions in the \u003cem\u003eRFC1\u003c/em\u003e gene were identified in 7 patients, including two siblings and 5 unrelated individuals. Comprehensive genetic testing for multiple genes associated with ataxia revealed a pathogenic expansion in \u003cem\u003eATXN2\u0026nbsp;\u003c/em\u003ein one patient. In addition, an intermediate expansion in \u003cem\u003eATXN1\u003c/em\u003e was found in one patient, and two intermediate \u003cem\u003eFGF14\u0026nbsp;\u003c/em\u003e(GAA)\u003csub\u003e200-249\u0026nbsp;\u003c/sub\u003e expansions, considered of uncertain pathogenicity, were also found. These are variants of uncertain pathogenicity, and to date we do not have additional information to allow us to solve these cases.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the following paragraphs we describe in more detail some of the more relevant findings.\u003c/p\u003e\n\u003cp\u003eINSERT FIGURE 2 HERE\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFamily 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFamily 1 comprises 17 individuals with either confirmed or self-reported cerebellar ataxia, with a mean age of onset of 39 years. Figure 2 shows the pedigree, indicating which individuals were included in our study, all of them of Hispanic ancestry. The index case (individual IV-7), a 54 year old woman, reported paroxysmal symptoms from age 43. These episodes were triggered by tobacco use, alcohol consumption, physical exertion, and emotional stress. The episodes were characterized by slurred speech, gait unsteadiness, confusion, and slow reactivity. Neurological examination revealed mild limb and gait ataxia without other major systemic neurological deficits. Oculomotor testing showed prominent abnormalities, with disruption of ocular fixation with abundant square wave jerks, alterations of ocular alignment with esophoria associated with diplopia, reduced saccade velocity (greater in the vertical plane), and hypometric saccades in all directions. She had no downbeat nystagmus (DBN). At time of last examination, she had a SARA score of 7, indicating mild ataxia. Genetic testing identified a pathogenic \u003cem\u003eFGF14\u0026nbsp;\u003c/em\u003e(GAA)\u003csub\u003e483\u003c/sub\u003e repeat expansion in the \u003cem\u003eFGF14\u003c/em\u003e gene, supporting the diagnosis of SCA27B (Table 2). The index\u0026rsquo;s brother, individual IV-9, described paroxysmal symptoms beginning at age 18. These episodes typically occur minutes after exposure to tobacco smoke, alcohol consumption, physical exercise, emotional stress, or high temperatures, such as on a hot day or after a warm shower. During these episodes, he experiences slurred speech, loss of balance, gait instability, drowsiness, and decreased alertness. At time of last examination, his SARA score was 5. He showed saccadic pursuit and no DBN. He had previously undergone genetic testing at a clinically-accredited laboratory, which returned negative results for expansions in \u003cem\u003eATXN1, ATXN2, ATXN3\u003c/em\u003e, and \u003cem\u003eATXN7\u003c/em\u003e. Subsequent genetic analysis identified a pathogenic \u003cem\u003eFGF14\u0026nbsp;\u003c/em\u003e(GAA)\u003csub\u003e450\u003c/sub\u003e repeat expansion (see Patient 12, Table 2).\u003c/p\u003e\n\u003cp\u003eTheir mother is also affected by late-onset, slowly progressing ataxia. Whereas no genetic result is available from her, her previous brain MRI showed hyperintensity of the superior cerebellar peduncles (SCP), which has been previously reported in SCA27B by Chen et al \u0026nbsp;[10] . Furthermore, a maternal aunt and a first-degree cousin of the proband (both affected, see III-4 and IV-13 on Figure 2) also have pathogenic \u003cem\u003eFGF14\u003c/em\u003e expansions of 350 and 433 GAA triplets, respectively (see Table 2). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eINSERT FIGURE 3 HERE\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFamily 2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFamily 2 corresponds to a family of 11 individuals with either self-reported or confirmed ataxia, most of them located in Punta Arenas, in the Chilean Patagonia. Figure 3 shows part of this family including the two individuals with ataxia who were genetically tested, both of them of Hispanic ancestry. The index case (II-3) is a female (see Figure 3 and Table 2) who at time of the study reported 8 years of progressive ataxia. She described gait instability, whose severity did not prevent her from carrying her daily activities, but worsened under stressful situations. She complained of diplopia and oscillopsia and her oto-neurological examination showed slow horizontal and vertical saccades, and no DBN. At last examination, her SARA score was 6, consistent with mild ataxia. The genetic test for this patient showed a pathogenic \u003cem\u003eFGF14\u0026nbsp;\u003c/em\u003e(GAA)\u003csub\u003e301\u003c/sub\u003e repeat expansion.\u003c/p\u003e\n\u003cp\u003eThe patient\u0026apos;s mother (individual I-1 in Figure 3 and Table 2) began exhibiting symptoms of ataxia at the age of 51. Clinical examination revealed impaired balance and gait, and vertical gaze paresis without DBN. Genetic analysis identified an expansion of 255 GAA triplet repeats in the \u003cem\u003eFGF14\u003c/em\u003e gene.\u003c/p\u003e\n\u003cp\u003eTable 2 presents a summary of the relevant findings of the individuals where FGF14 mutations were identified. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eINSERT TABLE 2 HERE\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFamily 3\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePreviously, we reported the case of a male with ataxia and cough, where biallelic pathogenic AAGGG expansions in \u003cem\u003eRFC1\u003c/em\u003e were identified [11]\u0026nbsp;.