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. 2025 Sep 20;272(9):636. doi: 10.1007/s00415-025-13387-4

Delineating the pathogenic threshold and phenotypic spectrum of SCA27B: findings from a large French–Canadian cohort

Pablo Iruzubieta 1,2,#, David Pellerin 1,4,5,#, Catherine Ashton 1,3,#, Felipe Villa 1, Mathilde Renaud 6,7, Marie-Josée Dicaire 1, Matt C Danzi 5, Mayra Aldecoa 1, Jean Mathieu 8, Rami Massie 1, Colin H Chalk 1, Anne-Louise Lafontaine 1, François Evoy 8, Marie-France Rioux 8, Jean-Denis Brisson 9,10, Kym M Boycott 11, Henry Houlden 4, Matthis Synofzik 12,13, Roberta La Piana 1,14, Stephan Zuchner 5, Antoine Duquette 15,16,17, Bernard Brais 1,17,18,✉
PMCID: PMC12450228  PMID: 40974444

Abstract

Background

Autosomal dominant spinocerebellar ataxia 27B (SCA27B), caused by an intronic (GAA•TTC) repeat expansion in FGF14, is a common cause of late-onset cerebellar ataxia, but its genotypic and phenotypic spectrum remains to be fully established.

Methods

We analysed the FGF14 (GAA•TTC) repeat expansion in a cohort of 134 patients with ataxia and 822 controls from Quebec. We conducted segregation study in large families to further characterize intergenerational repeat instability.

Results

We found a significant enrichment of (GAA•TTC)≥200 alleles in the ataxia cohort compared to controls (53.0%, 71/134, vs 3.6%, 30/822, p < 0.0001), including for (GAA•TTC)200–249 alleles (8.2% vs 2.6%, p = 0.0026). We identified 12 ataxic patients with a phenotype compatible with SCA27B carrying a (GAA•TTC)200–249 expansion supporting the pathogenicity of these alleles in some patients. We further delineated the phenotype of 125 symptomatic individuals from 69 families who carried an FGF14 (GAA•TTC)≥200 repeat expansion. Patients with (GAA•TTC)200–249, (GAA•TTC)250–299, and (GAA•TTC)≥300 had a similar phenotype. We observed that 14% of patients with episodic symptoms (13/92) had severe episodes that were initially misdiagnosed as stroke, vestibular neuritis, Wernicke’s encephalopathy, or seizures.

Discussion and conclusion

This large cohort demonstrates that (GAA•TTC)200–249 alleles are enriched in patients with ataxia compared to controls and can be pathogenic for SCA27B, supporting the need to define a lower pathogenic threshold in the presence of specific clinical criteria.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00415-025-13387-4.

Keywords: Ataxia, SCA27B, FGF14, French–Canadian

Introduction

Spinocerebellar ataxia 27B (SCA27B), also referred to as GAA-FGF14-related ataxia (MIM #620,174), is an increasingly recognised common cause of late-onset cerebellar ataxia (LOCA). The disease is due to a heterozygous (GAA•TTC) repeat expansion in the first intron of the fibroblast growth factor 14 (FGF14) gene. SCA27B accounts for 5–61% of previously undiagnosed cases of sporadic and familial LOCA in various cohorts of European descent [1–16]. The highest prevalence has been documented in the French–Canadian population, likely due to a founder effect [3, 11]. Although SCA27B has also been found in East Asian populations [17–21], its frequency is significantly lower, accounting for 0–1.7% in cohorts from China and Japan [12].

The core features of SCA27B include a relatively late age of onset (on average 60 years, with some individuals after 75 years of age) [22] of a mostly pure, slowly progressive cerebellar ataxia with common episodic symptoms and ocular motor cerebellar signs, particularly downbeat nystagmus [8, 11, 15, 23]. Gait, stance, and lower limb ataxia seem to contribute the most to the severity of ataxia compared to upper limb ataxia or dysarthria, which are less severe and less frequent [5, 8, 15]. A large proportion of cases have episodic symptoms at disease onset, ranging from 13% [15] to 93% [24], with most series documenting between 30 and 50% [5, 8, 11, 14]. The described episodic symptoms include episodic ataxia, dysarthria, visual disturbances (diplopia, oscillopsia), vertigo/dizziness, and “brain fog” [2, 25, 26]. Méreaux et al. have proposed a core clinical triad to help distinguish cases of SCA27B from other LOCAs: disease onset ≥ 45 years, presence of downbeat nystagmus, and episodic features [8]. Several open-label series have shown that a large proportion of patients with SCA27B benefit from treatment with 4-aminopyridine [27]. Previous studies suggest that episodic symptoms are particularly responsive to this drug [11, 15, 25]. In comparison, acetazolamide does not appear to be as beneficial as 4-aminopyridine, with more than half of patients reporting no benefit [2].

The two discovery papers describing SCA27B defined the pathogenic threshold as at least 250 GAA triplet repeats, based on segregation studies in families and test of association in case–control series [11, 13]. Repeat lengths of 250–299 repeats are generally considered pathogenic but incompletely penetrant, while larger expansions are deemed highly penetrant [22]. A potentially lower pathogenic threshold has been suggested by four studies showing significant enrichment of (GAA•TTC)200–249 alleles in ataxic patients compared with controls [18, 24, 28, 29], and three studies showed segregation with disease of alleles in this range in five small families with late-onset, slowly progressive ataxia [4, 8, 24]. Nonetheless, current published data remains insufficient to definitively establish (GAA•TTC)200–249 expansions as pathogenic for SCA27B.

Similar to other triplet repeat expansions, intergenerational [8, 11, 30] and somatic instability [31] has been described at the FGF14 (GAA•TTC) repeat locus. Factors such as parental sex, as well as the expansion motif and size have been shown to influence intergenerational instability [8, 11, 31]. However, analysis of expansion dynamics and the impact of interruptions on intergenerational instability in large families is still lacking, limiting our understanding of intergenerational stability.

In this study, we reassessed certain features of SCA27B that are less well studied, including the intergenerational instability of the FGF14 repeat locus, the pathogenicity of (GAA•TTC)200–249 alleles, and the impact of sex on disease severity. Moreover, building on our previously described French–Canadian cohort [2, 11], we further expand characterisation of the phenotypic spectrum.

