Intronic GAA repeat expansion in FGF14 (GAA-FGF14) has been associated with SCA27B, a late-onset, slowly progressive autosomal dominant disease [1, 3]. Typical clinical manifestations of GAA-FGF14 ataxia are episodic vertigo and ataxia, while imaging and neuropathological findings show cerebellar vermis atrophy [1, 2]. In this study, we identified two unrelated individuals (0.3%) with GAA-FGF14 ataxia through a screen of 664 unrelated individuals with undiagnosed LOCA. GAA-FGF14 repeat expansion was also present in 16 affected relatives of the two probands. Our analyses suggested that intergenerational variation in GAA repeat number could be related to the gender of parent transmitting the pathogenic allele. Brain MRI showed slight to moderate cerebellar atrophy. Clinical assessments and SSR recordings in the current study indicated that even pre-symptomatic GAA-FGF14 patients could exhibit sympathetic nerve involvement, although the involvement was not sufficiently severe to induce clinical symptoms.

The morbidity rates of repeat expansion disorders have been reported to vary among geographic regions. For instance, GGC repeat expansion in NOTCH2NLC, which causes neuronal intranuclear inclusion disease, is rare in European cohorts [23, 24]. Similarly, GAA repeat expansion in FXN is rarely observed among sub-Saharan Africans, Amerindians, and people from China, Japan, and Southeast Asia [25]. Other studies suggest that high variability in the morbidity rates of repeat expansion disorders is associated with founder effects [26]. Moreover, expanded alleles can be linked to a single or predominant haplotype [25, 26]. Previous studies had shown that GAA-FGF14 ataxia may not be as common in the Japanese ataxia cohort (1.1%) [10]. In this study, GAA-FGF14 ataxia comprised only 0.3% (2/664) of our Chinese undiagnosed LOCA cohort, which was substantially lower than the French Canadian ataxia cohort (61%), European ataxia cohorts (5.4–51%), Indian ataxia cohort (10%), Brazilian ataxia cohorts (9%) and Australian ataxia cohorts (9.5%) [1, 3,4,5,6,7]. As we were preparing this report, we noticed that another research group found the low frequency (1.3%) of GAA-FGF14 ataxia in Chinese LOCA cohort [9]. This striking difference further illustrates the regional variability of GAA-FGF14 ataxia incidence. However, the high proportion (619/664, 93.2%) of sporadic patients in our cohort might have contributed to the observed low frequency of GAA‐FGF14 ataxia in our study. The sporadic patients with nonhereditary ataxia, such as immune‐associated cerebellar ataxia, might have been included in our cohort. On the other hand, the higher proportion (2/38, 5.3%) of GAA‐FGF14 ataxia in the LOCA cohort with an autosomal dominant family history indicates that the repeat expansion analysis of FGF14 in Chinese LOCA patients is needed, especially when the proband has an autosomal dominant family history. As with other repeat expansion disorders, future studies in larger cohorts are needed to more rigorously compare GAA-FGF14 frequency between regions.

Short tandem repeats show relatively low stability between generations. For example, the number of GAA repeats in FXN tended to contract in paternal transmissions, but might expand or contract in maternal transmissions [27]. In our cohort, parental gender also appeared to affect GAA repeat number in subsequent generations. In particular, the number of GAA repeats in FGF14 typically expanded in maternal transmissions and contracted in paternal transmissions, which was consistent with observations reported by Pellerin and colleagues [1]. Moreover, the contractions of repeat number in FXN were discovered in the male germline by Pianese and co-workers [27]. Further study in larger cohorts will potentially help to clarify the patterns of variation in GAA-FGF14 repeat number in the male germline.

Five individuals who suffer from GAA-FGF14 ataxia in our families have undergone brain MRI which indicated slight to moderate cerebellar atrophy. None of the patients exhibits brainstem atrophy. In previous studies, the brain MRI showed that GAA-FGF14 patients had mild to moderate cerebellar atrophy [1, 2]. Our MRI results further support these findings. However, slight cerebellar atrophy was observed in two of our patients, despite having a SARA score ≥ 3. This indicates that some GAA-FGF14 patients have developed symptoms of ataxia without apparent cerebellar atrophy. It is important to note that the repeat expansion analysis of FGF14 is needed for patients who present symptoms of ataxia without apparent cerebellar atrophy on brain MRI.

Previous studies have described urinary urgency (28%) and erectile dysfunction (13%) as symptoms of autonomic dysfunction in GAA-FGF14 patients [2]. In our research, although two patients in the symptomatic stage suffered from frequent micturition, urgent urination, and uracratia, these symptoms could be related to chronic cystitis or pelvic floor dysfunction. It is worth noting that secondary factors, such as age and chronic disease, can lead to false-positive results of autonomic dysfunction in late-onset diseases. Moreover, the low frequency of occurrence of these symptoms suggests that sympathetic nerve involvement might not reach a severity level high enough to induce clinical symptoms in our GAA-FGF14 cohort. However, it is also possible that the relatively low rates of these symptoms may be an effect of the limited sample size. Thus, as with other unanswered questions in this rare disorder, systematic and quantitative evaluation of sympathetic nerve involvement in GAA-FGF14 ataxia requires study in a larger cohort.

The abnormal SSR responses can be considered evidence of sweating dysfunction [28]. The 2nd to 9th thoracic segments regulates the skin of the upper limbs and the 10th thoracic to 3rd lumbar segments regulates the skin of the lower extremities [28]. SSR alterations have been previously described in several spinocerebellar ataxia (SCA) subtypes, including spinocerebellar ataxia 2 (SCA2), spinocerebellar ataxia 3 (SCA3), and spinocerebellar ataxia 49 (SCA49) [29,30,31,32]. In our study, quantitative evaluation of sympathetic nerve involvement by SSR recordings revealed that SSR amplitude was lower in GAA-FGF14 patients in pre-symptomatic stage compared to healthy controls, and further decreased in the symptomatic stage. Additionally, SSR amplitude recording in the upper limbs exhibited a negative correlation with disease severity, whereas no significant correlation was observed for lower limb SSR amplitude. These data indicate that the sympathetic nerves arise from 2nd to 9th thoracic segments are preferentially involved in GAA-FGF14 ataxia. Our findings suggest that reduced amplitude of SSR could potentially serve as a clinical indicator of GAA-FGF14 ataxia. However, further studies, including additional clinical assessments such as heart rate variability [33], are needed to comprehensively evaluate sympathetic nerve involvement in GAA-FGF14 ataxia.

In conclusion, the current study identified two families with GAA-FGF14 ataxia, illustrating the low incidence of GAA-FGF14 ataxia among Chinese LOCA cases. Repeat expansion analysis of FGF14 is recommended for patients presenting with LOCA, especially when there is a history of autosomal dominant inheritance in the family. The gender of parents transmitting pathogenic GAA-FGF14 ataxia alleles also appeared to be related to variation in repeat number between generations. Reduced SSR amplitude also emerged as a salient feature in GAA-FGF14 patients warranting further exploration as a potential clinical indicator for diagnosis of GAA-FGF14 ataxia. Our findings can help guide future studies of the molecular mechanisms responsible for tandem repeat expansion and facilitate improved clinical diagnosis of GAA-FGF14 ataxia.