Identification of FGF14 GAA expansions in Polish patients with undiagnosed cerebellar ataxia – a preliminary study

Identification of FGF14 GAA expansions in Polish patients with undiagnosed cerebellar ataxia – a preliminary study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report Identification of FGF14 GAA expansions in Polish patients with undiagnosed cerebellar ataxia – a preliminary study Marta Matlawska, Karolina Ziora-Jakutowicz, Marie-Josee Dicaire, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7463343/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction: Spinocerebellar ataxia type 27B (SCA27B), caused by an intronic GAA repeat expansion in the FGF14 gene, has recently emerged as a major cause of late-onset cerebellar ataxia (LOCA). Its prevalence and clinical profile in Central and Eastern Europe remain largely unknown. Objective: To determine the frequency and phenotypic characteristics of FGF14 GAA·TTC repeat expansions, a large cohort of Polish patients with undiagnosed adult-onset cerebellar ataxia was investigated. Methods: We retrospectively analyzed 701 patients (age of onset ≥25 years) with adult-onset cerebellar ataxia of unknown etiology, previously tested negative for SCA1, SCA2, SCA3, SCA8, and RFC1 expansions. GAA·TTC repeat lengths were assessed using long-range and repeat-primed PCR. Expansions ≥250 repeats were classified as pathogenic. Clinical and MRI data were evaluated where available. A control group of 66 neurologically healthy individuals was also screened. Results: Pathogenic FGF14 expansions (≥250 repeats) were identified in 4.4% (31/701) of patients, including 23 with fully penetrant (≥300) and 8 with incompletely penetrant (250–299) alleles. No pathogenic expansions were found in controls. The mean age of onset was 49.8 years. Common symptoms included balance and gait disturbances, cerebellar syndrome, and episodic features such as diplopia. Cerebellar atrophy was present in 45% of patients with available MRI. No significant correlation between repeat length and age of onset was observed. Summary: Our findings confirm that FGF14 repeat expansions are an underrecognized cause of LOCA in Poland and support their inclusion in standard genetic testing for adult-onset ataxias. Further studies are warranted to better define penetrance and genotype–phenotype correlations. SCA27B FGF14 expansion spinocerebellar ataxia neurodegenerative disorders Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Autosomal dominant spinocerebellar ataxias (SCAs) are a genetically and clinically heterogeneous group of neurodegenerative disorders characterized by progressive degeneration of cerebellar neurons. Despite continuous advancements in diagnostic tools, including sequencing technologies, the molecular basis of SCA remains unknown in a significant proportion of patients. An intronic GAA·TTC repeat expansion in the FGF14 gene has recently been described as the cause of autosomal dominant spinocerebellar ataxia 27B (SCA27B) [ 1,2,3 ]. It is currently assumed that expansions of 250-299 GAA·TTC repeats are pathogenic, yet incompletely penetrant, while larger expansions are deemed pathogenic and highly penetrant [ 2,4 ]. Studies involving different cohorts of patients with late-onset cerebellar ataxia (LOCA, AOO <30 years) of unknown etiology have shown that SCA27B accounts for 10 to 60% of cases [ 1,2 ]. The pathogenic threshold and phenotypic spectrum of SCA27B still remain to be fully characterized. The classic phenotype of SCA27B includes gait ataxia, downbeat nystagmus, and the occurrence of episodic symptoms [ 2,5 ]. It is postulated that SCA27B is currently the most frequently identified type of autosomal dominant ataxia among patients in whom the genetic cause of another LOCA could not yet be determined. In this paper, we present the results of our preliminary study on the assessment of the frequency of SCA27B in a cohort of Polish patients with spinocerebellar ataxia of unknown etiology. Methods Patients and clinical data: Inclusion criteria for the study comprised adult- onset cerebellar ataxia (AOO ≥25 years, range 25 - 83 years) of unknown etiology, with negative test results for SCA1, SCA2, SCA3, SCA8, and RFC1 -related ataxia. A group of 701 patients (344 females and 357 males) with LOCA of unknown etiology was recruited retrospectively from patients referred to the Genetic Clinic of the Institute of Psychiatry and Neurology from all over Poland. Cases of MSA-C (Multiple System Atrophy- Cerebellar Type) were excluded from this study. The control group consisted of 66 healthy individuals (33 females and 33 males) without neurological symptoms, and the mean age was 69 years. In the patient’s group, 11/31 individuals with an FGF14 repeat expansion had previously undergone brain MRI. The results of clinical examination are shown in Figure 1. Informed written consent to genetic testing was obtained from all participants, with a consent to participate in scientific research. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The protocol was approved by the Local Bioethics Committee at the Institute of Psychiatry and Neurology in Warsaw. Molecular examinations: The GAA·TTC expansions were studied according to the standard protocol [4]. Expansions larger than 250 GAA·TTC repeats were considered pathogenic. Molecular studies were performed at the Department of Genetics of the Institute of Psychiatry and Neurology in Poland and the Montreal Neurological Institute-Hospital – Mcgill University in Canada. Statistical analysis: Statistical analyses were performed in R 4.5.0 and Rstudio software. Pearson’s coefficients were used to determine the correlation between the age of onset (AOO) and the number of GAA repeats, assuming statistically significant values when p < 0.05. Results We examined 701 probands with adult- onset cerebellar ataxia. Positive family history of ataxia was found in 172 patients, while 529 patients were sporadic cases. Their mean age at examination was 60,5 years. Among them, 3.3% (23/701) had a confirmed GAA·TTC repeat expansion in FGF14 within the fully penetrant range (301–583 repeats). An additional 1.1% (8/701) had expansions in the incompletely