Journal of Movement Disorders

Letters to the editor

Clinical and Genetic Features of Huntington’s Disease Patients From Republic of Serbia: A Single-Center Experience: Nikola Kresojević, Ivana Perović, Iva Stanković, Aleksandra Tomić, Milica Jecˇmenica Lukic´, Vladana Marković, Tanja Stojković, Gorana Mandić, Milena Janković, Ana Marjanović, Marija Branković, Ivana Novaković, Igor Petrović, Nataša Dragašević, Elka Stefanova, Marina Svetel, Vladimir Kostić; J Mov Disord. 2023;16(3):333-335. Published online June 9, 2023; DOI: https://doi.org/10.14802/jmd.23028; Funded: Ministry of Education (Serbia), Science of the Republic of Serbia

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Pallidal Deep Brain Stimulation for Refractory Celiac-Related Myoclonus: Jinyoung Youn, Elizabeth Slow, Robert Chen, Andres M. Lozano, Alfonso Fasano; J Mov Disord. 2023;16(3):325-327. Published online June 9, 2023; DOI: https://doi.org/10.14802/jmd.23006; Funded: University of Toronto, University Health Network

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Review Article

GBA1 Variants and Parkinson’s Disease: Paving the Way for Targeted Therapy: Young Eun Huh, Tatiana Usnich, Clemens R. Scherzer, Christine Klein, Sun Ju Chung; J Mov Disord. 2023;16(3):261-278. Published online June 12, 2023; DOI: https://doi.org/10.14802/jmd.23023; Funded: National Research Foundation of Korea, Ministry of Science and ICT, Asan Institute for Life Sciences, Asan Medical Center

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Abstract PDF: Glucosylceramidase beta 1 (GBA1) variants have attracted enormous attention as the most promising and important genetic candidates for precision medicine in Parkinson’s disease (PD). A substantial correlation between GBA1 genotypes and PD phenotypes could inform the prediction of disease progression and promote the development of a preventive intervention for individuals at a higher risk of a worse disease prognosis. Moreover, the GBA1-regulated pathway provides new perspectives on the pathogenesis of PD, such as dysregulated sphingolipid metabolism, impaired protein quality control, and disrupted endoplasmic reticulum-Golgi trafficking. These perspectives have led to the development of novel disease-modifying therapies for PD targeting the GBA1-regulated pathway by repositioning treatment strategies for Gaucher’s disease. This review summarizes the current hypotheses on a mechanistic link between GBA1 variants and PD and possible therapeutic options for modulating GBA1-regulated pathways in PD patients.

Case Report

Rapid-Onset Dystonia and Parkinsonism in a Patient With Gaucher Disease: Ellen Hertz, Grisel Lopez, Jens Lichtenberg, Dietrich Haubenberger, Nahid Tayebi, Mark Hallett, Ellen Sidransky; J Mov Disord. 2023;16(3):321-324. Published online June 13, 2023; DOI: https://doi.org/10.14802/jmd.23074; Funded: National Human Genome Research Institute, National Institutes of Health

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Abstract PDF Supplementary Material: Biallelic mutations in GBA1 cause the lysosomal storage disorder Gaucher disease, and carriers of GBA1 variants have an increased risk of Parkinson’s disease (PD). It is still unknown whether GBA1 variants are also associated with other movement disorders. We present the case of a woman with type 1 Gaucher disease who developed acute dystonia and parkinsonism at 35 years of age during a recombinant enzyme infusion treatment. She developed severe dystonia in all extremities and a bilateral pill-rolling tremor that did not respond to levodopa treatment. Despite the abrupt onset of symptoms, neither Sanger nor whole genome sequencing revealed pathogenic variants in ATP1A3 associated with rapid-onset dystonia-parkinsonism (RDP). Further examination showed hyposmia and presynaptic dopaminergic deficits in [18F]-DOPA PET, which are commonly seen in PD but not in RDP. This case extends the spectrum of movement disorders reported in patients with GBA1 mutations, suggesting an intertwined phenotype.

