REM sleep behavior disorder (RBD), is a prodromal synucleinopathy affecting a subset of Parkinson’s disease (PD) patients and associated with neuropsychiatric symptoms. This study compared the genetic profiles of 13,020 PD patients with probable RBD (PD + RBD) and 5403 without (PD-RBD) using genome-wide association study (GWAS). RBD was assessed by questionnaires or self-reporting. Potential genetic correlations between neuropsychiatric traits and PD + RBD were assessed using linkage disequilibrium score regression. The top variant in the SNCA locus was associated with PD + RBD (rs10005233-T, OR = 1.21, 95% CI = 1.16–1.27, p = 1.81e−15). PD risk variants in SNCA (rs5019538-G, OR = 0.85, 95% CI = 0.81–0.89, p = 2.46e−10; rs356182-G, OR = 0.89, 95% CI = 0.84–0.95, p = 0.0001) and LRRK2 loci (rs34637584, OR = 0.41, 95% CI = 0.28–0.61, p = 1.04e−5) were associated with reduced PD + RBD risk. A suggestive genetic correlation between attention deficit hyperactivity disorder and PD + RBD was observed but was not statistically significant after correction. These findings highlight genetic distinctions between PD + RBD and PD-RBD, offering insights into PD stratification and potential subtype-specific treatments.

BACKGROUND:Leucine-rich repeat kinase 2 (LRRK2) p.L1795F variant was proposed as a genetic risk factor for Parkinson's disease (PD). However, its prevalence, phenotype, and origin remain unknown. OBJECTIVE:The aim was to evaluate the frequency and phenotype of p.L1795F in early-onset PD (EOPD) and familial PD compared to healthy controls (HC) in Central Europe. METHODS:Whole-exome sequencing was used to screen 219 EOPD and familial PD patients of Central Europeans compared to HC. Sanger sequencing assessed segregation. Detailed clinical phenotype was evaluated for all positive carriers. RESULTS:p.L1795F was identified in 1.37% (3/219) and 3.23% of familial cases (3/93), with no carriers among HCs (0/303). Segregation analysis confirmed association with PD. Carriers were traced to the eastern Slovak-Hungarian region. It also appears to be associated with a more aggressive phenotype. CONCLUSION:Our data indicate that p.L1795F contributes to PD in Central Europe. Further exploration in larger cohorts is warranted to establish its contribution to global PD risk.

Background: To date, no studies comparing complication rates between patients with nutritional percutaneous endoscopic gastrostomy (N-PEG) and Parkinson’s disease (PD) patients with percutaneous endoscopic gastro-jejunostomy (JET-PEG) for treatment administration have been published. Our study aimed to compare complication rates and the number of re-endoscopies between N-PEG and JET-PEG patients. Methods: Individuals requiring N-PEG or JET-PEG insertion between 2014 and 2021 were included in this single-center retrospective observational study. Complications were divided into time-related medical and technical complications. Reasons for post-insertion re-endoscopies and their number were also analyzed. Results: Eighty-seven subjects, 47 (54.02%) in JET-PEG group and 40 (45.98%) in the N-PEG group, were included. Early and technical complications were more frequent in JET-PEG vs. N-PEG subjects (70% vs. 10% [p < 0.001], and 54.5% vs. 5.1% [p < 0.001], respectively). The presence of psychiatric disease was associated with a higher number of early complications (p < 0.002). All three types of complications were significantly more frequent in subjects where a healthcare professional did not handle PEG (p < 0.001). Subjects with JET-PEG required a higher number of re-endoscopies compared to the N-PEG group (57.1% vs. 35%, p = 0.05). Conclusions: Complications are significantly more common in individuals with JET-PEG than those with N-PEG, which can be attributed to higher mobility in PD patients.

