Heterogeneous nonataxic phenotypes of spinocerebellar ataxia in a Taiwanese population

Abstract Background Spinocerebellar ataxia (SCA) presents with variable clinical presentations in addition to ataxia. The aim of this study was to reappraise the diverse nonataxic clinical characteristics of the five most common SCA subtypes in the Asian population. Methods The clinical presentations of 90 patients with genetically confirmed SCA1, SCA2, SCA3, SCA6, or SCA17 were assessed retrospectively between November 2008 and September 2018 at a tertiary referral center in Taiwan. Results Parkinsonism was the most common nonataxic phenotype (21.1%), with a greater prevalence than Caucasian and other Asian SCA carriers. Patients with parkinsonism feature had fewer CAG repeats in SCA2 (31.0 ± 4.5 vs. 36.9 ± 6.0, p = .03) and SCA3 (65.6 ± 7.9 vs. 70.0 ± 4.2, p = .02) compared to those with pure ataxia presentation. The average age of symptom onset was significantly higher in the parkinsonism group of SCA2 (51.5 ± 8.9 vs. 35.3 ± 12.6 years, p = .007) than those with pure ataxia. Focal or segmental dystonia was identified in 4.4% of SCA patients (n = 2 each SCA2 and SCA3). Nonmotor symptoms, including impaired cognition (6.1% of SCA2 and 8.3% of SCA3 patients) and depression (9.1% of SCA2 and 8.3% of SCA3 patients), were also common nonataxic features in our SCA patients. Conclusions Parkinsonism, dystonia, and cognitive‐psychiatric symptoms are common features in patients with SCA mutations in our population. Our study identifies a different clinical spectrum of SCA1, SCA2, SCA3, SCA6, and SCA17 compared to Caucasians.

These nonataxic clinical presentations have also been reported to predict clinical progression and prognosis (Kuo et al., 2017;Monte et al., 2017).
Although the number of pathological CAG repeats is the major determinant of phenotypic variation, the comorbid nonataxic phenotypes vary among diverse ethnic groups (Storey, 2016). For example, studies have shown that Asian patients with SCA2 may initially present as idiopathic Parkinson's disease (PD), but rarely in Western countries. In addition, SCA10 is frequently associated with epilepsy in Mexicans but manifests as pure cerebellar ataxia in Brazilians (Teive et al., 2011). Although these heterogeneous clinical manifestations are mainly attributed to the length of nucleotide repeats and presence of interrupted expansion affecting mRNA transcription and translation (McFarland et al., 2014;Rossi, Perez-Lloret, Doldan, et al., 2014), other undefined genetic modifiers may affect the phenotype of SCA. Few studies have examined the full nonataxic clinical spectrum in patients with SCA, especially in Asians (Lee et al., 2011). Therefore, we aimed to reappraise the diverse nonataxic clinical characteristics of the five most common SCA subtypes in the East Asian population and to compare them with other ethnic groups.

| Patients
We retrospectively identified patients who had genetically confirmed mutations in SCA1, SCA2, SCA3, SCA6, or SCA17 at the Department of Medical Genetics in National Taiwan University Hospital between November 2008 and September 2018. Demographic data, clinical manifestations, clinical course, and the results of brain imaging studies and neurophysiological tests were obtained by reviewing the medical records of individual patients. Disease duration was defined as the interval between onset of initial neurological symptoms and the date that the genetic study was performed. Disease severity was measured using the modified Rankin Scale (mRS) when the genetic study was performed and at the last follow-up in the hospital. The cognitive function and psychiatric status, including anxiety and depression, were retrieved from the medical records.
All patients who were recorded to have cognitive decline received cognitive evaluation by the Mini-Mental State Examination (MMSE) (Folstein, Folstein, & McHugh, 1975) with an MMSE score ≤25 being the cutoff for identifying a significant cognitive impairment, as well as impairments of instrumental activities of daily living (e.g., inability to manage finances and cope in social situations). Depression was evaluated by Beck Depression Inventory (Beck, Steer, Ball, & Ranieri, 1996), and anxiety was evaluated by Beck Anxiety Inventory (Beck, Epstein, Brown, & Steer, 1988 Demographic data, clinical presentations, and
The cutoff value for the pathologic CAG repeat number of SCA17 has not been clearly elucidated. Early reports proposed that SCA17 with a repeat number of 47 or more was suggested (Kim et al., 2009). However, the repeat number was then gradually lowered, and some later studies even suggested 41 repeats could be pathologic (Nanda, Jackson, Schwankhaus, & Metzer, 2007). In this study, the cutoff number for the pathological repeats of SCA17 is 49 and hence all the five patients presenting with SCA17 have repeat number in the intermediate range.
Detail clinical information was available from 90 patients out of 187 patients with genetic confirmation, and we therefore analyzed the nonataxic clinical presentations in these 90 patients. We did not enroll asymptomatic carriers in this study.
Among the 90 symptomatic carriers (47.8% males), the average age of symptom onset was 41.6 ± 14.9 years and age of examination 45.0 ± 14.4 years. Disease duration was estimated to be 8.4 ± 11.8 years. The mean initial mRS was 1.7 ± 1.2. After an average follow-up of 32.3 ± 36.4 months, the mean mRS was TA B L E 1 Demographics, clinical characteristics, and number of CAG repeats for patients with SCA in the current study    The patient had post-traumatic epilepsy.
2.4 ± 1.5. Detailed demographic data, clinical presentations, genetic results, and functional status among different subtypes are given in Table 1.