Original Article

KMT2B-Related Dystonia in Indian Patients With Literature Review and Emphasis on Asian Cohort: Debjyoti Dhar, Vikram V Holla, Riyanka Kumari, Neeharika Sriram, Jitender Saini, Ravi Yadav, Akhilesh Pandey, Nitish Kamble, Babylakshmi Muthusamy, Pramod Kumar Pal; J Mov Disord. 2023;16(3):285-294. Published online June 13, 2023; DOI: https://doi.org/10.14802/jmd.23035; Funded: National Institute of Mental Health, Indian Council for Medical Research Fund

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Abstract PDF Supplementary Material: Objective
aaMutations in the KMT2B gene have been identified in patients previously diagnosed with idiopathic dystonia. Literature on KMT2B-related dystonia is sparse in the Indian and Asian populations.
Methods
aaWe report seven patients with KMT2B-related dystonia studied prospectively from May 2021 to September 2022. Patients underwent deep clinical phenotyping and genetic testing by whole-exome sequencing (WES). A systematic literature search was performed to identify the spectrum of previously published KMT2B-related disorders in the Asian subcontinent.
Results
aaThe seven identified patients with KMT2B-related dystonia had a median age at onset of four years. The majority experienced onset in the lower limbs (n = 5, 71.4%), with generalization at a median duration of 2 years. All patients except one had complex phenotypes manifesting as facial dysmorphism (n = 4), microcephaly (n = 3), developmental delay (n = 3), and short stature (n = 1). Magnetic resonance imaging (MRI) abnormalities were present in four cases. WES revealed novel mutations in the KMT2B gene in all patients except one. Compared to the largest cohort of patients with KMT2B-related disorders, the Asian cohort, comprising 42 patients, had a lower prevalence of female patients, facial dysmorphism, microcephaly, intellectual disability, and MRI abnormalities. Protein-truncating variants were more prevalent than missense variants. While microcephaly and short stature were more common in patients with missense mutations, facial dysmorphism was more common in patients with truncating variants. Deep brain stimulation, performed in 17 patients, had satisfactory outcomes.
Conclusion
aaThis is the largest series of patients with KMT2B-related disorders from India, further expanding the clinico-genotypic spectrum. The extended Asian cohort emphasizes the unique attributes of this part of the world.

Viewpoint

From Evidence to the Dish: A Viewpoint of Implementing a Thai-Style Mediterranean Diet for Parkinson’s Disease: Onanong Phokaewvarangkul, Nitinan Kantachadvanich, Vijittra Buranasrikul, Appasone Phoumindr, Saisamorn Phumphid, Priya Jagota, Roongroj Bhidayasiri; J Mov Disord. 2023;16(3):279-284. Published online June 19, 2023; DOI: https://doi.org/10.14802/jmd.23021; Funded: Thailand Science Research and Innovation, Chulalongkorn University

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Letter to the editor

Dystonic Opisthotonus in Kufor-Rakeb Syndrome: Expanding the Phenotypic and Genotypic Spectrum: Sandeep Gurram, Vikram V Holla, Riyanka Kumari, Debjyoti Dhar, Nitish Kamble, Ravi Yadav, Babylakshmi Muthusamy, Pramod Kumar Pal; J Mov Disord. 2023;16(3):343-346. Published online July 25, 2023; DOI: https://doi.org/10.14802/jmd.23098; Funded: Parkinson’s Disease and Movement Disorders Research Fund, Indian Council of Medical Research

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Original Article

Clinical Characteristics, Genetic Features, and Long-Term Outcome of Wilson’s Disease in a Taiwanese Population: An 11-Year Follow-Up Study: Sung-Pin Fan, Yih-Chih Kuo, Ni-Chung Lee, Yin-Hsiu Chien, Wuh-Liang Hwu, Yu-Hsuan Huang, Han-I Lin, Tai-Chung Tseng, Tung-Hung Su, Shiou-Ru Tzeng, Chien-Ting Hsu, Huey-Ling Chen, Chin-Hsien Lin, Yen-Hsuan Ni; J Mov Disord. 2023;16(2):168-179. Published online March 6, 2023; DOI: https://doi.org/10.14802/jmd.22161; Funded: National Taiwan University Hospital