Pathogenic variants in LRRK2 are one of the most common genetic risk factors for Parkinson’s disease (PD). Recently, the lesser-known p.L1795F variant was proposed as a strong genetic risk factor for PD, however, further families are currently lacking in literature. A multicentre young onset and familial PD cohort (n = 220) from 9 movement disorder centres across Central Europe within the CEGEMOD consortium was screened for rare LRRK2 variants using whole exome sequencing data. We identified 4 PD cases with heterozygous p.L1795F variant. All 4 cases were characterised by akinetic-rigid PD phenotype with early onset of severe motor fluctuations, 2 receiving LCIG therapy and 2 implanted with STN DBS; all 4 cases showed unsatisfactory effect of advanced therapies on motor fluctuations. Our data also suggest that p.L1795F may represent the most common currently known pathogenic LRRK2 variant in Central Europe compared to the more studied p.G2019S, being present in 1.81% of PD cases within the Central European cohort and 3.23% of familial PD cases. Together with the ongoing clinical trials for LRRK2 inhibitors, this finding emphasises the urgent need for more ethnic diversity in PD genetic research.

Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), known as Hashimoto's encephalopathy (HE), represents a heterogeneous group of neurological and neuropsychiatric symptoms associated with a presence of antithyroid antibodies in case of other causes of encephalopathy were excluded. Clinical symptoms most commonly includes acute onset of encephalopathy, behaviour changes and cognitive dysfunction, epileptic seizures as well as cerebellar and extrapyramidal symptoms. Corticoids provides rapid and sustained therapeutic benefit in most patients and only a few patients require other immunosuppressive therapy such as plasmapheresis, intravenous immunoglobulins, or others. We present the cases of two patients with acute onset of encephalopathy, status epilepticus based on SREAT, with rapid improvement after steroid treatment.

Objective REM sleep behavior disorder (RBD) is a prodromal synucleinopathy, reported in a subset of Parkinson’s disease (PD) patients, and associated with neuropsychiatric symptoms in PD. We aimed to compare the genetic background of PD patients with probable RBD (PD+RBD) and PD patients without probable RBD (PD-RBD). Furthermore, we examined genetic correlations and potential causal associations between multiple neuropsychiatric traits and PD+RBD. Methods We performed a genome-wide association study (GWAS) including 5,403 PD+RBD and 13,020 PD-RBD. To test for genetic correlations and potential causal associations between neuropsychiatric traits and PD+RBD, we used linkage disequilibrium score regression and Mendelian randomization. Results The SNCA locus was associated with PD+RBD compared to PD-RBD (rs10005233, OR=1.21, 95% CI=1.16-1.27, p =1.81e-15). Further examination of known genetic loci associated with PD from the most recent PD GWAS in Europeans and Asians identified additional variants associated with reduced risk for PD+RBD: two in the SNCA locus (rs5019538-G, OR=0.85, 95% CI=0.81-0.89, p =2.46E-10; rs356182-G, OR=0.89, 95% CI=0.84-0.95, p =0.0001), and one in the LRRK2 locus (rs34637584, p.G2019S, OR=0.41, 95% CI=0.28-0.61, p =1.04E-5). We found a potential genetic correlation between attention deficit hyperactivity disorder (ADHD) and PD+RBD, which was not statistically significant after correction for multiple comparisons. No causative association emerged between PD and neuropsychiatric traits. Interpretation Genetic variants contribute to the occurrence of RBD in PD, further distinguishing between the PD+RBD and PD-RBD subtypes. Understanding the mechanisms underlying these genetic associations could contribute to the development of subtype-specific treatments.

