Skip to content


BMC Neurology

Open Access
Open Peer Review

This article has Open Peer Review reports available.

How does Open Peer Review work?

Clinical analysis of adult-onset spinocerebellar ataxias in Thailand

  • Pairoj Boonkongchuen1,
  • Sunsanee Pongpakdee2,
  • Panitha Jindahra1,
  • Chutima Papsing1,
  • Powpong Peerapatmongkol1,
  • Suppachok Wetchaphanphesat3,
  • Supachai Paiboonpol4,
  • Charungthai Dejthevaporn1,
  • Surat Tanprawate5,
  • Angkana Nudsasarn5,
  • Chanchai Jariengprasert6,
  • Dittapol Muntham7,
  • Atiporn Ingsathit7 and
  • Teeratorn Pulkes1Email author
Contributed equally
BMC Neurology201414:75

Received: 26 February 2014

Accepted: 2 April 2014

Published: 5 April 2014



Non-ataxic symptoms of spinocerebellar ataxias (SCAs) vary widely and often overlap with various types of SCAs. Duration and severity of the disease and genetic background may play a role in such phenotypic diversity. We conducted the study in order to study clinical characteristics of common SCAs in Thailand and the factors that may influence their phenotypes.


131 (49.43%) out of 265 Thai ataxia families with cerebellar degeneration had positive tests for SCA1, SCA2, Machado-Joseph disease (MJD) or SCA6. The study evaluated 83 available families including SCA1 (21 patients), SCA2 (15), MJD (39) and SCA6 (8). Comparisons of frequency of each non-ataxic sign among different SCA subtypes were analysed. Multivariate logistic regression analyses were undertaken to analyze parameters in association with disease severity and size of CAG repeat.


Mean ages at onset were not different among patients with different SCAs (40.31 ± 11.33 years, mean ± SD). Surprisingly, SCA6 patients often had age at onset and phenotypes indistinguishable from SCA1, SCA2 and MJD. Frequencies of ophthalmoparesis, nystagmus, hyperreflexia and areflexia were significantly different among the common SCAs, whilst frequency of slow saccade was not. In contrast to Caucasian patients, parkinsonism, dystonia, dementia, and facial fasciculation were uncommon in Thai patients. Multivariate logistic regression analysis demonstrated that ophthalmoparesis (p < 0.001) and sensory impairment (p = 0.025) were associated with the severity of the disease.


We described clinical characteristics of the 4 most common SCAs in Thailand accounting for almost 90% of familial spinocerebellar ataxias. There were some different observations compared to Caucasian patients including earlier age at onset of SCA6 and the paucity of extrapyramidal features, cognitive impairment and facial fasciculation. Severity of the disease, size of the pathological CAG repeat allele, genetic background and somatic heterogeneity of pathological alleles may influence clinical expressions of these common SCAs.


Autosomal dominant cerebellar ataxiaSpinocerebellar ataxiaSCASaccadeOphthalmoplegia


Spinocerebellar ataxias (SCAs) are genetically heterogeneous neurodegenerative disorders associated with progressive ataxia or less commonly episodic ataxia. Adult-onset patients mainly inherit the condition by autosomal dominant transmission. Phenotypes often accompany various non-ataxic signs including saccadic abnormalities, ophthalmoplegia, extrapyramidal features, pyramidal signs, polyneuropathy, amyotrophy, fasciculation, dementia, and macular degeneration [1]. To date, the Human Genome Nomenclature Committee has assigned types of SCAs into SCA1 to SCA37 in association with 31 chromosomal loci and genes [15]. Machado-Joseph disease (MJD) or SCA3 is generally the most common form of SCA worldwide [68]. Other common types of SCAs in various ethnic groups include SCA1, SCA2, SCA6, SCA7 and dentatorubro-pallidoluysian atrophy (DRPLA). All these common SCAs are caused by expansions of polyglutamine-encoding CAG repeat [1].

Phenotypes of different SCAs often overlap and are indistinguishable resulting in a difficulty in making clinical diagnosis. However, some clinical clues and epidemiological data of common SCAs in each population may be helpful for setting up appropriate diagnostic genetic tests [9, 10]. For example, pyramidal signs are more common in SCA1 and SCA3 while peripheral neuropathy is more common in SCA2 [9, 11, 12]. Slow saccades may be more prevalent in SCA2 [13, 14]. Sizes of expanded repeat allele, age at onset, age, and disease duration have been described as factors that might influence clinical expression of the common SCAs [1517]. Although neuropathology of the polyglutamine-associated SCAs is generally widespread over the cerebellum, brainstem and cerebral hemisphere in the advance stage of the diseases [18], observations of some non-ataxic signs such as slow saccade in presymptomatic carriers or at the early symptomatic stage suggest that other neurons apart from cerebellar neurons may also be similarly vulnerable to the pathological process caused by the polyglutamine-associated SCAs [19, 20]. Slow saccade represents loss of excitatory burst neuronal function, whose neurons initiate the pulse sequence of saccadic eye movement [21]. Therefore degenerative process of those neurons in brainstem should take place at a very early stage of the disease in those patients [19, 22]. Although slow saccades in SCA2 patients may be influenced by the size of polyglutamine tract [17], this mechanism cannot solely explain the presence or absence of slow saccades in all SCA2 patients. Other genetic factors may also play a role in selective neuronal susceptibility and phenotypic expression of the polyglutamine-associated SCAs [23].

MJD is the most common SCA in the Thai population followed by SCA1, SCA2 and SCA6 [24]. Over the past 15 years, the study group has had experience of seeing over a hundred Thai SCA families. Interestingly, we have hardly observed some of the frequently described non-ataxic signs comprising facial fasciculation, parkinsonism, dystonia, and dementia in those patients. This finding implies that those signs might be less common compared to previous reports of other ethnic groups. Furthermore, slow saccade was commonly observed in all subtypes of the common SCAs. Therefore the study was conducted in order to analyze the clinical characteristics of the Thai patients with adult-onset SCAs and identify factors that may influence the clinical expression of SCAs. Since we have observed a clinical concordance in the patients from the same family, we thus recruited only the index patient from each family into the study.