\u0026nbsp;Now, we have confirmed that his two sisters exhibiting chronic cough and sensory neuropathy also carry biallelic \u003cem\u003eRFC1\u003c/em\u003e expansions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMRI Findings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe brain MRI performed on six patients with SCA27B revealed hyperintensity of the midbrain and superior cerebellar peduncles bilaterally, in addition to cerebellar atrophy. Figure 4 shows representative images of the individual IV-9 from Family 1 (see Figure 2), highlighting cerebellar atrophy and the SCP sign.\u003c/p\u003e\n\u003cp\u003eINSERT FIGURE 4. HERE\u0026nbsp;\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis manuscript presents the largest genetic study of Chilean individuals with ataxia to date. Interestingly, this survey was only answered by specialists from the Chilean capital city of Santiago, but our study recruited individuals currently being attended in the Northern and Southern regions of the country as well. Our study reflects that, while ataxia is a well-known syndrome and several molecular tests are available, even in a country of middle income like Chile, many patients continue to undergo a diagnostic odyssey, with many years and several referrals before obtaining a diagnosis. In the present work, a research collaboration has made possible to complete the genetic study for this cohort and reach a diagnosis in a significant proportion of cases. Our results point to relevant issues in planning the future implementation of genomic services in patients and families with ataxia in Chile. Namely, newly recognized expansions in the \u003cem\u003eRFC1\u003c/em\u003e and \u003cem\u003eFGF14\u003c/em\u003e genes account for a relevant proportion of the cases, and they have recognizable clinical features that may guide the diagnostic process, in terms of age of onset and temporal pattern of symptoms. These genotype-phenotype correlations are especially relevant because testing for gene expansions is labor intensive and can be expensive, therefore justifying the use of a multi-tiered workup, and also because they may provide guidelines regarding outcome and treatment response. In our sample, among those individuals who had a SCA27B the median AAO was over 30 years of age. Furthermore, we have preliminary observations that all three of these individuals who have received 4-amynopiridine have benefited from it. This is in line with previous reports that show that there is a reduction of symptoms with its use, surpassing that of acetazolamide, considered the first-line treatment for episodic ataxia [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. A longer follow-up will be required to show whether this effect is sustained over time.\u003c/p\u003e\u003cp\u003eWe performed an MRI on three confirmed cases of SCA27B. Cerebellar atrophy was identified in all patients, which has been usually described in patients with genetic ataxias, as well as hyperintensity in the midbrain and superior cerebellar peduncles. The last was recently reported as the Superior Cerebellar Peduncle Sign, which has been recognized as a potentially characteristic finding of patients with SCA27B by Chen et al., [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], being present in up to 60% of patients. The pathophysiology of this sign is not been completely understood, but theory points to potential vasogenic edema. This highlights the potential role of MRI as a complementary tool to guide genetics testing if signs, such as the SCP sign, are proven to be specific. However, larger cohort studies determining the sensitivity and specificity of the SCP sign are needed before establishing the diagnostic value of this sign. An important point to notice is that the SCP sign can be missed on T2w axial images and may only be observed on high-resolution T2/FLAIR 3D sequences, which points to the need for acquiring appropriate MRI sequences. Nevertheless, this sequence can be acquired on clinical MRI equipment.\u003c/p\u003e\u003cp\u003eIn this cohort, out of 56 patients, only one individual was found to carry an \u003cem\u003eATXN2\u003c/em\u003e expansion, and one carried an intermediate expansion in \u003cem\u003eATXN1.\u003c/em\u003e As our project was set up following the model of the \u0026ldquo;Undiagnosed diseases\u0026rdquo; unit, our cohort received the more challenging cases. For instance, previously we had published a series of 10 unrelated individuals with confirmed SCA3 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn total,, we were able to solve 17/56 cases, or 30.3%. Considering only index cases, our genetic study solved 26% of cases (11/43). As hereditary ataxias display significant genetic heterogeneity, we expect that as a follow up step to this study we can increase this yield using a more individualized approach, like the one proposed by P\u0026eacute;rez-Maturo et al [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eEstablishing the molecular cause of cerebellar ataxia is a necessary step toward providing adequate genetic counseling, and helping to predict a patient\u0026rsquo;s clinical course and establish necessary follow ups.\u003c/p\u003e\u003cp\u003eAs Latin American countries advance toward better healthcare services, these results should be taken into account when designing programs for molecular diagnosis of ataxia and related neurological conditions across the continent.