Over the last two decades, we have witnessed major developments in neurogenetic research, the aetiopathogenesis and possible treatment options. Although substantial progress has been made, the first genome-wide studies have explained relatively little of the heritability of most complex traits, leading to a theory that a more fine-scale analysis considering the characteristics of individual populations may hold the key to the missing heritability. In contrast to the Western part of Europe, where the genetics of movement disorders have been thoroughly studied, genetic reports from patients of Central European ancestry have been scarce as cohorts from this region were rarely included and their genetic background remains unknown. Therefore, the Central European Group on Genetics of Movement Disorders (CEGEMOD) has been established to address this gap, representing a collaboration between nine tertiary movement disorder centres from Slovakia, Czech Republic, Poland and Hungary (Figure 1 and Appendix). The CEGEMOD consortium aims to create a collaborative network that will establish a Central European based registry of movement disorder patients, with focus on Parkinson's disease (PD): atypical parkinsonism such as multiple system atrophy, progressive supranuclear palsy, Lewy body dementia and corticobasal syndrome; prodromal PD (with and without rapid eye movement sleep behaviour disorder) [1] and ataxia. The emphasis is on building a framework for future collaborative studies that will lead to the identification of genetic risk factors and to explore the genotype–phenotype correlations (disease subtypes, age at onset, motor and non-motor symptoms), leading to the investigation of new, population-based diagnostic and therapeutic interventions. To achieve this goal, we have established a partnership with the Institute of Neurology, University College London, UK, for their technical support to enable the development of local facilities through education and training. To date, nearly 3500 individuals have been enrolled, making our consortium the largest ethnically matched case–control cohort of Central Europe (Table S1). Each site uses uniform diagnostic criteria and collects a standardized set of clinical and demographic variables. Our pilot study assessing the contribution of rare LRRK2 pathogenic variants to PD confirmed that most LRRK2 variants which are pathogenic in PD in North and West Europe are not a frequent cause of PD in Central Europe. Additionally, we identified a c.1256C>T (p.Ala419Val) LRRK2 variant that is highly population-specific and mostly observed in South and East Asians, in two PD patients of Hungarian origin [2]. These findings highlight the potential difference of ethnic background across European countries considering migration patterns, settled ethnic minorities and their genetic influence. The largest ethnic minority of Central Europe, the Roma population, has already been shown to have a common South Asian genetic origin [3] and to harbour several rare disease-causing variants, although a genetic background of parkinsonism and ataxia specifically has never been studied in this population. Correspondingly, in a related project aimed at the genetics of dystonia, we have already identified two novel founder mutations in this population—the VPS16 c.559C>T (p.Arg187*) recurrent variant present only in the Roma population [4] and the WARS2 exon 2 deletion reported only in subjects of Slovak origin so far [5]. Miriam Ostrozovicova: Conceptualization; project administration; writing – original draft; investigation. Petr Dusek: Conceptualization; investigation; resources; writing – review and editing. Milan Grofik: Conceptualization; investigation; resources; writing – review and editing. Vladimir Han: Conceptualization; investigation; writing – review and editing; resources. Petr Holly: Conceptualization; investigation; writing – review and editing; resources. Robert Jech: Conceptualization; investigation; resources; writing – review and editing. Peter Klivenyi: Conceptualization; investigation; resources; writing – review and editing. Norbert Kovacs: Conceptualization; investigation; resources; writing – review and editing. Kristina Kulcsarova: Conceptualization; investigation; resources; writing – review and editing. Egon Kurca: Conceptualization; investigation; resources; writing – review and editing. Alexandra Lackova: Conceptualization; investigation; resources; writing – review and editing. Veronika Magocova: Conceptualization; investigation; resources; writing – review and editing. Jan Necpal: Conceptualization; investigation; writing – review and editing; resources. David Pinter: Investigation; conceptualization; writing – review and editing; resources. Evzen Ruzicka: Conceptualization; investigation; resources; writing – review and editing. Tereza Serranova: Conceptualization; resources; writing – review and editing; investigation. Katarzyna Smilowska: Conceptualization; investigation; resources; writing – review and editing. Igor Straka: Conceptualization; investigation; resources; writing – review and editing. Tatiana Svorenova: Conceptualization; investigation; resources; writing – review and editing. Gertrud Tamas: Conceptualization; investigation; resources; writing – review and editing. Peter Valkovic: Conceptualization; investigation; resources; writing – review and editing. Katerina Zarubova: Conceptualization; investigation; resources; writing – review and editing. Henry Houlden: Writing – review and editing; conceptualization; project administration; supervision; resources. Mie Rizig: Conceptualization; project administration; supervision; resources; writing – original draft. Matej Skorvanek: Conceptualization; writing – original draft; project administration; funding acquisition; investigation; resources. This study was funded from the Slovak Grant and Development Agency under contracts APVV-18-0547 and APVV-22-0279 and by the Slovak Scientific Grant Agency under contract VEGA 1/0712/22; it was also supported by the Operational Programme Integrated Infrastructure, funded by the ERDF (ITMS2014+:313011V455). The Czech Centre was supported by the National Institute for Neurological Research (Programme EXCELES, ID Project No. LX22NPO5107), funded by the European Union, Next Generation EU, and by the Czech Health Research Council grant NU21-04-00535. P.K. (Szeged Centre) was supported by TKP-2021-EGA-32. None of the authors have a conflict of interest to disclose. Dusek Petr, Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic. [email protected] Holly Petr, Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic. [email protected] Jech Robert, Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic. [email protected] Ruzicka Evzen, Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic. [email protected] Serranova Tereza, Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic. [email protected] Zarubova Katerina, Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Prague, Czech Republic. [email protected] Klivenyi Peter, Department of Neurology, University of Szeged, Szeged, Hungary. [email protected] Kovacs Norbert, University of Pecs, Medical School, Department of Neurology and HUN-REN–PTE Clinical Neuroscience MR Research Group. [email protected] Pinter David, University of Pecs, Medical School, Department of Neurology and HUN-REN–PTE Clinical Neuroscience MR Research Group. [email protected] Tamas Gertrud, Department of Neurology, Semmelweis University, Budapest, Hungary. [email protected] Smilowska Katarzyna, Department of Neurology Silesian Centre of Neurology, Katowice, Poland. [email protected] Grofik Milan, Department of Neurology, Commenius University and University Hospital Martin, Martin, Slovak Republic. [email protected] Han Vladimir, Department of Neurology, Safarik University and L. Pasteur University Hospital Kosice, Slovak Republic. [email protected] Kulcsarova Kristina, Department of Neurology, Safarik University and L. Pasteur University Hospital Kosice, Slovak Republic. [email protected] Kurca Egon, Department of Neurology, Commenius University and University Hospital Martin, Martin, Slovak Republic. [email protected] Lackova Alexandra, Department of Neurology, Safarik University and L. Pasteur University Hospital Kosice, Slovak Republic. [email protected] Magocova Veronika, Department of Neurology, Safarik University and L. Pasteur University Hospital Kosice, Slovak Republic. [email protected] Necpal Jan, Department of Neurology, Zvolen Hospital, Zvolen, Slovak Republic. [email protected] Ostrozovicova Miriam, Department of Neurology, Safarik University and L. Pasteur University Hospital Kosice, Slovak Republic. [email protected]; [email protected] Skorvanek Matej, Department of Neurology, Safarik University and L. Pasteur University Hospital Kosice, Slovak Republic. [email protected] Straka Igor, Second Department of Neurology, Comenius University in Bratislava Faculty of Medicine, University Hospital Bratislava, Bratislava, Slovak Republic. [email protected] Svorenova Tatiana, Department of Neurology, Safarik University and L. Pasteur University Hospital Kosice, Slovak Republic. [email protected] Valkovic Peter, Second Department of Neurology, Comenius University in Bratislava Faculty of Medicine, University Hospital Bratislava, Bratislava, Slovak Republic; Institute of Normal and Pathological Physiology, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovak Republic [email protected] Houlden Henry, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK. [email protected] Rizig Mie, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK. [email protected] Data sharing not applicable to this article as no datasets were generated or analysed during the current study. Table S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

