Evaluation of Various Movement Disorders in Patients of Genetically Proven Spinocerebellar Ataxia: A Study from a Tertiary Care Center in Northern India

Abstract

Background:

Movement disorders are one of the prominent nonataxic symptoms in patients of spinocerebellar ataxia (SCA). The type of movement disorder may provide clinical clue to the type of SCA.

Objective:

The objective of this study is to evaluate various movement disorders in patients of genetically proven SCAs and to establish a probable clinico-genetic correlation.

Methods:

Ninety-Five patients of genetically proven SCAs were assessed for the presence of various movement disorders.

Results:

Patients with SCA (75.8% males) with at least one movement disorder contributed 43.16%. Age for onset of movement disorder was 43.39 ± 13.43 years. SCA-12 (38.95%) was the most common subtype. Among the patients with at least one movement disorder, action tremor of hands contributed majority (90.2%). Dystonia and parkinsonism were present in 17.07% and 12.2% of patients (with movement disorder), respectively. Action tremor of hands was present in 34 patients with SCA-12 (91.89%), and 20 patients (54.05%) had onset of hand tremor preceding the onset of ataxia. Majority of patients with SCA-12 (81%) were of the same ethnic origin belonging to Agrawal community. Patients with movement disorder had a later onset (45 ± 13.88 years) of ataxic symptoms compared to those without a movement disorder (32.8 ± 11.92) (P = <0.0005). There was no significant association between severity of ataxia and presence of movement disorder.

Conclusion:

Movement disorders are present in about 43% of patients with SCA and can precede or succeed the onset of ataxia. Tremor onset SCA predicted SCA-12, especially in Agrawal community.

INTRODUCTION

Spinocerebellar ataxias (SCAs) are common degenerative ataxia syndrome. The global prevalence of SCA is estimated to be approximately 1–5:100,000 populations, with SCA-3 being the most common variety.[1] The prevalence of SCA varies depending on the place of birth, race, and founder effect. SCA-2 is probably the most common type of adult-onset SCA seen in India with considerable frequency in eastern India (Sinha et al.,[2] 57.1%; Chakravarty and Mukherjee,[3] 28.6%; and Pulai et al.,[4] 40%). Similarly, Saleem et al.[5] (North India) and Khadilkar et al.[6] (West India), in their studies, reported SCA-2 as the most prevalent variety. SCA-3 is slightly more common (Chakravarty and Mukherjee[3] 35.7%) in ethnic Bengali families.

Various nonataxia features are observed in SCAs. Both hypo- and hyper-kinetic movement disorders are described along with cerebellar features, and their prominence often poses a diagnostic challenge. However, the presence of these movement disorders may provide clinical clue to genetic type of SCA and subsequently can help in prioritizing the requests for mutation analysis.

Although a large number of studies of SCA have been published from India, none of them have looked at this aspect of the cohort. The aim of this study was to evaluate various movement disorders in patients of genetically proven SCAs and to establish a probable clinico-genetic correlation.

METHODS

In this single-center cross-sectional study, participants were recruited (October 2015–January 2017) from ataxia clinic of a tertiary care hospital in North India. Under a uniform protocol, approved by the Institute Ethical Committee, written informed consent was taken. Participants with genetically proven type of SCA were randomly enrolled in the study. Participants with known recessive/X-linked/mitochondrial ataxias were excluded from the study. The genotyping was performed in the Council for Scientific and Industrial Research Institute of Genomics and Integrative Biology, New Delhi, under other research protocol of one of the authors (AKS).

Clinical evaluation

Detailed history taking and thorough clinical examination were done for all participants recruited in the study. Severity of ataxia was measured using scale for the assessment and rating of ataxia (SARA[7] score ranges from 0 to 40 with 0 indicating the absence of ataxia and 40 the most severe degree of ataxia). Participants were evaluated for the presence of various movement disorders by movement disorder experts (VG, AKS). Severity of various movement disorders was scored using following scales: for dystonia: Fahn-Marsden dystonia scales,[8] for tremor: Fahn, Tolosa, and Marin rating scale,[9] and for parkinsonism: unified Parkinson's disease rating scale (UPDRS).[10]

Statistical analysis

The data were summarized and analyzed using the Statistical Package for the Social Sciences (SPSS Version 14, STATA Corp, TEXAS, USA) software. Continuous variables were expressed as mean ± standard deviation and categorical variables as number or percentage. For comparison of categorical data, Chi-square test was used between two groups. Paired t-test was used for comparison of continuous data. Independent t-test was used to find relationship between severity of ataxia and movement disorder. P < 0.05 was considered significant in this study.

