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Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.

Background: Myoclonus and tremor are common movement disorder phenomenologies in steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT). Pure ataxia without encephalopathy has rarely been reported. Case report: We report 21- and 40-year-old females who presented with subacute pure ataxia without encephalopathy. After immunotherapies, both exhibited initial improvement of ataxia, and subsequently remained in plateau phase. Discussion: This treatable disorder should be added to the differential diagnoses of progressive cerebellar ataxia, and anti-thyroid peroxidase and anti-thyroglobulin should be considered as part of the workup. It is crucial not to misdiagnose SREAT presenting with pure cerebellar ataxia as degenerative or spinocerebellar ataxia.

Aberrant sensory processing plays a fundamental role in the pathophysiology of dystonia; however, its underpinning neural mechanisms in relation to dystonia phenotype and genotype remain unclear. We examined temporal and spatial discrimination thresholds in patients with isolated laryngeal form of dystonia (LD), who exhibited different clinical phenotypes (adductor vs. abductor forms) and potentially different genotypes (sporadic vs. familial forms). We correlated our behavioral findings with the brain gray matter volume and functional activity during resting and symptomatic speech production. We found that temporal but not spatial discrimination was significantly altered across all forms of LD, with higher frequency of abnormalities seen in familial than sporadic patients. Common neural correlates of abnormal temporal discrimination across all forms were found with structural and functional changes in the middle frontal and primary somatosensory cortices. In addition, patients with familial LD had greater cerebellar involvement in processing of altered temporal discrimination, whereas sporadic LD patients had greater recruitment of the putamen and sensorimotor cortex. Based on the clinical phenotype, adductor form-specific correlations between abnormal discrimination and brain changes were found in the frontal cortex, whereas abductor form-specific correlations were observed in the cerebellum and putamen. Our behavioral and neuroimaging findings outline the relationship of abnormal sensory discrimination with the phenotype and genotype of isolated LD, suggesting the presence of potentially divergent pathophysiological pathways underlying different manifestations of this disorder.

Dong-Hwan Kim,1 Ubonvan Termsarasab,1 Hyun-Jong Cho,2 In-Soo Yoon,3 Jae-Young Lee,1 Hyun Tae Moon,1 Dae-Duk Kim1 1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; 2College of Pharmacy, Kangwon National University, Chuncheon, Republic of Korea; 3College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam, Republic of Korea Abstract: Low-molecular-weight heparin (LMWH)–stearylamine (SA) conjugates (LHSA)-based self-assembled nanoparticles were prepared for intravenous delivery of docetaxel (DCT). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide were used as coupling agents for synthesis of LHSA conjugates. The physicochemical properties, in vitro antitumor efficacy, in vitro cellular uptake efficiency, in vivo antitumor efficacy, and in vivo pharmacokinetics of LHSA nanoparticles were investigated. The LHSA nanoparticles exhibited a spherical shape with a mean diameter of 140–180 nm and a negative surface charge. According to in vitro release and in vivo pharmacokinetic test results, the docetaxel-loaded LHSA5 (LMWH:SA =1:5) nanoparticles exhibited sustained drug release profiles. The blank LHSA nanoparticles demonstrated only an insignificant cytotoxicity in MCF-7 and MDAMB 231 human breast cancer cells; additionally, higher cellular uptake of coumarin 6 (C6) in MCF-7 and MDAMB 231 cells was observed in the LHSA5 nanoparticles group than that in the C6 solution group. The in vivo tumor growth inhibition efficacy of docetaxel-loaded LHSA5 nanoparticles was also significantly higher than the Taxotere®-treated group in the MDAMB 231 tumor-xenografted mouse model. These results indicated that the LHSA5-based nanoparticles could be a promising anticancer drug delivery system. Keywords: amphiphilic polymer, docetaxel, drug delivery, low-molecular-weight heparin, self-assembled nanoparticle

Background: Paraneoplastic movement disorders in prostate cancer are rare, and to our knowledge paraneoplastic myoclonus has not previously been reported. Case Report: We report two men with adenocarcinoma of the prostate who developed isolated alcohol-responsive action myoclonus of one leg. Myoclonus was absent at rest but triggered by movement, standing, or walking. Evaluations excluded malignant invasion of the nervous system, and testing for commercial paraneoplastic antibodies in serum and cerebrospinal fluid were unrevealing. Both patients experienced significant improvement with alcohol, and sodium oxybate was used in one patient with good initial benefit. Discussion: Alcohol-responsive leg myoclonus might be a novel paraneoplastic syndrome associated with prostate cancer. The nature of the syndrome and the source of the myoclonus are currently unknown.

Background: ATP1A3-related disorders include rapid-onset dystonia–parkinsonism (RDP or DYT12), alternating hemiplegia of childhood (AHC), and CAPOS syndrome (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss). Case Report: We report two cases with intermediate forms between RDP and AHC. Patient 1 initially presented with the AHC phenotype, but the RDP phenotype emerged at age 14 years. The second patient presented with levodopa-responsive paroxysmal oculogyria, a finding never before reported in ATP1A3-related disorders. Genetic testing confirmed heterozygous changes in the ATP1A3 gene in both patients, one of them novel. Discussion: Intermediate phenotypes of RDP and AHC support the concept that these two disorders are part of a spectrum. We add our cases to the phenotype–genotype correlations of ATP1A3-related disorders.

