Warning: fopen(/home/virtual/e-jmd/journal/upload/ip_log/ip_log_2023-03.txt): failed to open stream: Permission denied in /home/virtual/lib/view_data.php on line 88 Warning: fwrite() expects parameter 1 to be resource, boolean given in /home/virtual/lib/view_data.php on line 89 Journal of Movement Disorders
Skip Navigation
Skip to contents

JMD : Journal of Movement Disorders

OPEN ACCESS
SEARCH
Search
Advanced Search
mobile menu button

Articles

Page Path
HOME > J Mov Disord > Volume 12(2); 2019 > Article
Brief communication
 The Effect of Globus Pallidus Interna Deep Brain Stimulation on a Dystonia Patient with the GNAL Mutation Compared to Patients with DYT1 and DYT6
Jong Hyeon Ahn1,2*orcid, Ah Reum Kim3,4*orcid, Nayoung K. D. Kim3, Woong-Yang Park3,5, Ji Sun Kim1,2, Minkyeong Kim1,2, Jongkyu Park6, Jung-Il Lee2,7, Jin Whan Cho1,2, Kyung Rae Cho2,7orcid, Jinyoung Youn1,2orcid
Journal of Movement Disorders 2019;12(2):120-124.
DOI: https://doi.org/10.14802/jmd.19006
Published online: May 30, 2019
  • 4,844 Views
  • 130 Download
  • 9 Crossref

1Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

2Neuroscience Center, Samsung Medical Center, Seoul, Korea

3Samsung Genome Institute, Samsung Medical Center, Seoul, Korea

4Medical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea

5Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea

6Department of Neurology, Soonchunhyang University Hospital, Gumi, Korea

7Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Corresponding author: Kyung Rae Cho, MD Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea / Tel: +82-2-6190-5261 / Fax: +82-2-3410-0048 / E-mail: krmd.cho@samsung.com
Corresponding author: Jinyoung Youn, MD, PhD Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea / Tel: +82-2-3410-0245 / Fax: +82-2-3410-0055 / E-mail: genian@skku.edu
*This authors contributed equally to this work.
• Received: January 9, 2019   • Revised: February 19, 2019   • Accepted: March 5, 2019

Copyright © 2019 The Korean Movement Disorder Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Full Article