RESULTS

Patient characteristics

A total of 95 genetically proven patients (75.8% males) with SCA were enrolled with mean age of patients 45.53 ± 13.96 years and age at the onset of ataxia of 38.27 ± 14.22 years. Average duration of ataxia was 5.2 ± 4.52 years. SCA-12 (38.95%) was the most common subtype in our study. SCA-2, SCA-3, and SCA-1 contributed 35.79%, 11.58%, and 10.53%, respectively. There were two patients with SCA-7 and one patient with SCA-6. Majority of patients with SCA-12 (30/37, 81%) were of the same ethnic origin belonging to Agrawal community. Other patient characteristics are detailed in Table 1.

Table 1.

Demography, clinical, and investigation parameters of the study patients with spinocerebellar ataxia (n=95)

Movement disorders

Forty-one (43.16%) patients had at least one movement disorder. Two movement disorders were present in 8 patients (SCA-12 = 7 and SCA-2 = 1). The mean age for onset and duration of movement disorder was 43.39 ± 13.43 and 6.55 ± 5.36 years, respectively. Among the patients with at least one movement disorder, action tremor of hands (other than intention type) contributed majority (37/41, 90.2%). Dystonia and parkinsonism were present in 17.1% (7/41) and 12.2% (5/41) of patients with movement disorder, respectively. Distribution of movement disorder across various SCA subtypes is given in Table 2.

Table 2.

Distribution of movement disorders across various spinocerebellar ataxia subtypes

All our patients had ataxia at time of recruitment. Onset of movement disorder preceded the onset of ataxia in 22 (53.67%) patients with mean age of precedence being 4.52 ± 2.76 years. Out of 34 patients with SCA-12 and movement disorder, 20 (58.8%) had onset of movement disorder (action tremors of hand) preceding onset of ataxia. Movement disorder preceded ataxia in one patient of SCA-2 and one patient of SCA-6. Details of each movement disorder are given below.

Tremor

Action tremor of hands (other than intention tremor) was present in 34 out of 37 patients with SCA-12 (91.89%), of which onset of tremor-predated ataxia in 20 (58.8%) patients. Tremor of hands coincided with onset of ataxia in 12 patients. Four patients of SCA-2 had action tremors of hands. Onset of tremor in these patients was succeeding the onset of ataxia. Action tremor of hands was not observed in any other SCA subtypes. Neck tremor was present in 14 (37.84%) patients with SCA-12 and two patients with SCA-2.

Focal dystonia

Three patients with SCA-12 had focal dystonia (2 had cervical dystonia and 1 had Meige's syndrome [oromandibular dystonia (OMD) and blepharospasm]). All the 3 patients with SCA-12 and dystonia had postural and kinetic tremors of both hands. Two patients with SCA-2 had cervical dystonia and one of them also had postural and kinetic tremor of both hands. Ataxia preceded onset of dystonia by 7 years in one of these patients. One patient with SCA-3 had right foot dystonia. The single SCA-6 patient had focal dystonia involving right-hand dystonia that preceded onset of ataxia by 5 years. Dystonia severity scale and dystonia movement scale of these patients are given in Table 3.

Table 3.

Data of various rating scales used in this study

Parkinsonism

Five patients (4 with SCA-12 and 1 with SCA-2) had features of parkinsonism in the form of rest tremor, rigidity, and bradykinesia. All these patients had onset of ataxia preceding the onset of parkinsonism symptoms. DAT scan was available in only one patient (SCA-12), which showed presynaptic dopaminergic dysfunction. Mean UPDRS (motor) score of these 5 patients is given in Table 3.

No movement disorder

Patients with SCA-1 or SCA-7 had no movement disorder.

Severity score of ataxia

The mean SARA score of patients with and without movement disorder was 14.40 ± 6.86 and 14.04 ± 5.87, respectively (P = 0.82). Patients with movement disorder had a later onset of ataxic symptoms compared to those without a movement disorder (P = <0.0005). Different tools used in this study and severity scores are given in Table 4.

Table 4.

Comparison of duration and severity of ataxia in patients with and without a movement disorder by independent t-test analysis

Other relevant neurological findings in these patients are given in supplementary content ^{(92.7KB, pdf)} .

Various co morbidities this SCA cohort is enlisted in supplementary Table ^{(266.8KB, tif)} .

Supplementary Table

Distribution of various comorbidities in spinocerebellar ataxia patients

DISCUSSION

Although many authors have reported phenotype-genotype correlation in patients of SCA,[3,4,11,12,13] this is the first Indian study that looked at various movement disorder in genetically proven SCA.