Background: Various movement disorders can be found in ataxia-telangiectasia (AT), including ataxia, dystonia, chorea, and myoclonus, but myoclonus has rarely been described as the predominant feature in AT. Case Report: We report two AT patients with prominent myoclonus in relative isolation, illustrating an unusual presentation of this disorder. Sequencing of the ATM gene in the first patient revealed a homozygous truncating mutation, c.5908C>T (p.Q1970*) in exon 38 of the ATM gene which has been previously reported as a founder mutation in the Costa Rican population. Discussion: Myoclonus can be a predominant or presenting feature in AT, even without dystonia.

Background: Four cases of paroxysmal kinesigenic dyskinesia (PKD) have been reported in individuals with proximal 16p11.2 microdeletions that include PRRT2. Case Report: We describe a fifth patient with PKD, features of Asperger’s syndrome, and mild language delays. Sanger sequencing of the PRRT2 gene did not identify any mutations implicated in PKD. However, microarray‐based comparative genomic hybridization (aCGH) detected a 533.9‐kb deletion on chromosome 16, encompassing over 20 genes and transcripts. Discussion: This case underscores the importance of aCGH testing for individuals with PKD who do not have PRRT2 mutations, particularly when developmental delays, speech problems, intellectual disability, and/or autism spectrum disorder are present.

• Micrographia, difficulty writing can impact a quality of life in Parkinson disease. • 4-Week handwriting exercise improved writing speed and manual fine motor function. • The exercise provides visual cueing and feedback. • Repetitive stimulation of locomotive circuit may result in neuroplasticity. Parkinson disease (PD) patients frequently experience micrographia and difficulty writing, which could potentially impact their quality of life. This study aimed to determine whether handwriting exercise could improve fine manual motor function in PD. The study was a randomized controlled trial assessing the efficacy of a 4-week handwriting exercise using a newly developed handwriting practice book. The primary endpoint was an improvement in the time used to complete the handwriting test. Secondary endpoints were accuracy of the writing performance, patient's subjective rating scale of their handwriting and a UPDRS part III motor examination. Of a total of 46 subjects, 23 were randomly assigned to the handwriting exercise group. After 4 weeks, the mean time used to complete the test was significantly lower in the exercise group, compared to the control group (143.43 ± 34.02 vs. 175 ± 48.88 s, p = 0.015). Mean time used to complete the handwriting test decreased from the baseline by 16.16% in the exercise group, but increased by 3.63% in the control group (p < 0.001). Significant improvements were also observed by assessing the subjective rating scale and the UPDRS part III scores. The 4-week handwriting exercise using the studied handwriting practice book appears to promote an improvement in writing speed and motor function of hands. The optimal duration and frequency of the exercise, the quantity and characteristic of the letters in the handwriting practice book, and the benefits of the exercise in other languages merit further studies. [ABSTRACT FROM AUTHOR]

A chitosan oligosaccharide (CSO)-indomethacin (IDM) conjugate (CI) was synthesized to fabricate chemosensitizing nanoparticles (NPs) for tumor-targeted drug delivery. IDM was conjugated to a CSO backbone via amide bond formation, of which successful synthesis was confirmed by proton-nuclear magnetic resonance analyses. Doxorubicin (DOX)-loaded CI (CI10/DOX; CI:DOX = 10:1 [w/w]) NPs with <75 nm of mean diameter, polydispersity index of ∼0.2, and positive zeta potential were prepared. The release of DOX from the NPs was enhanced at acidic pH (pH 5.5 and 6.8) compared to physiological pH (pH 7.4). The release of IDM increased in the presence of A549 cell lysates. In A549 cells (human lung carcinoma cells), more efficient cellular uptake of CI10/DOX NPs than that of free DOX was observed by using confocal laser scanning microscopy and flow cytometry. The in vitro cytotoxicity of CI10/DOX NPs in A549 cells was higher than those of free DOX and CI NPs with free DOX groups. In vivo pharmacokinetic studies after intravenous administration in rats showed significantly lower clearance of DOX from NPs compared with the free DOX group. Tumor targetability of the developed CI NPs was also verified by a real-time optical imaging study. In summary, the chemosensitizing CI/DOX NP with enhanced anticancer activity, prolonged blood circulation, and passive tumor targeting can be a promising anticancer drug delivery system for tumor-targeted therapy. Statement of Significance Chemosensitizing nanoparticles (NPs) based on amphiphilic chitosan oligosaccharide-indomethacin (CSO-IDM; CI) conjugate were developed for tumor-targeted delivery of doxorubicin (DOX). IDM was introduced to the CSO backbone as a hydrophobic residue to synthesize an amphiphilic conjugate and a chemosenstizer of DOX for improving antitumor efficacies. IDM, conjugated to CSO, may inhibit the efflux of cellular uptaken DOX via multidrug resistance-associated protein (MRP) and subsequently augment the anti-proliferation potentials of DOX in A549 cells (MRP-expressed human lung cancer cells). Chemosensitizing properties of developed CI NPs were assessed in cell culture models and the tumor targetability of CI/DOX NPs was demonstrated in A549 tumor-xenografted mouse model by a real-time optical imaging. Developed CI NPs can be used as a multifunctional nanosystem for the therapy of MRP-expressed cancers. [ABSTRACT FROM AUTHOR]

