Clinical analysis of adult-onset spinocerebellar ataxias in Thailand

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 [1‐5]. Machado-Joseph disease (MJD) or SCA3 is generally the most common form of SCA worldwide [6‐8]. 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 [15‐17]. 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.

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 [30‐32]. 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, 34‐37]. 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 [41‐43]. 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 [44‐47]. 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.