Download PDF Download PDF

  • Objective
    The aim of this study was to investigate the efficacy of globus pallidus interna deep brain stimulation (GPi-DBS) for treating dystonia due to the GNAL mutation.
  • Methods
    We provide the first report of a dystonia patient with a genetically confirmed GNAL mutation in the Korean population and reviewed the literature on patients with the GNAL mutation who underwent GPi-DBS. We compared the effectiveness of DBS in patients with the GNAL mutation compared to that in patients with DYT1 and DYT6 in a previous study.
  • Results
    Patients with the GNAL mutation and those with DYT1 had higher early responder rates (GNAL, 5/5, 100%; DYT1, 7/7, 100%) than did patients with DYT6 (p = 0.047). The responder rates at late follow-up did not differ statistically among the three groups (p = 0.278). The decrease in the dystonia motor scale score in the GNAL group was 46.9% at early follow-up and 63.4% at late follow-up.
  • Conclusion
    GPi-DBS would be an effective treatment option for dystonia patients with the GNAL mutation who are resistant to medication or botulinum toxin treatment.
  • Keywords: Deep brain stimulation; GNAL; Dystonia; DYT25
GNAL (OMIM #615073) mutations have recently been identified as responsible for primary dystonia [1]. The GNAL mutation typically presents as adult onset (mean 32 years) craniocervical dystonia. Focal or segmental dystonia has also been reported, but generalized dystonia is relatively rare [1]. Deep brain stimulation (DBS) is an important therapeutic strategy for patients with dystonia who are unsuccessfully treated with medication or botulinum toxin injections. The efficacy and safety of globus pallidus interna (GPi) DBS has been well established for generalized or segmental primary dystonia in previous trials [2]. However, treatment for patients with the GNAL mutation has not been studied, and the efficacy and safety of DBS for these patients is not yet known. We reviewed previous reports of patients with the GNAL mutation who underwent GPi-DBS and reported the case of a patient with generalized dystonia due to the GNAL mutation who was successfully treated with bilateral GPi-DBS.
Patient and molecular genetic diagnosis using next-generation sequencing
We provide the first report of a Korean patient genetically confirmed to have the GNAL mutation by using next-generation sequencing. Genomic DNA was extracted from a patient blood sample. Whole exome sequencing (WES) was performed as follows. First, raw data were filtered for splice sites of known target genes and nonsynonymous coding regions related to dystonia. Second, variants with a minor allele frequency < 1% were filtered out based on population databases, including in-house and normal Korean datasets. Subsequently, strong candidates were evaluated according to American College of Medical Genetics, 2015 guidelines [3].
Comparison with previous reports of GNAL treated with GPi-DBS
We obtained studies from the PubMed database (http://www.ncbi.nlm.nih.gov/pubmed/) and Google Scholar by searching for keywords including GNAL, DYT25, and deep brain stimulation. We selected patients genetically confirmed to have the GNAL mutation who underwent GPi-DBS. The control group was identified by searching for keywords including DYT1, DYT6, TOR1A, THAP1, deep brain stimulation, and long-term follow up. We selected a study that included both DYT1 and DYT6 patients who underwent DBS surgery and reported follow-up data for more than 2 years. We excluded studies that did not identify the clinical character of each dystonia group or only included a specific phenotype. For the selected reports, we summarized the clinical characteristics and the effectiveness of the surgery compared with DYT1 and DYT6.
Statistical analysis
We compared the patients with the GNAL mutation with previous reports of patients with DYT1 and DYT6 [4]. Group comparisons were performed with the chi-squared test or analysis of variance depending on the variable. A responder was defined as a patient who showed more than a 25% improvement in motor score on the dystonia scale [5]. A p value < 0.05 was considered statistically significant. Statistical analysis was performed with IBM SPSS (version 25.0; IBM Corp., Armonk, NY, USA) software for Windows.
Ethical approval
This study was approved by the Institutional Review Board of Samsung Medical Center, Seoul, Korea (IRB No. 2019-01-012), and the patient provided informed consent to participate.
Clinical description and genetic findings
A 19-year-old, right-handed male was referred with generalized dystonia from age 12. He had no perinatal problems and reached normal developmental milestones by the age 12. He had no family history of dystonia or other neurologic diseases. The dystonia started at his trunk and spread to the other parts of the body. Upon neurological examination, his trunk deviated to the right side, and he had left shoulder elevation, left torticollis, and right laterocollis. Dystonia was present in both hands, especially when straightening his arms. The patient did not show any other abnormal movements, such as parkinsonism or myoclonus. Ceruloplasmin, a 24-hour urine test for copper levels, brain MRI, and whole spine MRI were normal. Levodopa (200 mg/day), trihexyphenidyl (12 mg/day), and baclofen (20 mg/day) were not effective. Additionally, botulinum toxin was injected to treat the truncal dystonia, but this treatment had little effect on the symptoms.
Bilateral GPi-DBS surgery was performed because of the insufficient response to the medication and botulinum toxin therapy. At the pre-DBS evaluation, the Burke-Fahn-Marsden dystonia rating scale (BFMDRS) motor section was scored 30 out of 120, and the disability scale was scored 10 out of 30 (Supplementary Video 1 in the online-only Data Supplement). Bilateral GPi-DBS was performed with standard stereotactic and microelectrode recording techniques (Supplementary Figure 1A in the online-only Data Supplement). Dystonia gradually improved after surgery. One year after surgery, the patient’s symptoms were improved, the BFMDRS motor section was rated 18 out of 120 and the disability score was 8 out of 30. The BFMDRS motor section was 9, and the disability score was 5 at two years after surgery (Supplementary Video 2 in the online-only Data Supplement). The patient showed an approximately 70% improvement in dystonia symptoms after surgery as estimated by the BFM-DRS score (from 30 to 9).