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Abstract PDF Supplementary Material: Objective
aaWilson’s disease (WD) is a rare genetic disorder of copper metabolism, and longitudinal follow-up studies are limited. We performed a retrospective analysis to determine the clinical characteristics and long-term outcomes in a large WD cohort.
Methods
aaMedical records of WD patients diagnosed from 2006–2021 at National Taiwan University Hospital were retrospectively evaluated for clinical presentations, neuroimages, genetic information, and follow-up outcomes.
Results
aaThe present study enrolled 123 WD patients (mean follow-up: 11.12 ± 7.41 years), including 74 patients (60.2%) with hepatic features and 49 patients (39.8%) with predominantly neuropsychiatric symptoms. Compared to the hepatic group, the neuropsychiatric group exhibited more Kayser-Fleischer rings (77.6% vs. 41.9%, p < 0.01), lower serum ceruloplasmin levels (4.9 ± 3.9 vs. 6.3 ± 3.9 mg/dL, p < 0.01), smaller total brain and subcortical gray matter volumes (p < 0.0001), and worse functional outcomes during follow-up (p = 0.0003). Among patients with available DNA samples (n = 59), the most common mutations were p.R778L (allelic frequency of 22.03%) followed by p.P992L (11.86%) and p.T935M (9.32%). Patients with at least one allele of p.R778L had a younger onset age (p = 0.04), lower ceruloplasmin levels (p < 0.01), lower serum copper levels (p = 0.03), higher percentage of the hepatic form (p = 0.03), and a better functional outcome during follow-up (p = 0.0012) compared to patients with other genetic variations.
Conclusion
aaThe distinct clinical characteristics and long-term outcomes of patients in our cohort support the ethnic differences regarding the mutational spectrum and clinical presentations in WD.

Letter to the editor

The Frequency of Korean Patients With Parkinson’s Disease Carrying GBA Mutations in a Subgroup With Age at Onset ≤ 55 Years Old: Jin Hwangbo, Myung Jun Lee, Sang Jin Kim, Jae‑Hyeok Lee; J Mov Disord. 2023;16(2):207-209. Published online March 7, 2023; DOI: https://doi.org/10.14802/jmd.22191; Funded: Pusan National University Yangsan Hospital

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Case Report

Novel Compound Heterozygous Mutations in the SYNE1 Gene in a Taiwanese Family: A Case Report and Literature Review: Chia-Yan Kuo, Pei Shan Yu, Chih-Ying Chao, Chun-Chieh Wang, Wen-Lang Fan, Yih-Ru Wu; J Mov Disord. 2023;16(2):202-206. Published online April 26, 2023; DOI: https://doi.org/10.14802/jmd.22105; Funded: Ministry of Science and Technology, Taiwan, Chang Gung Memorial Hospital

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Abstract PDF Supplementary Material: Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene are associated with substantial clinical heterogeneity. Here, we report the first case of SYNE1 ataxia in Taiwan due to two novel truncating mutations. Our patient, a 53-year-old female, exhibited pure cerebellar ataxia with c.1922del in exon 18 and c. C3883T mutations in exon 31. Previous studies have indicated that the prevalence of SYNE1 ataxia among East Asian populations is low. In this study, we identified 27 cases of SYNE1 ataxia from 22 families in East Asia. Of the 28 patients recruited in this study (including our patient), 10 exhibited pure cerebellar ataxia, and 18 exhibited ataxia plus syndromes. We could not find an exact correlation between genotypes and phenotypes. Additionally, we established a precise molecular diagnosis in our patient’s family and extended the findings on the ethnic, phenotypic, and genotypic diversity of the SYNE1 mutational spectrum.

Original Article

Safinamide as an Adjunct to Levodopa in Asian and Caucasian Patients With Parkinson’s Disease and Motor Fluctuations: A Post Hoc Analysis of the SETTLE Study: Roongroj Bhidayasiri, Takayuki Ishida, Takanori Kamei, Ryan Edbert Husni, Ippei Suzuki, Shey Lin Wu, Jin Whan Cho; J Mov Disord. 2023;16(2):180-190. Published online April 26, 2023; DOI: https://doi.org/10.14802/jmd.22196; Funded: Eisai Co. Ltd., Newron Pharmaceuticals, Merck Serono

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Abstract PDF Supplementary Material: Objective
Safinamide is a selective, reversible monoamine oxidase B inhibitor with demonstrated efficacy and tolerability in placebo-controlled studies and is clinically useful for patients with motor fluctuations. This study evaluated the efficacy and safety of safinamide as a levodopa adjunct therapy in Asian patients with Parkinson’s disease.
Methods
Data from 173 Asian and 371 Caucasian patients from the international Phase III SETTLE study were included in this post hoc analysis. The safinamide dose was increased from 50 mg/day to 100 mg/day if no tolerability issues occurred at week 2. The primary outcome was the change from baseline to week 24 in daily ON-time without troublesome dyskinesia (i.e., ON-time). Key secondary outcomes included changes in Unified Parkinson’s Disease Rating Scale (UPDRS) scores.
Results
Safinamide significantly increased daily ON-time relative to placebo in both groups (least-squares mean: 0.83 hours, p = 0.011 [Asians]; 1.05 hours, p < 0.0001 [Caucasians]). Motor function relative to placebo (UPDRS Part III) improved significantly in Asians (-2.65 points, p = 0.012) but not Caucasians (-1.44 points, p = 0.0576). Safinamide did not worsen Dyskinesia Rating Scale scores in either subgroup, regardless of the presence or absence of dyskinesia at baseline. Dyskinesia was largely mild for Asians and moderate for Caucasians. None of the Asian patients experienced adverse events leading to treatment discontinuation.
Conclusion
Safinamide as a levodopa adjunct is well tolerated and effective in reducing motor fluctuations in both Asian and Caucasian patients. Further studies to investigate the real-world effectiveness and safety of safinamide in Asia are warranted.