We reviewed medical records of all patients with progressive cerebellar ataxia, who were tested for SCA1, SCA2, MJD, SCA6, SCA7 and DRPLA at the Division of Neurology, Department of Medicine, Ramathibodi Hospital. After undertaking intensive investigations, some of the patients were identified by other diagnoses including cerebellar variant of multiple system atrophy, neurogenic weakness, ataxia and retinitis pigmentosa (NARP) and autoimmune cerebellar disorders. The remaining patients were from 265 families. 131 families (49.43%) tested positive for SCA1 (38 families), SCA2 (22), MJD (61) and SCA6 (10). 75 of those families (57.25%) had family history of ataxia. The study identified SCA1, SCA2, MJD, or SCA6 mutations in almost 90% of the patients in the familial group (75 of 86 families), while only 31% of the sporadic cases (56 of 179 cases) were identified as one of these common SCAs (Table 1). We have not identified patients with SCA7 and DRPLA so far. Details of the frequencies of SCAs were listed in Table 1.
Table 1

Frequencies of the common spinocerebellar ataxias in Thai patients


Familial group (%) N = 86

Sporadic group (%) N = 179

Total (%) n = 265


19 (22.10)

19 (10.61)

38 (14.34)


10 (11.63)

12 (6.70)

22 (8.30)


40 (46.51)

21 (11.73)

61 (23.02)


6 (6.98)

4 (2.23)

10 (3.77)


75 (87.21)

56 (31.28)

131 (49.43)

Patients without mutation

11 (12.79)

123 (68.72)

134 (50.57)

Abbreviations as follows: SCA spinocerebellar ataxia, MJD Machado-Joseph disease.

The study subsequently enrolled 83 index patients with SCA1, SCA2, MJD and SCA6 from the database, who were available for clinical review and examination. All accessible family members were also evaluated. However, statistical analyses only used data of the index cases. The examination processes were undertaken at 4 participating hospitals during April 2010 to June 2013. All of the participants were evaluated by T.P. and P.B., or S.Po., or P.J. except for 2 families, who live in rural areas of Phayao province in the northern part of Thailand. They were examined by P.J. and S.T. Collected patient’s profiles and clinical data included sex, the family’s hometown, age at onset, disease duration, age at diagnosis, family pedigrees, cerebellar signs, fundoscopic examination, eye movement abnormalities, nystagmus, muscle tone, tendon reflexes, Babinski’s sign, parkinsonism, dystonia, chorea, dementia (Mini-mental state examination), fasciculation, sensory examination (vibration, joint position and pin prick sensations) and scale for the assessment and rating of ataxia (SARA). All patients provided both verbal and written informed consent. The research protocol was approved by the ethics committee or hospital ethical review board of every participating university and hospital.

Genetic analysis

DNA samples were extracted from peripheral leukocyte by phenol-chloroform method or using QIAGEN DNA purification kit (QIAGEN, CA, USA). Fluorescently-labelled PCR of the expanded repeat alleles of the ATXN1 (ataxin 1), ATXN2, ATXN3, CACNA1A (alpha 1A subunit, P/Q type voltage-dependent calcium channel: SCA6), ATXN7 and ATN1 (atrophin 1: DRPLA) genes were performed by using primer sets as previously described methods [9, 11, 2528]. The allele sizes were then determined by running the PCR products on Beckman CEQ8800 DNA Analysis System (Beckman Coulter, CA, USA). Sizes of CAG repeat of both normal and pathological alleles of each chromosome were calculated by comparing results with the size of a normal control sample, of which the sizes were prior defined by direct sequencing. In order to avoid a false negative result caused by a very large expanded allele failing to be amplified by using regular PCR [29]. all samples whose results showed patterns of homozygous wild-type alleles of ATXN1, ATXN2 and ATXN3, were subsequently re-analyzed by performing long-range PCR using LA Taq polymerase (TaKaRa, Chiba, Japan).

Statistical analysis

Results were expressed as means ± standard deviations. One-way analysis of variance (ANOVA) was used to compare means of each continuous variable among different SCAs. Categorical variables were compared by using chi squared test. Test results considered significant differences at the level of p-value < 0.05. Comparisons of clinical characteristics between groups of patients with SARA score <15 and ≥15 were determined by logistic regression analysis. The results were expressed as odd ratio (OR), 95% confidence intervals (CI) and p-values. After a number of univariate predictive factors had been determined, forward stepwise selection was carried out to determine the appropriate multivariate model. Factors selected for the multivariate model were those found significant in the univariate model. Results were considered statistically significant for p <0.10 of univariate and p <0.05 of multivariate analysis. Whether size of the pathological SCA3 repeat allele influences the clinical outcomes was tested by logistic regression analysis and then adjusted with other factors including age at onset, age, sex and duration of the disease. All analyses were performed using STATA version 12 (Stata Corp., College Station, TX, USA).


Patient characteristics

MJD is the most common type of adult-onset spinocerebellar ataxias in the study followed by SCA1, SCA2 and SCA6, respectively (Table 1). Eighty-three index patients were enrolled on the study including 39 MJD patients, 21 SCA1, 15 SCA2 and 8 SCA6 patients. Analyses of their family pedigrees identified at least 297 affected relatives. Overall patient characteristics are summarized in Table 2.
Table 2

Comparison of clinical profile and features of unrelated Thai patients with SCA1, SCA2, MJD and SCA6







Total numbers






Sex (M/F)






Age at onset (years)


 Mean age at onset













15 – 55

19 - 60

16 - 64

34 - 58


Duration (years)


 Mean duration













1 - 20

1 - 10

0.25 - 22

1 - 18


Positive family history (%)

16 (76.2)

13 (86.7)

32 (82.1)

7 (87.5)


CAG repeat size (repeats)















41 – 65

32 - 52

62 - 78

21 - 23


Clinical features (%)


 Slow saccade

12 (57.1)

7 (46.7)

21 (53.9)

2 (25)


 Horizontal nystagmus

5 (23.8)

4 (26.7)

34 (87.2)

6 (75)


 Vertical nystagmus

0 (0)

1 (6.7)