Genetic tests for DYT1 (TOR1A) and DYT6 (THAP1) were negative. WES was performed and analyzed for known dystonia target genes, and the test revealed heterozygosity for c.1060G>A(p. Val354Met), a missense mutation in exon 12 of the GNAL gene that was previously reported as a pathogenic variant (Supplementary Figure 1B in the online-only Data Supplement) [6].
Literature review of the efficacy of GPi-DBS in dystonia patients with the GNAL mutation
We reviewed patients with the GNAL mutation who underwent GPi-DBS [7-10]. A total of eight patients were evaluated, and demographic and dystonia-related information are summarized in Table 1. Three patients had generalized dystonia, four had segmental dystonia, and one had cervical dystonia. Five patients had early follow-up clinical data and showed good responses to GPi-DBS. All four patients who had late follow-up records showed a significant reduction in the dystonia motor scale score.
Comparisons of GNAL patients with DYT1 and DYT6
Brüggemann et al. [4] reported short- and long-term outcomes for chronic GPi-DBS in DYT1, DYT6, and non-DYT patients. We excluded non-DYT patients because the previous study did not perform a genetic test for the GNAL mutation. We compared the clinical characteristics and effect of GPi-DBS for GNAL patients with a previous study (Table 2). Patients with the GNAL mutation had an older age of onset than did patients with DYT1 and DYT6 (p < 0.001). Time until first DBS (p = 0.055) did not differ statistically. Four patients with the GNAL mutation were assessed with the BFMDRS, and the other three patients were assessed with the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). The baseline dystonia motor scale score did not differ in patients assessed with the BFMDRS (p = 0.100). Five patients in the GNAL group had early follow-up data, and these individuals had a higher responder rate (5/5, 100%) than did those in the DYT6 group. Patients with DYT1 also showed a higher responder rate than did patients with DYT6 (p = 0.047). The responder rates at late follow-up did not differ statistically among the three groups (p = 0.278). The decrease in the dystonia motor scale score in the GNAL group was 46.9% at early follow-up and 63.4% at late follow-up.
This study reviewed dystonia patients with the GNAL mutation who underwent DBS and found that these individuals had good responses to DBS. We also reported the first genetically confirmed case of generalized dystonia with the GNAL mutation in a Korean patient.
The patient with the GNAL mutation showed a good response at early and late follow-up. Five patients with the GNAL mutation had data available within one year after DBS. All five patients were classified as DBS responders and had a high reduction in the dystonia motor scale score. Brüggemann et al. [4] reported that the effect of DBS appears to be less predictable in patients with DYT6. These authors also reported that DYT6 had a lower responder rate at early follow-up and a similar responder rate at late follow-up. In our study, patients with the GNAL mutation had a higher response rate than did patients with DYT6 at early follow-up, and the response to DBS was sustained at late followup, similar to the response observed in the DYT1 and DYT6 groups. This result suggests that similar to patients with DYT1, bilateral GPi-DBS would be an effective treatment for patients with the GNAL mutation. Whether this robust effect of DBS surgery for patients with the GNAL mutation is due to their clinical characteristics, such as older age at onset, short time from onset to DBS, or dystonia distribution, remains uncertain. However, the genotype of dystonia patients contributes to the DBS response. In this regard, we suggest that GPi-DBS would be a good treatment option for dystonia patients with the GNAL mutation if they have the proper phenotype, such as cervical, craniocervical, or generalized dystonia, especially in patients who show unsatisfactory results with medication or botulinum toxin treatment.
The GNAL mutation was identified as causative for dystonia in 2013 [1]. The prevalence of the GNAL mutation in dystonia is estimated to be less than 1% [1,6]. Cervical dystonia is the most common phenotype (93%) associated with the GNAL mutation, followed by cranial (57%) and speech (44%) involvement [1]. Generalized dystonia is reported to have an incidence of only 11% among GNAL mutations. Our patient had childhood-onset generalized dystonia, which is an unusual phenotype among patients with the GNAL mutation. WES revealed heterozygosity for c.1060G>A(p.Val354Met), a missense mutation in exon 12 of the GNAL gene. This variant was previously reported as pathogenic in a 48-year-old male patient with familial segmental dystonia [6]. There is a significant clinical difference between the two patients. The previous patient had a family history of dystonia and segmental dystonia (cranial-laryngeal-cervical). However, our patient had no familial history and presented with childhood onset truncal dystonia, which progressed to generalized dystonia. To date, various dystonia phenotypes, including craniocervical dystonia, focal limb dystonia, and laryngeal dystonia, have been associated with the GNAL mutation. Further studies are needed to determine the phenotype-genotype matching of this mutation.
This study had several limitations. Our results were based on a literature review and a reported clinical feature. Thus, limited clinical information was available. Additionally, different clinical scales were used to assess dystonia severity depending on the study. Another limitation is the possibility of publication bias, and this study included only a limited number of patients. Therefore, the results should be interpreted carefully.
In summary, bilateral GPi-DBS can be an effective treatment option for dystonia patients with the GNAL mutation who are resistant to medical therapy or botulinum toxin treatment.
The online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.19006.

