Spinocerebellar Ataxia 12(SCA12) is a rare form of SCA, predominantly reported in the ethnic Agarwal population originating from North India. It generally presents with late onset upper limb tremor followed by ataxia. 1 Tremor in SCA12 remains poorly studied to date. Since action tremor is the most common and earliest sign in SCA12, it is often mis‐diagnosed as Essential tremor. 2
In SCA12, CAG repeat associated neuro‐toxic protein accumulation accelerates degeneration in the cerebello‐cortical region. 3 Since toxic protein associated neuro‐degeneration is a diffuse process, one may expect appendicular features of SCA12 to reflect symmetry. But asymmetrical hand tremor was documented in one patient of Indian origin by Kalia et al. 4 They stated that previous reports did not comment about tremor symmetry, this remains largely true to date. In this paper we have tried to explore if asymmetry of symptoms in SCA12 is an exception or a common finding.
We studied 22 cases of SCA12 with a focus on laterality and associated phenomenology of symptoms. Mean disease duration in our study population was 8.2 (±4.7) years. Tremor was clinically analyzed by a movement disorders neurologist. The findings have been summarized in Table 1. When we look into upper limb findings, all 22 (100%) patients had intention tremor, 21 (95%) had dysmetria, 21 (95%) patients had postural tremor and 12 had rest tremor. Interestingly, postural tremor did not depict re‐emergence, which is commonly seen in Parkinson's disease.
TABLE 1.
Appendicular features of SCA 12 – We focused on tremor and dysmetria in upper and lower limb. Majority of upper limb shows asymmetry, in postural>rest>action tremor. In lower limb, dysmetria although common is symmetrical and action tremor is rare. Holmes' tremor was seen in several patients and Parkinsonism was rare
| S No. | *Asymmetry in UL tremor | UL Postural tremor | UL Action tremor | UL Rest tremor | UL Dysmetria | Parkinsonism | Holmes' Tremor | DD | LL Action Tremor | LL Dysmetria |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Present | R > L | Symmetry | Absent | Symmetry | — | 7 yr | Absent | Symmetry | |
| 2 | Present | Absent | Symmetry | L > R | L > R | — | 6 yr | Absent | Symmetry | |
| 3 | Absent | Symmetry | Symmetry | Symmetry | R > L | — | Present | 16 yr | Absent | Symmetry |
| 4 | Present | R > L | Symmetry | R > L | Symmetry | — | Present | 10 yr | Absent | Symmetry |
| 5 | Present | Symmetry | Symmetry | L > R | Absent | — | Present | 9 yr | Absent | Symmetry |
| 6 | Present | R > L | Symmetry | R > L | R > L | Parkinsonism+ | Present | 5 yr | Absent | Symmetry |
| 7 | Present | L > R | Symmetry | L > R | Symmetry | — | Present | 7 yr | Absent | Symmetry |
| 8 | Present | R > L | Symmetry | L > R | Symmetry | — | Present | 4 yr | Absent | Absent |
| 9 | Present | R > L | Symmetry | Absent | R > L | — | Present | 20 yr | Absent | Symmetry |
| 10 | Present | R > L | Symmetry | Absent | Symmetry | — | 7 yr | Absent | Absent | |
| 11 | Present | R > L | Symmetry | Absent | Symmetry | — | 14 yr | Symmetry | Absent | |
| 12 | Present | R > L | R > L | Absent | R > L | — | 5 yr | Absent | Symmetry | |
| 13 | Present | L > R | Symmetry | L > R | R > L | — | Present | 3 yr | Absent | Symmetry |
| 14 | Present | L > R | Symmetry | Absent | Symmetry | Parkinsonism+ | 6 yr | Absent | Symmetry | |
| 15 | Present | R > L | R > L | Absent | R > L | — | 14 yr | Absent | Symmetry | |
| 16 | Present | L > R | Symmetry | Absent | Symmetry | — | 5 yr | Absent | Symmetry | |
| 17 | Present | R > L | Symmetry | R > L | Symmetry | — | Present | 5 yr | Absent | Absent |
| 18 | Absent | Symmetry | Symmetry | Symmetry | L > R | — | Present | 14 yr | Absent | Symmetry |
| 19 | Present | R > L | R > L | R > L | R > L | — | Present | 10 yr | Absent | Absent |
| 20 | Present | L > R | R > L | L > R | R > L | — | Present | 1 yr | Absent | Symmetry |
| 21 | Present | R > L | Symmetry | Absent | Symmetry | — | 3 yr | Absent | Symmetry | |
| 22 | Present | L > R | Symmetry | Absent | Symmetry | — | 10 yr | Absent | Absent |
Asymmetry*: The patient was said to have asymmetrical tremor, if any/all of rest, action or postural tremor were asymmetrical. Parkinsonism: If any patient had bradykinesia or/and rigidity they were said to have Parkinsonism.