Azathioprine is used for immunosuppression in myasthenia gravis (MG). We report a patient with seropositive MG who developed a brainstem lymphoma 4 years after being treated with azathioprine and review the literature on the occurrence of lymphoma in this patient population. An 82-year-old man with ocular MG who had been on azathioprine for 4 years developed subacute worsening of bulbar symptoms including diplopia, dysarthria and dysphagia mimicking MG exacerbation. Neuroimaging followed by biopsy showed brainstem diffuse large B-cell lymphoma (DLBCL). To our knowledge this is the first reported patient with brainstem DLBCL after azathioprine treatment in MG. Lymphoma has been reported in MG patients treated with azathioprine, although the incidence is unknown. We suggest reduction of azathioprine dose and subsequent discontinuation, if possible, in MG patients who are in remission. Special caution should be taken with elderly patients and Epstein-Barr virus serology prior to initiation may be useful in this population, but this requires further study. [ABSTRACT FROM AUTHOR]

Summary Skeletal muscles undergo atrophy in response to diseases and aging. Here we report that mitofusin 2 (Mfn2) acts as a dominant suppressor of neuromuscular synaptic loss to preserve skeletal muscles. Mfn2 is reduced in spinal cords of transgenic SOD1 G93A and aged mice. Through preserving neuromuscular synapses, increasing neuronal Mfn2 prevents skeletal muscle wasting in both SOD1 G93A and aged mice, whereas deletion of neuronal Mfn2 produces neuromuscular synaptic dysfunction and skeletal muscle atrophy. Neuromuscular synaptic loss after sciatic nerve transection can also be alleviated by Mfn2. Mfn2 coexists with calpastatin largely in mitochondria-associated membranes (MAMs) to regulate its axonal transport. Genetic inactivation of calpastatin abolishes Mfn2-mediated protection of neuromuscular synapses. Our results suggest that, as a potential key component of a novel and heretofore unrecognized mechanism of cytoplasmic protein transport, Mfn2 may play a general role in preserving neuromuscular synapses and serve as a common therapeutic target for skeletal muscle atrophy. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Roy N. Alcalay received consulting fees from Avrobio, Caraway, Ono Therapeutics, GSK, Merck, Sanofi, Janssen and grants from the Michael J. Fox Foundation, DOD, the Parkinson’s Disease Foundation, and the NIH. Melinda Barkhuizen received a PhD scholarship from the National Research Foundation of South Africa (grant numbers 89230 and 98217) and internal funding from the research center where the study was conducted (DST/NWU Preclinical Drug Development Platform, North-West University, South Africa); Ampath Pathology laboratories in South Africa donated services in the form of drawing participant blood for DNA extractions, Several neurologists in South Africa assisted the authors with identifying patients with Parkinson`s disease and referring them to the genotyping study; the North-West University, South Africa provided Ethical oversight and approval of the genotyping project. Vincenzo Bonifati received grants from Stichting Parkinson Fonds (Netherlands) and Alzheimer Nederland, he received honoraria from the International Parkinson and Movement Disorder Society (MDS), for lectures and as Chair of the International Congress Scientific Program Committee (2020-2021), and from Elsevier Ltd. as co-Editor in Chief of the journal Parkinsonism & Related Disorders (2018-current); he is unpaid member of the Stichting Parkinson Fonds (Netherlands). Kathrin Brockmann received grants from the German Federal Ministry of Education and Research (BMBF; PDStrat; FKZ 031L0137B) and from the German Center for Neurodegenerative Diseases (DZNE), consulting fees from Abbvie, Lundbeck, UCB, Zambon, Roche, and honoraria from Abbvie and UCB. Jordi Clarimon is full-time employee at Lundbeck A/S (Denmark). Mario Cornejo-Olivas has subcontracts with Cleveland Clinic and San Marcos Foundation for recruiting participants for the LARGE PD study in Peru. Jean-Christophe Corvol received grants from Sanofi and the Michael J. Fox Foundation, consulting fees from Biogen, UCB, Denali, Idorsia, Prevail therapeutics, Theranexus, and honoraria from Biogen. Joana Damásio received honoraria from Zambon Pharmaceuticals. Anna De Rosa received grants for ROPAD – the Rostock International Parkinson’s Disease Study, sponsored by Centogene and grants from Zambon and AIFA (Italian Agency of Drug), and she is member of the advisory board at BIAL. Joaquim Ferreira received grants from Fundação MSD (Portugal), Novartis, Medtronic, and Abbvie, and lecture fees from Lundbeck, Abbvie, BIAL, Biogen, Sunovion Pharmaceuticals, ONO, Affiris, and Zambon, payment for expert testimony from Novartis, and he participates in advisory boards of Lundbeck, Abbvie, BIAL, Affiris, Sunovion Pharmaceuticals, and Zambon; he is employed by CNS (Campus Néurologico Sénior) and the Medical Faculty of Lisbon. Emilia Gatto received consulting fees from Bago Argentina, honoraria from Bago Argentina,UCB, IPMDS, and Europharm, and participates in advisory boards of Bago Argentina and UCB. Nir Giladi received grants from the Michael J Fox Foundation, The National Parkinson Foundation, The European Union, The Israel Science Foundation Teva, NNE program, Biogen, Ionis, Sieratzki Family Foundation, and The Aufzien Academic Center in Tel-Aviv University; he holds royalties or licenses at Lysosomal Therapeutics (LTI); he received consulting fees from Sionara, NeuroDerm, Pharma2B, Denali, Neuron23, Sanofi-Genzyme, Biogen, and Abbvie; he received honoraria from Abbvie, Sanofi-Genzyme, and the Movement Disorder Society. Nobutaka Hattori received grants from the Japan Society for the Promotion of Science (JSPS; 18H04043, 21H04820, 19K22603), the Japan Agency for Medical Research and Development (AMED; JP20dm0307101, JP20dm0207070, JP20ek0109358, JP19ek0109393, JP19gm0710011, JP19km0405206), Health Labour Sciences Research Grant (20FC1049, H29-FC1-062, H29-FC1-033), and the Japan Science and Technology Agency (JPMJMS2024-5); he participates in advisory boards at Dai-Nippon Sumitomo Pharma, Takeda Pharmaceutical, Kyowa Kirin, TEIJIN PHARMA LIMITED, Novartis Pharma, Ono Pharmaceutical, Biogen Idec Japan, and Kissei Pharmaceutical; he receives consulting fees from Hisamitsu Pharma; he received honoraria from Dai-Nippon Sumitomo Pharma, Takeda Pharmaceutical, Kyowa Kirin, AbbVie GK, Nippon Boehringer Ingelheim, Otsuka Pharmaceutical, Novartis Pharma, Bristol-Myers Squibb, Ono Pharmaceutical, FP Pharmaceutical, Eisai, Kissei Pharmaceutical, Nihon Medi-physics, and Daiichi Sankyo; he received payment for expert testimony from Mitsubishi Tanabe Pharma; he received support for attending meeting from Takeda Pharmaceutical, and Kyowa Kirin; he has 17 patents planned or pending and 5 issued; he is Team Leader at the Neurodegenerative Disorders Collaborative Laboratory, RIKEN Center for Brain Science; he holds equity stock (8%) of PARKINSON Laboratories Co. Ltd., unrelated to the submitted work. Silvia Jesús has received grants from “Consejería de Salud y Familias” PI-0459-2018, “acción B Clínicos-Investigdores” B-0007-2019 and from the “instituto de Salud Carlos III” PI-18/01898; she received honoraria from Abbvie, Bial, Merz, UCB, Italfarmaco, Zambon and Server. Valtteri Kaasinen received grants from Turku University Foundation, Päivikki and Sakari Sohlberg Foundation, and the Finnish Cultural Foundation; he received consulting fees from Nordic Infucare, Abbvie, and Adamant Health; he received honoraria from Nordic Infucare and Abbvie; he received Support for attending meetings and/or travel from Nordic Infucare; he participates on a Data Safety Monitoring Board or Advisory Board at Nordic Infucare and Abbvie; he is board member of the Finnish Neurological Society. Christine Klein received royalties from Oxford University Press; she received consulting fees from Centogene and Retromer Therapeutics; she received payment or honoraria from Desitin Pharma; she received support to attend meetings from the Movement Disorder Society; she participates on a Data Safety Monitoring Board or Advisory Board at the Else Kroener Fresenius Foundation. Peter Klivenyi received honoraria from Abbvie and Medtronic. Vladimir Kostic received Grant 17590 from the Ministry of Education, Science and Technological Development of Serbia; he received honoraria from Novartis and Boehringer Ingelheim. Shen-Yang Lim received the following grants, (i) Stipend - Global Parkinson’s Genetics Program (GP2) Working Group Co-Lead Award, from the Michael J. Fox Foundation, (ii) Michael J. Fox Foundation (Grant 18305: "Identifying leucocyte and urine biomarkers in PD patients with LRRK2 G2385R variant"). George Mellick received grants from the National Health and Medical Research Foundation, Australia (APP1151854, APP1084560). Lukasz Milanowski received grants from the Polish National Agency for Academic Exchange Iwanowska’s Fellowship PPN/IWA/2018/1/00006/U/00001/01, the APDA, the Foundation for Polish Science (FNP) and the Haworth Family Professorship in Neurodegenerative Diseases Fund. Pablo mir received grants from the Spanish Ministry of Science and Innovation (RTC2019-007150-1), the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER, PI19/01576), and the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PE-0210-2018); he received payment or honoraria for lectures from Abbvie, Abbott, and Zambon; he received Support for attending meetings and travel from Abbvie. Shalini Padmanabhan is employed by the Michael J. Fox Foundation. Andreas Puschmann received grants from Region Skåne, Sweden, Skåne University Hospital, Sweden, The Swedish Parkinson Academy, The Swedish Parkinson Foundation (Parkinsonfonden), MultiPark – a strategic research environment at Lund University, and Bundy Academy, Sweden; he received honoraria from Elsevier (Associate editor for Parkinsonism and Related Disorders), from the International Parkinson and Movement Disorder Society (MDS), and from the International Association of Parkinsonism and Related Disorders; he received support for travels from the International Association of Parkinsonism and Related Disorders; he is board member of the International Association of Parkinsonism and Related Disorders. Mariana Spitz received funding from Centogene for the ROPAD study; she received support for travels from Roche. Justin Solle is employed by the Michel J. Fox Foundation. Oksana Suchowersky received grants from Roche and WaveLifeSciences; she holds royalties or licenses at UpToDate; she received consulting fees from Abbvie and Sunovion; she received honoraria from the World Parkinson Conference; she participates in advisory boards at Alexion; she is board member of the Parkinson Society Alberta. Pichet Termsarasab received book royalties from Elsevier and Springer Nature Switzerland; he received honoraria for manuscript writing from MedLink Neurology and for lectures from Viatris. Bart van de Warrenburg received grants from Radboudumc, ZonMW, Hersenstichting, Gossweiler Foundation, and the Michael J Fox Foundation; he holds royalties or licenses at BSL Springer Nature; he received consulting fees from uniQure; he received honoraria from UKM Medical Center Kuala Lumpur; he participates in Medical advisory board of patient organizations (unpaid); he is unpaid member of Steering committees or executive boards of various research consortia; he received a wearable sensor set by Brugling Fund/Hersenstichting. Caroline H. Williams-Gray collaborates with Astra-Zeneca on the microbiome in Parkinson’s disease; she received consultancy fees from Modus Outcomes and Evidera, Inc./GlaxoSmithKline; she received honoraria from Profile Pharma Limited. Eva-Juliane Vollstedt, Harutyun Madoev, Anna Aasly, Azlina Ahmad-Annuar, Bashayer Al-Mubarak, Victoria Alvarez, Ignacio Amorin, Grazia Annesi, David Arkadir, Soraya Bardien, Roger A. Barker, A. Nazli Basak, Agnita Boon, Laura Brighina, Andrea Carmine Belin, Jonathan Carr, Leonor Correia Guedes, David Crosiers, Parimal Das, Patricia de Carvalho Aguiar, Jolanta Dorszewska, Sibel Ertan, Rosangela Ferese, Gençer Genç, Pilar Gómez-Garre, Hasmet Hanagasi, Faycal Hentati, Dorota Hoffman-Zacharska, Sergey N. Illarioshkin, Joseph Jankovic, Anneke Kievit, Dariusz Koziorowski, Andrea A. Kühn, Anthony E. Lang, Chin-Hsien Lin, Katja Lohmann, Vladana Markovic, Mika Henrik Martikainen, Marcelo Merello, Özgür Öztop-Çakmak, Márcia Mattos Gonçalves Pimentel, Teeratorn Pulkes, Ekaterina Rogaeva, Esther M. Sammler, Maria Skaalum Petersen, Matej Skorvanek, Ai Huey Tan, Avner Thaler, Vitor Tumas, Enza Maria Valente, Ruey-Mei Wu, Baorong Zhang, and Alexander Zimprich report no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Vollstedt et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Freezing of gait (FOG) is one of the most disabling symptoms of Parkinsonism. Moreover, it does not respond well to medication. Visual cues have been shown to alleviate FOG in Parkinsonism; however, their efficacy is inconsistent. Currently, most mobile cueing devices are used as an open-loop cueing system, which requires manual control to enable constant visual cues. Thus, such devices may not be suitable for some people, especially those who have attention deficits. In addition, objective measurements of FOG in real-life situations remain challenging. Therefore, we developed a smart-ankle laser as a closed-loop cueing system that can detect the patient's walking pattern and automatically project a laser line that follows each walking step, thus requires less attention. Real-time motion was also recorded within the device for FOG measurement. We studied the efficacy of the device in three Parkinsonism patients with FOG (one man and two women, aged 58-76 years) immediately after use and two patients at 1-week follow-up. Gait speed, Timed Up and Go test performance, stride length, and % FOG improved with the use of the laser, without adverse effects.

Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited., Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD., Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed., Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published., Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Writer's cramp (WC) dystonia is a rare disease that causes abnormal postures during the writing task. Successful research studies for WC and other forms of dystonia are contingent on identifying sensitive and specific measures that relate to the clinical syndrome and achieve a realistic sample size to power research studies for a rare disease. Although prior studies have used writing kinematics, their diagnostic performance remains unclear., Objective: This study aimed to evaluate the diagnostic performance of automated measures that distinguish subjects with WC from healthy volunteers., Methods: A total of 21 subjects with WC and 22 healthy volunteers performed a sentence-copying assessment on a digital tablet using kinematic and hand recognition softwares. The sensitivity and specificity of automated measures were calculated using a logistic regression model. Power analysis was performed for two clinical research designs using these measures. The test and retest reliability of select automated measures was compared across repeat sentence-copying assessments. Lastly, a correlational analysis with subject- and clinician-rated outcomes was performed to understand the clinical meaning of automated measures., Results: Of the 23 measures analyzed, the measures of word legibility and peak accelerations distinguished subjects with WC from healthy volunteers with high sensitivity and specificity and demonstrated smaller sample sizes suitable for rare disease studies, and the kinematic measures showed high reliability across repeat visits, while both word legibility and peak accelerations measures showed significant correlations with the subject- and clinician-rated outcomes., Conclusions: Novel automated measures that capture key aspects of the disease and are suitable for use in clinical research studies of WC dystonia were identified. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