Supplementary Video Legends

Video 1. Preoperative state: dystonic posture was present in both hands, cervical and trunk and was aggravated by turning or walking.

Supplementary Video Legends

Video 2. Postoperative state: dystonic posture improved after bilateral globus pallidus interna deep brain stimulation surgery, especially while walking.

Supplementary Figure 1

A fusion image of the preoperative magnetic resonance image and a postoperative computed tomography image show deep brain stimulation electrodes located bilaterally on the globus pallidus (A). GNAL c.1060 G>A(p.Val354Met) (B).
jmd-19006-suppl.pdf

Conflicts of Interest

The authors have no financial conflicts of interest.

This work was supported by the KRIBB Research Initiative Program and by the Basic Science Research Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2014M3C9A2064619). This work was also supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT, Ministry of Science and ICT) (NRF-2017R1A2B4005276). The funding body had no role in study design, data collection, or analysis, decision to publish, or preparation of the manuscript.
Table 1.
Demographic and clinical characteristics of patients with the GNAL mutation
Case 1[9] Case 2[9] Case 3[9] Case 4[7] Case 5[8] Case 6[8] Case 7[10] Case 8 (index patient)
Distribution Segmental Cervical Generalized Segmental Segmental Segmental Generalized Generalized
Sex Female Male Female Female Male Female Female Male
Family history Y Y Y Y Y Y N N
Age at onset, year 38 42 18 54 36 42 47 12
Years until first DBS 15 11 23 6 19 20 n.a 7
DBS settings Left GPi: 0–3+, 4 V, 90 μs, 185 Hz Left GPi-1: C+0-, 3 V, 90 μs, 125 Hz Left GPi: C+1-, 4.5 V, 60 μs, 145 Hz Left GPi: C+8-, 2.3 V, 120 μs, 180 Hz Left GPi: C+1-, 2.5 V, 90 μs, 130 Hz Left GPi-1: C+0-, 1.25 V, 60 μs, 125 Hz n.a Left GPi: C+2-, 2.5 V, 150 μs, 150 Hz
Left GPi-2: C+1, 3 V, 90 μs, 125 Hz Left GPi-2: C+1-, 2 V, 60 μs, 125 Hz
Right GPi: 8–11+, 6 V, 120 μs, 185 Hz Right GPi-1: C+1-, 3 V, 90 μs, 125 Hz Right GPi: C+5-, 4.2 V, 90 μs, 145 Hz Right GPi: C+0-, 2.3 V, 120 μs, 180 Hz Right GPi: - 8+9, 2 V, 90 μs, 130 Hz Right GPi-1: C+1-, 2.15 V, 60 μs, 125 Hz Right GPi: C+2-, 2.5 V, 150 μs,150 Hz
Right GPi-2: C+0-, 3 V, 90 μs, 125 Hz Right GPi-2: C+2-, 60 μs, 125 Hz
Dystonia Motor Scale, Preoperative n.a 24† 21† 26* 16* 12* 22† 30*
Response rate (%)
 Early follow-up (1–12 months) n.a 29.2† 28.6† n.a 68.7* n.a. 68.2† 40.0*
 Late follow-up (12–96 months) n.a 45.8† 57.1† 80.8* n.a n.a n.a 70.0*