Methods

Participant enrolment

Three cohorts were included in this study (Supplementary Fig. 1). First, to assess the allele distribution of the FGF14 repeat in control individuals, we genotyped an unselected control cohort of 822 individuals from Quebec, Canada, mostly composed of individuals of French–Canadian ancestry. This unselected cohort includes healthy individuals at time of exam or non-ataxic individuals with various neuromuscular disorders. Second, we included 134 index patients with late-onset ataxia (defined as age of onset > 30 years) referred to the ataxia clinic at the Montreal Neurological Hospital, the Centre Hospitalier Universitaire de Montréal, and the Clinique des Maladies Neuromusculaires de Saguenay, all in Quebec, Canada. 92.5% of index patients were French–Canadian (124/134). Patients with early cognitive impairment, severe spasticity, or multisystemic features were excluded as well as patients with clinically established cerebellar MSA (MSA-C) based on clinical and neuroimaging criteria [32]. Third, a cohort of 83 patients with various hereditary ataxias and MSA-C was screened for FGF14 expansions to assess the distribution of the expansion in other forms of ataxia and to evaluate the frequency of (GAA•TTC)200–249 alleles (Supplementary Fig. 2, Supplementary Table 1).

Diagnostic testing for SCA27B was performed using an established protocol, as described previously [33]. (GAA•TTC) expansion size was defined as the number of pure GAA•TTC repeats. The institutional review board of the Montreal Neurological Hospital (MPE-CUSM-15–915 and CHUM- ND02.045) approved this study and all participants provided written informed consent.

Deep phenotyping

Patients were evaluated in person, when possible, and longitudinal review of clinical records was conducted using a standardised data form. Age of onset was considered as the age at onset of the first manifestation of disease, whether episodic or permanent. Disease severity was assessed using the Scale for the Assessment and Rating of Ataxia (SARA) [34], and disability was assessed with the Spinocerebellar Degeneration Functional Scale (SDFS) [35] (0: no functional handicap; 1: no functional handicap but signs at examination; 2: mild, able to run, walking unlimited; 3: moderate, unable to run, limited walking without help; 4: severe, walking with one stick; 5: walking with two sticks; 6: unable to walk, requiring wheelchair; 7: confined to the bed).

Statistical analysis

We assessed enrichment of (GAA•TTC)200–249, (GAA•TTC)250–299, and (GAA•TTC)≥300 alleles in patients compared to controls using the Fisher’s exact test. Effect sizes were reported as odds ratio (OR) with 95% confidence intervals (CIs). We assessed differences between groups with the Mann–Whitney U test for continuous variables and Fisher’s exact test for categorical variables. Comparisons between multiple groups were computed with the Fisher’s exact test for categorical variables and the Kruskal–Wallis test for continuous variables. Correlations were calculated using the Pearson’s correlation coefficient for normally distributed variables or the Spearman’s rank correlation coefficient for ordinal variables or non-normally distributed variables. We assessed normal distribution using the Kolmogorov–Smirnov test. We estimated the longitudinal progression of ataxia severity (SARA scores) and disability (SDFS scores) over the disease course using a linear mixed-effects model fitted by the restricted maximum likelihood method (R packages: lme4 and lmerTest). We analyzed the data in R (version 4.3) and Graphpad Prism 8.0.1. P value of < 0.05 was considered significant and all analyses were two-sided.

Results

Frequency of the FGF14 repeat expansion in controls and patients

We compared the frequency of (GAA•TTC)200–249, (GAA•TTC)250–299, and (GAA•TTC)≥300 alleles in 134 index patients with late-onset ataxia of unknown cause and 822 control individuals (Fig. 1, Supplementary Fig. 1).

Fig. 1.

Fig. 1

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Allele distribution in the control and the ataxia cohorts. The frequency of (GAA•TTC)200–249 (OR 3.41, 95% CI 1.56–7.29; Fisher´s exact test, p = 0.0026), (GAA•TTC)250–299 (OR 12.51, 95% CI 4.73–32.25; Fisher´s exact test, p < 0.0001), and (GAA•TTC)≥300 (OR 221.5, 95% CI 58.83–933.6; Fisher´s exact test, p < 0.0001) expansions was significantly higher in patients with ataxia than in controls. Non-GAA-pure expansions had a similar proportion in patients and controls (OR 0.68, 95% CI 0.06–4.14; Fisher´s exact test, p = 0.71)

Of 134 index patients, 60 carried a (GAA•TTC)≥250 FGF14 repeat expansion, confirming the diagnosis of SCA27B (44.8%, 60/134). In comparison, only nine of the 822 controls carried a (GAA•TTC)≥250 expansion (1.1%) (OR 73.24, 95% CI 34.56–151.0; Fisher´s exact test, p < 0.0001). Among 134 patients, 9.7% (13 individuals) carried a (GAA•TTC)250–299 expansion, compared to 0.9% (7/822) of controls (OR 12.51, 95% CI 4.73–32.25; Fisher´s exact test, p < 0.0001). Expansion of (GAA•TTC)≥300 repeats were observed in 35.1% of patients (47/134) and in 0.2% of controls (2/822) (OR 221.5, 95% CI 58.83–933.6; Fisher´s exact test, p < 0.0001) (Fig. 1, Supplementary Fig.  3 A). The two control individuals carrying a (GAA•TTC)≥300 expansion were last examined at age 55 and 71, respectively. The first one had a normal exam while the second had tremor but no signs of ataxia. Moreover, (GAA•TTC)200–249 expansions were significantly enriched in patients (8.2%, 11/134) compared to controls (21/822, 2.6%) (OR 3.41, 95% CI 1.56–7.29; Fisher´s exact test, p = 0.0026). However, when the range included (GAA•TTC)180–249 expansions, no significant differences were found between patients (8.9%, 11/134) and controls (5.2%, 43/822) (OR 1.62, 95% CI 0.82–3.20; Fisher´s exact test, p = 0.16). Similar proportions of non-GAA-pure expansions were found in patients (0.7%, 1/134) and controls (1.1%, 9/822) (OR 0.68, 95% CI 0.06–4.14; Fisher´s exact test, p = 0.99). Apart from two controls carrying a [(GAA)n(GCA)m] expansion, the remaining carried a (GAAGGA) expansion.

