The effectiveness of physiotherapy for patients with isolated cervical dystonia: an updated systematic review and meta-analysis.

BACKGROUND: Cervical dystonia is a movement disorder typically characterized by a patterned and twisting movement of sustained or intermittent muscle contractions. Recently, new clinical trials are emerging, highlighting the potential benefit of physiotherapy (PT) on disease outcomes. Thus, the objective of this review is to update the effectiveness of PT on cervical dystonia disease outcomes and subsequently perform a meta-analysis. METHODS: Interventional studies published in English with adult patients with isolated cervical dystonia following a physiotherapy program were included. Relevant articles were searched in PubMed (MEDLINE), Web of Science, and Scopus. Cochrane and Joanna Briggs Institute risk of bias checklists were used for quality reporting. Meta-analysis was done using Review Manager 5.3 statistical software and a pooled mean difference for pain was presented. RESULTS: Fourteen articles were included in the review and two articles were included in the meta-analysis. The meta-analysis revealed that PT intervention had a significant effect on pain reduction scale (-5.00, 95% CI -6.26, -3.74) when used as an additional therapy with botulinum toxin (BoNT) injection. Additionally, findings indicate a possible positive effect of PT disease severity, disability, and quality of life. CONCLUSIONS: Physiotherapy in addition to BoNT is recommended to decrease pain. The findings suggest a reduction of disease severity, disability, and improvement in quality of life. The variety in the type and duration of PT interventions did not allow a clear recommendation of a specific type of PT.

The Growing Role of Telerehabilitation and Teleassessment in the Management of Movement Disorders in Rare Neurological Diseases: A Scoping Review.

Background: People with rare neurological diseases (RNDs) often experience symptoms related to movement disorders, requiring a multidisciplinary approach, including rehabilitation. Telemedicine applied to rehabilitation and symptom monitoring may be suitable to ensure treatment consistency and personalized intervention. The objective of this scoping review aimed to emphasize the potential role of telerehabilitation and teleassessment in managing movement disorders within RNDs. By providing a systematic overview of the available literature, we sought to highlight potential interventions, outcomes, and critical issues. Methods: A literature search was conducted on PubMed, Google Scholar, IEEE, and Scopus up to March 2024. Two inclusion criteria were followed: (1) papers focusing on telerehabilitation and teleassessment and (2) papers dealing with movement disorders in RNDs. Results: Eighteen papers fulfilled the inclusion criteria. The main interventions were home-based software and training programs, exergames, wearable sensors, smartphone applications, virtual reality and digital music players for telerehabilitation; wearable sensors, mobile applications, and patient home video for teleassessment. Key findings revealed positive outcomes in gait, balance, limb disability, and in remote monitoring. Limitations include small sample sizes, short intervention durations, and the lack of standardized protocols. Conclusion: This review highlighted the potential of telerehabilitation and teleassessment in addressing movement disorders within RNDs. Data indicate that these modalities may play a major role in supporting conventional programs. Addressing limitations through multicenter studies, longer-term follow-ups, and standardized protocols is essential. These measures are essential for improving remote rehabilitation and assessment, contributing to an improved quality of life for people with RNDs.

Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort.

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.

Polysomnographic Predictors of Sleep, Motor, and Cognitive Dysfunction Progression in Parkinson's Disease.

PURPOSE OF REVIEW: Sleep disturbances are an important nonmotor feature of Parkinson's disease (PD) that can cause polysomnographic (PSG) alterations. These alterations are already present in early PD and may be associated with a specific disease course. This systematic review describes the role of PSG variables as predictors of sleep dysfunction, motor and cognitive dysfunction progression in PD. RECENT FINDINGS: Nineteen longitudinal cohort studies were included. Their main findings were that (1) REM sleep behavioral events, REM sleep without atonia (RSWA), and electroencephalography (EEG) changes (mainly microsleep instability) are predictors of the development of REM sleep behavior disorder (RBD); (2) RBD, RSWA, and lower slow-wave sleep energy predict motor progression; (3) RBD, EEG slowing, and sleep spindles changes are predictors of cognitive deterioration; and (4) OSA is associated with severe motor and cognitive symptoms at baseline, with inconsistent findings on the effect of continuous positive airway pressure (CPAP) therapy for these symptoms. The results of our systematic review support a role of the video-PSG in disease progression prediction in PD and its usefulness as a biomarker. However, future studies are needed to investigate whether treatment of these PSG abnormalities and sleep disturbances may have a neuroprotective effect on disease progression.