penetrant range (250–299 repeats). In total, we found 31 individuals (4.4%) carrying an FGF14 repeat expansion larger than 250 GAA·TTC repeat units. The median size of the expanded allele was 345 GAA·TTC repeats. We also identified 2 patients carrying a non-pathogenic GAAGGA expansion. Among the 31 identified patients with SCA27B, 11 cases were familial, 14 had no family history, and this information was not available for 6 patients. The mean age of onset in patients with confirmed SCA27B was 49.8 (range 34-79 years). One of the patients had biallelic expansions (287/383 GAA·TTC repeats), however, no significant difference in the course of the disease was observed compared to patients with expansion. Due to the lack of SARA scale data, we were unable to assess disease progression. In our study, 4 patients with an intermediate allele, i.e. 200-249 GAA·TTC repeats (9/224, 9/232, 100/237 and 38/244 GAA·TTC), presented ataxia, including balance disturbances (4/4), gait disturbances (3/4), dysarthria (1/4), cerebellar atrophy and generalized brain atrophy (2/4). However, apart from excluding SCA1, SCA2, SCA3 and SCA8, we did not have the results of more detailed studies (e.g. WES, WGS) excluding other types of SCA in the indicated patients. In the control group, no alleles larger than 187 GAA·TTC repeats were identified (range 8–187 GAA·TTC). Our study demonstrated no significant inverse correlation between the number of GAA·TTC repeats and the age of onset in 25 patients (Pearson coefficient: r = -0.342, p = 0.087). Clinical data based on the available patients medical files are presented in Figure 1. The most common clinical feature was imbalance, observed in 68% of patients (17/25), followed by gait ataxia in 56% (14/25) and cerebellar syndrome in 40% (10/25). Dysarthria was reported in 36% (9/25), while ataxia, cognitive impairments, and episodic symptoms were each present in 24% (6/25) of the patients. Other frequent findings included: nystagmus (any type): 20% (5/25), cerebellar atrophy: 16% (4/25), appendicular ataxia, tremor, horizontal gaze-evoked nystagmus, global brain atrophy, headache, and dysmetria: each observed in 16% (4/25). Oculomotor abnormalities, pyramidal symptoms, spasticity, and head tremor: each found in 12% (3/25). Less commonly reported symptoms (8%, 2/25) included: dysdiadochokinesia, slurred speech, choking, bradykinesia, diplopia or blurry vision, scanning speech, dysphagia, decreased muscle tension, proprioceptive sensory disturbances, and upper limb dysmetria. Rare findings, each observed in a single patient (4%, 1/25), were dizziness/vertigo, hearing loss, cardiomyopathy, and spastic-parietic gait. These results indicate a predominance of core cerebellar features, particularly imbalance and gait disturbance, alongside a range of additional motor, sensory, and episodic symptoms in patients with FGF14 -related ataxia. Discussion Autosomal dominant SCA27B is a late-onset ataxia, commonly preceded by an episodic onset, with the onset of permanent symptoms often occurring in the fifth to seventh decade of life [2,5] . In our cohort, the median age at onset was 50 years (30-79 years). The clinical phenotype in Polish patients with SCA27B is similar to that of other published cohorts, with a predominance of gait ataxia, horizontal-gaze evoked nystagmus, dysarthria, and episodic symptoms [1,2,5-1 5 ]. We found no significant correlation between the number of GAA repeats and the age of onset, although we observed a trend: r = -0.342 p = 0.087. According to the previous epidemiological data, the highest percentage of patients with confirmed SCA27B (61%) is noted in the French-Canadian population, which is related to a founder effect [ 2] . Cohort ethnicity No. of patients diagnosed with SCA27B (≥250 GAA·TTC) References: French Canadian 40/66 (61%) [2] Spanish 18/107 (28.1%) [16] German 34/148 (23%) [15] Australian 3/20 (15%) [2] Greek 19/160 (11.9%) [8] Italian 53/396 (13.4%) [11] Dutch 28/248(11%) [12] Brasilian 8/93 (9%) [6] Cyprus 12/155 (7.7%) [9] USA 55/732 (7.5%) [14] Serbian 9/167 (5.4%) [13] Northern Finnish 5/96 (5.2%) [17] Jewish 2/91 (2.2%) [7] Japanese 8/460 (1.7%) [18] Chinese 12/1216 (1.0%) [19] Table 1. Number of patients diagnosed with SCA27B in different ethnicity cohorts. In a study of 701 Polish patients with spinocerebellar ataxia of unknown cause, 31 cases were found to carry a repeat expansion in FGF14 , which stands for approximately 4.4%. Our results indicate that Poland currently has one of the lowest percentage of patients with SCA27B in Europe, taking into account data from other Europeans cohorts (German, Italian, Dutch and Spanish [Table 1., 11,12,15, 16 ]. Our results are more comparable with data from Jewish, Cyprus, Serbian and Northern Finnish population [ 7,9 ,13,17 ]. However, this data may be significantly underestimated, due to the limited number of patients included in the studies, as well as the small number of comparative data from other cohorts in the world. A lower percentage of diagnosed SCA27B cases has been described only in East Asia (ex. Japan, China), which may be related to the specificity of the region and the low frequency of alleles ≥250 GAA in the Japanese and Chinese population compared to the Caucasian population, which is explained by different polymorphisms [ 18,19 ]. Data from European cohorts indicates that SCA27B is a common cause of autosomal dominant ataxia and points for the need of implementation of this type of SCA into the basic diagnostic protocol [ 1,9 ,11,12,13 ]. The occurrence of episodic symptoms, the late age of onset, cerebellar ocular motor signs and the slowly progressive course of the disease should trigger evaluation for SCA27B [2 ]. Vestibular hypofunction has also been observed, often with dizziness and loss of balance [ 2,5]. The occurrence of rare cases of young adults (≥25 years) with SCA27B indicates that the diagnosis should also be considered in younger individuals with a suggestive phenotype and an otherwise negative genetic workup [5, 8,9] .The spectrum of symptoms observed in the cohort of Polish patients—with a predominance of balance disturbances, gait ataxia, and cerebellar syndrome, along with the