6 (15.4)

3 (37.5)



6 (28.6)

3 (20.0)

26 (66.7)

2 (25)


 Pale optic disc

1 (4.8)

0 (0)

2 (5.1)

1 (12.5)



19 (90.5)

5 (33.3)

26 (66.7)

7 (87.5)


 Babinski’s sign

11 (52.4)

5 (33.3)

17 (43.6)

5 (62.5)



0 (0)

5 (35.7)

9 (23.1)

0 (0)


 Sensory impairment

4 (19.0)

3 (20.0)

9 (23.1)

0 (0)



0 (0)

0 (0)

0 (0)

0 (0)



1 (4.8)

0 (0)

1 (2.6)

0 (0)



0 (0)

0 (0)

1 (2.6)

0 (0)



0 (0)

1 (6.7)

0 (0)

1 (12.5)


 Facial fasciculation

2 (9.5)

0 (0)

5 (12.8)

0 (0)




 Mean scale













4 - 30

9 - 20

8 - 35

3.5 - 27


*Continuous variables were analyzed by using ANOVA. Comparisons of frequencies of clinical profiles and features were analyzed by using Fisher’s exact test.

**P < 0.05 is considered as significant difference.

Abbreviations as follows: SCA spinocerebellar ataxia, MJD Machado-Joseph disease, SD standard deviation, SARA scale for the assessment and rating of ataxia.

Thailand is geographically divided into six regions comprising central, north, northeast, east, west and south. Most of the patients in the study lived in central, north, west and northeast of Thailand. Only four patients were referred from eastern (2) and southern (2) regions (Figure 1). In central, western and northern regions, we identified patients with SCA1, SCA2, MJD and SCA6. However, almost all families living in the northeastern region were SCA1 and MJD. Only one family was SCA2 and no SCA6 family was identified in the region.
Figure 1

Map of Thailand illustrates the distribution of the frequencies of the common SCAs.

General factors including gender, age at onset, duration of disease, positive family history and SARA scale were not different among the different types of SCAs (Table 2). Average age at onset was around late thirties to early forties in all groups. SCA6 did not correlate with later age at onset compared to the other SCAs (43.5±6.76, mean±SD). Furthermore, none of the studied SCA6 patients had age at onset after 60 years. Durations of the disease and SARA scales were similar in all groups.

Clinical features

Gait ataxia or unsteadiness was the presenting symptom in all cases. Arm incoordination and cerebellar dysarthria generally followed within a few to several years. Limb ataxia was sometimes asymmetrical; however difference of severity was frequently not in a large degree. Truncal ataxia was uncommon until the advance stage of the disease. In the early stage, neurological signs including dysmetric saccades, nystagmus and pyramidal signs particularly increased tendon reflexes and spastic tone in both legs could often be observed. We had the opportunity to examine several asymptomatic carriers of MJD at the age between 22 to 30 years. Some of them had brisk tendon reflexes and mild spasticity in both legs, although they did not have gait unsteadiness.

Frequencies of nystagmus, upward gaze paresis, hyperreflexia and areflexia were significantly different among different subtypes of SCAs (Table 1). Nystagmus was commonly gaze-evoked type. Horizontal nystagmus was more common than vertical nystagmus. It was relatively more common in MJD and SCA6 than the other types. Ophthalmoparesis was invariably upward direction and it was significantly more frequent in MJD than other SCAs. Almost all patients who exhibited upward gaze paresis, were nuclear type. Supranuclear gaze paresis was rare in the patients studied and it was observed in only a few patients in the early stage of the disease. Severe ophthalmoparesis in all directions was observed in only a few patients with advance stage of SCA1 and MJD.

Increased tone and tendon reflexes were generally more prominent in the lower extremities. It was common in all studied subtypes of SCAs except SCA2. It was noted that almost all patients with SCA1 (90%) developed pyramidal signs. One of the only two SCA1 patients, who did not have pyramidal signs, had severe generalized dystonia. Areflexia was often observed in only ankle reflexes and it was less often accompanied with absent knee reflexes or generalized areflexia. Absent ankle reflexes were also observed in the presence of brisk knee reflexes and Babinski’s sign. Areflexia was not apparent in both SCA1 and SCA6 in the study. Sensory symptoms were usually subtle and the impairment of vibration or pin prick sensations was observed in about one-fifth of the SCA1, SCA2 and MJD patients. Only two patients studied (SCA2 and MJD) had severe axonal sensorimotor polyneuropathy. They developed generalised areflexia, marked distal wasting, mild distal weakness and sensory loss in gloves and stockings pattern since the early stage of the disease.

Abnormal saccadic eye movements were demonstrated in all subtypes of the studied SCAs. Slow saccades were found in about half of the patients. With the exception of SCA6, it was observed in only a quarter of the patients. However, frequencies of slow saccades were not different among different SCAs (p = 0.454). Dysmetric saccades (both hypermetric and hypometric saccades) and impairment of vestibulo-ocular-reflex suppression were also identified in a large proportion of the examined patients of all SCA subtypes. However, we did not systematically record this data from the beginning of the study.

Facial fasciculation, dystonia, chorea and cognitive impairment were uncommon in the patients studied. Facial fasciculation was only observed in a few patients with SCA1 and MJD. Both periorbital and orolingual distribution was equally observed, and it was often asymmetry. Fasciculation was much rarer in the extremities. Dystonia was actually observed in only two families with SCA1 and MJD. The SCA1 patient had severe generalized dystonia and the MJD patient had unilateral foot dystonia prominently only while walking. None of the patients studied had signs of parkinsonism. Generalized chorea was present in two unrelated MJD patients including one index case and one affected family members (not included in the analysis). Both patients were in the advanced stage. One of the patients had been wheel-chair bound and the other had been confined to bed for over 3 years.

