Epidemiological, clinical, and genotype characterization of spinocerebellar ataxia type in families in Buriram province, northeast Thailand

After approval of our study protocol by the Ethical Committee on Human Rights Related to Research Involving Human Subjects, Buriram Hospital (ref. No. BR.0027.102.3/199) and obtaining informed consent from each patient participant, we conducted a cross-sectional observational study of 24 patients with autosomal dominant SCA from 13 families who were recruited from Buriram province in northeast Thailand between December 2009 and January 2014. Each patient gave a detailed clinical history and was examined by an experienced neurologist.

The profile and clinical data for each patient included sex, family hometown, age at onset, disease duration, age at diagnosis, family pedigree, history of smoking or alcohol drinking, eye movement abnormalities, nystagmus, cerebellar signs, fundoscopic examination, muscle tone and power, tendon reflexes, Babinski sign, parkinsonism, dystonia, chorea, dementia (screened by Mini–Mental State Examination), fasciculation, sensory examination testing for vibration, joint position and pinprick sensation, and SARA score.

DNA samples were extracted from peripheral blood leukocytes using a phenol–chloroform method or a Qiagen DNA purification kit. Fluorescent-labeled polymerase chain reaction (PCR) amplification of the expanded repeat alleles of 6 genes, ataxin-1 (ATXN1), ataxin-2 (ATXN2), ataxin-3 (ATXN3), α-1A subunit, P/Q type voltage-dependent calcium channel (CACNA1A: SCA6), ataxin-7, and atrophin-1 (ATN1; DRPLA), was performed using primer sets from previously described methods [19, 20, 21, 22, 23]. The allele sizes were then determined by running the PCR products on a CEQ 8800 Genetic Analysis System (Beckman Coulter). Sizes of CAG repeats 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 previously defined by direct Sanger sequencing. To avoid a false negative result caused by a very large expanded allele failing to be amplified by using regular PCR [24], all samples whose results showed patterns of homozygous wild-type alleles of ATXN1, ATXN2, and ATXN3 were subsequently reanalyzed by performing long-range PCR using TaKaRa LA Taq polymerase.

All statistical analyses were conducted using SPSS for Windows version 11.0. The mean, proportion, and range were determined. Chi-square and unpaired t tests were used to analyze possible associations between the type of SCA and sex, age, family history, and clinical features. Furthermore, we analyzed associations between the type of SCA and any underlying disease, age at onset, body weight, smoking status, family history, alcohol consumption, sex, head injury history, and SARA. P < 0.05 was considered significant.

Buriram province in northeast Thailand is divided geographically into 22 districts (amphoes). All families with SCA living in Buriram province have either SCA1 or MJD (SCA3) (Figure 1). In 13 autosomal dominant families with SCA, 7 (54%) tested positive for SCA1, 6 (46%) for MJD, and none for SCA2 and SCA6. This suggests that MJD and SCA1 are more common in the autosomal dominant families with ataxia in Buriram. A total of 24 index patients from Table 1 (3 of 13 SCA1 cases did not have a family history) were enrolled in the study, including 11 patients with MJD (46%) and 13 with SCA1 (54%).

The average age of the recruited patients was 43.7 years (range 20–72 years), whereas the average age at disease onset was 36.9 years (range 20–59 years). Overall patient characteristics, including sex, family history, clinical features including slow saccade, upward gaze paresis, horizontal nystagmus, vertical nystagmus, pale optic disc, hyperreflexia, Babinski sign, areflexia, sensory impairment, and parkinsonism, are summarized in Table 1.

Figure 1

All patients with SCA showed gait ataxia as a presenting symptom of the disease; gait problems were earlier in onset and more severely affected than speech problems. Other cerebellar features, such as arm incoordination and cerebellar dysarthria, commonly followed within a few years. Mildly asymmetrical limb ataxia was present in most cases. In advanced stages of the disease, truncal ataxia was present in all cases leading to bed-bound disability.

In the early stages, pyramidal signs, predominantly increased tendon reflexes and spastic tone in both legs, could frequently be detected as hyperreflexia was evident in most cases (79%). Areflexia was seen in 4 patients (16%). Babinski sign was found in only 3 (13%) patients. The presence of any pyramidal signs was not significantly different between MJD and SCA1. Extrapyramidal features appeared to be uncommon in the patients studied. Parkinsonism was observed in a few cases, while chorea and dystonia was not detected in any of the cases (if parkinsonism is found only at a late stage of the disease or in patients with long disease duration, already severely ataxic with mild parkinsonism, it may be worth to mention, because at the later stage, more system involvement would be observed; for clinical clues at an early stage, this sign may not be helpful).

Gaze-evoked nystagmus was a common sign. Horizontal nystagmus was more common than vertical nystagmus. Horizontal nystagmus and upward gaze paresis were significantly associated with MJD (Table 1). Abnormal saccadic eye movements were demonstrated in both subtypes of SCAs. Slow saccades were found in about 18 (75%) of the patients. Slow saccades were not different between SCA1 and MJD (P = 0.65). Impairment of the accuracy of the saccade or dysmetric saccade was also identified in most patients for both SCA subtypes.

In comparing the clinical features of study participants, 15 SCA patients had SARA ≥15; 7 of these cases were SCA1 and 8 were MJD. Demographic data such as sex, family history of SCA, underlying medical problems, onset age >35 years, body weight >60 kg, smoking, and alcohol drinking were compared between the 2 groups based on SARA score. There were no significant differences in demographic data between the groups with SARA ≥15 and SARA <15 (Table 2).