Identifying extracerebellar characteristics in a large cohort of 319 Chinese patients with spinocerebellar ataxia type 3

To the Editor: Spinocerebellar ataxia type 3 (SCA3) is the predominant subtype, representing 48–73% of all SCAs in the Chinese population.^[1] It primarily manifests as progressive ataxia, characterized by unsteady gait, dysarthria, and limb clumsiness, due to cerebellar and interconnected gray matter damage. Notably, extracerebellar features such as extrapyramidal and oculomotor abnormalities, and spasticity, often remain underrecognized. This complexity can lead to misdiagnosis, underscoring the necessity for a more comprehensive understanding of both cerebellar and extracerebellar symptoms.

Extracerebellar manifestations in SCA3 are significantly associated with prognosis, especially in the absence of disease-modifying treatments. The Inventory of Non-Ataxia Signs (INAS) offers a standardized method for assessing the presence and severity of extracerebellar signs and symptoms.^[2] Despite the lack of effective gene therapy, managing some extracerebellar features can markedly improve the quality of life for SCA3 patients, emphasizing the importance of these symptoms’ recognition by clinicians.

In this study, we characterized the extracerebellar features and their determinants in a large cohort of 319 individuals from 284 distinct SCA3 families, aiming to enhance the understanding of these manifestations and assist in customizing treatment strategies. The Ethics Committees of the Second Affiliated Hospital of Zhejiang University approved the trial (No. 2015-048) and all participants provided written informed consent. We conducted a prospective analysis on SCA3 individuals recruited from the Second Affiliated Hospital of Zhejiang University between March 2015 and September 2023. Peripheral blood samples were collected for ATXN3 CAG repeat number verification.

Demographic data, including gender, age, disease duration, and disease stage, were meticulously gathered. To evaluate the severity of the disease, this study utilized clinical scales such as the Scale for the Assessment and Rating of Ataxia (SARA), the International Cooperative Ataxia Rating Scale (ICARS), and INAS. The INAS comprises 30 items, each corresponding to one of the following 16 symptoms or signs: areflexia, hyperreflexia, extensor plantar response, spasticity, paresis, muscle atrophy, fasciculations, myoclonus, rigidity, chorea, dystonia, resting tremor, sensory symptoms, brainstem oculomotor signs, urinary dysfunction, and cognitive impairment. Brainstem oculomotor signs include ophthalmoparesis on horizontal gaze, ophthalmoparesis on vertical gaze, and saccadic slowing. Each item was evaluated for its presence or absence during analysis. The INAS count ranges from 0, indicating no extracerebellar involvement, to 16, representing the most severe extracerebellar manifestations. The disease stage of SCA3 patients is categorized into three stages: the first stage, characterized by gait difficulties without the need for assistance; the second stage, where gait difficulties necessitate assistance but not the use of a wheelchair; and the third stage, requiring the use of a wheelchair or confinement to bed.

All continuous variables were represented as mean ± standard deviation, while categorical variables were expressed in terms of numbers or percentages. For continuous variables that followed a normal distribution, comparisons were made using the Student’s t-test, whereas the chi-squared test was employed for categorical variables. The associations between the INAS score and various covariates were evaluated using the Spearman’s correlation test. Furthermore, logistic regression analysis was applied to examine the relationships among ATXN3 CAG repeat numbers, age at visit, age at onset (AAO), disease duration, clinical stage, SARA, ICARS, and each extracerebellar symptom. To assess differences in INAS scores between follow-up patients and baseline measurements, the Mann–Whitney U test was utilized. A P-value of less than 0.05 was considered to indicate statistical significance. All statistical analyses were conducted using SPSS version 22.0 (IBM, Armonk, NY, USA).