We also analysed 83 patients with an alternative diagnosis, including cases of genetic ataxia (other than SCA27B) and MSA-C (Supplementary Table 1). Most of them (92.8%, 77/83) carried (GAA•TTC)<200 alleles. A (GAA•TTC)200–249 allele was observed in 5 patients (6.0%), including one with Friedreich ataxia, one with SYNE1-related ataxia, and three with MSA-C. Of note, none of them had a phenotype suggestive of SCA27B (ie. downbeat nystagmus, or clear episodic onset). One patient (1.3%) carried a non-GAA-pure expansion.

Intergenerational instability of the FGF14 (GAA•TTC) repeat

We further characterised the intergenerational instability of the FGF14 (GAA•TTC) repeat locus in our cohort (Fig. 2). We analysed 131 intergenerational transmission events, including 84 maternal (median allele size: 89 triplets, IQR 10–257.75) and 47 paternal (median allele size: 205 repeats, IQR 43–308.5) transmissions. As previously reported [30], parental alleles with fewer than 30 repeats were stably transmitted, regardless of parental sex. Maternal alleles larger than 30 repeats (n = 58) expanded in most transmissions (79.3%, 46/58), while the remainder were stable (19.0%, 11/58) (Fig. 2). Only one transmission of 212 GAA repeats showed a short contraction of three repeats. There was a significant correlation between the size of the transmitted maternal allele (above 30 repeats) and the extent of expansion on transmission (Pearson’s correlation coefficient = 0.51, R2 = 0.26, p < 0.0001) (Fig. 2b). In comparison, paternal alleles larger than 30 repeats contracted in most transmissions (91.7%, 33/36), while it was stably passed in the rest of events (8.3%, 3/36). We observed a significant negative correlation between the size of the transmitted paternal allele (above 30 repeats) and the extent of contraction on transmission (Pearson’s correlation coefficient =  − 0.71, R2 = 0.50, p < 0.0001) (Fig. 2b). These results confirm that repeat instability is primarily influenced by allele size and sex of the transmitting parent [8, 11, 30]. We next examined the impact of parental age on repeat instability, considering only transmissions involving alleles larger than 30 repeat units. In maternal transmissions, we identified a significant positive association between maternal age and repeat size change (β = 1.39, p < 0.0001), indicating that each additional year of maternal age was associated with an average increase of 1.39 repeats. In contrast, no such association was observed in paternal transmissions (β = –0.71, p = 0.61).

Fig. 2.

Fig. 2

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Intergenerational instability of the FGF14 (GAA•TTC) repeat locus. A) Analysis of GAA repeat size changes across 131 intergenerational transmissions, including 84 maternal and 47 paternal events. B) Change in GAA repeat length across 131 intergenerational transmissions. The y-axis shows the change in repeat length from parent to child. In A and B, alleles inherited from the mother are shown in blue and those from the father in orange. Contractions are plotted below the dashed lines while expansions are plotted above them

Next, we examined whether the risk of inheriting an expanded allele differed if being inherited from the mother or the father. Only families in which all children of an affected parent were genotyped, regardless of their clinical status, were included in this analysis. In total, we genotyped 56 children of mothers and 15 children of fathers carrying a pathogenic allele; 31 of the maternal group (55.4%) and 11 of the paternal group (73.3%) inherited the expanded allele. These results suggest that both mothers and fathers are at similar risk of transmitting the expanded allele to their children (Fisher´s exact test, p = 0.64).

We also characterised the instability of interrupted FGF14 alleles across generations. Interrupted alleles were defined as showing a polymorphic non-GAA-pure sequence either at the beginning or within the repeat locus. Twenty-eight alleles from twenty-five individuals from five families carrying an interrupted (GAA•TTC) allele were analysed (Fig. 3 and Supplementary Fig. 4). The size of the interruption remained stable across all 21 examined transmission events, while the length of the uninterrupted (GAA•TTC) tract varied proportionally to the transmitted allele size and the sex of the transmitting parent (Supplementary Fig. 4).

Fig. 3.

Fig. 3

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Sizes of non-GAA-pure interruptions (blue) and (GAA•TTC) tracts (orange) in 28 alleles with interrupted FGF14 alleles. The alleles were derived from 25 individuals across five families. While the (GAA•TTC) repeat varied within families, the size of the non-GAA-pure interruptions remained stable

Deep phenotyping of affected individuals carrying a (GAA•TTC)200–249 expansion

As the pathogenicity of (GAA•TTC)200–249 alleles remains to be unequivocally established, we further studied individuals carrying such expansions. As mentioned earlier, (GAA•TTC)200–249 repeat expansions were significantly enriched in cases with ataxia compared to controls (OR 3.41, 95% CI 1.56–7.29; Fisher´s exact test, p = 0.0026) (Fig. 1).

Within the cohorts of controls, patients with unsolved ataxia, and patients with ataxia and an alternative diagnosis, as well as their relatives, we identified 53 individuals carrying a (GAA•TTC)200–249 expansion (Supplementary Fig. 2). More than half (31/53) were controls or unaffected relatives of patients with ataxia (median repeat size: 222 repeats, IQR 214–235). Four of these individuals were asymptomatic relatives of patients with SCA27B. Five patients (9.4%; 5/53) had ataxia other than SCA27B, including Friedreich ataxia in one, SYNE1 ataxia in one and MSA-C in three (mean repeat size: 229 repeats, IQR 223–235). The remaining 17 patients were individuals with unsolved ataxia. Of those, 12 (22.6%, 12/53) had a phenotype compatible with SCA27B (median repeat size: 230.5 repeats, IQR: 224.25–240.5) while the others (9.3%, 5/54) had an atypical presentation (ie. additional non-cerebellar features in the absence of typical SCA27B symptoms, like episodic onset or downbeat nystagmus), suggestive of another, yet to be identified, ataxia (median repeat size: 204 repeats, IQR 203–225).

We found no statistically significant difference in the median repeat size between the different groups (Kruskal–Wallis test, p = 0.11), although we observed a trend toward larger allele size in patients with a phenotype compatible with SCA27B compared to patients with an atypical phenotype (median size 230.5 vs 204, Mann–Whitney U test, p = 0.06) (Fig. 4).

Fig. 4.