Disease severity and non-ataxic symptoms

Comparisons of demographic data and clinical features between patients with SARA ≥ 15 and <15 are shown in Table 3. Since age at onset and age are correlated, they theoretically may cause multicollinearity. Therefore, we applied two separate models of logistic regression analyzes by using age at onset or age as parameter. After performing multivariate analysis, ophthalmoparesis and sensory impairment were shown to be independently associated with disease severity by both models (Table 4). Age was also a factor associated with severity of the disease when age at onset was excluded from the analysis (model 2 in Table 4).
Table 3

Comparison of baseline factors between SARA ≥15 and SARA <15 groups


SARA ≥15 N = 49 (%)

SARA <15 N = 34 (%)





23 (46.9)

14 (41.2)


Age onset (years); mean (SD)

42.1 (11.1)

37.5 (11.3)


Age when exam (years); mean (SD)

50.5 (11.7)

39.5 (11.3)


Duration (years); mean (SD)

8.9 (5.1)

3.4 (2.2)


SCA Type


 SCA 1

13 (26.5)

8 (23.5)


 SCA 2

6 (12.2)

9 (26.5)


 SCA 3

26 (53.1)

13 (38.2)


 SCA 6

4 (8.2)

4 (11.8)


Family history

44 (89.8)

24 (70.6)


Slow saccades

29 (59.2)

14 (41.2)


Horizontal nystagmus

32 (65.3)

17 (50)


Vertical nystagmus

8 (16.3)

2 (5.9)


Upward gaze paresis

31 (63.3)

6 (17.6)



37 (75.5)

20 (58.8)



10 (20.4)

4 (11.8)


Babinski’s sign

26 (53.1)

12 (35.3)


Sensory impairment

14 (28.6)

2 (5.9)


Optic atrophy

4 (8.2)

0 (0)


Table 4

Univariate and multivariate logistic regression analyses of parameters associated with more severe ataxia group (SARA ≥ 15); (Tables show only significant parameters)

Univariate analysis


All 4 common SCAs

MJD, SCA1 and SCA2


Odd ratio (95% CI)


Odd ratio (95% CI)


Age at onset (years)

1.04 (0.99-1.08)


1.04 (1.01-1.09)


Age when assessment (years)

1.08 (1.04-1.13)


1.08 (1.04-1.14)


Positive family history

3.67 (1.12-11.97)


5.13 (1.43-18.37)



8.07 (2.80-23.10)


7.25 (2.45-21.41)


Sensory impairment

6.40 (1.35-30.37)


6.32 (1.32-30.31)


Babinski’s sign

not significant


2.67 (1.01-7.07)


Multivariate logistic regression analysis: model 1 Consider age at onset as parameter


All 4 common SCAs

MJD, SCA1 and SCA2


Odd ratio (95% CI)

p -value

Odd ratio (95% CI)

p -value


8.19 (2.74-24.44)


7.56 (2.44-23.42)


Sensory impairment

6.64 (1.27-34.71)


6.82 (1.29-36.01)


Model 2 Consider age as parameter


All 4 common SCAs

MJD, SCA1 and SCA2


Odd ratio (95% CI)

p -value

Odd ratio (95% CI)

cx -value

Age when assessed

1.07 (1.02-1.13)


1.08 (1.03-1.14)



6.18 (1.90-20.03)


5.62 (1.64-19.26)


Sensory impairment

9.28 (1.43-60.07)


9.41 (1.40-63.34)


Sizes of expanded SCA3 alleles and non-ataxic symptoms

Univariate logistic regression analysis revealed that size of the pathological SCA3 repeat allele >70 was associated with the presence of increased tendon reflexes (OR = 5.33, 95% CI = 1.17-25.21, p = 0.03). However, the association was excluded after adjustment with age, age at onset, sex and disease duration (OR = 2.38, 95% CI = 0.56-10.03, p = 0.24).


Overall, MJD was the most common SCA in Thailand similar to other East Asian countries except Korea, in which SCA2 appeared to be the most common SCA [30]. DRPLA is rare in Chinese and Thais, while it is relatively common in Japan, Singapore and Korea [3032]. Apart from MJD, SCA1 and SCA2 are also prevalent in most East Asian populations, in contrast to Japanese, in which SCA6 and SCA31 are the second common SCA, and frequencies of SCA1 and SCA2 are less common [31, 33]. We described clinical characteristics of the four most common SCAs in Thailand including MJD, SCA1, SCA2 and SCA6. This data showed that the main clinical features of Thai patients were similar to the previous reports of other ethnic groups to some extent [9, 13, 15, 16, 3437]. However, there were also noticeable differences in some aspects between Thai patients and patients of other ethnic groups including (1) frequent observation of slow saccades in all of the studied types of SCA; (2) the relatively less frequent neuropathy and more frequent pyramidal signs in SCA2; (3) the relatively earlier onset of SCA6 in Thais; and (4) the scarcity of extrapyramidal features and cognitive impairment. Nevertheless, phenotypes of the common SCAs are generally very heterogeneous and frequencies of associated non-ataxic symptoms among different populations are widely diverse. Therefore, the findings are not surprising. However, these data suggest that the clinical clues for differential diagnosis of the common types of SCAs such as age at onset, slow saccade and areflexia may be less useful in the Thai patients.

Slow saccade has been well-known as one of the major non-ataxic features of SCA2 [9, 17, 22, 38]. Reduced saccadic velocity can be apparent in presymptomatic carriers of SCA2 implying that oculomotor pontine nuclei likely to be susceptible to neurodegenerative process similar to cerebellar neurons [19]. Previous evidence also suggested that the occurrence of slow saccade might be associated with size of the pathological repeat alleles and its severity was subsequently progressive over time [17, 22]. Slow saccade was less often reported in association with SCA1, MJD and SCA6 [39], though our data showed similar frequencies of slow saccade among these SCAs. So the mechanism underlying the susceptibility of specific neurons other than cerebellar neurons to the neurodegenerative process caused by these polyglutamine diseases is likely to be complex and may involve other genetic factors apart from specific genes and the size of the pathological repeat alleles.