presence of episodic symptoms and dysarthria corresponds to the clinical phenotype of SCA27B described in other cohorts worldwide [ 1,6,7,9,11,13-17 ]. As a limitation, no data on the presence of downbeat nystagmus, a hallmark feature of SCA27B [ 1,2,6,8,9,11, ], was available in our cohort. Neuroimaging in SCA27B usually shows mild to moderate cerebellar atrophy, especially in the vermis [1,2,5] . In 11/31 of our patients with SCA27B and available MRI results, we observed cerebellar atrophy in 5/11 (45%) which is a common hallmark of SCA27B [ 14 ]. Cerebral atrophy was observed in 2/11 cases (18%), suggesting that this change is either uncommon or may appear in later stages of the disease. However, changes of this type are also observed in many other types of SCA, so they are not specific for SCA27B. Moreover, in our patients we did not observe any signs of hyperintensity in the superior cerebellar peduncles (SCP), which have been observed in different cohorts, but FLAIR T2-weighted images were not available for review [ 11 ]. To date, this is the only epidemiological investigation of SCA27B in a large cohort of Polish patients with late-onset, undiagnosed ataxia. Although rarer than in other European cohorts, these findings support the inclusion of this form of ataxia in routine diagnostics. However, our study has several important limitations. It was retrospective in nature, and the patients were recruited from across Poland, which often meant very limited access to detailed medical records. The lack of SARA scale scores for patients with confirmed SCA27B, as well as the absence of neuroimaging data for more than half of the patients, makes it impossible to assess the long-term progression of the disease. Additionally, it was not possible to perform segregation studies in any of the families. More detailed studies are needed to thoroughly characterize the clinical phenotype of SCA27B and the frequency of mutations in the range of incomplete and full penetrance of the FGF14 gene in the cohort of Polish patients. Declarations Funding: The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Conflicts of interest: All authors declare no conflict of interest during this research. Data availability: The datasets generated during and/or analysed during the current study are not publicly available due to institutional policy restricting the sharing of sensitive clinical and genetic data. This policy is in place to ensure compliance with ethical standards, informed consent limitations, and applicable data protection regulations, including the national General Data Protection Regulation (GDPR) and relevant national laws. However, the data are available from the corresponding author on reasonable request. Author contributions: Drafting of the manuscript: MM Patient medical examination: JP and KZJ Genetic analyses: MM, DP, MJD, EED, AS Data analysis: MM, DP and AS. Manuscript review for intellectual content: MM, JP, KZJ, DP, MJD, BB, PI, EED and AS References Pellerin D, Iruzubieta P, Xu IRLet al (2025) Recent Advances in the Genetics of Ataxias: An Update on Novel Autosomal Dominant Repeat Expansions. Curr Neurol Neurosci Rep. 16;25(1):16. Pellerin D, Danzi MC, Wilke C, et al (2023) Deep intronic FGF14 GAA repeat expansion in late-onset cerebellar ataxia. 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Neurol Genet 11:e200244 Milovanović A, Dragaševic-Mišković N, Thomsen M, et al (2024) RFC1 and FGF14 repeat expansions in Serbian patients with cerebellar ataxia. Mov Disord Clin Pract 11:626–633 Abou Chaar W, Eranki AN, Stevens Haet al (2024) Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B). Ann Neurol 96(6):1092-1103 Mohren L, Erdlenbruch F, Leitão Eet al (2024) Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions. Nat Commun 3;15(1):7665 Iruzubieta P, Pellerin D, Bergareche A, et al. (2023) Frequency and phenotypic spectrum of spinocerebellar ataxia 27B and other genetic ataxias in a Spanish cohort of late-onset cerebellar ataxia. Eur J Neurol 30:3828–3833 Kytövuori L, Pellerin D, Kärppä M, et al (2025) FGF14 (GAA∙TTC) repeat expansion-related ataxia SCA27B is common in Northern Finland. Parkinsonism Relat Disord. 137:107943. Miyatake S, Doi H, Yaguchi H, et al (2024) Complete nanopore repeat sequencing of SCA27B (GAA- FGF14 ataxia) in Japanese. J Neurol Neurosurg Psychiatry. 95(12):1187-1195 Ouyang R, Wan L, Pellerin D, et al (2024) The genetic landscape and phenotypic spectrum of GAAFGF14 ataxia in China: a large cohort study. EbioMedicine. 102:105077. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7463343","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":507171127,"identity":"d504d061-08e7-4a72-8372-cd01a10b2bba","order_by":0,"name":"Marta Matlawska","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6klEQVRIiWNgGAWjYLCCB0AswcB84ACDAYibAMQFeDUwNiSAtbAlIGkxIEoLD0wZAS260w4/f5BQc9hesv3Mx8MFBXcY+NlzDJgL8Ggxu51m2JBw7HDibJ7cDYdnGDxjkOx5Y8A8A6+WBKAWttsJcgxALTwGhxkMbgBt4cGrJf1jQ8K/2/Zy/G8egLXYE9aSY9iQ2HabcbZEDgPEFgnCWgpnJPb9T5w545kB0C+HeSTOPCs4jN8v6Rs+fPiWZi9xPvnx54I/h+X425M3Pi6owK0FBTADMQ+IcZhIDRAtqIxRMApGwSgYBUAAAL/NVu39W1MLAAAAAElFTkSuQmCC","orcid":"","institution":"Institute of Psychiatry and Neurology","correspondingAuthor":true,"prefix":"","firstName":"Marta","middleName":"","lastName":"Matlawska","suffix":""},{"id":507171128,"identity":"a28e63f3-5452-456d-b075-f7eded6a6d13","order_by":1,"name":"Karolina Ziora-Jakutowicz","email":"","orcid":"","institution":"Institute of Psychiatry and Neurology","correspondingAuthor":false,"prefix":"","firstName":"Karolina","middleName":"","lastName":"Ziora-Jakutowicz","suffix":""},{"id":507171129,"identity":"ae29dd3a-cbde-4c08-92b2-205648bb7343","order_by":2,"name":"Marie-Josee Dicaire","email":"","orcid":"","institution":"McGill University","correspondingAuthor":false,"prefix":"","firstName":"Marie-Josee","middleName":"","lastName":"Dicaire","suffix":""},{"id":507171130,"identity":"be0114e1-7e24-4095-bb0f-5387f3d61ab0","order_by":3,"name":"Joanna Pera","email":"","orcid":"","institution":"Jagiellonian University Medical Colledge","correspondingAuthor":false,"prefix":"","firstName":"Joanna","middleName":"","lastName":"Pera","suffix":""},{"id":507171131,"identity":"58397d88-4ab0-44ee-be31-4b0af5b6ddd3","order_by":4,"name":"David