The study cohort included 319 individuals diagnosed with SCA3, comprising 148 males and 171 females. This group included 295 patients with manifesting conditions alongside 24 pre-symptomatic carriers. The onset of symptoms AAO presented a mean age of 39.1 ± 12.2 years, spanning a range from 5–71 years old. The duration of the disease across participants averaged 6.1 ± 4.1 years, with a spectrum ranging from those newly diagnosed to those with a 28-year history of SCA3. The INAS score, used to quantify the presence and severity of extracerebellar symptoms, yielded a mean value of 3.13 ± 1.98, with observed individual scores varying between 0–11 [Supplementary Table 1, http://links.lww.com/CM9/C80].

Hyperreflexia emerged as the most prevalent extracerebellar feature within the study’s SCA3 population, followed in frequency by extensor plantar response, rigidity, areflexia, brainstem oculomotor signs, and spasticity. Notably, less common were myoclonus, resting tremor, and chorea/dyskinesia. A significant finding was that 18.0% (53/295) of patients experienced urinary dysfunction, while cognitive impairment was present in 14.9% (44/295), and sensory symptoms were noted in 10.2% (30/295) of the cohort. Analysis of pre-symptomatic individuals revealed that 41.7% (10/24) exhibited hyperreflexia, and 16.7% (4/24) demonstrated extensor plantar responses, highlighting these as the most frequent early clinical signs [Supplementary Figure 1, http://links.lww.com/CM9/C80].

Through Spearman’s correlation analysis, positive correlations were found between INAS scores and SARA and ICARS scores (r_s = 0.446 and 0.448, respectively; all P <0.001), with a negative correlation observed with AAO (r_s = −0.214, P <0.001). Higher INAS scores also correlated with longer disease duration and more expanded CAG repeats (r_s = 0.304 and 0.225, respectively; all P <0.0001), as shown in Supplementary Figure 1, http://links.lww.com/CM9/C80. The logistic regression indicated that increased CAG repeats were significantly related to the extensor plantar response (hazard ratio = 1.092, 95% confidence interval [CI] [1.013–1.156], P = 0.003) and dystonia (hazard ratio = 1.115, 95% CI [1.012–1.229], P = 0.027). Early AAO and higher SARA scores were associated with greater spasticity (hazard ratio = 0.959, 95% CI [0.937–0.981], P = 0.001 and hazard ratio = 1.054, 95% CI [1.011–1.100], P = 0.014, respectively). Conversely, later AAO and higher ICARS scores were linked to sensory symptoms (hazard ratio = 1.040, 95% CI [1.006–1.075], P = 0.021 and hazard ratio = 1.039, 95% CI [1.015–1.065], P = 0.002, respectively). Disease duration was a predictor for urinary dysfunction (hazard ratio = 1.122, 95% CI [1.049–1.201], P = 0.001), and advanced disease stages were predictive of dystonia (hazard ratio = 2.537, 95% CI [1.602–4.018], P<0.001). Older age at diagnosis was associated with cognitive impairment, along with higher SARA scores and a longer sequence of normal CAG repeats (hazard ratio = 1.052, 95% CI [1.021–1.084], P = 0.001; hazard ratio = 1.056, 95% CI [1.003–1.112], P = 0.038; hazard ratio = 1.046, 95% CI [1.011–1.083], P = 0.010, respectively) [Supplementary Table 2, http://links.lww.com/CM9/C80].

In our one-year follow-up of 49 patients, changes in INAS scores were evaluated using the Mann–Whitney U test. The analysis revealed an increase from baseline scores (2.73 ± 1.56) to one-year follow-up scores (3.94 ± 2.23), with a statistically significant rise (U = 831.000, Z = −2.675, P = 0.007), suggesting a progression in extracerebellar symptoms. In contrast, no significant change was detected in the Activities of Daily Living (ADL) scores over the same period (U = 1053.500, Z = −1.109, P = 0.267). SCA3 is recognized as the most common form of spinocerebellar ataxia worldwide, and this prevalence is mirrored in China. The disease’s onset is difficult to pinpoint, owing to its gradual development and the early presence of extracerebellar symptoms such as atypical tendon reflexes, various pathological signs, urinary issues, and cognitive impairments. This subtleness often results in misdiagnosis. Evaluating these extracerebellar features over time is crucial for grasping the disease’s variability and guiding therapeutic strategies.