Impact Statement: Despite increasing evidence implicating the important role of TDP-43 in the pathogenesis of a wide range of age-related neurodegenerative diseases, there is limited study of TDP-43 proteinopathy and its association with mitochondria during normal aging. Our findings of cytoplasmic accumulation of TDP-43 that is highly colocalized with mitochondria in neurons in selective brain regions in young animals in the absence of neuronal loss provide a novel insight into the development of TDP-43 proteinopathy and its contribution to neuronal loss.

Background: Juvenile forms of parkinsonism are rare conditions with onset of bradykinesia, tremor and rigidity before the age of 21 years. These atypical presentations commonly have a genetic aetiology, highlighting important insights into underlying pathophysiology. Genetic defects may affect key proteins of the endocytic pathway and clathrin-mediated endocytosis (CME), as in DNAJC6-related juvenile parkinsonism., Objective: To report on a new patient cohort with juvenile-onset DNAJC6 parkinsonism-dystonia and determine the functional consequences on auxilin and dopamine homeostasis., Methods: Twenty-five children with juvenile parkinsonism were identified from a research cohort of patients with undiagnosed pediatric movement disorders. Molecular genetic investigations included autozygosity mapping studies and whole-exome sequencing. Patient fibroblasts and CSF were analyzed for auxilin, cyclin G-associated kinase and synaptic proteins., Results: We identified 6 patients harboring previously unreported, homozygous nonsense DNAJC6 mutations. All presented with neurodevelopmental delay in infancy, progressive parkinsonism, and neurological regression in childhood. 123 I-FP-CIT SPECT (DaTScan) was performed in 3 patients and demonstrated reduced or absent tracer uptake in the basal ganglia. CSF neurotransmitter analysis revealed an isolated reduction of homovanillic acid. Auxilin levels were significantly reduced in both patient fibroblasts and CSF. Cyclin G-associated kinase levels in CSF were significantly increased, whereas a number of presynaptic dopaminergic proteins were reduced., Conclusions: DNAJC6 is an emerging cause of recessive juvenile parkinsonism-dystonia. DNAJC6 encodes the cochaperone protein auxilin, involved in CME of synaptic vesicles. The observed dopamine dyshomeostasis in patients is likely to be multifactorial, secondary to auxilin deficiency and/or neurodegeneration. Increased patient CSF cyclin G-associated kinase, in tandem with reduced auxilin levels, suggests a possible compensatory role of cyclin G-associated kinase, as observed in the auxilin knockout mouse. DNAJC6 parkinsonism-dystonia should be considered as a differential diagnosis for pediatric neurotransmitter disorders associated with low homovanillic acid levels. Future research in elucidating disease pathogenesis will aid the development of better treatments for this pharmacoresistant disorder. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

Purpose of Review: This article provides an overview of the approach to chorea in clinical practice, beginning with a discussion of the phenomenologic features of chorea and how to differentiate it from other movement disorders. The diagnostic approach, clinical features of important acquired and genetic choreas, and therapeutic principles are also discussed. Practical clinical points and caveats are included., Recent Findings: C9orf72 disease is the most common Huntington disease phenocopy, according to studies in the European population. Anti-IgLON5 disease can present with chorea. The role of immunotherapies in Sydenham chorea has increased, and further clinical studies may be useful. Benign hereditary chorea is a syndrome or phenotype due to mutations in several genes, including NKX2-1, ADCY5, GNAO1, and PDE10A. New-generation presynaptic dopamine-depleting agents provide more options for symptomatic treatment of chorea with fewer adverse effects. Deep brain stimulation has been performed in several choreic disorders, but features other than chorea and the neurodegenerative nature should be taken into consideration. Studies on genetic interventions for Huntington disease are ongoing., Summary: Clinical features remain crucial in guiding the differential diagnosis and appropriate investigations in chorea. Given the complexity of most choreic disorders, treating only the chorea is not sufficient. A comprehensive and multidisciplinary approach is required.

Introduction: Chronic immune sensorimotor polyradiculopathy (CISMP) is a chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) variant affecting both sensory and motor nerve roots without evidence of peripheral nerve demyelination., Methods: We report a case series of 9 patients with CISMP, identified from 2 tertiary centers. Clinical, electrodiagnostic, and neuroradiologic features, and treatment responses, were retrospectively reviewed., Results: Patients presented with sensorimotor deficits and hypo-/areflexia, predominantly involving lower extremities. Three had cranial nerve involvement. Electrodiagnostic findings in all patients localized to roots proximal to dorsal root ganglia, without evidence of peripheral nerve demyelination. Cerebrospinal fluid examination revealed an albuminocytologic association. Eight patients exhibited gadolinium enhancement and thickening of multiple spinal nerve roots and/or cranial nerves. All patients demonstrated good responses to immunotherapies., Discussion: CISMP is similar to CIDP in many aspects, but lacks typical electrodiagnostic findings of peripheral nerve demyelination. It is important to recognize this unusual and treatable entity. Muscle Nerve 59:658-664, 2019., (© 2019 Wiley Periodicals, Inc.)