Not only is the frequency of peripheral neuropathy often more common in SCA2 than the other common subtypes, the SCA2 patients also develop polyneuropathy at an early stage of the disease [40]. A large European study revealed that the occurrence of peripheral neuropathy in SCA2 was not associated with disease duration. In contrast to MJD and SCA6, polyneuropathy might relate to disease duration, which tended to develop in the later stage [15]. These data implied that a susceptibility to neuropathy was greater associated with the trinucleotide repeat expansion in ATXN2 gene than the others. Although polyneuropathy was less frequent in the Thai SCA2 patients compared to other ethnic groups, and frequencies of polyneuropathy were not much different between SCA2 and MJD. The study also observed that evidence of peripheral neuropathy appeared to be occurrence in the early stage of SCA2 in contrast to a later stage in association with MJD similar to previous reports.

SCA6 has been generally known to be progressive ataxia with later onset compared to SCA1, SCA2 and MJD, in which age at onset may be after 60 years old [4143]. Some evidence suggested that age at onset of SCA6 might be inversely related to size of CAG repeats, with the larger size of the CAG repeats more likely to be associated with the early age at onset [42]. All of the patients studied had sizes of CAG repeats of 23 or lower, thus it is unlikely that this finding related to the size of CAG repeat. However, the study group is small. So we then further reviewed medical records of all of the ten SCA6 families in our clinics. Of the 18 patients from unrelated 10 SCA6 families, mean age of onset was 42.6 years, range 34–61 years. Only one patient had age at onset over 60 years old. Regarding the data of age at onset of the Thai SCA6 patients together with a high frequency of prominent pyramidal signs, nystagmus and saccadic abnormalities, it is difficult to clinically distinguish SCA6 from MJD, SCA1 and SCA2.

In the study, the Thai SCA patients rarely exhibit parkinsonism, dystonia, dementia and facial fasciculation. Parkinsonism has been reported to be relatively common in SCA2 and SCA3 [4447]. None of the studied patients exhibited parkinsonian features. In the study, we evaluated cognitive functions by using history taking and bedside examination. Almost all of the patients did not clinically have cognitive impairment and dementia. It was quite uncommon even in the late stage of the disease. Regarding dystonia, it has not been a commonly described non-ataxic feature of SCAs [48], dystonia is also extremely rare in the Thai patients.

The multiple regression analyses suggested that the development of ophthalmoparesis and polyneuropathy may be associated with severity of the disease and age of the patients rather than the subtypes of SCAs. However, the study had some limitations. The sample size is relatively small since we recruited only index cases of each family. So the study performed two logistic regression analyses including: (1) all patients together, and (2) all patients except SCA6. Since underlying pathological process of SCA6 is a small CAG expansion, which is different from other SCAs studied. Secondly, a large proportion of our patients were of low socioeconomic and low-educated status. They might give inaccurate data of some important information such as age at onset and disease duration.


In summary, MJD, SCA1, SCA2 and SCA6 are common in Thai adult-onset cerebellar degeneration, in contrast to SCA7 and DRPLA which are rare. The Thai patients with MJD, SCA1, SCA2 and SCA6 often exhibited a similar non-ataxic phenotype including pyramidal features prominently in lower limbs, saccadic abnormalities and less often peripheral neuropathy. The study shows that slow saccades and age onset are of no value for differential diagnosis of the common SCA subtypes in Thailand. Thus, it is essential to set up an effective referral system for reachable genetic diagnosis of a panel of at least the four common SCAs in Thailand.




Spinocerebellar ataxia


Machado-Joseph disease


Dentatorubro-pallidoluysian atrophy


Scale for the assessment and rating of ataxia


One-way analysis of variance


Odd ratio

95% CI: 

95% confidence interval.



We are grateful to all participants and their family members. We would like to acknowledge Ass. Prof. Supoch Tunlayadechanont, Dr. Jesada Keandoungchun, Dr. Chonticha Prasartsakulchai, Asso. Prof. Siwaporn Chankrachang, Ms. Manisa Busabaratana, Ms. Aruchalean Taweewongsounton and all residents in Neurology at the Ramathibodi Hospital for their help. We thank to Mr. Maurice M. Broughton for his help with English editing and to Miss Natsharee Pulkes for her help with drawing the figure. This study was supported by the Biomedical Research Grant, Ramathibodi Hospital, Mahidol University (47008), the Wiwat Raksriaksorn Fund (3001179) and the Neurogenetic Fund (3001180) of the Ramathibodi Foundation. This study was approved by the ethical clearance committee on human rights related to research involving human subjects, Faculty of Medicine, Ramathibodi Hospital, Mahidol University (ID07-46-22, ID 03-53-19).

Authors’ Affiliations

Department of Medicine, Division of Neurology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Division of Medicine, Bhumibol Adulyadej Hospital, Bangkok, Thailand
Department of Medicine, Division of Neurology, Buriram Hospital, Buriram, Thailand
Department of Medicine, Division of Neurology, Ratchaburi Hospital, Ratchaburi, Thailand
Department of Internal Medicine, The Northern Neuroscience Center and Division of Neurology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
Department of Otolaryngology, Division of Otoneurology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Section for Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand


  1. Klockgether T, Paulson H: Milestones in ataxia. Mov Disord. 2011, 26 (6): 1134-1141. 10.1002/mds.23559.View ArticlePubMedPubMed CentralGoogle Scholar
  2. Serrano-Munuera C, Corral-Juan M, Stevanin G, San Nicolas H, Roig C, Corral J, Campos B, de Jorge L, Morcillo-Suarez C, Navarro A, Forlani S, Durr A, Kulisevsky J, Brice A, Sánchez I, Volpini V, Matilla-Dueñas A: New subtype of spinocerebellar ataxia with altered vertical eye movements mapping to chromosome 1p32. JAMA neurology. 2013, 70 (6): 764-771. 10.1001/jamaneurol.2013.2311.View ArticlePubMedGoogle Scholar
  3. Wang JL, Yang X, Xia K, Hu ZM, Weng L, Jin X, Jiang H, Zhang P, Shen L, Guo JF, Li N, Li YR, Lei LF, Zhou J, Du J, Zhou YF, Pan Q, Wang J, Wang J, Li RQ, Tang BS: TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing. Brain. 2010, 133 (Pt 12): 3510-3518.View ArticlePubMedGoogle Scholar
  4. Kobayashi H, Abe K, Matsuura T, Ikeda Y, Hitomi T, Akechi Y, Habu T, Liu W, Okuda H, Koizumi A: Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement. Am J Hum Genet. 2011, 89 (1): 121-130. 10.1016/j.ajhg.2011.05.015.View ArticlePubMedPubMed CentralGoogle Scholar
  5. Jiang H, Zhu HP, Gomez CM: SCA32: an autosomal dominant cerebellar ataxia with azoospermia maps to chromosome 7q32-q33. (Abstract). Mov Disord. 2010, 25: S129-10.1002/mds.22880.View ArticleGoogle Scholar
  6. Martins S, Calafell F, Gaspar C, Wong VC, Silveira I, Nicholson GA, Brunt ER, Tranebjaerg L, Stevanin G, Hsieh M, Soong BW, Loureiro L, Dürr A, Tsuji S, Watanabe M, Jardim LB, Giunti P, Riess O, Ranum LP, Brice A, Rouleau GA, Coutinho P, Amorim A, Sequeiros J: Asian origin for the worldwide-spread mutational event in Machado-Joseph disease. Arch Neurol. 2007, 64 (10): 1502-1508. 10.1001/archneur.64.10.1502.View ArticlePubMedGoogle Scholar
  7. Tang B, Liu C, Shen L, Dai H, Pan Q, Jing L, Ouyang S, Xia J: Frequency of SCA1, SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA CAG trinucleotide repeat expansion in patients with hereditary spinocerebellar ataxia from Chinese kindreds. Arch Neurol. 2000, 57 (4): 540-544. 10.1001/archneur.57.4.540.View ArticlePubMedGoogle Scholar
  8. Takano H, Cancel G, Ikeuchi T, Lorenzetti D, Mawad R, Stevanin G, Didierjean O, Durr A, Oyake M, Shimohata T, Sasaki R, Koide R, Igarashi S, Hayashi S, Takiyama Y, Nishizawa M, Tanaka H, Zoghbi H, Brice A, Tsuji S: Close associations between prevalences of dominantly inherited spinocerebellar ataxias with CAG-repeat expansions and frequencies of large normal CAG alleles in Japanese and Caucasian populations. Am J Hum Genet. 1998, 63 (4): 1060-1066. 10.1086/302067.View ArticlePubMedPubMed CentralGoogle Scholar
  9. Giunti P, Sabbadini G, Sweeney MG, Davis MB, Veneziano L, Mantuano E, Federico A, Plasmati R, Frontali M, Wood NW: The role of the SCA2 trinucleotide repeat expansion in 89 autosomal dominant cerebellar ataxia families. Frequency, clinical and genetic correlates. Brain. 1998, 121 (Pt 3): 459-467.View ArticlePubMedGoogle Scholar
  10. Riess O, Rub U, Pastore A, Bauer P, Schols L: SCA3: neurological features, pathogenesis and animal models. Cerebellum. 2008, 7 (2): 125-137. 10.1007/s12311-008-0013-4.View ArticlePubMedGoogle Scholar
  11. Giunti P, Sweeney MG, Spadaro M, Jodice C, Novelletto A, Malaspina P, Frontali M, Harding AE: The trinucleotide repeat expansion on chromosome 6p (SCA1) in autosomal dominant cerebellar ataxias. Brain. 1994, 117 (Pt 4): 645-649.View ArticlePubMedGoogle Scholar
  12. Maschke M, Oehlert G, Xie TD, Perlman S, Subramony SH, Kumar N, Ptacek LJ, Gomez CM: Clinical feature profile of spinocerebellar ataxia type 1–8 predicts genetically defined subtypes. Mov Disord. 2005, 20 (11): 1405-1412. 10.1002/mds.20533.View ArticlePubMedGoogle Scholar
  13. Sinha KK, Worth PF, Jha DK, Sinha S, Stinton VJ, Davis MB, Wood NW, Sweeney MG, Bhatia KP: Autosomal dominant cerebellar ataxia: SCA2 is the most frequent mutation in eastern India. J Neurol Neurosurg Psychiatry. 2004, 75 (3): 448-452. 10.1136/jnnp.2002.004895.View ArticlePubMedPubMed CentralGoogle Scholar
  14. Seifried C, Velazquez-Perez L, Santos-Falcon N, Abele M, Ziemann U, Almaguer LE, Martinez-Gongora E, Sanchez-Cruz G, Canales N, Perez-Gonzalez R, Velázquez-Manresa M, Viebahn B, Stuckrad-Barre S, Klockgether T, Fetter M, Auburger G: Saccade velocity as a surrogate disease marker in spinocerebellar ataxia type 2. Ann N Y Acad Sci. 2005, 1039: 524-527. 10.1196/annals.1325.059.View ArticlePubMedGoogle Scholar
  15. Schmitz-Hubsch T, Coudert M, Bauer P, Giunti P, Globas C, Baliko L, Filla A, Mariotti C, Rakowicz M, Charles P, Ribai P, Szymanski S, Infante J, van de Warrenburg BP, Dürr A, Timmann D, Boesch S, Fancellu R, Rola R, Depondt C, Schöls L, Zdienicka E, Kang JS, Döhlinger S, Kremer B, Stephenson DA, Melegh B, Pandolfo M, di Donato S, du Montcel ST, Klockgether T: Spinocerebellar ataxia types 1, 2, 3, and 6: disease severity and nonataxia symptoms. Neurology. 2008, 71 (13): 982-989. 10.1212/01.wnl.0000325057.33666.72.View ArticlePubMedGoogle Scholar