Fig. 4

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Patients with (GAA•TTC)200–249 expansions. 53 patients carrying a (GAA•TTC)200–249 allele were identified and grouped according to their clinical status and phenotype (unaffected carriers, patients with a confirmed alternative diagnosis, patients with unsolved ataxia and a phenotype compatible with SCA27B, and patients with unsolved ataxia and a phenotype atypical for SCA27B). No statistically significant difference in the median repeat size was found between the four groups (Kruskal–Wallis test, p = 0.11). Affected and unaffected individuals from confirmed SCA27B families are shown in blue

Five ataxic individuals from three families carrying a (GAA•TTC)200–249 allele had a positive family history for confirmed SCA27B (Fig. 5). Additional segregation studies in six individuals from six families were compatible with pathogenicity (Suppl. Figure 5). However, (GAA•TTC)200–299 expansions were also found in unaffected relatives in three out of nine of these families (Fig. 5 and Suppl. Figure 3).

Fig. 5.

Fig. 5

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Family trees showing co-occurrence of affected individuals carrying (GAA•TTC)200–249 alleles repeats (A.III.7, A.III.12, B.III.3, B.III.6), and alleles (GAA•TTC)≥250. Some asymptomatic individuals also carry (GAA•TTC)200–249 alleles (A.III.3, A.III.9, A.III.11) supporting the incomplete penetrance of such alleles. Age at last exam was noted for asymptomatic individuals carrying a 200–249 repeat allele

Deep phenotyping of the French–Canadian cohort

We analysed the phenotype of 125 patients with ataxia carrying a (GAA•TTC)≥200 allele, from 69 families. Eighty-two have been previously reported [2, 11]. All but seven were of French–Canadian origin. All non-French–Canadian patients were of European ancestry, except for one individual of Mizrahi Jewish Iraqi descent. The phenotype of our patients with SCA27B was generally similar to that described in previous studies [12]. Specifically, the median age at onset of permanent symptoms was 60 years (IQR 50–67 years), 76% (92/121) of patients had episodic symptoms, and 50% (60/119) had downbeat nystagmus. All three features, composing the ‘key clinical triad’, were present in 37% of patients (44/120). Repeat size of the largest allele was inversely correlated with age of onset (Fig. 6a, Pearson’s correlation coefficient =  − 0.40, R2 = 0.16, p < 0.0001).

Fig. 6.

Fig. 6

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Clinical characterization and disease progression in SCA27B. a Inverse correlation between age of onset and repeat size. Pearson’s correlation coefficient = −0.40, R2 = 0.16, p < 0.0001. b Distribution of scores per SARA items represented as a fraction of the total SARA score. c Longitudinal intra-individual progression of ataxia severity as assessed by SARA relative to disease duration (50 observations from 21 patients). Observations from the same patient are connected by a dotted line. SARA score increased on average by 0.22 points/year of disease duration. The solid black line shows the average progression of the SARA score over disease duration across all patients as modelled by a linear mixed-effects model accounting for disease duration as fixed effect (p = 0.016). d Longitudinal intra-individual progression of functional impairment as assessed by SDFS score relative to disease duration (182 observations from 51 patients). Observations from the same patient are connected by a dotted line. SDFS score increased on average by 0.16 points/year of disease duration (linear mixed-effects model, p < 0.0001)

We next compared the clinical features of patients stratified by allele size—(GAA•TTC)200–249, (GAA•TTC)250–299, and (GAA•TTC)≥300 (Table 1)—and found similar clinical profiles across all three groups. However, the age at onset of permanent gait ataxia was significantly later in patients with a (GAA•TTC)250–299 expansion (median 64.5 years, IQR 61.8–70) compared to those with a (GAA•TTC)≥300 expansion (median 57, IQR 50–66.2; Kruskal–Wallis test, p = 0.0061; Dunn’s post hoc test with Bonferroni correction, p = 0.0084). Episodic diplopia was also more common in patients with a (GAA•TTC)≥300 expansion (74%, 35/47) compared to those with a (GAA•TTC)200–249 expansion (30%, 3/10; global Fisher´s exact test, p = 0.029; pairwise comparison, p = 0.011). Lastly, tremor was more common in patients with a (GAA•TTC)200–249 expansion (46.2%, 6/13) compared to patients with a (GAA•TTC)250–299 expansion (0%, 0/15; global Fisher´s exact test, p = 0.019; pairwise comparison, p = 0.0098) (Table 1).

Table 1.

Phenotype features in patients with 200–249, 250–299 and > 300 GAA repeats

200–249 (n = 17) 250–299 (n = 17)  ≥ 300 (n = 91) p value
N Proportion N Proportion N Proportion
Male 8/17 47% 12/17 71% 43/91 47% 0.23
Female 9/17 53% 5/17 29% 48/91 53%
Positive family history 11/15 73% 13/16 81% 74/85 87% 0.3
Affected parent 5/15 33% 12/16 75% 60/80 75% 0.095
Affected father 5/5 100% 5/12 42% 24/60 40% 0.030 (200–249 vs 250–299 p = 0.044; 200–249 vs > 300, p = 0.014)
Affected mother 0/5 0% 7/12 58% 36/60 60%
Episodic onset 11/17 65% 11/16 69% 70/88 80% 0.29
AAO episodic symptoms median (IQR) 52 (46–58) 56 (51.5–60.5) 51 (40–62) 0.46
AAO permanent symptoms median (IQR) 62 (59.8–65.8) 64.5 (61.8–70) 57 (50–66.2) 0.006 (250–299 vs > 300, p = 0.008)
Age at last examination median (IQR) 66 (56–72) 76 (71–81) 68.5 (61.8–75) 0.003 (200–249 vs 250–299 p = 0.0043; 250–299 vs > 300, p = 0.008)
Episodic imbalance 8/13 62% 7/9 78% 54/63 86% 0.10
Episodic vertigo 5/11 45% 4/7 57% 23/45 51% 0.50
Episodic diplopia 3/10 30% 7/10 70% 35/47 74% 0.029 (200–249 vs > 300, p = 0.011)
Episodic dysarthria 4/11 36% 6/9 67% 31/49 63% 0.27
Episodic limb ataxia 2/8 25% 1/4 25% 5/24 21% 1.00
Exercise intolerance 3/10 30% 0/2 0% 11/23 48% 0.43
Alcohol intolerance 4/10 40% 8/16 50% 39/63 62% 0.34
Impaired balance 11/14 79% 16/17 94% 77/87 89% 0.46
Visual symptoms2 9/13 69% 12/17 71% 52/81 64% 0.90
Vertigo 8/10 80% 6/15 40% 30/69 43% 0.10
Walking aid 7/11 64% 12/13 31/45 69% 0.20
Age at walking aid median (IQR) 65 (60–73.5) 73 (70–78) 71 (62–75) 0.13
Gait ataxia 13/17 76% 16/17 94% 78/87 90% 0.33
Upper limb ataxia 9/14 64% 9/11 82% 43/62 69% 0.61
Lower limb ataxia 12/17 71% 14/16 88% 62/88 70% 0.43
Dysarthria 9/17 53% 8/17 47% 40/86 47% 0.96
Cerebellar oculomotor syndrome 11/17 65% 11/16 69% 65/86 76% 0.54
Downbeat nystagmus 6/17 35% 8/16 50% 46/86 53% 0.41
Reduced vibration sensation 5/14 36% 5/16 31% 34/77 44% 0.61
Hyporreflexia 4/16 25% 3/17 18% 18/86 21% 0.87
Hyperreflexia 4/16 25% 1/17 6% 10/86 12% 0.22
Spasticity 2/13 15% 1/17 6% 4/82 5% 0.25
Key triad3 5/15 33% 6/16 38% 33/87 38% 0.94
Tremor 6/13 46% 0/15 0% 13/72 18% 0.019 (200–249 vs 250–299, p = 0.0098)
Vermis atrophy 1/2 50% 4/8 50% 25/36 69% 0.40
Polyneuropathy on EMG 1/4 25% 2/4 50% 5/23 22% 0.55
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1When p value < 0.05 (significant), in brackets is shown the comparison/s that are significant between individual groups. 2Including diplopia, visual blurring, fixation problems. 3Permanent onset > 45yo, episodic onset, downbeat nystagmus