Background: Myoclonus and tremor are common movement disorder phenomenologies in steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT). Pure ataxia without encephalopathy has rarely been reported., Case Report: We report 21- and 40-year-old females who presented with subacute pure ataxia without encephalopathy. After immunotherapies, both exhibited initial improvement of ataxia, and subsequently remained in plateau phase., Discussion: This treatable disorder should be added to the differential diagnoses of progressive cerebellar ataxia, and anti-thyroid peroxidase and anti-thyroglobulin should be considered as part of the workup. It is crucial not to misdiagnose SREAT presenting with pure cerebellar ataxia as degenerative or spinocerebellar ataxia., Competing Interests: Funding: None. Conflicts of Interest: The authors report no conflict of interest. Ethics Statement: All patients that appear on video have provided written informed consent; authorization for the videotaping and for publication of the videotape was provided.

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized by neurofibrillary tangles (NFTs), senile plaques (SPs), and a progressive loss of neuronal cells in selective brain regions. Rab10, a small Rab GTPase involved in vesicular trafficking, has recently been identified as a novel protein associated with AD. Interestingly, Rab10 is a key substrate of leucine-rich repeat kinase 2 (LRRK2), a serine/threonine protein kinase genetically associated with the second most common neurodegenerative disease Parkinson's disease. However, the phosphorylation state of Rab10 has not yet been investigated in AD. Here, using a specific antibody recognizing LRRK2-mediated Rab10 phosphorylation at the amino acid residue threonine 73 (pRab10-T73), we performed immunocytochemical analysis of pRab10-T73 in hippocampal tissues of patients with AD. pRab10-T73 was prominent in NFTs in neurons within the hippocampus in all cases of AD examined, whereas immunoreactivity was very faint in control cases. Other characteristic AD pathological structures including granulovacuolar degeneration, dystrophic neurites and neuropil threads also contained pRab10-T73. The pRab10-T73 immunoreactivity was diminished greatly following dephosphorylation with alkaline phosphatase. pRab10-T73 was further found to be highly co-localized with hyperphosphorylated tau (pTau) in AD, and demonstrated similar pathological patterns as pTau in Down syndrome and progressive supranuclear palsy. Although pRab10-T73 immunoreactivity could be noted in dystrophic neurites surrounding SPs, SPs were largely negative for pRab10-T73. These findings indicate that Rab10 phosphorylation could be responsible for aberrations in the vesicle trafficking observed in AD leading to neurodegeneration.

Dystonic storm is a frightening hyperkinetic movement disorder emergency. Marked, rapid exacerbation of dystonia requires prompt intervention and admission to the intensive care unit. Clinical features of dystonic storm include fever, tachycardia, tachypnea, hypertension, sweating and autonomic instability, often progressing to bulbar dysfunction with dysarthria, dysphagia and respiratory failure. It is critical to recognize early and differentiate dystonic storm from other hyperkinetic movement disorder emergencies. Dystonic storm usually occurs in patients with known dystonia, such as DYT1 dystonia, Wilson's disease and dystonic cerebral palsy. Triggers such as infection or medication adjustment are present in about one-third of all events. Due to the significant morbidity and mortality of this disorder, we propose a management algorithm that divides decision making into two periods: the first 24 h, and the next 2-4 weeks. During the first 24 h, supportive therapy should be initiated, and appropriate patients should be identified early as candidates for pallidal deep brain stimulation or intrathecal baclofen. Management in the next 2-4 weeks aims at symptomatic dystonia control and supportive therapies.

Isolated focal dystonias are a group of disorders with diverse symptomatology but unknown pathophysiology. Although recent neuroimaging studies demonstrated regional changes in brain connectivity, it remains unclear whether focal dystonia may be considered a disorder of abnormal networks. We examined topology as well as the global and local features of large-scale functional brain networks across different forms of isolated focal dystonia, including patients with task-specific (TSD) and nontask-specific (NTSD) dystonias. Compared with healthy participants, all patients showed altered network architecture characterized by abnormal expansion or shrinkage of neural communities, such as breakdown of basal ganglia-cerebellar community, loss of a pivotal region of information transfer (hub) in the premotor cortex, and pronounced connectivity reduction within the sensorimotor and frontoparietal regions. TSD were further characterized by significant connectivity changes in the primary sensorimotor and inferior parietal cortices and abnormal hub formation in insula and superior temporal cortex, whereas NTSD exhibited abnormal strength and number of regional connections. We suggest that isolated focal dystonias likely represent a disorder of large-scale functional networks, where abnormal regional interactions contribute to network-wide functional alterations and may underline the pathophysiology of isolated focal dystonia. Distinct symptomatology in TSD and NTSD may be linked to disorder-specific network aberrations., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objectives/hypothesis: Our aims are to 1) illustrate the complexity and phenomenological richness of the embouchure; 2) delineate the main clinical features of non-dystonic embouchure problems (NED) versus embouchure dystonia (ED); and 3) provide a practical framework for physicians who may encounter a patient with embouchure dysfunction., Study Design: We performed retrospective chart and video review and report 139 instrumentalists with embouchure dysfunction evaluated over a 15-year period., Results: Included in this group are 109 ED patients (20 newly reported and 89 previously published) and 30 NED patients. Non-dystonic embouchure problems included the overuse syndrome, infraorbital neuropathy, and orbicularis oris tears, among others., Conclusions: Based on this experience, the largest series presented to date, we propose a practical guide to help evaluate patients with embouchure dysfunction in the office., Level of Evidence: 4. Laryngoscope, 126:1327-1333, 2016., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Spinal-generated movement disorders (SGMDs) include spinal segmental myoclonus, propriospinal myoclonus, orthostatic tremor, secondary paroxysmal dyskinesias, stiff person syndrome and its variants, movements in brain death, and painful legs-moving toes syndrome. In this paper, we review the relevant anatomy and physiology of SGMDs, characterize and demonstrate their clinical features, and present a practical approach to the diagnosis and management of these unusual disorders.

