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Letter to the editor
“Subthreshold” Expansions in Individuals With Otherwise-Typical Clinicoradiological Features of GAA-FGF14-Related Cerebellar Ataxia (SCA27B) -
Yuan Ye Beh1
, Roberta La Piana2, Yi Wen Tay3, Jun Ping Chua1, Rose Izura Abdul Hamid4, Jeffrey Wei Yang Tee1, Andrew Leslie Lee1, Akmal Mukhlis Abdul Sahak1, Jie Ping Schee1, Khean Jin Goh1, Pablo Iruzubieta2, Ai Huey Tan1, David Pellerin2, Shen-Yang Lim1
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Journal of Movement Disorders 2026;19(2):228-231.
DOI: https://doi.org/10.14802/jmd.25290
Published online: December 10, 2025
1Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
2Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
3Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
4Hospital Raja Perempuan Zainab II, Kota Bahru, Kelantan, Malaysia
- Corresponding author: Shen-Yang Lim, MD, FRACP, FASc Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia / Tel: +603-7949-2891 / E-mail: limshenyang@gmail.com
• Received: November 1, 2025 • Revised: November 26, 2025 • Accepted: December 9, 2025
Copyright © 2026 The Korean Movement Disorder Society
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Dear Editor,
Recently, the identification of GAA repeat expansions in the first intron of the fibroblast growth factor 14 (FGF14) gene has clarified many previously unresolved cases of late-onset cerebellar ataxia (accounting for 9% to 61% across different ethnic cohorts), and these cases are now classified as spinocerebellar ataxia 27B (SCA27B) [1]. To date, >1,500 individuals have been diagnosed with SCA27B [1], although cases appear to be less common in Asia [2]. In general, GAA repeat expansion sizes ≥250 are considered pathogenic with incomplete penetrance, whereas those >300 are highly penetrant [1]. Most, if not all, genetic and phenotypic studies of SCA27B, including those characterizing neuroimaging features [1,3], have adopted the ≥250 GAA repeat threshold as the criterion for a confirmatory diagnosis. Here, we describe two Malaysian patients of Chinese ancestry who had “subthreshold” repeat expansion but exhibited both clinicodemographic and neuroimaging features suggestive of SCA27B.
The first patient (CA-44) was a 78-year-old male who presented with progressive gait imbalance leading to recurrent falls since the age of 73. Other symptoms included episodic vertigo and dysarthria. There was no tremor, rapid eye movement sleep behavior symptoms, or autonomic symptoms. His late brother was reported to have late-onset Parkinson’s disease. His only prior medical history was coronary artery bypass, and he did not consume significant amounts of alcohol. Examination revealed severe gait ataxia and mild slurred and staccato speech, with slight dysmetria in the upper limbs (Supplementary Video 1). There was no tremor or rigidity. Eye movements were normal (including pursuit and vertical saccades), and there was no nystagmus. Proprioception in the feet was intact, and ankle jerks were absent, consistent with advanced age. There was no postural hypotension. His Montreal Cognitive Assessment (MoCA) score was 20/30, indicating mild-to-moderate impairment (the patient had 11 years of formal education), with deficits in visuospatial function and verbal fluency.
The second patient (CA-14) was a 76-year-old male who similarly presented with progressive gait imbalance beginning at age 64, with fluctuations in severity throughout the day. The only significant comorbidity was ischemic heart disease with coronary stenting; he did not consume significant amounts of alcohol. Notably, his 60-year-old sister (CA-80) also demonstrated a mild ataxic syndrome, with symptom onset at 57 years. An examination of patient CA-14 at the age of 70 years revealed a wide-based gait and an inability to perform tandem walking (Supplementary Video 2). Speech was moderately slurred and staccato in nature. There was no downbeat nystagmus, although mild right horizontal nystagmus and hypometric vertical saccades were observed. The Halmagyi head thrust was abnormal, with a single catch-up saccade elicited on thrust to either side. His Scale for the Assessment and Rating for Ataxia score at the last review (age 75 years) was 22/40 (7/5/0/3/1/1/2/3), and his MoCA score was 26/30.