BACKGROUND:An increased prevalence of Parkinson's disease (PD) disease has been previously reported in subjects with Fabry disease (FD) carrying alpha-galactosidase (GLA) mutations and their first-line relatives. Moreover, decreased alpha-galactosidase A (AGLA) enzymatic activity has been reported among cases with PD compared to controls.OBJECTIVE:The aim of our study was to determine the prevalence of FD among patients with PD.METHODS:We recruited 236 consecutive patients with PD from February 2018 to December 2020. Clinical and sociodemographic data, including the MDS-UPDRS-III scores and HY stage (the Hoehn and Yahr scale), were collected, and in-depth phenotyping was performed in subjects with identified GLA variants. A multistep approach, including standard determination of AGLA activity and LysoGb3 in males, and next-generation based GLA sequencing in all females and males with abnormal AGLA levels was performed in a routine diagnostic setting.RESULTS:The mean age of our patients was 68.9 ± 8.9 years, 130 were men (55.1%), and the mean disease duration was 7.77 ± 5.35 years. Among 130 men, AGLA levels were low in 20 patients (15%), and subsequent Lyso-Gb3 testing showed values within the reference range for all tested subjects. In 126 subsequently genetically tested patients, four heterozygous p.(Asp313Tyr) GLA variants (3.2%, MAF 0.016) were identified; all were females. None of the 4 GLA variant carriers identified had any clinical manifestation suggestive of FD.CONCLUSIONS:The results of this study suggest a possible relationship between FD and PD in a small proportion of cases. Nevertheless, the GLA variant found in our cohort is classified as a variant of unknown significance. Therefore, its pathogenic causative role in the context of PD needs further elucidation, and these findings should be interpreted with caution.