Background: Paraneoplastic movement disorders in prostate cancer are rare, and to our knowledge paraneoplastic myoclonus has not previously been reported., Case Report: We report two men with adenocarcinoma of the prostate who developed isolated alcohol-responsive action myoclonus of one leg. Myoclonus was absent at rest but triggered by movement, standing, or walking. Evaluations excluded malignant invasion of the nervous system, and testing for commercial paraneoplastic antibodies in serum and cerebrospinal fluid were unrevealing. Both patients experienced significant improvement with alcohol, and sodium oxybate was used in one patient with good initial benefit., Discussion: Alcohol-responsive leg myoclonus might be a novel paraneoplastic syndrome associated with prostate cancer. The nature of the syndrome and the source of the myoclonus are currently unknown.

Aberrant sensory processing plays a fundamental role in the pathophysiology of dystonia; however, its underpinning neural mechanisms in relation to dystonia phenotype and genotype remain unclear. We examined temporal and spatial discrimination thresholds in patients with isolated laryngeal form of dystonia (LD), who exhibited different clinical phenotypes (adductor vs. abductor forms) and potentially different genotypes (sporadic vs. familial forms). We correlated our behavioral findings with the brain gray matter volume and functional activity during resting and symptomatic speech production. We found that temporal but not spatial discrimination was significantly altered across all forms of LD, with higher frequency of abnormalities seen in familial than sporadic patients. Common neural correlates of abnormal temporal discrimination across all forms were found with structural and functional changes in the middle frontal and primary somatosensory cortices. In addition, patients with familial LD had greater cerebellar involvement in processing of altered temporal discrimination, whereas sporadic LD patients had greater recruitment of the putamen and sensorimotor cortex. Based on the clinical phenotype, adductor form-specific correlations between abnormal discrimination and brain changes were found in the frontal cortex, whereas abductor form-specific correlations were observed in the cerebellum and putamen. Our behavioral and neuroimaging findings outline the relationship of abnormal sensory discrimination with the phenotype and genotype of isolated LD, suggesting the presence of potentially divergent pathophysiological pathways underlying different manifestations of this disorder.

Saccades are rapid eye movements designed to shift the fovea to objects of visual interest. Abnormalities of saccades offer important clues in the diagnosis of a number of movement disorders. In this review, we explore the anatomy of horizontal and vertical saccades, discuss practical aspects of their examination, and review how saccadic abnormalities in hyperkinetic and hypokinetic movement disorders aid in diagnosis, with video demonstration of classic examples. Documentation of the ease of saccade initiation, range of motion and conjugacy of saccades, speed and accuracy of saccades, dynamic saccadic trajectory, and the presence or absence of saccadic intrusions and oscillations are important components of this exam. We also provide a practical algorithm to demonstrate the value of saccades in the differential diagnosis of the movement disorders patient.

Background: ATP1A3-related disorders include rapid-onset dystonia-parkinsonism (RDP or DYT12), alternating hemiplegia of childhood (AHC), and CAPOS syndrome (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss)., Case Report: We report two cases with intermediate forms between RDP and AHC. Patient 1 initially presented with the AHC phenotype, but the RDP phenotype emerged at age 14 years. The second patient presented with levodopa-responsive paroxysmal oculogyria, a finding never before reported in ATP1A3-related disorders. Genetic testing confirmed heterozygous changes in the ATP1A3 gene in both patients, one of them novel., Discussion: Intermediate phenotypes of RDP and AHC support the concept that these two disorders are part of a spectrum. We add our cases to the phenotype-genotype correlations of ATP1A3-related disorders.

Background: Various movement disorders can be found in ataxia-telangiectasia (AT), including ataxia, dystonia, chorea, and myoclonus, but myoclonus has rarely been described as the predominant feature in AT., Case Report: We report two AT patients with prominent myoclonus, illustrating an unusual presentation of this disorder. Sequencing of the ATM gene in the first patient revealed a homozygous truncating mutation, c.5908C>T (p.Q1970*) in exon 38 of the ATM gene, which has been previously reported as a founder mutation in the Costa Rican population., Discussion: Myoclonus can be a predominant or presenting feature in AT, even without dystonia.