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFUNDING DECLARATION\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was funded by Foundation Diagnosis, a nonprofit organization based in Providencia, Santiago, Chile (RPJ N\u0026deg;294390); by Hospital Cl\u0026iacute;nico-Faculty of Medicine, Universidad de Chile (OAIC FGF 14 Project IE 62/24); by Clinica MEDS (Fondo Semilla 2024, PI MMC); by Canadian Institutes of Health Research (Grant 189963 to BB),\u0026nbsp;and by UCL Queen Square Institute of Neurology in the University College London. D.P. holds a fellowship award from the Canadian Institutes of Health Research. B.P.G holds a fellowship from Agencia Nacional de Investigaci\u0026oacute;n y Desarrollo, ANID, Chile. N.D. holds a fellowship award from the NIHR UCLH BRC.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful to Dr. Roberta La Piana for her insightful comments regarding the neuroimages, as well as to all the patients that participated in the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOMPLIANCE WITH ETHICAL STANDARDS AND CONSENT TO PARTICIPATE\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures performed in this study were in accordance with the ethical standards of the institutional review board of Universidad de Chile, where the study was carried out, with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study protocol, \u0026quot;Creaci\u0026oacute;n de una Unidad de Enfermedades sin Diagn\u0026oacute;stico en la Universidad de Chile\u0026rdquo; was reviewed and approved by the Comit\u0026eacute; de \u0026Eacute;tica de la Investigaci\u0026oacute;n en Seres Humanos (CEISH) de la Facultad de Medicina de la Universidad de Chile N\u0026deg; 092-2021, on October 12\u003csup\u003eth\u003c/sup\u003e, 2021, and renewed on April 11\u003csup\u003eth\u003c/sup\u003e 2023. Prior to participation, all individuals provided written informed consent after receiving a comprehensive explanation of the study\u0026apos;s purpose, procedures, potential risks, and benefits. Participant confidentiality and privacy were rigorously maintained throughout the study, with all data being anonymized to protect personal identities.\u003c/p\u003e\n\u003cp\u003eCLINICAL TRIAL NUMBER: Not applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eJayadev S, Bird TD. Hereditary ataxias: Overview. Genetics in Medicine. 2013.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePellerin D, Wilke C, Trasch\u0026uuml;tz A, Nagy S, Curr\u0026ograve; 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. 2023;95.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDavies K, Szmulewicz DJ, Corben LA, Delatycki M, Lockhart PJ. RFC1 -Related Disease. Neurol Genet. 2022;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSaffie Awad P, Vial Undurraga F, Chan\u0026aacute;-Cuevas P. Clinical features of 63 patients with ataxia. Rev Med Chil. 2018;146.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJardim LB, Hasan A, Kuo S, han, Maga\u0026ntilde;a JJ, Fran\u0026ccedil;a M, Marques W et al. An Exploratory Survey on the Care for Ataxic Patients in the American Continents and the Caribbean. Cerebellum. 2023;22.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchmitz-H\u0026uuml;bsch T, Du Montcel ST, Baliko L, Berciano J, Boesch S, Depondt C et al. Scale for the assessment and rating of ataxia: Development of a new clinical scale. Neurology. 2006;66.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBonnet C, Pellerin D, Roth V, Cl\u0026eacute;ment G, Wandzel M, Lambert L et al. Optimized testing strategy for the diagnosis of GAA-FGF14 ataxia/spinocerebellar ataxia 27B. Sci Rep. 2023;13.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCortese A, Reilly M, Houlden H. RFC1 CANVAS / Spectrum Disorder. Gene Reviews (R) Internet. 1993rd\u0026ndash;2025th ed. Seattle, WA: University of Washington; 2020.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSandford E, Burmeister M. Genes and genetic testing in hereditary ataxias. Genes (Basel). 2014.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen S, Ashton C, Sakalla R, Clement G, Planel S, Bonnet C et al. Involvement of the Superior Cerebellar Peduncles in GAA- FGF14 Ataxia. Neurol Genet. 2025;11.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMiranda MC, Diaz M, Hughes RG, Barreto MY, Nakousi NC, Campero MS et al. CANVAS: una nueva etiolog\u0026iacute;a de la ataxia del adulto. La asociaci\u0026oacute;n con tos orienta al diagn\u0026oacute;stico. Comunicaci\u0026oacute;n de 2 pacientes Late-Onset Cerebellar Ataxia with Neuropathy: Uncovering the Role of RFC1 Gene Mutations. Rev Med Chil [Internet]. 2023 [cited 2025 Jul 2];151:524\u0026ndash;9. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.scielo.cl/pdf/rmc/v151n4/0717-6163-rmc-151-04-0524.pdf\u003c/span\u003e\u003cspan address=\"https://www.scielo.cl/pdf/rmc/v151n4/0717-6163-rmc-151-04-0524.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMiranda M. Diagn\u0026oacute;stico de Ataxia espino-cerebelosa tipo 3 (Enfermedad de Machado-Joseph) en Chile. Rev Med Chil [Internet]. 2015 [cited 2025 Jul 2];143:126\u0026ndash;7. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.scielo.cl/pdf/rmc/v143n1/art19.pdf\u003c/span\u003e\u003cspan address=\"https://www.scielo.cl/pdf/rmc/v143n1/art19.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePerez Maturo J, Zavala L, Vega P, Gonz\u0026aacute;lez-Mor\u0026oacute;n D, Medina N, Salinas V et al. Overwhelming genetic heterogeneity and exhausting molecular diagnostic process in chronic and progressive ataxias: facing it up with an algorithm, a gene, a panel at a time. J Hum Genet. 2020;65.