Among patients with episodic symptoms, triggers included physical activity (49.3%, 37/75), alcohol intake (46.7%, 35/75), fatigue (36.0%, 27/75), stress (16.0%, 12/75), caffeine intake (16.0%, 12/75), and bright light (11.6%, 10/86). Median age of onset of the episodic symptoms was 52.5 years (IQR 42–61 years) and the earliest age of onset in our cohort was 27 years. Median time from episodic to permanent symptoms was 3 years (IQR 0.5–8.5 years). Episodes lasted minutes in two thirds of patients (34/51), and their frequency was usually daily (46.2%, 18/39) or weekly (43.6%, 17/39). To assess whether initial episodic symptoms influenced the time at onset of permanent ataxia, we compared the age at onset of permanent symptoms in patients with and without episodic onset. No significant difference was observed between the groups (median of 60 years old in both groups, Mann–Whitney U test, p = 0.47). Notably, among patients with episodic onset, 13 of 92 (14%) experienced acute episodes that led to emergency department visits, with some requiring hospital admission. These episodes were often initially misdiagnosed as vertebrobasilar transient ischemic attack, vestibular neuritis, Wernicke encephalopathy, or focal seizures.

Cross-sectional SARA scores were available for 64 patients. Total scores correlated with disease duration (Pearson’s correlation coefficient = 0.50, R2 = 0.25, p < 0.0001) (Supplementary Fig. 6a) but not with the size of the largest allele (Pearson’s correlation coefficient = −0.04, R2 = 0.02, p = 0.92) (Supplementary Fig. 6b). Gait and stance ataxia were the main contributors to the total SARA score, followed by lower limb ataxia. In contrast, speech and sitting were less severely impaired (Fig. 6b). Longitudinal SARA scores were available for 21 patients (Fig. 6c) and SDFS scores for 50 patients (Fig. 6d). SARA score increased on average by 0.22 points/year of disease duration (t test, p = 0.016) while SDFS score increased on average by 0.16 points/year of disease duration (t test, p < 0.0001).

Effect of sex on disease phenotype and severity

Recent studies have suggested a trend toward more severe disease progression in women with SCA27B compared with men [14, 36]. Moreover, a previous study from our group suggested, based on a small number of cases, that female patients may exhibit a higher degree of somatic instability in post-mortem brain tissue [31]. Based on these preliminary observations, we investigated whether patient sex influenced disease severity in our cohort. Allele distribution and disease duration were similar in males and females (Suppl. Figure 7). Median age at onset of permanent symptoms was also similar in males and females (60 years in both; Mann–Whitney U test, p = 0.99), and sex was not a significant predictor of age at onset in a linear regression model adjusted for repeat size (p = 0.61) (Fig. 7a-b). Furthermore, no differences in the frequency of phenotypic features were observed between females and males (Supplementary Table 2) and we found no significant difference in disease progression between females and males as measured by SARA score (linear mixed-effects model, p = 0.67) (Fig. 7c) and SDFS (linear mixed-effects model, p = 0.61) (Fig. 7d).

Fig. 7.

Fig. 7

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Effect of sex on age at onset and disease progression in SCA27B a Median age at onset by sex showed no significant differences between females and males. Mann–Whitney U test: p = 0.98. b Relationship between repeat size and age at onset stratified by sex of the patient. c Longitudinal intra-individual progression of ataxia severity as assessed by SARA relative to disease duration in men and women. d Longitudinal intra-individual progression of functional impairment as assessed by SDFS score relative to disease duration in men and women

Discussion

By studying large French–Canadian families, we assembled a cohort of 125 patients with SCA27B, offering new insights into the clinical and genetic spectrum of this recently described ataxia. This represents one of the largest regional series to date, with systematically collected family data that shed further light on intergenerational transmission dynamics, the pathogenic potential of (GAA•TTC)200–249 alleles, and possible sex-related effects on clinical presentation.

In agreement with four previous studies, our results confirmed that (GAA•TTC)≥200 alleles are significantly enriched in patients with unsolved ataxia compared to controls [18, 24, 28, 29]. Further, one of these studies even proposed a lower pathogenic threshold of 180 repeat units. However, we did not observe a significant enrichment of (GAA•TTC)180–249 alleles in patients compared to controls, warranting caution in interpreting the pathogenicity of alleles shorter than 200 repeat units. Conversely, non-GAA-pure expansions had a similar frequency in both controls and patients (Fig. 1), further supporting the non-pathogenicity of these alleles [24, 37].