Pellerin","email":"","orcid":"","institution":"McGill University","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Pellerin","suffix":""},{"id":507171132,"identity":"0362a1ee-8d4f-463c-bed3-c5db57bc70c0","order_by":5,"name":"Bernard Brais","email":"","orcid":"","institution":"McGill University","correspondingAuthor":false,"prefix":"","firstName":"Bernard","middleName":"","lastName":"Brais","suffix":""},{"id":507171133,"identity":"21386702-6965-43e5-af19-962140a87fd5","order_by":6,"name":"Pablo Iruzubieta","email":"","orcid":"","institution":"McGill University","correspondingAuthor":false,"prefix":"","firstName":"Pablo","middleName":"","lastName":"Iruzubieta","suffix":""},{"id":507171134,"identity":"9f55c96c-06b4-4120-a5f0-0e79f59d72ea","order_by":7,"name":"Ewelina Elert-Dobkowska","email":"","orcid":"","institution":"Institute of Psychiatry and Neurology","correspondingAuthor":false,"prefix":"","firstName":"Ewelina","middleName":"","lastName":"Elert-Dobkowska","suffix":""},{"id":507171135,"identity":"f6193561-1f45-4239-89ae-612e21c73ddf","order_by":8,"name":"Anna Sulek","email":"","orcid":"","institution":"Lazarski University","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"","lastName":"Sulek","suffix":""}],"badges":[],"createdAt":"2025-08-26 13:23:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7463343/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7463343/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90485492,"identity":"0b179376-02ed-44ab-9000-1844e0ec56f4","added_by":"auto","created_at":"2025-09-03 08:47:12","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":206273,"visible":true,"origin":"","legend":"\u003cp\u003eFrequency [%] of neurological symptoms in 25 patients with available medical history and confirmed GAA expansion ≥250\u003c/p\u003e","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-7463343/v1/61f68200641dd387035110ba.png"},{"id":90487352,"identity":"d18b1104-d333-4831-8f3b-543088a99c2f","added_by":"auto","created_at":"2025-09-03 09:03:12","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":794239,"visible":true,"origin":"","legend":"\u003cp\u003eMolecular analysis of the \u003cem\u003eFGF14 \u003c/em\u003eGAA repetitive locus: electropherograms of the amplified\u003cem\u003e FGF14\u003c/em\u003e repetitive locus using long- range PCR : (A) Heterozygote 10/33 GAA; (B) Homozygote 38/38 GAA; (C) Heterozygote 62/140 GAA with nonpathogenic expansion on second allele, (D) Agarose gel electrophoresis of LR-PCR amplicons with ≥250 GAA (900bp) on the expanded allele: S – size standard; NC – negative control, (E) Electropherograms of the amplified\u003cem\u003e FGF14 \u003c/em\u003erepetitive locus using repeat - primed PCR: characteristic sawtooth profile for patient with ≥250 GAA expansion\u003c/p\u003e","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-7463343/v1/e44a1f5934d5859be62adecb.png"},{"id":90485486,"identity":"6596a448-6c52-4a6a-925f-13a134aa1fb1","added_by":"auto","created_at":"2025-09-03 08:47:12","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":85307,"visible":true,"origin":"","legend":"\u003cp\u003eHeterozygote 10/33 GAA\u003c/p\u003e","description":"","filename":"Fig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-7463343/v1/f5ad85f7dfb5ec9f11bcb135.png"},{"id":90487051,"identity":"0b00171e-dac5-4016-a264-3153f2865dd3","added_by":"auto","created_at":"2025-09-03 08:55:12","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":59820,"visible":true,"origin":"","legend":"\u003cp\u003eHomozygote 38/38 GAA\u003c/p\u003e","description":"","filename":"Fig.4.png","url":"https://assets-eu.researchsquare.com/files/rs-7463343/v1/01d92ddb0ff7910fb8ea3902.png"},{"id":90485496,"identity":"a090f202-b859-495d-aafa-0b27c875531b","added_by":"auto","created_at":"2025-09-03 08:47:12","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":129356,"visible":true,"origin":"","legend":"\u003cp\u003eHeterozygote 62/140 GAA with nonpathogenic expansion on second allele\u003c/p\u003e","description":"","filename":"Fig.5.png","url":"https://assets-eu.researchsquare.com/files/rs-7463343/v1/2635f7eaffec66a1d4160dc3.png"},{"id":90487055,"identity":"4fe4f4bb-7f9f-4f15-aa0f-f5ca44f7c228","added_by":"auto","created_at":"2025-09-03 08:55:12","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":368577,"visible":true,"origin":"","legend":"\u003cp\u003eAgarose gel electrophoresis of LR-PCR amplicons with ≥250 GAA (900bp) on the expanded allele: S – size standard; NC – negative control,\u003c/p\u003e","description":"","filename":"Fig.6.png","url":"https://assets-eu.researchsquare.com/files/rs-7463343/v1/e9f80720661f88b40875aa35.png"},{"id":90487353,"identity":"b38c1bed-9729-421e-94a1-09d9dceed072","added_by":"auto","created_at":"2025-09-03 09:03:13","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":293103,"visible":true,"origin":"","legend":"\u003cp\u003eElectropherograms of the amplified\u003cem\u003e FGF14\u003c/em\u003e repetitive locus using repeat - primed PCR: characteristic sawtooth profile for patient with ≥250 GAA expansion\u003c/p\u003e","description":"","filename":"Fig.7.png","url":"https://assets-eu.researchsquare.com/files/rs-7463343/v1/aa433dde3b0cb2a86fae738b.png"},{"id":90767615,"identity":"4375eb9c-33ac-43cb-a876-87f07687d23a","added_by":"auto","created_at":"2025-09-07 20:46:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2130776,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7463343/v1/8b055e7e-fa8a-4b91-85ae-870d925544d3.