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Summary of the sample characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"581\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 46.8158%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFemale sex n(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 53.1842%;\"\u003e\n \u003cp\u003e38(67.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 46.8158%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at Onset (range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 53.1842%;\"\u003e\n \u003cp\u003e18-64 yo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 46.8158%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAncestry\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 53.1842%;\"\u003e\n \u003cp\u003eEuropean n=2\u003c/p\u003e\n \u003cp\u003eHispanic n= 54\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 46.8158%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHad previous negative genetic tests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 53.1842%;\"\u003e\n \u003cp\u003en = 6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 46.8158%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFamilial cases\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 53.1842%;\"\u003e\n \u003cp\u003e19 individuals from\u0026nbsp;6 families\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Clinical features of 8 patients with SCA27B\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"755\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.037%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.12698%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient 7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0529%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient 12\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.73016%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient 10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.73016%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient 13\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0529%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient 11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient 8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient 9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePatient 16\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.037%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePedigree\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.12698%;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0529%;\"\u003e\n \u003cp\u003eIV-9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.73016%;\"\u003e\n \u003cp\u003eIV-7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.73016%;\"\u003e\n \u003cp\u003eIII-4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0529%;\"\u003e\n \u003cp\u003eIV-13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003eII-3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003eI-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.037%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFamily\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.12698%;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0529%;\"\u003e\n \u003cp\u003eFamily 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.73016%;\"\u003e\n 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\u003c/td\u003e\n \u003ctd style=\"width: 8.73016%;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0529%;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.037%;\"\u003e\n \u003cp\u003eFGF14 GAA alleles expansion repeats\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.12698%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e10/331\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0529%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e47/450\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.73016%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e41/483\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.73016%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e11/350\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0529%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e22/433\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e10/301\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8/255\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e250/260\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.037%;\"\u003e\n \u003cp\u003eAge at onset of episodic symptom(s) (if episodic)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.12698%;\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0529%;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.73016%;\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.73016%;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0529%;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.037%;\"\u003e\n \u003cp\u003ePotential triggers of episodic symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.12698%;\"\u003e\n \u003cp\u003eSensory overload\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0529%;\"\u003e\n \u003cp\u003eHot weather, smokin, alcohol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.73016%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.73016%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0529%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003eYes/Stress\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003eAnesthesia, vaccines, heat\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.037%;\"\u003e\n \u003cp\u003eExercise-induced perception of