* Burke-Fahn-Marsden Dystonia Rating Scale,

† Toronto Western Spasmodic Torticollis Rating Scale.

DBS: deep brain stimulation, GPi: globus pallidus interna.

Table 2.
Comparison of the clinical characteristics and effectiveness of DBS
GNAL[7-10] DYT1[4] DYT6[4] p value
No. of patients 8 9 8
Distribution generalized/segmental/focal 3/4/1 8/0/1 5/3/0 0.143‡
Male/female 3/5 3/6 7/1 0.051‡
Family history positive/negative/unknown 6/2/0 5/4/0 4/3/1 0.551‡
Age at onset (year)
 Mean (SD) 36.4 (13.8) 11.2 (6.6) 10.0 (3.3) < 0.001§
 Range 14– 54 2–23 6–15
Years until first DBS
 Mean (SD) 14.4 (6.6) 20.1 (11.1) 27.0 (10.8) 0.055§
 Range 6–23 5–41 11–46
Dystonia scale, preoperative
 Motor, mean (SD) 21.0 (8.4)*, 22.3 (1.5)† 43.8 (30.7)* 37.0 (15.9)* 0.100§ǁ
Responder rate motor BFMDSR, n (%)
 Early follow-up (1–16 months) 5/5 (100) 7/7 (100) 4/7 (57.1) 0.047‡
 Late follow-up (22–96 months) 4/4 (100) 5/8 (62.5) 6/7 (85.7) 0.278‡
Reduction of dystonia scale (%)
 Early follow-up (1–16 months) 46.9 60 32 n.a
 Late follow-up (22–96 months) 63.4 44 42 n.a

* Burke-Fahn-Marsden Dystonia Rating Scale (BFMDSR),

† Toronto Western Spasmodic Torticollis Rating Scale,

‡ statistical analysis was performed with chi-square test,

§ statistical analysis was performed with analysis of variance,

ǁ comparison of the patients who were assessed by the BFMDSR.

DBS: deep brain stimulation.

  • 1. Fuchs T, Saunders-Pullman R, Masuho I, Luciano MS, Raymond D, Factor S, et al. Mutations in GNAL cause primary torsion dystonia. Nat Genet 2013;45:88–92.ArticlePubMedPDF
  • 2. Kupsch A, Benecke R, Müller J, Trottenberg T, Schneider GH, Poewe W, et al. Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N Engl J Med 2006;355:1978–1990.ArticlePubMed
  • 3. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405–424.ArticlePubMedPMCPDF
  • 4. Brüggemann N, Kühn A, Schneider SA, Kamm C, Wolters A, Krause P, et al. Short- and long-term outcome of chronic pallidal neurostimulation in monogenic isolated dystonia. Neurology 2015;84:895–903.ArticlePubMedPMC
  • 5. Volkmann J, Wolters A, Kupsch A, Müller J, Kühn AA, Schneider GH, et al. Pallidal deep brain stimulation in patients with primary generalised or segmental dystonia: 5-year follow-up of a randomised trial. Lancet Neurol 2012;11:1029–1038.ArticlePubMed
  • 6. LeDoux MS, Vemula SR, Xiao J, Thompson MM, Perlmutter JS, Wright LJ, et al. Clinical and genetic features of cervical dystonia in a large multicenter cohort. Neurol Genet 2016;2:e69.ArticlePubMedPMC
  • 7. Ziegan J, Wittstock M, Westenberger A, Dobričić V, Wolters A, Benecke R, et al. Novel GNAL mutations in two German patients with sporadic dystonia. Mov Disord 2014;29:1833–1834.ArticlePubMed
  • 8. Carecchio M, Panteghini C, Reale C, Barzaghi C, Monti V, Romito L, et al. Novel GNAL mutation with intra-familial clinical heterogeneity: expanding the phenotype. Parkinsonism Relat Disord 2016;23:66–71.ArticlePubMed
  • 9. Sarva H, Trosch R, Kiss ZHT, Furtado S, Luciano MS, Glickman A, et al. Deep brain stimulation in isolated dystonia with a GNAL mutation. Mov Disord 2019;34:301–303.ArticlePubMed
  • 10. Pandey S, Sankhla CS, Ramprasad VL, Geetha TS. Novel GNAL mutation in an Indian patient with generalized dystonia and response to deep brain stimulation. Parkinsonism Relat Disord 2019;Jan. 14. [Epub]. https://doi.org/10.1016/j.parkreldis.2019.01.011. Article