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Identification of FGF14 GAA expansions in Polish patients with undiagnosed cerebellar ataxia – a preliminary study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAutosomal dominant spinocerebellar ataxias (SCAs) are a genetically and clinically heterogeneous group of neurodegenerative disorders characterized by progressive degeneration of cerebellar neurons. Despite continuous advancements in diagnostic tools, including sequencing technologies, the molecular basis of SCA remains unknown in a significant proportion of patients. An intronic GAA\u0026middot;TTC repeat expansion in the \u003cem\u003eFGF14\u003c/em\u003e gene has recently been described as the cause of autosomal dominant spinocerebellar ataxia 27B (SCA27B) [\u003cstrong\u003e1,2,3\u003c/strong\u003e]. It is currently assumed that expansions of 250-299 GAA\u0026middot;TTC repeats are pathogenic, yet incompletely penetrant, while larger expansions are deemed pathogenic and highly penetrant [\u003cstrong\u003e2,4\u003c/strong\u003e]. Studies involving different cohorts of patients with late-onset cerebellar ataxia (LOCA, AOO \u0026lt;30 years) of unknown etiology have shown that SCA27B accounts for 10 to 60% of cases [\u003cstrong\u003e1,2\u003c/strong\u003e]. The pathogenic threshold and phenotypic spectrum of SCA27B still remain to be fully characterized. The classic phenotype of SCA27B includes gait ataxia, downbeat nystagmus, and the occurrence of episodic symptoms [\u003cstrong\u003e2,5\u003c/strong\u003e]. It is postulated that SCA27B is currently the most frequently identified type of autosomal dominant ataxia among patients in whom the genetic cause of another LOCA could not yet be determined.\u003c/p\u003e\n\u003cp\u003eIn this paper, we present the results of our preliminary study on the assessment of the frequency of SCA27B in a cohort of Polish patients with spinocerebellar ataxia of unknown etiology.\u0026nbsp;\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u0026nbsp;Patients and clinical data:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInclusion criteria for the study comprised adult- onset cerebellar ataxia (AOO \u0026ge;25 years, range 25 - 83 years) of unknown etiology, with negative test results for SCA1, SCA2, SCA3, SCA8, and \u003cem\u003eRFC1\u003c/em\u003e-related ataxia. A group of 701 patients (344 females and 357 males) with LOCA of unknown etiology was recruited retrospectively from patients referred to the Genetic Clinic of the Institute of Psychiatry and Neurology from all over Poland. Cases of MSA-C (Multiple System Atrophy- Cerebellar Type) were excluded from this study. The control group consisted of 66 healthy individuals (33 females and 33 males) without neurological symptoms, and the mean age was 69 years. In the patient\u0026rsquo;s group, 11/31 individuals with an \u003cem\u003eFGF14\u0026nbsp;\u003c/em\u003erepeat expansion had previously undergone brain MRI.\u0026nbsp;The results of clinical examination are shown in Figure 1. Informed\u0026nbsp;written consent to genetic testing was obtained from all participants,\u0026nbsp;with a consent to participate in scientific research. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The protocol was approved by the Local Bioethics Committee at the Institute of Psychiatry and Neurology in Warsaw.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Molecular examinations:\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The GAA\u0026middot;TTC expansions were studied according to the standard protocol [4]. Expansions larger than 250 GAA\u0026middot;TTC repeats were considered pathogenic. Molecular studies were performed at the Department of Genetics of the Institute of Psychiatry and Neurology in Poland and the Montreal Neurological Institute-Hospital \u0026ndash; Mcgill University in Canada.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Statistical analysis:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStatistical analyses were performed in R 4.5.0 and Rstudio software. Pearson\u0026rsquo;s coefficients were used to determine the correlation between the age of onset (AOO) and the number of GAA repeats, assuming statistically significant values when p \u0026lt; 0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eWe examined 701 probands with adult- onset cerebellar ataxia. Positive family history of ataxia was found in 172 patients, while 529 patients were sporadic cases. Their mean age at examination was 60,5 years. Among them, 3.3% (23/701) had a confirmed GAA\u0026middot;TTC repeat expansion in \u003cem\u003eFGF14\u003c/em\u003e within the fully penetrant range (301\u0026ndash;583 repeats). An additional 1.1% (8/701) had expansions in the incompletely penetrant range (250\u0026ndash;299 repeats). In total, we found 31 individuals (4.4%) carrying an \u003cem\u003eFGF14\u003c/em\u003e repeat expansion larger than 250 GAA\u0026middot;TTC repeat units. The median size of the expanded allele was 345 GAA\u0026middot;TTC repeats. We also identified 2 patients carrying a non-pathogenic GAAGGA expansion.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eAmong the 31 identified patients with SCA27B, 11 cases were familial, 14 had no family history, and this information was not available for 6 patients. The mean age of onset in patients with confirmed SCA27B was 49.8 (range 34-79 years). One of the patients had biallelic expansions (287/383 GAA\u0026middot;TTC repeats), however, no significant difference in the course of the disease was observed compared to patients with expansion. Due to the lack of SARA scale data, we were unable to assess disease progression. \u0026nbsp;In our study, 4 patients with an intermediate allele, i.e. 200-249 GAA\u0026middot;TTC repeats (9/224, 9/232, 100/237 and 38/244 GAA\u0026middot;TTC), presented ataxia, including balance disturbances (4/4), gait disturbances (3/4), dysarthria (1/4), cerebellar atrophy and generalized brain atrophy (2/4). However, apart from excluding SCA1, SCA2, SCA3 and SCA8, we did not have the results of more detailed studies (e.g. WES, WGS) excluding other types of SCA in the indicated patients. In the control group, no alleles larger than 187 GAA\u0026middot;TTC repeats were identified (range 8\u0026ndash;187 GAA\u0026middot;TTC). Our study demonstrated no significant inverse correlation between the number of GAA\u0026middot;TTC repeats and the age of onset in 25 patients (Pearson coefficient: r = -0.342, p = 0.087).