Mutated ATP10B increases Parkinson's disease risk by compromising lysosomal glucosylceramide export.

Parkinson's disease (PD) is a progressive neurodegenerative brain disease presenting with a variety of motor and non-motor symptoms, loss of midbrain dopaminergic neurons in the substantia nigra pars compacta and the occurrence of α-synuclein-positive Lewy bodies in surviving neurons. Here, we performed whole exome sequencing in 52 early-onset PD patients and identified 3 carriers of compound heterozygous mutations in the ATP10B P4-type ATPase gene. Genetic screening of a Belgian PD and dementia with Lewy bodies (DLB) cohort identified 4 additional compound heterozygous mutation carriers (6/617 PD patients, 0.97%; 1/226 DLB patients, 0.44%). We established that ATP10B encodes a late endo-lysosomal lipid flippase that translocates the lipids glucosylceramide (GluCer) and phosphatidylcholine (PC) towards the cytosolic membrane leaflet. The PD associated ATP10B mutants are catalytically inactive and fail to provide cellular protection against the environmental PD risk factors rotenone and manganese. In isolated cortical neurons, loss of ATP10B leads to general lysosomal dysfunction and cell death. Impaired lysosomal functionality and integrity is well known to be implicated in PD pathology and linked to multiple causal PD genes and genetic risk factors. Our results indicate that recessive loss of function mutations in ATP10B increase risk for PD by disturbed lysosomal export of GluCer and PC. Both ATP10B and glucocerebrosidase 1, encoded by the PD risk gene GBA1, reduce lysosomal GluCer levels, emerging lysosomal GluCer accumulation as a potential PD driver.

Alpha-synuclein repeat variants and survival in Parkinson's disease.

OBJECTIVES: To determine whether α-synuclein dinucleotide repeat (REP1) genotypes are associated with survival in Parkinson's disease (PD). METHODS: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium provided REP1 genotypes and baseline and follow-up clinical data for cases. The primary outcome was time to death. Cox proportional hazards regression models were used to assess the association of REP1 genotypes with survival. RESULTS: Twenty-one sites contributed data for 6,154 cases. There was no significant association between α-synuclein REP1 genotypes and survival in PD. However, there was a significant association between REP1 genotypes and age at onset of PD (hazard ratio: 1.06; 95% confidence interval: 1.01-1.10; P value = 0.01). CONCLUSIONS: In our large consortium study, α-synuclein REP1 genotypes were not associated with survival in PD. Further studies of α-synuclein's role in disease progression and long-term outcomes are needed.

Gait initiation in Parkinson's disease: comparison of timing and displacement during anticipatory postural adjustments as a function of motor severity and apathy in a large cohort.