In this investigation, we scrutinized the extracerebellar features and their determinants among a substantial cohort of 319 Chinese individuals with SCA3. When compared to a longitudinal study of 172 SCA3 patients from RISCA and EUROSCA cohorts, our cohort had similar INAS scores to them.^[3] Predominantly, hyperreflexia surfaced as the most frequent extracerebellar feature within our cohort, succeeded by extensor plantar response, rigidity, areflexia, brainstem oculomotor signs, and spasticity. This contrasts with the findings of Schmitz-Hübsch et al^[4], who identified brainstem oculomotor signs, sensory symptoms, areflexia, urinary dysfunction, and spasticity as the most common symptoms. This discrepancy in the extracerebellar feature presentation between the cohorts suggests a potential influence of genetic background on these clinical manifestations. Less prevalent symptoms included myoclonus, resting tremor, and chorea/dyskinesia. Notably, the prevalence of common symptoms was consistent in the 24 pre-symptomatic individuals from our study group.

An inverse correlation was observed between INAS scores and AAO, suggesting an association of earlier onset with an increased prevalence of the extracerebellar symptoms. The result is similar to a previous study.^[5] Conversely, disease duration, the number of expanded CAG repeats, and higher SARA and ICARS scores, as well as advanced disease stages, were positively correlated with INAS scores. Specifically, an early AAO was predictive of increased spasticity, whereas urinary dysfunction manifested more frequently at later stages of the disease. Patients with early onset disease exhibited fasciculations, myoclonus, and brainstem oculomotor signs more commonly, whereas sensory symptoms were typically noted in patients with late-onset SCA3. Additionally, a greater number of expanded CAG repeats and more severe disease stages were frequently associated with dystonia, while elevated ICARS scores correlated with brainstem oculomotor signs. Although the pathophysiological mechanisms underpinning dystonia remain incompletely elucidated, it is hypothesized to involve anomalies in basal ganglia and cerebellar outputs. These findings are critical for tailoring clinical management strategies for SCA3 patients.

To evaluate extracerebellar feature progression in SCA3, we analyzed INAS scores from 49 patients at baseline and after one year. This analysis showed an increase in scores over time, indicating worsening extracerebellar symptoms. However, increases in INAS scores do not consistently align with disease duration. Certain symptoms, such as hyperreflexia and nystagmus, may diminish due to the involvement of the peripheral nervous system and the saccade system, respectively.^[2] Additionally, INAS scores can change following symptomatic treatment, underscoring the importance of extended follow-up for precise disease monitoring. Our study provides insights into the progression of extracerebellar features in SCA3. Current treatments mainly aim to improve quality of life, as options for disease modification are limited. Cerebellar ataxia is the primary symptom and disability source in SCA3 patients, but the extracerebellar symptoms are closely tied to prognosis. The INAS scale, critical for assessing these symptoms, facilitates the timely identification and management of the extracerebellar features, improving patient quality of life.

Our findings provide valuable insights into the extracerebellar manifestations of SCA3, emphasizing the importance of a comprehensive clinical assessment to improve disease management and patient quality of life. The study also highlights the potential of INAS scores as biomarkers for SCA3 progression. Nevertheless, the limitations, including the short follow-up period and the small number of pre-symptomatic patients, warrant further investigation to enhance early intervention and treatment strategies. This comprehensive analysis of Chinese SCA3 patient cohort to date not only deepens our understanding of the disease’s clinical diversity but also aids in informing personalized treatment approaches.

Acknowledgments

We gratefully acknowledge all participants for their help and willingness to participate in this study.

Funding

This work was supported by the National Natural Science Foundation of China to Zhiying Wu (Nos. 82071260, 82230062).

Conflicts of interest

None.