Letter to the editor

Absence of Alpha-Synuclein Pathology in the Stomach of a Patient With Prodromal Dementia With Lewy Bodies: Chaewon Shin, Seong-Ik Kim, Sung-Hye Park, Jung Hwan Shin, Chan Young Lee, Han-Joon Kim, Hyuk-Joon Lee, Seong-Ho Kong, Yun-Suhk Suh, Han-Kwang Yang, Beomseok Jeon; J Mov Disord. 2023;16(2):213-216. Published online April 26, 2023; DOI: https://doi.org/10.14802/jmd.22219; Funded: Seoul National University Hospital, Chungnam National University Sejong Hospital, National Research Foundation of Korea

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Review Article

A Brief History of NBIA Gene Discovery: Susan J. Hayflick; J Mov Disord. 2023;16(2):133-137. Published online April 26, 2023; DOI: https://doi.org/10.14802/jmd.23014; Funded: National Institutes of Health, Nuclear Energy Institute, National Institute of Neurological Disorders and Stroke, National Institute of Child Health and Human Development, NBIA Disorders Association, Hoffnungsbaum e.V., AISNAF

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Abstract PDF: Neurodegenerative disorders associated with high basal ganglia iron are known by the overarching term of ‘NBIA’ disorders or ‘neurodegeneration with brain iron accumulation’. Discovery of their individual genetic bases was greatly enabled by the collection of DNA and clinical data in just a few centers. With each discovery, the remaining idiopathic disorders could be further stratified by common clinical, radiographic or pathological features to enable the next hunt. This iterative process, along with strong and open collaborations, enabled the discoveries of PANK2, PLA2G6, C19orf12, FA2H, WDR45, and COASY gene mutations as underlying PKAN, PLAN, MPAN, FAHN, BPAN, and CoPAN, respectively. The era of Mendelian disease gene discovery is largely behind us, but the history of these discoveries for the NBIA disorders has not yet been told. A brief history is offered here.

Brief communication

Sex and Gender Influence Urinary Symptoms and Management in Multiple System Atrophy: Elke Schipani Bailey, Sara J. Hooshmand, Negin Badihian, Paola Sandroni, Eduardo E. Benarroch, James H. Bower, Phillip A. Low, Wolfgang Singer, Elizabeth A. Coon; J Mov Disord. 2023;16(2):196-201. Published online May 24, 2023; DOI: https://doi.org/10.14802/jmd.23016; Funded: National Center for Advancing Translational Sciences, National Institutes of Health, Michael J. Fox Foundation, Bishop Dr. Karl Golser Foundation, Sturm Foundation, Mayo Center for Regenerative Medicine, Mayo Funds

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Abstract PDF: Objective
Multiple system atrophy (MSA) is characterized by urinary dysfunction, yet the influence of sex and gender on urinary symptoms and treatment is unclear. We sought to characterize sex and gender differences in the symptomatology, evaluation, and management of urinary dysfunction in patients with MSA.
Methods
Patients with MSA evaluated at our institution were reviewed and stratified by sex.
Results
While the prevalence of urinary symptoms was similar in male and female patients, incontinence was more common in females. Despite this, males and females underwent postvoid residual (PVR) measurement at similar rates. While catheterization rates were similar when PVR was measured, males were more than twice as likely to be catheterized than females in the absence of PVR measurement.
Conclusion
Urinary symptoms are common in MSA, but their presentation differs between males and females. The difference in catheterization rates may be driven by a gender disparity in referrals for PVR, which can guide treatment.

Letter to the editor

Investigation of the Long-Term Effects of Amantadine Use in Parkinson’s Disease: Sangmin Park, Jung Hwan Shin, Seung Ho Jeon, Chan Young Lee, Han-Joon Kim, Beomseok Jeon; J Mov Disord. 2023;16(2):224-226. Published online May 24, 2023; DOI: https://doi.org/10.14802/jmd.23037; Funded: Seoul National University Hospital

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