Introduction: Gait initiation is preceded by three anticipatory postural adjustment (APA) phases. In Parkinson's disease (PD) generated force, displacement and timing during APA differ from healthy controls. APA might be influenced by disease status, weight or emotion. It is unknown how motor severity, disease duration or presence of apathy influences APA timing and displacement. Methods: We included 99 people with PD and 50 healthy controls (HC) to perform five gait initiation trials following an auditory cue. Force plates measured timing and center of pressure (CoP) displacement during APA phases. Results: Time to gait initiation (tGI) was higher in the PD group (p < 0.001, t = 2.74, 95%CI (0.008, 0.066)). The first two APA phases (APA1 and APA2a) lasted longer in PD (respectively p < 0.001, t = 3.87, 95%CI (0.091, 0.28) and p < 0.001, t = 4.1, 95%CI (0.031, 0.091)). Mean CoP displacement, variability in timing and displacement did not differ. A multiple regression model was used to determine if clinical variables were related to gait initiation parameters. tGI was predicted by age (p < 0.001) and weight (p = 0.005). The duration of APA1 was predicted by weight (p = 0.006) and APA2a by age (p < 0.001). Variability in duration of the locomotor phase (LOC) was predicted by age (p < 0.001). Conclusion: tGI and initial APA phases are longer in PD than in HC. There are no significant differences in variability of timing or displacement between the two groups. Gait initiation parameters are independent of disease duration, motor severity, medication usage or apathy in PD. Our findings suggest that cueing does not speed up gait initiation but reduces variability.

A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants.

BACKGROUND: Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive. METHODS AND RESULTS: We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. CONCLUSIONS: Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

Multicentric Clinical Data Collection: A Game-Changer for Rare Neurological Diseases.

Although neuropsychiatric symptoms are a hallmark of the behavioral variant of frontotemporal degeneration (FTD), there is limited evidence on the optimal therapeutic management of these symptoms. In this issue, Katisko et al. report real-world multicentric data on the use of psychopharmacological medication in newly diagnosed patients with FTD. Such reports contribute to knowledge sharing between clinicians caring for patients with FTD. Here, we outline how improved collection of clinical data can assure more robust evidence for future therapies in FTD and other rare neurological diseases.

Exome Sequencing and Multigene Panel Testing in 1,411 Patients With Adult-Onset Neurologic Disorders.

Background and Objectives: Owing to their extensive clinical and molecular heterogeneity, hereditary neurologic diseases in adults are difficult to diagnose. The current knowledge about the diagnostic yield and clinical utility of exome sequencing (ES) for neurologic diseases in adults is limited. This observational study assesses the diagnostic value of ES and multigene panel analysis in adult-onset neurologic disorders. Methods: From January 2019 through April 2022, ES-based multigene panel testing was conducted in 1,411 patients with molecularly unexplained neurologic phenotypes at the Ghent University Hospital. Gene panels were developed for ataxia and spasticity, leukoencephalopathy, movement disorders, paroxysmal episodic disorders, neurodegeneration with brain iron accumulation, progressive myoclonic epilepsy, and amyotrophic lateral sclerosis. Single nucleotide variants, small indels, and copy number variants were analyzed. Across all panels, our analysis covered a total of 725 genes associated with Mendelian inheritance. Results: A molecular diagnosis was established in 10% of the cases (144 of 1,411) representing 71 different monogenic disorders. The diagnostic yield depended significantly on the presenting phenotype with the highest yield seen in patients with ataxia or spastic paraparesis (19%). Most of the established diagnoses comprised disorders with an autosomal dominant inheritance (62%), and the most frequently mutated genes were NOTCH3 (13 patients), SPG7 (11 patients), and RFC1 (8 patients). 34% of the disease-causing variants were novel, including a unique likely pathogenic variant in APP (Ghent mutation, p.[Asn698Asp]) in a family presenting with stroke and severe cerebral white matter disease. 7% of the pathogenic variants comprised copy number variants detected in the ES data and confirmed by an independent technique. Discussion: ES and multigene panel testing is a powerful and efficient tool to diagnose patients with unexplained, adult-onset neurologic disorders.

COVID19-associated new-onset movement disorders: a follow-up study.