Introduction: Sixteen subjects with biallelic WARS2 variants encoding the tryptophanyl mitochondrial aminoacyl-tRNA synthetase, presenting with a neonatal- or infantile-onset mitochondrial disease, have been reported to date. Here we present six novel cases with WARS2-related diseases and expand the spectrum to later onset phenotypes including dopa-responsive early-onset parkinsonism and progressive myoclonus-ataxia. Methods: Six individuals from four families underwent whole-exome sequencing within research and diagnostic settings. Following the identification of a genetic defect, in-depth phenotyping and protein expression studies were performed. Results: A relatively common (gnomAD MAF = 0.0033) pathogenic p.(Trp13Gly) missense variant in WARS2 was detected in trans in all six affected individuals in combination with different pathogenic alleles (exon 2 deletion in family 1; p.(Leu100del) in family 2; p.(Gly50Asp) in family 3; and p.(Glu208*) in family 4). Two subjects presented with action tremor around age 10-12 years and developed tremor-dominant parkinsonism with prominent neuropsychiatric features later in their 20s. Two subjects presented with a progressive myoclonusataxia dominant phenotype. One subject presented with spasticity, choreo-dystonia, myoclonus, and speech problems. One subject presented with speech problems, ataxia, and tremor. Western blotting analyses in patientderived fibroblasts showed a markedly decreased expression of the full-length WARS2 protein in both subjects carrying p.(Trp13Gly) and an exon-2 deletion in compound heterozygosity. Conclusions: This study expands the spectrum of the disease to later onset phenotypes of early-onset tremordominant parkinsonism and progressive myoclonus-ataxia phenotypes.

Lyzozómové ochorenia sú skupinou dedičných metabolických porúch spôsobených mutáciami v génoch kódujúcich rozpustné lyzozomálne hydrolázy, čo vedie k progresívnemu hromadeniu nedegradovaných makromolekúl do životne dôležitých orgánov a tkanív. Fenotypovo sú tieto poruchy charakterizované pestrým klinickým obrazom s kombináciou viscerálnych, očných, hematologických, skeletálnych a neurologických prejavov, pričom postihnutie extrapyramidového systému je obzvlášť časté. Počas posledných rokov sa dosiahol významný pokrok v liečbe týchto ochorení so zameraním na rôzne inovatívne terapeutické prístupy. Cieľom tohto prehľadu je zamerať sa na klinické rozpoznanie najčastejších lyzozómových ochorení s extrapyramídovou manifestáciou (Gaucherova choroba, Fabryho choroba a Niemann-Pickova choroba typ C, Tay-Sachsova choroba) a súčasne dostupné možnosti liečby.