\u003c/p\u003e\n\u003cp\u003eClinical data based on the available patients medical files are presented in Figure 1. The most common clinical feature was imbalance, observed in 68% of patients (17/25), followed by gait ataxia in 56% (14/25) and cerebellar syndrome in 40% (10/25). Dysarthria was reported in 36% (9/25), while ataxia, cognitive impairments, and episodic symptoms were each present in 24% (6/25) of the patients. Other frequent findings included: nystagmus (any type): 20% (5/25), cerebellar atrophy: 16% (4/25), appendicular ataxia, tremor, horizontal gaze-evoked nystagmus, global brain atrophy, headache, and dysmetria: each observed in 16% (4/25). Oculomotor abnormalities, pyramidal symptoms, spasticity, and head tremor: each found in 12% (3/25). Less commonly reported symptoms (8%, 2/25) included: dysdiadochokinesia, slurred speech, choking, bradykinesia, diplopia or blurry vision, scanning speech, dysphagia, decreased muscle tension, proprioceptive sensory disturbances, and upper limb dysmetria. Rare findings, each observed in a single patient (4%, 1/25), were dizziness/vertigo, hearing loss, cardiomyopathy, and spastic-parietic gait. These results indicate a predominance of core cerebellar features, particularly imbalance and gait disturbance, alongside a range of additional motor, sensory, and episodic symptoms in patients with \u003cem\u003eFGF14\u003c/em\u003e-related ataxia.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAutosomal dominant SCA27B is a late-onset ataxia, commonly preceded by an episodic onset, with the onset of permanent symptoms often occurring in the fifth to seventh decade of life \u003cstrong\u003e[2,5]\u003c/strong\u003e. In our cohort, the median age at onset was 50 years (30-79 years). The clinical phenotype in Polish patients with SCA27B is similar to that of other published cohorts, with a predominance of gait ataxia, horizontal-gaze evoked nystagmus, dysarthria, and episodic symptoms \u003cstrong\u003e[1,2,5-1\u003c/strong\u003e\u003cstrong\u003e5\u003c/strong\u003e]. We found no significant correlation between the number of GAA repeats and the age of onset, although we observed a trend: r = -0.342 p = 0.087.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;According to the previous epidemiological data, the highest percentage of patients with confirmed SCA27B (61%) is noted in the French-Canadian population, which is related to a founder effect [\u003cstrong\u003e2]\u003c/strong\u003e.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"491\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCohort ethnicity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo. of patients diagnosed with SCA27B (\u0026ge;250 GAA\u0026middot;TTC)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eReferences:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFrench Canadian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e40/66 (61%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e[2]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSpanish\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e18/107 (28.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e[16]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGerman\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e34/148 (23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e[15]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAustralian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3/20 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e[2]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGreek\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e19/160 (11.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e[8]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eItalian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e53/396 (13.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e[11]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDutch\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e28/248(11%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e[12]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBrasilian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8/93 (9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e[6]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCyprus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12/155 (7.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e[9]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e55/732 (7.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e[14]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSerbian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9/167 (5.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e[13]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNorthern Finnish\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5/96 (5.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e[17]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eJewish\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2/91 (2.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e[7]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eJapanese\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8/460 (1.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e[18]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eChinese\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12/1216 (1.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e[19]\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eNumber of patients diagnosed with SCA27B in different ethnicity cohorts. \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn a study of 701 Polish patients with spinocerebellar ataxia of unknown cause, 31 cases were found to carry a repeat expansion in \u003cem\u003eFGF14\u003c/em\u003e, which stands for approximately 4.4%. Our results indicate that Poland currently has one of the lowest percentage of patients with SCA27B in Europe, taking into account data from other Europeans cohorts (German, Italian, Dutch and Spanish \u003cstrong\u003e[Table 1., 11,12,15,\u003c/strong\u003e\u003cstrong\u003e16\u003c/strong\u003e].\u0026nbsp;Our results are more comparable with data from Jewish, Cyprus, Serbian and Northern Finnish population [\u003cstrong\u003e7,9\u003c/strong\u003e\u003cstrong\u003e,13,17\u003c/strong\u003e].