Figure & Data

References

    Citations

    Citations to this article as recorded by  
    • Isolated dystonia: clinical and genetic updates
      Aloysius Domingo, Rachita Yadav, Laurie J. Ozelius
      Journal of Neural Transmission.2021; 128(4): 405.     CrossRef
    • Abnormal cerebellar function and tremor in a mouse model for non‐manifesting partially penetrant dystonia type 6
      Meike E. Heijden, Dominic J. Kizek, Ross Perez, Elena K. Ruff, Michelle E. Ehrlich, Roy V. Sillitoe
      The Journal of Physiology.2021; 599(7): 2037.     CrossRef
    • Pallidal Deep Brain Stimulation for Monogenic Dystonia: The Effect of Gene on Outcome
      Stephen Tisch, Kishore Raj Kumar
      Frontiers in Neurology.2021;[Epub]     CrossRef
    • Arching deep brain stimulation in dystonia types
      Han-Joon Kim, Beomseok Jeon
      Journal of Neural Transmission.2021; 128(4): 539.     CrossRef
    • The Efficacy and Predictors of Using GPi-DBS to Treat Early-Onset Dystonia: An Individual Patient Analysis
      Wenxiu Chen, Houyou Fan, Guohui Lu, Fushun Wang
      Neural Plasticity.2021; 2021: 1.     CrossRef
    • Deep brain stimulation in dystonia: State of art and future directions
      A. Macerollo, V. Sajin, M. Bonello, D. Barghava, S. H Alusi, P. R Eldridge, J. Osman-Farah
      Journal of Neuroscience Methods.2020; 340: 108750.     CrossRef
    • Successful Pallidal Stimulation in a Patient with KMT2B-Related Dystonia
      Jun Kyu Mun, Ah Reum Kim, Jong Hyeon Ahn, Minkyeong Kim, Jin Whan Cho, Jung-Il Lee, Kyung Rae Cho, Jinyoung Youn
      Journal of Movement Disorders.2020; 13(2): 154.     CrossRef
    • Clinical characteristics of ataxia-telangiectasia presenting dystonia as a main manifestation
      Minkyeong Kim, Ah Reum Kim, Jongkyu Park, Ji Sun Kim, Jong Hyeon Ahn, Woong-Yang Park, Nayoung K.D. Kim, Chung Lee, Nam-Soon Kim, Jin Whan Cho, Jinyoung Youn
      Clinical Neurology and Neurosurgery.2020; 199: 106267.     CrossRef
    • Reply to: The Spectrum of Movement Disorders in 18p Deletion Syndrome
      David Crosiers, Bettina Blaumeiser, Gert Van Goethem
      Movement Disorders Clinical Practice.2019; 6(8): 731.     CrossRef

    JMD : Journal of Movement Disorders
    © The Korean Movement Disorder Society.