BACKGROUND: Neurological symptoms are common manifestation in acute COVID-19. This includes hyper- and hypokinetic movement disorders. Data on their outcome, however, is limited. METHODS: Cases with new-onset COVID-19-associated movement disorders were identified by searching the literature. Authors were contacted for outcome data which were reviewed and analyzed. RESULTS: Movement disorders began 12.6 days on average after the initial onset of COVID-19. 92% of patients required hospital admission (mean duration 23 days). In a fraction of patients (6 of 27; 22%; 4 males/2 females, mean age 66.8 years) the movement disorder (ataxia, myoclonus, tremor, parkinsonism) was still present after a follow-up period of 7.5 ± 3 weeks. Severe COVID-19 in general and development of encephalopathy were risk factors, albeit not strong predictors, for the persistence. CONCLUSIONS: The prognosis of new-onset COVID-19-associated movement disorder appears to be generally good. The majority recovered without residual symptoms within several weeks or months. Permanent cases may be due to unmasking of a previous subclinical movement disorder or due to vascular/demyelinating damage. Given the relatively low response rate of one third only and the heterogeneity of mechanisms firm conclusions on the (long-term) outome cannot, however, be drawn.

Establishing an online resource to facilitate global collaboration and inclusion of underrepresented populations: Experience from the MJFF Global Genetic Parkinson's Disease Project.

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.

Guanosine triphosphate cyclohydrolase 1 promoter deletion causes dopa-responsive dystonia.

BACKGROUND: Autosomal dominant dopa-responsive dystonia (AD-DRD) is caused by a biochemical defect primarily resulting from guanosine triphosphate cyclohydrolase 1 gene (GCH1) mutations. Few families have been reported without mutations in GCH1. METHODS: Genome-wide linkage analysis and positional cloning to identify the genetic defect in a Belgian AD-DRD family was carried out. RESULTS AND CONCLUSION: In this study, we report on the identification and characterization of a novel 24-kb deletion spanning exon 1 and the 5' regulatory region of GCH1 causing a wide spectrum of motor and nonmotor symptoms in a large Belgian AD-DRD family. This large-scale deletion of regulatory sequences leads to decreased GCH1 activity in all carriers, most probably resulting from allelic loss of transcription. We mapped the breakpoints of this deletion to the nucleotide level, allowing the development of a straightforward polymerase chain reaction assay for fast, efficient detection of this large deletion, which will prove valuable for preimplantation genetic diagnosis.

Apathy in Parkinson's Disease: Defining the Park Apathy Subtype.

Apathy is a neurobehavioural symptom affecting Parkinson's disease patients of all disease stages. Apathy seems to be associated with a specific underlying non-motor disease subtype and reflects dysfunction of separate neural networks with distinct neurotransmitter systems. Due to the complicated neuropsychiatric aetiology of apathy, clinical assessment of this invalidating non-motor symptom remains challenging. We aim to summarize the current findings on apathy in Parkinson's disease and highlight knowledge gaps. We will discuss the prevalence rates across the different disease stages and suggest screening tools for clinically relevant apathetic symptoms. We will approach the fundamental knowledge on the neural networks implicated in apathy in a practical manner and formulate recommendations on patient-tailored treatment. We will discuss the Park apathy phenotype in detail, shedding light on different clinical manifestations and implications for prognosis. With this review, we strive to distil the vast available theoretical knowledge into a clinical and patient-oriented perspective.

Impaired bed mobility in prediagnostic and de novo Parkinson's disease.