\u0026nbsp;However, this data may be significantly underestimated, due to the limited number of patients included in the studies, as well as the small number of comparative data from other cohorts in the world. A lower percentage of diagnosed SCA27B cases has been described only in East Asia (ex. Japan, China), which may be related to the specificity of the region and the low frequency of alleles \u0026ge;250 GAA in the Japanese and Chinese population compared to the Caucasian population, which is explained by different polymorphisms [\u003cstrong\u003e18,19\u003c/strong\u003e].\u0026nbsp;Data from European cohorts indicates that SCA27B is a common cause of autosomal dominant ataxia and points for the need of implementation of this type of SCA into the basic diagnostic protocol [\u003cstrong\u003e1,9\u003c/strong\u003e\u003cstrong\u003e,11,12,13\u003c/strong\u003e]. The occurrence of episodic symptoms, the late age of onset, cerebellar ocular motor signs and the slowly progressive course of the disease should trigger evaluation for SCA27B \u003cstrong\u003e[2\u003c/strong\u003e]. Vestibular hypofunction has also been observed, often with dizziness and loss of balance [\u003cstrong\u003e2,5].\u003c/strong\u003e The occurrence of rare cases of young adults (\u0026ge;25 years) with SCA27B indicates that the diagnosis should also be considered in younger individuals with a suggestive phenotype and an otherwise negative genetic workup \u003cstrong\u003e[5,\u003c/strong\u003e\u003cstrong\u003e8,9]\u003c/strong\u003e.The spectrum of symptoms observed in the cohort of Polish patients\u0026mdash;with a predominance of balance disturbances, gait ataxia, and cerebellar syndrome, along with the presence of episodic symptoms and dysarthria corresponds to the clinical phenotype of SCA27B described in other cohorts worldwide [\u003cstrong\u003e1,6,7,9,11,13-17\u003c/strong\u003e]. As a limitation, no data on the presence of downbeat nystagmus, a hallmark feature of SCA27B [\u003cstrong\u003e1,2,6,8,9,11,\u003c/strong\u003e], was available in our cohort.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNeuroimaging in SCA27B usually shows mild to moderate cerebellar atrophy, especially in the vermis \u003cstrong\u003e[1,2,5]\u003c/strong\u003e. In 11/31 of our patients with SCA27B and available MRI results, we observed cerebellar atrophy in 5/11\u0026nbsp;(45%) which is a common hallmark of SCA27B [\u003cstrong\u003e14\u003c/strong\u003e]. Cerebral atrophy was observed in 2/11 cases (18%), suggesting that this change is either uncommon or may appear in later stages of the disease. \u0026nbsp;However, changes of this type are also observed in many other types of SCA, so they are not specific for SCA27B. Moreover, in our patients we did not observe any signs of hyperintensity in the superior cerebellar peduncles (SCP), which have been observed in different cohorts, but FLAIR T2-weighted images were not available for review [\u003cstrong\u003e11\u003c/strong\u003e].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;To date, this is the only epidemiological investigation of SCA27B in a large cohort of Polish patients with late-onset, undiagnosed ataxia. Although rarer than in other European cohorts, these findings support the inclusion of this form of ataxia in routine diagnostics. However, our study has several important limitations. It was retrospective in nature, and the patients were recruited from across Poland, which often meant very limited access to detailed medical records. The lack of SARA scale scores for patients with confirmed SCA27B, as well as the absence of neuroimaging data for more than half of the patients, makes it impossible to assess the long-term progression of the disease. Additionally, it was not possible to perform segregation studies in any of the families. More detailed studies are needed to thoroughly characterize the clinical phenotype of SCA27B and the frequency of mutations in the range of incomplete and full penetrance of the \u003cem\u003eFGF14\u003c/em\u003e gene in the cohort of Polish patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u0026nbsp;\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eConflicts of interest:\u003c/strong\u003e All authors declare no conflict of interest during this research.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eData availability:\u003c/strong\u003e The datasets generated during and/or analysed during the current study are not publicly available due to institutional policy restricting the sharing of sensitive clinical and genetic data. This policy is in place to ensure compliance with ethical standards, informed consent limitations, and applicable data protection regulations, including the national General Data Protection Regulation (GDPR) and relevant national laws. However, the data are available from the corresponding author on reasonable request.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u0026nbsp;\u003c/strong\u003eDrafting of the manuscript: MM Patient medical examination: JP and KZJ Genetic analyses: MM, DP, MJD, EED, AS Data analysis: MM, DP and AS. Manuscript review for intellectual content: MM, JP, KZJ, DP, MJD, BB, PI, EED and AS\u003c/p\u003e\n\n\n\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePellerin D, Iruzubieta P, Xu IRLet al (2025) Recent Advances in the Genetics of Ataxias: An Update on Novel Autosomal Dominant Repeat Expansions. Curr Neurol Neurosci Rep. 16;25(1):16. \u003c/li\u003e\n\u003cli\u003ePellerin D, Danzi MC, Wilke C, et al (2023) Deep intronic \u003cem\u003eFGF14\u003c/em\u003e GAA repeat expansion in late-onset cerebellar ataxia. N Engl J Med 388:128\u0026ndash;141\u003c/li\u003e\n\u003cli\u003eRafehi H, Read J, Szmulewicz DJ, et al (2023) An intronic GAA repeat expansion in \u003cem\u003eFGF14\u003c/em\u003e causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14. Am J Hum Genet 110:105\u0026ndash;119\u003c/li\u003e\n\u003cli\u003eBonnet C, Pellerin D, Roth V, et al (2023) Optimized testing strategy for the diagnosis of GAA-FGF14 ataxia/spinocerebellar ataxia 27B. Sci Rep13:9737\u003c/li\u003e\n\u003cli\u003ePellerin D, Danzi M, Renaud M, et al (2024) GAA-FGF14-Related Ataxia. In: Adam MP, Feldman J, Mirzaa GM, et al. (eds) GeneReviews\u0026reg;, University of Washington; Seattle, pp 1993\u0026ndash;2025.