imbalance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.12698%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0529%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.73016%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.73016%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0529%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.037%;\"\u003e\n \u003cp\u003eEthanol intolerance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.12698%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0529%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.73016%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.73016%;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0529%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003eNot assessed (does not drink alcohole)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.037%;\"\u003e\n \u003cp\u003eSuperior Cerebellar Peduncle Sign on MRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.12698%;\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0529%;\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.73016%;\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003cp\u003e(Faint)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8.73016%;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.0529%;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.7566%;\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"the-cerebellum","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cere","sideBox":"Learn more about [The Cerebellum](http://link.springer.com/journal/12311)","snPcode":"12311","submissionUrl":"https://submission.nature.com/new-submission/12311/3","title":"The Cerebellum","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Repeat expansions, Latin American population, Neurogenetics, SCA27B, CANVAS syndrome","lastPublishedDoi":"10.21203/rs.3.rs-7103872/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7103872/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eINTRODUCTION: The diagnosis of hereditary ataxias caused by repeat expansions continue to present unique methodological challenges, especially for developing countries where genomic medicine services are not well established. The purpose of this work is to present a cohort of patients who presented with adult-onset ataxia of suspected genetic etiology, but had remained undiagnosed until now. They were analyzed for a set of repeat expansions including the genes causing the more recently identified types, SCA27B\u003cem\u003e \u003c/em\u003eand \u003cem\u003eRFC1\u003c/em\u003e-related CANVAS. PATIENTS AND\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMETHODS: We followed an IRB-approved protocol to recruit adult patients with a possible diagnosis of hereditary cerebellar ataxia. All individuals signed an informed consent form, and after a neurological evaluation, DNA samples from blood were obtained. In selected cases, a complete vestibular function evaluation and brain magnetic resonance imaging was acquired.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRESULTS: In 17 of the 56 studied cases (including 11 of 43 index cases) we established a genetic diagnosis, which demonstrates that this is a promising approach to adult-onset ataxias in a population that remains underrepresented in worldwide genomic studies. We identified 9 individuals with SCA27B and 7 with CANVAS syndrome, highlighting the epidemiological relevance of these newly recognized etiologies, an information useful for planning the allocation of resources towards improving the access to genomic medicine in in our region.\u003c/p\u003e","manuscriptTitle":"Repeat Expansions in a Chilean Cohort With Adult-Onset Cerebellar Ataxia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-25 06:45:42","doi":"10.21203/rs.3.rs-7103872/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-26T09:25:15+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-15T03:02:19+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-14T19:03:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"231465451694456442556768920817389072019","date":"2025-07-24T13:23:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"124770817514262335646036535379491893710","date":"2025-07-23T15:09:28+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-22T16:57:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-16T03:56:42+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-16T03:55:12+00:00","index":"","fulltext":""},{"type":"submitted","content":"The Cerebellum","date":"2025-07-11T18:00:54+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"the-cerebellum","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cere","sideBox":"Learn more about [The Cerebellum](http://link.springer.com/journal/12311)","snPcode":"12311","submissionUrl":"https://submission.nature.com/new-submission/12311/3","title":"The Cerebellum","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"82c00d17-803f-4d6f-90fc-f872231ae77f","owner":[],"postedDate":"July 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-29T16:03:45+00:00","versionOfRecord":{"articleIdentity":"rs-7103872","link":"https://doi.org/10.1007/s12311-025-01937-5","journal":{"identity":"the-cerebellum","isVorOnly":false,"title":"The Cerebellum"},"publishedOn":"2025-12-22 15:58:32","publishedOnDateReadable":"December 22nd, 2025"},"versionCreatedAt":"2025-07-25 06:45:42","video":"","vorDoi":"10.1007/s12311-025-01937-5","vorDoiUrl":"https://doi.org/10.1007/s12311-025-01937-5","workflowStages":[]},"version":"v1","identity":"rs-7103872","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7103872","identity":"rs-7103872","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}