Abbreviations: UL, Upper limb; LL, Lower Limb; DD, Disease duration: time since onset of first symptom.
Twenty (91%) patients had asymmetrical upper limb tremor and 10 (45%) had asymmetrical dysmetria. Out of these 20 patients, 19(90%), 10 (83%) and 5 (29%) had asymmetry in postural, rest and intention tremor respectively. Notably, postural tremor showed the highest rate of asymmetry. Only two patients had symmetry in upper limb tremor at presentation but their symptoms started 14 and 16 years ago respectively. Even in these two patients, tremor began on one side and took 5–7 years to equally involve the upper limbs. Twelve patients had simultaneous rest, postural and action tremor, which is defined as Holmes' tremor (HT). 5 When analyzing lower limb data, only one patient had action tremor and it was symmetrical. Sixteen patients had dysmetria, all of which was symmetrical.
Our findings suggest that asymmetry is a commonly found character of upper limb tremor in SCA12, which can be seen in the representative video segments (Video 1), provided as a supplement to this manuscript. Written informed consent was obtained and ethical approval was taken. Theoretically, HT can be found in any cerebellar outflow tract disorder, but we duly document it in SCA12 for the first time. 5
Video 1.
In the upper limb – Patient 1, has asymmetrical rest and postural tremor with symmetrical dysmetria and intention tremor, Holmes' tremor is present. Patient 2 has asymmetrical postural tremor, intention tremor and dysmetria. Patient 3 has asymmetrical postural tremor but symmetrical dysmetria, rest and intention tremor, Holmes' tremor and head tremor were present. Patient 4 has asymmetrical dystonic posturing and postural tremor (Right>Left) but symmetrical intention tremor. In the lower limbs – Patient 3 had symmetrical dysmetria but no intention tremor. Asymmetrical upper limb tremor and dysmetria along with symmetrical lower limb dysmetria was commonly seen in our cohort of patients with SCA12. Video content can be viewed at https://onlinelibrary.wiley.com/doi/10.1002/mdc3.13237
Lower limb tremor was found in only one patient, and it was symmetrical. Dysmetria was more common in lower limbs as compared to tremor, and that too was symmetrical. The clear incongruence in upper and lower limb symptoms in tremor disorders is well reported but unexplained. Well‐developed laterality in the upper limbs might make central oscillations manifest better on one side. These oscillations may be dampened in the lower limb due to more crosstalk between bilateral neural tracts.
Through our preliminary observation, we conclude that asymmetrical upper limb tremor is a hallmark of SCA12.
Author Roles
(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique; (4) Supervision.
S.B.: 1A, 1B, 1C, 2C, 3A, 3B
S.C.: 2A, 2C, 3B
U.S.: 1C, 2C, 3C
P.B.: 1C, 2C, 3C
H.K.: 1A, 1B, 1C, 2A, 3B, 4
Disclosures
Ethical Compliance Statement
This study was approved by the Institute of Neurosciences Kolkata, Institutional Ethics Committee. Written informed consent to publish case reports and videos was obtained from all participants. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflicts of Interest
Institutional research fund of HK was used for this study. The authors declare no conflicts of interest relevant to this work.
Financial Disclosures for the Previous 12 Months
The authors declare that there are no additional disclosures to report.
Relevant disclosures and conflicts of interest are listed at the end of this article.
References
- 1. Choudhury S, Chatterjee S, Chatterjee K, et al. Clinical characterization of genetically diagnosed cases of spinocerebellar ataxia type 12 from India. Mov Disord Clin Pract 2018;5(1):39–46. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Kumar D, Srivastava AK, Faruq M, Gundluru VR. Spinocerebellar ataxia type 12: an update. Ann Mov Disord 2019;2(2):48. [Google Scholar]
- 3. O'Hearn EE, Hwang HS, Holmes SE, et al. Neuropathology and cellular pathogenesis of spinocerebellar a taxia type 12. Mov Disord 2015;30(13):1813–1824. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Kalia LV, Rockman‐Greenberg C, Borys A, Lang AE. Tremor in spinocerebellar ataxia type 12. Mov Disord Clin Pract 2014;1(1):76–78. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Ivan Donaldson CDM, Schneider S, Bhatia KP. Symptomatic tremors. In: Ivan Donaldson CDM, Schneider S, Bhatia KP, eds. Marsden's Book of Movement Disorders; Oxford, United Kingdom: Oxford University Press; 2012:710–723. [Google Scholar]