The present study assessed demographic features of varied types of movement disorders in 95 genetically proven SCA patients. At least one type of movement disorder was present in 43.16% of patients. In 22 patients (53.67%), movement disorder was the initial symptom. Intention tremor, a part of cerebellar syndrome, was present in all patients. Action tremor of hands other than intention tremor (postural/kinetic) was the most frequent movement disorder at onset, seen most commonly in SCA-12 subtype.

In 2002, Garcia Ruiz et al.[14] reported tremor as the most common “movement disorder” in SCA patients. However, most of the tremors encountered in SCA patients may be a part of the cerebellar syndrome including head tremor (titubation), postural, action, and intention tremors of the hand; truncal tremor (titubation) during stance and action; and intention tremors of the legs.

Action tremor of hands as the presenting feature of SCA-12 is reported earlier in literature.[15] In 2001, Srivastava et al.[11] had reported hand tremor as the initial symptom in 4 out of 6 (67%) SCA-12 patients. In our study, 54.05% of patients of SCA-12 had action tremor of hands as the first symptom. Srivastava et al. has not mentioned details of patients having neck tremor. We had 14 patients of SCA-12 with neck tremor. However, onset of neck tremor was not clear in these patients. All our patients with tremor received treatment with long-acting propranolol and reported mild-to-moderate improvement.

In our study, dystonia was present in 17.07% of patients of SCA. In a systematic review by Rossi et al.,[16] the presence of dystonia suggested SCA-3, SCA-17, or dentatorubral-pallidoluysian atrophy. However, dystonia in SCA-2, with a frequency as high as 61%, has been reported in some series.[17] Dystonia can also be a less frequent but relevant nonataxic symptom of SCA-12 and SCA-6, like in our study. An initial presentation with dystonia has been documented in SCA-1 and SCA-2 (cervical dystonia) and in SCA-14 and SCA-6 (writer's cramp).[17,18,19] In our patients of SCA-12 with dystonia, it was not clear whether movement disorder predated onset of ataxia. One patient with SCA-2 and SCA-6 had onset of dystonia preceding ataxia by 5 and 7 years, respectively. One of our SCA-12 patients had both OMD and blepharospasm. He received botulinum toxin and responded well.

In our study, parkinsonism features are observed in four patients with SCA-12 and in one patient with SCA-2. All these five patients had appearance of these features years after onset of ataxia and were naïve to L-dopa at the time of recruitment. Only one patient had TRODAT scan suggestive of presynaptic dopaminergic involvement. Single or multiple parkinsonian features can be observed in SCA patients, particularly in those with SCA-2, SCA-3, or SCA-17.[20] The spectrum varies from just some limb rigidity alongside a marked cerebellar syndrome to a levodopa-responsive, Parkinson's disease-like picture without any cerebellar signs.[20]

The Parkinsonian phenotype of SCA-2 is more common in Asian than in non asian patients.[21,22,23] Parkinsonism features in patients of SCA-12 have been reported in literature.[15] However, screening for SCA mutations in patients with parkinsonism without a cerebellar syndrome is recommended only for SCA-2 (especially in Asian ethnic groups) and SCA-17 in families with autosomal dominant parkinsonism.

We observed that patients with movement disorder have a later age of onset of ataxia (P < 0.0001). Duration of ataxia at time of recruitment, in patients of SCA, with and without movement disorder was 4.30 ± 4. 9 and 5.96 ± 4.12 (years), respectively.

However, we could not find any significant difference in severity of ataxia between those patients with or without movement disorder. Fourteen (14.74%) patients had negative family history of ataxia. This may be due to inadequate history or censor effect.

In our study, SCA-12 contributed majority of SCA patients, 38.95%. This was in contrary to previous studies from India,[3,4,5,6] where SCA-2 was most prevalent (as these studies are old, and at that time, SCA-12 was not screened). SCA-12 is now very common SCA in India and has been well reported in previous studies.[11,24] Sinha et al.[24] reported 21 genetically proven SCA-12 (12 families) and 11 of these were from a specific ethnic caste, Agrawal. A clinical and molecular study by Garg et al.[25] also showed SCA-12 as the most common cause of SCA in Agarwal ethnic population (56.6%). In this study, too majority of patients with SCA-12 (81%) were of the same ethnic origin belonging to Agrawal community.

A similar study with larger sample size also looking at the correlation of trinucleotide expansion with severity of ataxia and movement disorder should be considered in future.

CONCLUSION

Movement disorders are present in about 43% of patients with SCA. Movement disorders can precede or succeed the onset of ataxia in SCA patients. Tremor onset SCA predicted SCA-12 subtype, especially in Agrawal community.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.