\u003c/li\u003e\n\u003cli\u003eNovis LE, Frezatti RS, Pellerin D, et al (2023) Frequency of GAA-FGF14 ataxia in a large cohort of Brazilian patients with unsolved adult-onset cerebellar ataxia. Neurol Genet 9:e200094\u003c/li\u003e\n\u003cli\u003eHalstuk O, Dayan R, Silverstein S, et al (2024) Low prevalence of SCA27B in adult-onset cerebellar ataxia cohort of Jewish ancestry. Parkinsonism Relat Disord 126:107067\u003c/li\u003e\n\u003cli\u003eKartanou C, Mitrousias A, Pellerin D, et al (2024) The \u003cem\u003eFGF14\u003c/em\u003e GAA repeat expansion in Greek patients with late-onset cerebellar ataxia and an overview of the SCA27B phenotype across populations. Clin Genet 105:446\u0026ndash;452\u003c/li\u003e\n\u003cli\u003eLivanos I, Votsi C, Michailidou K, et al (2025) The \u003cem\u003eFGF14\u003c/em\u003e GAA repeat expansion is a major cause of ataxia in the Cypriot population. Brain Commun 7:fcae479\u003c/li\u003e\n\u003cli\u003eHengel H, Pellerin D, Wilke C, et al (2023) As frequent as polyglutamine spinocerebellar ataxias: SCA27B in a large German autosomal dominant ataxia cohort. Mov Disord 38:1557\u0026ndash;1558\u003c/li\u003e\n\u003cli\u003eSatolli S, Rossi S, Vegezzi E, et al (2024) Spinocerebellar ataxia 27B: a frequent and slowly progressive autosomal-dominant cerebellar ataxia\u0026mdash;experience from an Italian cohort. J Neurol 271:5478\u0026ndash;5488\u003c/li\u003e\n\u003cli\u003eIgnjatijevic A, Boorsma F, Wierenga E, et al (2025) High prevalence of the intronic GAA-FGF14 repeat expansion in Dutch patients with late-onset ataxia. Neurol Genet 11:e200244\u003c/li\u003e\n\u003cli\u003eMilovanović A, Draga\u0026scaron;evic-Mi\u0026scaron;ković N, Thomsen M, et al (2024) RFC1 and \u003cem\u003eFGF14\u003c/em\u003e repeat expansions in Serbian patients with cerebellar ataxia. Mov Disord Clin Pract 11:626\u0026ndash;633\u003c/li\u003e\n\u003cli\u003eAbou Chaar W, Eranki AN, Stevens Haet al (2024) Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B). Ann Neurol 96(6):1092-1103\u003c/li\u003e\n\u003cli\u003eMohren L, Erdlenbruch F, Leit\u0026atilde;o Eet al (2024) Identification and characterisation of pathogenic and non-pathogenic \u003cem\u003eFGF14\u003c/em\u003e repeat expansions. Nat Commun 3;15(1):7665\u003c/li\u003e\n\u003cli\u003eIruzubieta P, Pellerin D, Bergareche A, et al. (2023) Frequency and phenotypic spectrum of spinocerebellar ataxia 27B and other genetic ataxias in a Spanish cohort of late-onset cerebellar ataxia. Eur J Neurol 30:3828\u0026ndash;3833\u003c/li\u003e\n\u003cli\u003eKyt\u0026ouml;vuori L, Pellerin D, K\u0026auml;rpp\u0026auml; M, et al (2025) FGF14 (GAA∙TTC) repeat expansion-related ataxia SCA27B is common in Northern Finland. Parkinsonism Relat Disord. 137:107943.\u003c/li\u003e\n\u003cli\u003eMiyatake S, Doi H, Yaguchi H, et al (2024) Complete nanopore repeat sequencing of SCA27B (GAA-\u003cem\u003eFGF14 \u003c/em\u003eataxia) in Japanese. J Neurol Neurosurg Psychiatry. 95(12):1187-1195\u003c/li\u003e\n\u003cli\u003eOuyang R, Wan L, Pellerin D, et al (2024) The genetic landscape and phenotypic spectrum of GAAFGF14 ataxia in China: a large cohort study. EbioMedicine. 102:105077.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"SCA27B, FGF14 expansion, spinocerebellar ataxia, neurodegenerative disorders","lastPublishedDoi":"10.21203/rs.3.rs-7463343/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7463343/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction: \u003c/strong\u003eSpinocerebellar ataxia type 27B (SCA27B), caused by an intronic GAA repeat expansion in the \u003cem\u003eFGF14\u003c/em\u003egene, has recently emerged as a major cause of late-onset cerebellar ataxia (LOCA). Its prevalence and clinical profile in Central and Eastern Europe remain largely unknown.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e To determine the frequency and phenotypic characteristics of \u003cem\u003eFGF14\u003c/em\u003e GAA·TTC repeat expansions, a large cohort of Polish patients with undiagnosed adult-onset cerebellar ataxia was investigated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We retrospectively analyzed 701 patients (age of onset ≥25 years) with adult-onset cerebellar ataxia of unknown etiology, previously tested negative for SCA1, SCA2, SCA3, SCA8, and \u003cem\u003eRFC1\u003c/em\u003eexpansions. GAA·TTC repeat lengths were assessed using long-range and repeat-primed PCR. Expansions ≥250 repeats were classified as pathogenic. Clinical and MRI data were evaluated where available. A control group of 66 neurologically healthy individuals was also screened.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Pathogenic \u003cem\u003eFGF14\u003c/em\u003eexpansions (≥250 repeats) were identified in 4.4% (31/701) of patients, including 23 with fully penetrant (≥300) and 8 with incompletely penetrant (250–299) alleles. No pathogenic expansions were found in controls. The mean age of onset was 49.8 years. Common symptoms included balance and gait disturbances, cerebellar syndrome, and episodic features such as diplopia. Cerebellar atrophy was present in 45% of patients with available MRI. No significant correlation between repeat length and age of onset was observed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSummary:\u003c/strong\u003e Our findings confirm that \u003cem\u003eFGF14\u003c/em\u003erepeat expansions are an underrecognized cause of LOCA in Poland and support their inclusion in standard genetic testing for adult-onset ataxias. Further studies are warranted to better define penetrance and genotype–phenotype correlations.\u003c/p\u003e","manuscriptTitle":"Identification of FGF14 GAA expansions in Polish patients with undiagnosed cerebellar ataxia – a preliminary study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-03 08:47:07","doi":"10.21203/rs.3.rs-7463343/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"de775901-2592-45b8-b876-4d4d8bb08168","owner":[],"postedDate":"September 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-08T13:46:30+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-03 08:47:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7463343","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7463343","identity":"rs-7463343","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}