The pathogenicity of (GAA•TTC)200–249 alleles still remains to be firmly established [12]. Although isolated patients with ataxia and expansions below 250 have been published [4, 8, 24, 28], the small number of patients and the paucity of familial segregation prevented to arrive at a consensus. Our observations of (GAA•TTC)200–249 alleles in affected individuals from large families with confirmed SCA27B provide convincing segregation data to support the pathogenicity of (GAA•TTC)200–249 alleles in some patients. Nonetheless, several unaffected relatives within the same families, as well as patients with an alternative cause of ataxia, were found to carry these alleles—supporting the notion of incomplete penetrance. Although dual genetic diagnoses have been reported [28, 38], patients in our study who carried a 200–249 allele alongside an alternative genetic cause of ataxia exhibited no clinical or radiological features typical of SCA27B. These findings argue against the pathogenicity of the FGF14 allele in these cases and instead support non-penetrance, although we cannot completely rule out a modifier effect of the FGF14 allele. These findings challenge the recently suggested assumption that all individuals carrying a pure (GAA•TTC)200–249 expansion are either premanifest or affected by SCA27B [39] and suggest that additional, unidentified genetic factors may influence penetrance, and highlight the importance of excluding other causes of ataxia in patients with expansions in this size range. Whether asymptomatic individuals carrying a (GAA•TTC)200–249 expansion will develop symptoms later in life remains unknown although our identification of asymptomatic individuals older than 70 years carrying such expansions provide further evidence for their incomplete penetrance [22]. Nonetheless, longitudinal follow-up will be essential to better define the penetrance of these alleles. Importantly, the phenotype was generally similar between patients carrying a (GAA•TTC)200–249 allele and those carrying a (GAA•TTC)≥250 allele (Table 1).

The large families recruited in this study enabled us to further characterize the intergenerational dynamics of the expansion, confirming a tendency for maternal alleles to expand and for paternal alleles to contract during transmission. Furthermore, our study suggests that maternal age also influences intergenerational instability, showing that offspring of older mothers generally inherit larger expansions. However, we did not observe a similar effect with fathers. This effect of parental age on intergenerational instability has been described in other repeat expansion disorders, such as myotonic dystrophy type 1 (DM1) [40]. Additionally, we observed that the interrupting motif remains stable during transmission, whereas the GAA•TTC tract is prone to instability. This is in agreement with previous studies showing that non-GAA-pure expansions remain stable during intergenerational transmission [30, 37]. Moreover, similar transmission dynamics have been described with interrupted motifs at other tandem repeat loci, like DMPK in DM1 [41]. Repeat motif, as well as parental sex, age, and allele size all appear to be major determinants of the extent of intergenerational instability. This is further influenced by the 5’-flanking sequence, with the common 5’-flanking variant found on shorter alleles stabilizing the repeat tract [30].

The clinical features in our cohort are similar to those of previously published series [1, 5–10, 14–16, 24]. Pyramidal signs, severe neuropathy and Parkinsonian features were rare in our cohort and should trigger investigation for alternative causes. The key triad (onset after age 45, downbeat nystagmus and episodic symptoms) was present in 44/120 (37%) of our patients. While it is a useful diagnostic clue when present, it should not be used to exclude the diagnosis due to its low sensitivity.

Furthermore, 14% of patients with episodic symptoms presented with acute severe episodes that led to visits to the emergency department or even hospital admission. Most of these episodes were initially misdiagnosed, emphasizing the importance for clinicians to recognise SCA27B as a potential cause of recurrent episodes of vertigo, nystagmus and/or gait ataxia that may present in the emergency department. Patients with episodic symptoms did not have an earlier onset of permanent symptoms, suggesting that the episodes do not accelerate disease progression. The presence of episodic symptoms in SCA27B is likely related to a functional channelopathy caused by loss of FGF14 function. Current evidence suggests that SCA27B is caused by transcriptional repression of FGF14 [11]. FGF14 is largely expressed in Purkinje neurons and is known to be a modulator of voltage-gated sodium channels at the axon initial segment [42]. Impairment of ion-channel kinetics, as previously shown with Fgf14 knockdown in mouse Purkinje cells [43], is consistent with the frequent episodic presentation in SCA27B.

Our work is also one of the few to present longitudinal data on patients with SCA27B, providing further evidence for the slow progression of this disease. The annual SARA progression rate in our cohort (0.22 points/year) was comparable to rates previously reported by Wilke et al. (0.23), Mohren et al. (0.30), and Wirth et al. (0.40). The slow annual progression raises concerns about the sensitivity of the SARA score as a sole measure of efficacy in future disease-modifying trials, highlighting the need for additional outcome measures. Digital-motor outcomes of gait and balance have been shown to be more sensitive to change in SCA27B than the SARA [26], while still allowing to capture gait and balance as the main drivers of SCA27B disease severity as shown here (Fig. 6B) and previously [15]. Furthermore, although sex influences intergenerational instability [8, 11], our study does not support that it significantly affects disease phenotype or severity.

Our study presents some limitations including the lack of longitudinal data on a significant proportion of patients, missing data on some patients that we were not able to reassess in person, and the absence of data on 4-aminopyridine treatment response. Moreover, our cohorts are mostly limited to one ethnicity, as most individuals are French Canadians, and some conclusions might not be applicable to other populations, especially of non-European ancestry.

In conclusion, our study of a large cohort of 125 patients with SCA27B provides strong evidence that (GAA•TTC)200–249 alleles can be pathogenic in some individuals. However, because these expansions are often non-penetrant, strict criteria based on segregation, clinical and MRI findings are necessary to confirm their pathogenicity on an individual basis. Furthermore, ruling out other genetic causes of ataxia is paramount in these patients [28]. We further highlight the importance of including SCA27B in the differential of acute episodic symptoms in the emergency room setting. Lastly, we studied the effect of sex on clinical severity and phenotype, showing no significant differences between males and females.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (TIF 94 KB) (94.3KB, tif)
Supplementary file2 (TIF 121 KB) (120.8KB, tif)
Supplementary file3 (TIF 214 KB) (213.6KB, tif)
Supplementary file4 (TIF 67 KB) (67.3KB, tif)
Supplementary file5 (TIF 73 KB) (73KB, tif)
Supplementary file6 (TIF 119 KB) (119.3KB, tif)
Supplementary file7 (TIF 106 KB) (105.6KB, tif)
Supplementary file8 (XLSX 11 KB) (10.7KB, xlsx)
Supplementary file9 (XLSX 10 KB) (10.2KB, xlsx)

Acknowledgements

This work was funded by the Fondation Groupe Monaco and the Canadian Institutes of Health Research (grant 189963) awarded to B.B and supported by the European Union, project European Rare Disease Research Alliance (ERDERA), GA n°101156595, funded under call HORIZON-HLTH-2023-DISEASE-07 (to M.S.). P.I. holds a Desjardins Clinical Fellowship at the Montreal Neurological Institute (McGill University) and D.P. holds a Fellowship Award from the Canadian Institutes of Health Research (CIHR).