BACKGROUND: Wearable technology research suggests that nocturnal movements are disturbed in early Parkinson's disease (PD). In this study, we investigate if patients also already experience impaired bed mobility before PD diagnosis. Furthermore, we explore its association with motor and nonmotor features and its value for phenoconversion and disease progression prediction. METHODS: PPMI data were downloaded for de novo PD subjects, subjects at-risk for developing a synucleinopathy (with isolated REM sleep behavior disorder, hyposmia or a pathogenic genetic variant) and controls. Impaired bed mobility was assessed with the MDS-UPDRS part 2 item 9. A frequency analysis was performed. Multivariable logistic regression analyses were used to investigate the association with other PD variables. Cox proportional-hazards models were used to test if difficulties with turning in bed could predict phenoconversion. Linear mixed models were used to evaluate if difficulties with turning in bed could predict disease progression. RESULTS: Of the at-risk subjects, 9.2-12.5% experienced difficulties with turning in bed vs. 25.0% of de novo PD subjects and 2.5% of controls. Impaired turning ability was associated with MDS-UPDRS motorscore (axial signs in the at-risk group, bradykinesia in the de novo PD group) and SCOPA-AUT score (gastrointestinal symptoms). In addition, difficulties with turning in bed were a significant predictor for phenoconversion in the at-risk group and for development of motor complications in the de novo PD group. CONCLUSION: Our findings suggest that difficulties with turning in bed can be helpful as clinical symptom for a prodromal PD screening and for motor complication prediction in early PD.

Natural History Study of STXBP1-Developmental and Epileptic Encephalopathy Into Adulthood.

BACKGROUND AND OBJECTIVES: Pathogenic STXBP1 variants cause a severe early-onset developmental and epileptic encephalopathy (STXBP1-DEE). We aimed to investigate the natural history of STXBP1-DEE in adults focusing on seizure evolution, the presence of movement disorders, and the level of functional (in)dependence. METHODS: In this observational study, patients with a minimum age of 18 years carrying a (likely) pathogenic STXBP1 variant were recruited through medical genetics departments and epilepsy centers. Treating clinicians completed clinical questionnaires and performed semistructured video examinations while performing tasks from the (modified) Unified Parkinson Disease Rating Scale when possible. RESULTS: Thirty adult patients were included for summary statistics, with video recordings available for 19 patients. The median age at last follow-up was 24 years (range 18-58 years). All patients had epilepsy, with a median onset age of 3.5 months. At last follow-up, 80% of adults had treatment-resistant seizures despite long periods of seizure freedom in 37%. Tonic-clonic, focal, and tonic seizures were most frequent in adults. Epileptic spasms, an unusual feature beyond infancy, were present in 3 adults. All individuals had developmental impairment. Periods of regression were present in 59% and did not always correlate with flare-ups in seizure activity. Eighty-seven percent had severe or profound intellectual disability, 42% had autistic features, and 65% had significant behavioral problems. Video examinations showed gait disorders in all 12 patients able to walk, including postural abnormalities with external rotation of the feet, broad-based gait, and asymmetric posture/dystonia. Tremor, present in 56%, was predominantly of the intention/action type. Stereotypies were seen in 63%. Functional outcome concerning mobility was variable ranging from independent walking (50%) to wheelchair dependence (39%). Seventy-one percent of adults were nonverbal, and all were dependent on caregivers for most activities of daily living. DISCUSSION: STXBP1-DEE warrants continuous monitoring for seizures in adult life. Periods of regression are more frequent than previously established and can occur into adulthood. Movement disorders are often present and involve multiple systems. Although functional mobility is variable in adulthood, STXBP1-DEE frequently leads to severe cognitive impairments and a high level of functional dependence. Understanding the natural history of STXBP1-DEE is important for prognostication and will inform future therapeutic trials.

Left-sided hemihypomimia in Parkinson's disease.

Parkinson's disease is known to present and mostly persist as an asymmetrical movement disorder in most cases. The asymmetry is mainly described in motor features such as bradykinesia, rigidity and tremor in upper and lower limbs. Unilateral hypomimia however, has only been reported in 14 patients, all of whom showed right-sided hemihypomimia. In this case report we describe the symptoms of a 51-year-old man with predominant left-sided Parkinson's disease in whom we discovered a left-sided hemihypomimia. We also briefly review the literature concerning hemihypomimia in Parkinson's disease. We conclude that a larger case series needs to be studied to further elucidate the pathophysiology and clinical implications of this observation.

REM sleep without atonia and nocturnal body position in prediagnostic Parkinson's disease.