  16. Durr A, Stevanin G, Cancel G, Duyckaerts C, Abbas N, Didierjean O, Chneiweiss H, Benomar A, Lyon-Caen O, Julien J, Serdaru M, Penet C, Agid Y, Brice A: Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular, and neuropathological features. Ann Neurol. 1996, 39 (4): 490-499. 10.1002/ana.410390411.View ArticlePubMedGoogle Scholar
  17. Velazquez-Perez L, Seifried C, Santos-Falcon N, Abele M, Ziemann U, Almaguer LE, Martinez-Gongora E, Sanchez-Cruz G, Canales N, Perez-Gonzalez R, Velázquez-Manresa M, Viebahn B, von Stuckrad-Barre S, Fetter M, Klockgether T, Auburger G: Saccade velocity is controlled by polyglutamine size in spinocerebellar ataxia 2. Ann Neurol. 2004, 56 (3): 444-447. 10.1002/ana.20220.View ArticlePubMedGoogle Scholar
  18. Seidel K, Siswanto S, Brunt ER, den Dunnen W, Korf HW, Rub U: Brain pathology of spinocerebellar ataxias. Acta Neuropathol. 2012, 124 (1): 1-21. 10.1007/s00401-012-1000-x.View ArticlePubMedGoogle Scholar
  19. Velazquez-Perez L, Seifried C, Abele M, Wirjatijasa F, Rodriguez-Labrada R, Santos-Falcon N, Sanchez-Cruz G, Almaguer-Mederos L, Tejeda R, Canales-Ochoa N, Fetter M, Ziemann U, Klockgether T, Medrano-Montero J, Rodríguez-Díaz J, Laffita-Mesa JM, Auburger G: Saccade velocity is reduced in presymptomatic spinocerebellar ataxia type 2. Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology. 2009, 120 (3): 632-635. 10.1016/j.clinph.2008.12.040.View ArticleGoogle Scholar
  20. Christova P, Anderson JH, Gomez CM: Impaired eye movements in presymptomatic spinocerebellar ataxia type 6. Arch Neurol. 2008, 65 (4): 530-536. 10.1001/archneur.65.4.530.View ArticlePubMedGoogle Scholar
  21. Geiner S, Horn AK, Wadia NH, Sakai H, Buttner-Ennever JA: The neuroanatomical basis of slow saccades in spinocerebellar ataxia type 2 (Wadia-subtype). Prog Brain Res. 2008, 171: 575-581.View ArticlePubMedGoogle Scholar
  22. Wadia N, Pang J, Desai J, Mankodi A, Desai M, Chamberlain S: A clinicogenetic analysis of six Indian spinocerebellar ataxia (SCA2) pedigrees. The significance of slow saccades in diagnosis. Brain. 1998, 121 (Pt 12): 2341-2355.View ArticlePubMedGoogle Scholar
  23. Laffita-Mesa JM, Bauer PO, Kouri V, Pena Serrano L, Roskams J, Almaguer Gotay D, Montes Brown JC, Martinez Rodriguez PA, Gonzalez-Zaldivar Y, Almaguer Mederos L, Cuello-Almarales D, Aguiar Santiago J: Epigenetics DNA methylation in the core ataxin-2 gene promoter: novel physiological and pathological implications. Hum Genet. 2012, 131 (4): 625-638. 10.1007/s00439-011-1101-y.View ArticlePubMedGoogle Scholar
  24. Sura T, Eu-Ahsunthornwattana J, Youngcharoen S, Busabaratana M, Dejsuphong D, Trachoo O, Theerasasawat S, Tunteeratum A, Noparutchanodom C, Tunlayadechanont S: Frequencies of spinocerebellar ataxia subtypes in Thailand: window to the population history?. J Hum Genet. 2009, 54 (5): 284-288. 10.1038/jhg.2009.27.View ArticlePubMedGoogle Scholar
  25. Giunti P, Sweeney MG, Harding AE: Detection of the Machado-Joseph disease/spinocerebellar ataxia three trinucleotide repeat expansion in families with autosomal dominant motor disorders, including the Drew family of Walworth. Brain. 1995, 118 (Pt 5): 1077-1085.View ArticlePubMedGoogle Scholar
  26. Warner TT, Williams LD, Walker RW, Flinter F, Robb SA, Bundey SE, Honavar M, Harding AE: A clinical and molecular genetic study of dentatorubropallidoluysian atrophy in four European families. Ann Neurol. 1995, 37 (4): 452-459. 10.1002/ana.410370407.View ArticlePubMedGoogle Scholar
  27. Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, Dobyns WB, Subramony SH, Zoghbi HY, Lee CC: Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet. 1997, 15 (1): 62-69. 10.1038/ng0197-62.View ArticlePubMedGoogle Scholar
  28. Stevanin G, Giunti P, Belal GD, Durr A, Ruberg M, Wood N, Brice A: De novo expansion of intermediate alleles in spinocerebellar ataxia 7. Hum Mol Genet. 1998, 7 (11): 1809-1813. 10.1093/hmg/7.11.1809.View ArticlePubMedGoogle Scholar
  29. Gan SR, Shi SS, Wu JJ, Wang N, Zhao GX, Weng ST, Murong SX, Lu CZ, Wu ZY: High frequency of Machado-Joseph disease identified in southeastern Chinese kindreds with spinocerebellar ataxia. BMC Med Genet. 2010, 11: 47-View ArticlePubMedPubMed CentralGoogle Scholar
  30. Jin DK, Oh MR, Song SM, Koh SW, Lee M, Kim GM, Lee WY, Chung CS, Lee KH, Im JH, Lee MJ, Kim JW, Lee MS: Frequency of spinocerebellar ataxia types 1,2,3,6,7 and dentatorubral pallidoluysian atrophy mutations in Korean patients with spinocerebellar ataxia. J Neurol. 1999, 246 (3): 207-210. 10.1007/s004150050335.View ArticlePubMedGoogle Scholar
  31. Maruyama H, Izumi Y, Morino H, Oda M, Toji H, Nakamura S, Kawakami H: Difference in disease-free survival curve and regional distribution according to subtype of spinocerebellar ataxia: a study of 1,286 Japanese patients. Am J Med Genet. 2002, 114 (5): 578-583. 10.1002/ajmg.10514.View ArticlePubMedGoogle Scholar