| Clinical presentation
Ataxia was the most common presentation in all patients with SCA (Table 1). Among symptomatic carriers, 83.3% initially manifested with ataxia; only three patients did not develop ataxia during the follow-up period. Parkinsonism was the most common nonataxic movement disorder (21.1%; SCA1, n = 1; SCA2, n = 6; SCA3, n = 10; SCA17, n = 2), followed by focal or segmental dystonia (4.4%, n = 2 for both SCA2 and SCA3) manifested as blepharospasm, cervical torsion, striatal hand, and striatal foot. Slow saccade was the most common eye abnormality (32.2%) in our study. Nystagmus occurred in 26.7% of patients and presented significantly more often in SCA3 patients. Ophthalmoplegia was observed in 4.4% of patients and only noted in patients with SCA3 (Table 1).
Among the 19 patients presenting with parkinsonism, it was the initial neurological presentation in 10% of our studied patients (n = 9). Ataxia developed 14.9 ± 24.6 months later in seven patients.
Most of the patients with parkinsonism were predominantly aki- 2.6 ± 1.1, p = .04, Table 2). In the subgroup analysis based on individual type of SCA, patients with parkinsonism were associated with a fewer number of CAG repeats in SCA2 (31.0 ± 4.5 vs. 36.9 ± 6.0, p = .03) and SCA3 (65.6 ± 7.9 vs. 70.0 ± 4.2, p = .02). The average age of symptom onset was significantly older in the parkinsonism group of SCA2 patients (51.5 ± 8.9 vs. 35.3 ± 12.6 years old, p = .007) but not SCA3. Demographic data, clinical presentation, and functional status did not vary significantly among patients with parkinsonism carrying different SCA mutations (Table S1).
The nonmotor symptoms observed in our patients included cognitive impairment, psychiatric symptoms, and seizure. Cognitive impairment was noted in seven patients (SCA2, n = 2; SCA3, n = 4; and SCA17, n = 1). Among the various SCA subtypes, cognitive dysfunction was more common and severe with SCA17 (50% vs. 6.1% and 8.3% for SCA2 and SCA3, respectively; Table 1). We found no remarkable cognitive decline in patients with SCA1 and SCA6.

TA B L E 2 Comparison of symptomatic SCA patients with and without parkinsonism
including impaired cognition and depression, were also common features in our SCA patients.
The prevalence was even greater than that reported in other Asian countries, such as Thailand and India (Boonkongchuen et al., 2014;Radhakrishnan et al., 2018). An intermediate number of CAG repeats were recognized as a risk factor for the clinical manifestation of parkinsonism in SCA2 and SCA3 (van Gaalen et al., 2011;Park et al., 2015;Subramony et al., 2002). One postmortem brain pathology study showed significant neuronal loss and depigmentation in the substantia nigra rather than neuronal loss in the cerebellum of patients with borderline repeat expansions in SCA2 and SCA3 (Park et al., 2015), which could partly explain the occurrence of the parkinsonism phenotype and good response of parkinsonism features to levodopa therapy in our study.
We also found that parkinsonism tended to manifest as akinetic-rigidity type rather than tremor-predominant type and one-tenth of  (van Gaalen et al., 2011;Park et al., 2015), it is recommended that Cognitive dysfunction, predominantly involving executive ability, visuospatial performance, and memory, has been reported in SCA patients as a result of impairment in subcortical structures and connections between the cerebellum and cerebral cortex (Coarelli et al., 2018;Fancellu et al., 2013). Among the various SCA subtypes, cognitive dysfunction is more common and severe in SCA17 than other subtypes of SCA. Compared to previous studies showing a high prevalence of dementia in SCA2 patients, affecting 24% of patients in a German population and 42% in a Chinese population, only 6.1% of SCA2 patients in our study had cognitive decline (Schols et al., 1997;Tang et al., 2000). In addition, the prevalence of impaired cognition was 8.3% among SCA3 patients in our study population. Our findings are in concordance with previous studies demonstrating that cognitive impairment is common in SCA17 but rare in SCA6 (Kawai, Suenaga, Watanabe, & Sobue, 2009 (Bruni et al., 2004;Rolfs et al., 2003). Neuronal intranuclear inclusion staining with anti-TATA boxbinding protein and antipolyglutamine was much more widely distributed throughout the brain gray matter in SCA17 than in other SCA subtypes (Rolfs et al., 2003). These neuropathological findings could partly explain the higher prevalence of cognitive-psychiatric symptoms in SCA17 than in other types of SCA.
In our study, the prevalence of depression in SCA2 (9.1%) and SCA3 (8.3%) was similar to the Indian population (Stezin et al., 2018 scores in all symptomatic patients as the main focus in this study is the nonataxic phenotypes. Future studies that combined both SARA scores and nonataxic phenotypes will be needed to know better about the possible different progression rates of ataxia and nonataxic features of SCA patients.
Our study provided nonataxic clinical characteristics of the five most common SCA subtypes in the East Asian population and may assist clinicians in identifying different subtypes of SCA patients.

ACK N OWLED G M ENTS
We thank all patients who participated in this study.

CO N FLI C T S O F I NTE R E S T S
None.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.