Both patients had late-onset cerebellar ataxia, albeit with different rates of deterioration. Patient CA-44’s condition declined from being able to walk independently with gait imbalance, without a walking aid, to becoming wheelchair dependent over three years (2020–2023). Patient CA-14 showed a more gradual course, declining from slowed but independent walking to wheelchair dependency over 12 years (2013–2025). Both patients underwent brain magnetic resonance imaging (MRI) and genetic testing. Brain MRI of patient CA-14 revealed mild cerebellar hemisphere and vermis atrophy, with a T2-hyperintense signal along the entire superior cerebellar peduncle (SCP). Brain MRI of patient CA-44 revealed mild-to-moderate cerebellar hemispheric and vermian atrophy with increased T2 signals along the SCP across all planes (Figure 1). These MRI findings are frequently observed in patients with SCA27B.1,4,5 Specifically, the involvement of the SCP has been observed in up to 59.8% of patients in a recently reported large cohort; these findings may orient the diagnostic process of symptomatic individuals towards SCA27B.3 CA-80 displayed similar findings (Figure 1). Interestingly, DNA samples from both patients (CA-14 and CA-44) were positive for intronic FGF14 GAA repeat expansions detected via repeat-primed polymerase chain reaction (Supplementary Material). CA-14 harbored 249 GAA repeats (199 on the short allele), whereas CA-44 carried 247 GAA repeats (15 on the short allele). CA-80 was subsequently tested and found to have a pathogenic GAA expansion with 258 repeats (205 on the short allele).
A systematic literature search on PubMed using the keywords “FGF14 GAA” OR “SCA27B” (including all papers published from 2023 to October 26, 2025) identified 95 records. After 17 nonrelevant articles were excluded, we scrutinized 29 papers that reported neuroimaging findings in SCA27B patients. Notably, cerebellar atrophy was the most commonly reported neuroimaging feature and was present in approximately 60%–97% of SCA27B patients [1,4,5]. Other reported neuroimaging abnormalities are summarized in Supplementary Table 1. Notably, all these studies included individuals with GAA repeat sizes ≥250.
To our knowledge, only one previous study reported neuroimaging findings in individuals with subpathogenic GAA repeat expansions (as part of a larger cohort predominantly comprising patients with pathogenic expansions). One patient (MGH-34) with 247 GAA repeats did not show SCP hyperintensity, whereas another patient (MGH-20) with 228 GAA repeats demonstrated SCP hyperintensity only on diffusion-weighted imaging (DWI) [6]. For our patients, DWI images were not available.
Our observations in these two symptomatic patients with borderline FGF14-GAA repeat expansions suggest a possible continuum of pathogenicity rather than a strict cutoff, which is consistent with recent findings showing significant enrichment of GAA ≥200–249 alleles in ataxic patients [7]. As MRI of the brain is often part of the initial workup of patients with late-onset cerebellar ataxia, the presence of SCP hyperintensities could help prompt or prioritize SCA27B genetic testing, especially in regions where access to genetic testing for movement disorders is limited. Nonetheless, it may be premature to regard this as a pathognomonic feature of SCA27B, as SCP hyperintensities have also been described in patients with other conditions, including POLR3A-related spastic ataxia, fragile X–associated tremor/ataxia syndrome, and even progressive supranuclear palsy [8-10]. However, in patients with subthreshold GAA repeat expansions, we suggest that these findings could be used as a supportive diagnostic feature. Collectively, our results highlight the need for an urgent large-scale re-evaluation of the current pathogenic threshold for FGF14-GAA repeat expansions. Further validation in larger, multiethnic cohorts is warranted to confirm the association between FGF14-GAA repeat expansions that are <250 in size and clinical and radiological manifestations of disease.
Supplementary Materials
The Data Supplement is available with this article at https://doi.org/10.14802/jmd.25290.
Supplementary Table 1.
Summary of other reported neuroimaging abnormalities in SCA27B patients with pathogenic threshold of GAA-FGF14 repeat expansions
Video 1.