Funding

Canadian Institutes of Health Research, 189963, Bernard Brais, European Rare Disease Research Alliance, 101156595, Matthis Synofzik

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Conflicts of interest

Matthis Synofzik has received consultancy honoraria from Ionis, UCB, Prevail, Orphazyme, Biogen, Servier, Reata, GenOrph, AviadoBio, Biohaven, Zevra, Lilly, Quince, Neurocrine, and Solaxa, all unrelated to the present manuscript.

Ethical approval

This study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki. The institutional review board of the Montreal Neurological Hospital (MPE-CUSM-15–915 and CHUM-ND02.045) approved this study and all participants provided written informed consent.

Footnotes

Pablo Iruzubieta, David Pellerin, and Catherine Ashton contributed equally to this paper.

References

  • 1.Abou Chaar W, Eranki AN, Stevens HA et al (2024) Clinical, radiological and pathological features of a large American cohort of spinocerebellar ataxia ( sca27b ). Ann Neurol 96:1092–1103. 10.1002/ana.27060 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Ashton C, Indelicato E, Pellerin D et al (2023) Spinocerebellar ataxia 27B: episodic symptoms and acetazolamide response in 34 patients. Brain Commun 5:1–5. 10.1093/braincomms/fcad239 [Google Scholar]
  • 3.Cuillerier A, Del Gobbo GF, Mackay L et al (2025) fgf14 gaa intronic expansion in unsolved adult-onset ataxia in the care4rare Canada consortium. Ann Clin Transl Neurol. 10.1002/acn3.70016 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Hengel 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 38:1557–1558. 10.1002/mds.29559 [DOI] [PubMed] [Google Scholar]
  • 5.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. 10.1111/ene.16039 [DOI] [PubMed] [Google Scholar]
  • 6.Kartanou C, Mitrousias A, Pellerin D et al (2024) The FGF14 GAA repeat expansion in Greek patients with late-onset cerebellar ataxia and an overview of the SCA27B phenotype across populations. Clin Genet. 10.1111/cge.14482 [DOI] [PubMed] [Google Scholar]
  • 7.Livanos I, Votsi C, Michailidou K et al (2024) The FGF14 GAA repeat expansion is a major cause of ataxia in the Cypriot population. Brain Commun 7:fcae479. 10.1093/braincomms/fcae479 [Google Scholar]
  • 8.Méreaux J-L, Davoine C-S, Pellerin D et al (2024) Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions. EBioMedicine 99:104931. 10.1016/j.ebiom.2023.104931 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.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. 10.1002/mdc3.14020 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Novis 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. 10.1212/NXG.0000000000200094 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Pellerin D, Danzi MC, Wilke C et al (2023) Deep intronic FGF14 GAA repeat expansion in late-onset cerebellar ataxia. N Engl J Med 388:128–141. 10.1056/NEJMoa2207406 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Pellerin D, Iruzubieta P, Xu IRL et al (2025) Recent advances in the genetics of ataxias: an update on novel autosomal dominant repeat expansions. Curr Neurol Neurosci Rep 25:16. 10.1007/s11910-024-01400-8 [DOI] [PubMed] [Google Scholar]
  • 13.Rafehi H, Read J, Szmulewicz DJ et al (2023) An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA27B/ATX-FGF14. Am J Hum Genet 110:105–119. 10.1016/j.ajhg.2022.11.015 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Satolli S, Rossi S, Vegezzi E et al (2024) Spinocerebellar ataxia 27B: a frequent and slowly progressive autosomal-dominant cerebellar ataxia—experience from an Italian cohort. J Neurol 271:5478–5488. 10.1007/s00415-024-12506-x [DOI] [PubMed] [Google Scholar]
  • 15.Wilke C, Pellerin D, Mengel D et al (2023) GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response. Brain. 10.1093/brain/awad157 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Wirth T, Clément G, Delvallée C et al (2023) Natural history and phenotypic spectrum of GAA-FGF14 sporadic late-onset cerebellar ataxia (SCA27B). Mov Disord 38:1950–1956. 10.1002/mds.29560 [DOI] [PubMed] [Google Scholar]
  • 17.Ando M, Higuchi Y, Yuan J et al (2023) Clinical variability associated with intronic FGF14 GAA repeat expansion in Japan. Ann Clin Transl Neurol. 10.1002/acn3.51936 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Miyatake S, Doi H, Yaguchi H et al (2024) Complete nanopore repeat sequencing of SCA27B (GAA- FGF14 ataxia) in Japanese. J Neurol Neurosurg Psychiatry 95:1187–1195. 10.1136/jnnp-2024-333541 [DOI] [PubMed] [Google Scholar]
  • 19.Mizushima K, Shibata Y, Shirai S et al (2024) Prevalence of repeat expansions causing autosomal dominant spinocerebellar ataxias in Hokkaido, the northernmost island of Japan. J Hum Genet 69:27–31. 10.1038/s10038-023-01200-x [DOI] [PubMed] [Google Scholar]
  • 20.Ouyang R, Wan L, Pellerin D et al (2024) The genetic landscape and phenotypic spectrum of GAA-FGF14 ataxia in China: a large cohort study. EBioMedicine 102:105077. 10.1016/j.ebiom.2024.105077 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Zheng Z-H, Cao C-Y, Cheng B et al (2024) Characteristics of tandem repeat inheritance and sympathetic nerve involvement in GAA-FGF14 ataxia. J Hum Genet 69:433–440. 10.1038/s10038-024-01262-5 [DOI] [PubMed] [Google Scholar]
  • 22.Pellerin D, Seemann J, Traschütz A et al (2024) Reduced age-dependent penetrance of a large fgf14 gaa repeat expansion in a 74-year-old woman from a German family with sca27b. Mov Disord 39:1892–1894. 10.1002/mds.29915 [DOI] [PubMed] [Google Scholar]