  32. Zhao Y, Tan EK, Law HY, Yoon CS, Wong MC, Ng I: Prevalence and ethnic differences of autosomal-dominant cerebellar ataxia in Singapore. Clin Genet. 2002, 62 (6): 478-481. 10.1034/j.1399-0004.2002.620610.x.View ArticlePubMedGoogle Scholar
  33. Sakai H, Yoshida K, Shimizu Y, Morita H, Ikeda S, Matsumoto N: Analysis of an insertion mutation in a cohort of 94 patients with spinocerebellar ataxia type 31 from Nagano, Japan. Neurogenetics. 2010, 11 (4): 409-415. 10.1007/s10048-010-0245-6.View ArticlePubMedPubMed CentralGoogle Scholar
  34. Schols L, Kruger R, Amoiridis G, Przuntek H, Epplen JT, Riess O: Spinocerebellar ataxia type 6: genotype and phenotype in German kindreds. J Neurol Neurosurg Psychiatry. 1998, 64 (1): 67-73. 10.1136/jnnp.64.1.67.View ArticlePubMedPubMed CentralGoogle Scholar
  35. Soong B, Cheng C, Liu R, Shan D: Machado-Joseph disease: clinical, molecular, and metabolic characterization in Chinese kindreds. Ann Neurol. 1997, 41 (4): 446-452. 10.1002/ana.410410407.View ArticlePubMedGoogle Scholar
  36. Matsumura R, Futamura N, Fujimoto Y, Yanagimoto S, Horikawa H, Suzumura A, Takayanagi T: Spinocerebellar ataxia type 6. Molecular and clinical features of 35 Japanese patients including one homozygous for the CAG repeat expansion. Neurology. 1997, 49 (5): 1238-1243. 10.1212/WNL.49.5.1238.View ArticlePubMedGoogle Scholar
  37. Soong BW, Lu YC, Choo KB, Lee HY: Frequency analysis of autosomal dominant cerebellar ataxias in Taiwanese patients and clinical and molecular characterization of spinocerebellar ataxia type 6. Arch Neurol. 2001, 58 (7): 1105-1109. 10.1001/archneur.58.7.1105.View ArticleGoogle Scholar
  38. Buttner N, Geschwind D, Jen JC, Perlman S, Pulst SM, Baloh RW: Oculomotor phenotypes in autosomal dominant ataxias. Arch Neurol. 1998, 55 (10): 1353-1357. 10.1001/archneur.55.10.1353.View ArticlePubMedGoogle Scholar
  39. Burk K, Fetter M, Abele M, Laccone F, Brice A, Dichgans J, Klockgether T: Autosomal dominant cerebellar ataxia type I: oculomotor abnormalities in families with SCA1, SCA2, and SCA3. J Neurol. 1999, 246 (9): 789-797. 10.1007/s004150050456.View ArticlePubMedGoogle Scholar
  40. Cancel G, Durr A, Didierjean O, Imbert G, Burk K, Lezin A, Belal S, Benomar A, Abada-Bendib M, Vial C, Guimaraes J, Chneiweiss H, Stevanin G, Yvert G, Abbas N, Saudou F, Lebre AS, Yahyaoui M, Hentati F, Vernant JC, Klockgether T, Mandel JL, Agid Y, Brice A: Molecular and clinical correlations in spinocerebellar ataxia 2: a study of 32 families. Hum Mol Genet. 1997, 6 (5): 709-715. 10.1093/hmg/6.5.709.View ArticlePubMedGoogle Scholar
  41. Schols L, Amoiridis G, Buttner T, Przuntek H, Epplen JT, Riess O: Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes?. Ann Neurol. 1997, 42 (6): 924-932. 10.1002/ana.410420615.View ArticlePubMedGoogle Scholar
  42. Ikeuchi T, Takano H, Koide R, Horikawa Y, Honma Y, Onishi Y, Igarashi S, Tanaka H, Nakao N, Sahashi K, Tsukagoshi H, Inoue K, Takahashi H, Tsuji S: Spinocerebellar ataxia type 6: CAG repeat expansion in alpha1A voltage-dependent calcium channel gene and clinical variations in Japanese population. Ann Neurol. 1997, 42 (6): 879-884. 10.1002/ana.410420609.View ArticlePubMedGoogle Scholar
  43. Gomez CM, Thompson RM, Gammack JT, Perlman SL, Dobyns WB, Truwit CL, Zee DS, Clark HB, Anderson JH: Spinocerebellar ataxia type 6: gaze-evoked and vertical nystagmus, Purkinje cell degeneration, and variable age of onset. Ann Neurol. 1997, 42 (6): 933-950. 10.1002/ana.410420616.View ArticlePubMedGoogle Scholar
  44. Tuite PJ, Rogaeva EA, St George-Hyslop PH, Lang AE: Dopa-responsive parkinsonism phenotype of Machado-Joseph disease: confirmation of 14q CAG expansion. Ann Neurol. 1995, 38 (4): 684-687. 10.1002/ana.410380422.View ArticlePubMedGoogle Scholar
  45. Lu CS, Wu Chou YH, Yen TC, Tsai CH, Chen RS, Chang HC: Dopa-responsive parkinsonism phenotype of spinocerebellar ataxia type 2. Mov Disord. 2002, 17 (5): 1046-1051. 10.1002/mds.10243.View ArticlePubMedGoogle Scholar
  46. Furtado S, Payami H, Lockhart PJ, Hanson M, Nutt JG, Singleton AA, Singleton A, Bower J, Utti RJ, Bird TD, de la Fuente-Fernandez R, Tsuboi Y, Klimek ML, Suchowersky O, Hardy J, Calne DB, Wszolek ZK, Farrer M, Gwinn-Hardy K, Stoessl AJ: Profile of families with parkinsonism-predominant spinocerebellar ataxia type 2 (SCA2). Mov Disord. 2004, 19 (6): 622-629. 10.1002/mds.20074.View ArticlePubMedGoogle Scholar
  47. Paulson HL: Dominantly inherited ataxias: lessons learned from Machado-Joseph disease/spinocerebellar ataxia type 3. Semin Neurol. 2007, 27 (2): 133-142. 10.1055/s-2007-971172.View ArticlePubMedGoogle Scholar
  48. van Gaalen J, Giunti P, van de Warrenburg BP: Movement disorders in spinocerebellar ataxias. Mov Disord. 2011, 26 (5): 792-800. 10.1002/mds.23584.View ArticlePubMedGoogle Scholar
  49. Pre-publication history

    1. The pre-publication history for this paper can be accessed here:


© Boonkongchuen et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.