A cerebellar assessment was performed on patient CA-44. Segment 1: The patient was only able to stand with constant support of one arm and demonstrated an ataxic gait, requiring one-arm assistance to walk a very short distance, with a tendency to lean backwards. Segment 2: Patient had limb ataxia, more prominent on the left side with clearly abnormal heel-shin dysmetria and mild-to-moderate dysdiadochokinesia on his left. Mild staccato speech was also observed.
Video 2.
A cerebellar assessment was performed on patient CA-14. Segment 1: The patient demonstrated a broad-based gait, requiring support of both arms to walk a very short distance. No obvious truncal ataxia was observed when sitting with arms outstretched. Segment 2: The patient demonstrated lower limb ataxia, more pronounced on the left side, with severely abnormal heel-shin dysmetria.
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Ethics Statement
The study was approved by the UMMC Human Research Ethics Committee (MREC ID NO: 20191010-7917) and conducted in accordance with the Declardation of Helsinki, with the patients providing written informed consent for study participation.
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Conflicts of Interest
The authors have no financial conflicts of interest.
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Funding Statement
This work was supported by the University of Malaya Parkinson’s Disease and Movement Disorders Research Program (PV035-2017) awarded to Shen- Yang Lim (SYL) and Ai Huey Tan (AHT).
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Acknowledgments
We are very grateful to the patients for their participation in and consent for this report.
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Author Contributions
Conceptualization: Shen-Yang Lim. Data curation: Shen-Yang Lim, David Pellerin, Pablo Iruzubieta, Yi Wen Tay. Funding acquisition: Shen-Yang Lim, Ai Huey Tan, David Pellerin. Investigation: Shen-Yang Lim, David Pellerin, Pablo Iruzubieta, Roberta La Piana. Methodology: all authors. Project administration: Shen-Yang Lim, Ai Huey Tan, Yi Wen Tay, David Pellerin. Supervision: Shen-Yang Lim, David Pellerin. Writing—original draft: Yuan Ye Beh. Writing—review & editing: all authors.
Notes
Figure 1.
Brain MRI findings in patients. A-D: FLAIR T2-weighted images of patient CA-44 (247/15 GAA repeats) show bilateral, symmetric T2 hyperintensity of the SCP (A), with clear visualization of the SCP decussation in the central midbrain (B), and corresponding coronal (C) and sagittal (D) views. E and F: Similar SCP hyperintensities are seen along the entire tract in patient CA-14 (249/199 GAA repeats). G: Mild-tomoderate cerebellar atrophy in patient CA-44. H: Bilateral, symmetric T2 hyperintensity of the SCP in the sister of patient CA-14 (258/205 GAA repeats). All arrows indicate T2 hyperintensity of the SCP. MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery; SCP, superior cerebellar peduncles.
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- 2. Sahak AMA, Tan AH, Ramli N, Tay YW, Lit LC, Chua JP, et al. Cerebellar ataxia due to FGF14 GAA repeat expansion: first Southeast Asian case and novel neuroimaging features. J Mov Disord 2025;18:382–384.ArticlePubMedPMCPDF
- 3. 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:e200253.ArticlePubMedPMC
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XML Download“Subthreshold” Expansions in Individuals With Otherwise-Typical Clinicoradiological Features of GAA-FGF14-Related Cerebellar Ataxia (SCA27B)
Figure 1. Brain MRI findings in patients. A-D: FLAIR T2-weighted images of patient CA-44 (247/15 GAA repeats) show bilateral, symmetric T2 hyperintensity of the SCP (A), with clear visualization of the SCP decussation in the central midbrain (B), and corresponding coronal (C) and sagittal (D) views. E and F: Similar SCP hyperintensities are seen along the entire tract in patient CA-14 (249/199 GAA repeats). G: Mild-tomoderate cerebellar atrophy in patient CA-44. H: Bilateral, symmetric T2 hyperintensity of the SCP in the sister of patient CA-14 (258/205 GAA repeats). All arrows indicate T2 hyperintensity of the SCP. MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery; SCP, superior cerebellar peduncles.
Figure 1.
“Subthreshold” Expansions in Individuals With Otherwise-Typical Clinicoradiological Features of GAA-FGF14-Related Cerebellar Ataxia (SCA27B)