  • 23.Rettenmaier LA (2025) Spinocerebellar ataxia type 27B can be suspected based on clinical phenotype: the Massachusetts General Hospital ataxia center experience. Cerebellum. 10.1007/s12311-025-01882-3 [DOI] [PubMed] [Google Scholar]
  • 24.Mohren L, Erdlenbruch F, Leitão E et al (2024) Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions. Nat Commun 15:7665. 10.1038/s41467-024-52148-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Foucard C, Belley M, Sangare A et al (2024) Paroxysmal ataxia. Neurol Genet 10:e200118. 10.1212/NXG.0000000000200118 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Seemann J, Traschütz A, Ilg W, Synofzik M (2023) 4-aminopyridine improves real-life gait performance in SCA27B on a single-subject level: a prospective n-of-1 treatment experience. J Neurol 270:5629–5634. 10.1007/s00415-023-11868-y [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Pellerin D, Danzi MC, Renaud M et al (2024) Spinocerebellar ataxia 27B: a novel, frequent and potentially treatable ataxia. Clin Transl Med 14:e1504. 10.1002/ctm2.1504 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Beijer D, Mengel D, Önder D et al (2025) The genetic landscape of sporadic adult-onset degenerative ataxia: a multi-modal genetic study of 377 consecutive patients from the longitudinal multi-centre SPORTAX cohort. EBioMedicine 115:105715. 10.1016/j.ebiom.2025.105715 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Pellerin D, Heindl F, Wilke C et al (2024) GAA-FGF14 disease: defining its frequency, molecular basis, and 4-aminopyridine response in a large downbeat nystagmus cohort. EBioMedicine. 10.1016/j.ebiom.2024.105076 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Pellerin D, Del Gobbo GF, Couse M et al (2024) A common flanking variant is associated with enhanced stability of the FGF14-SCA27B repeat locus. Nat Genet 56:1366–1370. 10.1038/s41588-024-01808-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Pellerin D, Méreaux J-L, Boluda S, et al (2024) Somatic instability of the FGF14-SCA27B GAA•TTC repeat 2 reveals a marked expansion bias in the cerebellum
  • 32.Wenning GK, Stankovic I, Vignatelli L et al (2022) The movement disorder society criteria for the diagnosis of multiple system atrophy. Mov Disord 37:1131–1148. 10.1002/mds.29005 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Bonnet C, Pellerin D, Roth V et al (2023) Optimized testing strategy for the diagnosis of GAA-FGF14 ataxia/spinocerebellar ataxia 27B. Sci Rep 13:9737. 10.1038/s41598-023-36654-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Schmitz-Hübsch T, du Montcel ST, Baliko L et al (2006) Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 66:1717–1720. 10.1212/01.wnl.0000219042.60538.92 [DOI] [PubMed] [Google Scholar]
  • 35.Anheim M, Monga B, Fleury M et al (2009) Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients. Brain 132:2688–2698. 10.1093/brain/awp211 [DOI] [PubMed] [Google Scholar]
  • 36.Genís D, Alemany B, Pellerin D et al (2025) Late-onset vestibulocerebellar ataxia: clinical and genetic studies in a long follow-up series of 50 patients. J Neurol. 10.1007/s00415-025-12964-x [DOI] [PubMed] [Google Scholar]
  • 37.Pellerin D, Iruzubieta P, Tekgül Ş et al (2023) Non-GAA repeat expansions in FGF14 are likely not pathogenic—reply to: “shaking up ataxia: FGF14 and RFC1 repeat expansions in affected and unaffected members of a Chilean fam. Mov Disord 38:1575–1577. 10.1002/mds.29552 [DOI] [PubMed] [Google Scholar]
  • 38.Hocquel A, Pellerin D, Méreaux JL et al (2025) Late-onset cerebellar ataxia in three European patients with repeat expansions in RFC1 and FGF14: a case series. J Neurol. 10.1007/s00415-025-13234-6 [DOI] [PubMed] [Google Scholar]
  • 39.Laß J, Thomsen M, Borsche M et al (2025) FGF14 repeat length and mosaic interruptions: modifiers of spinocerebellar ataxia 27B? Brain J Neurol. 10.1093/brain/awaf183 [Google Scholar]
  • 40.Morales F, Vásquez M, Cuenca P et al (2015) Parental age effects, but no evidence for an intrauterine effect in the transmission of myotonic dystrophy type 1. Eur J Hum Genet 23:646–653. 10.1038/ejhg.2014.138 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Braida C, Stefanatos RKA, Adam B et al (2010) Variant CCG and GGC repeats within the CTG expansion dramatically modify mutational dynamics and likely contribute toward unusual symptoms in some myotonic dystrophy type 1 patients. Hum Mol Genet 19:1399–1412. 10.1093/hmg/ddq015 [DOI] [PubMed] [Google Scholar]
  • 42.Laezza F, Lampert A, Kozel MA et al (2009) FGF14 n-terminal splice variants differentially modulate Nav1.2 and Nav1.6-encoded sodium channels. Mol Cell Neurosci 42:90–101. 10.1016/j.mcn.2009.05.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Wang Q, Bardgett ME, Wong M et al (2002) Ataxia and paroxysmal dyskinesia in mice lacking axonally transported FGF14. Neuron 35:25–38. 10.1016/S0896-6273(02)00744-4 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary file1 (TIF 94 KB) (94.3KB, tif)
Supplementary file2 (TIF 121 KB) (120.8KB, tif)
Supplementary file3 (TIF 214 KB) (213.6KB, tif)
Supplementary file4 (TIF 67 KB) (67.3KB, tif)
Supplementary file5 (TIF 73 KB) (73KB, tif)
Supplementary file6 (TIF 119 KB) (119.3KB, tif)
Supplementary file7 (TIF 106 KB) (105.6KB, tif)
Supplementary file8 (XLSX 11 KB) (10.7KB, xlsx)
Supplementary file9 (XLSX 10 KB) (10.2KB, xlsx)

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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