BACKGROUND: Sleep disturbances are features of Parkinson's disease (PD), that can already occur before PD diagnosis. The most investigated prodromal PD sleep disorder is REM sleep behavior disorder (RBD). The relation between other polysomnographic (PSG) alterations and the prediagnostic stages of PD, however, is less clear. METHODS: We performed a retrospective case-control study to characterize polysomnographic alterations in PD and prediagnostic PD. We included 63 PD subjects (33 subjects that underwent a video-PSG before PD diagnosis [13 with and 20 without RBD] and 30 subjects that underwent a PSG after PD diagnosis) and 30 controls. PSGs were analyzed for sleep stages, different RSWA variables, body position, arousals, periodic limb movements, and REM density. RESULTS: Higher subscores of all RSWA variables were observed in subjects with PD and prediagnostic PD (with and without RBD). Total RSWA, tonic RSWA and chin RSWA severity were significant predictors for all PD and prediagnostic PD groups. Our study also shows a higher percentage of nocturnal supine body position in all PD and prediagnostic PD groups. Supine body position percentage is the highest in the PD group and has a positive correlation with time since diagnosis. CONCLUSIONS: These findings suggest that increased total, tonic and chin RSWA as well as nocturnal supine body position are already present in prediagnostic PD, independently of RBD status. Prospective longitudinal studies are necessary to confirm the additional value of these PSG abnormalities as prodromal PD biomarkers.

Contribution of rare homozygous and compound heterozygous VPS13C missense mutations to dementia with Lewy bodies and Parkinson's disease.

Dementia with Lewy bodies (DLB) and Parkinson's disease (PD) are clinically, pathologically and etiologically disorders embedded in the Lewy body disease (LBD) continuum, characterized by neuronal α-synuclein pathology. Rare homozygous and compound heterozygous premature termination codon (PTC) mutations in the Vacuolar Protein Sorting 13 homolog C gene (VPS13C) are associated with early-onset recessive PD. We observed in two siblings with early-onset age (< 45) and autopsy confirmed DLB, compound heterozygous missense mutations in VPS13C, p.Trp395Cys and p.Ala444Pro, inherited from their healthy parents in a recessive manner. In lymphoblast cells of the index patient, the missense mutations reduced VPS13C expression by 90% (p = 0.0002). Subsequent, we performed targeted resequencing of VPS13C in 844 LBD patients and 664 control persons. Using the optimized sequence kernel association test, we obtained a significant association (p = 0.0233) of rare VPS13C genetic variants (minor allele frequency ≤ 1%) with LBD. Among the LBD patients, we identified one patient with homozygous missense mutations and three with compound heterozygous missense mutations in trans position, indicative for recessive inheritance. In four patients with compound heterozygous mutations, we were unable to determine trans position. The frequency of LBD patient carriers of proven recessive compound heterozygous missense mutations is 0.59% (5/844). In autopsy brain tissue of two unrelated LBD patients, the recessive compound heterozygous missense mutations reduced VPS13C expression. Overexpressing of wild type or mutant VPS13C in HeLa or SH-SY5Y cells, demonstrated that the mutations p.Trp395Cys or p.Ala444Pro, abolish the endosomal/lysosomal localization of VPS13C. Overall, our data indicate that rare missense mutations in VPS13C are associated with LBD and recessive compound heterozygous missense mutations might have variable effects on the expression and functioning of VPS13C. We conclude that comparable to the recessive inherited PTC mutations in VPS13C, combinations of rare recessive compound heterozygous missense mutations reduce VPS13C expression and contribute to increased risk of LBD.

Polysomnographic phenotype of isolated REM sleep without atonia.

OBJECTIVE: Isolated REM sleep without atonia (iRSWA) is regarded as a prodromal phase of REM sleep behavior disorder and synucleinopathies. In iRSWA patients, we investigated the polysomnographic characteristics that are known to be altered in (prodromal) Parkinson's disease (PD): periodic limb movements of sleep [PLMS] (increased), REM density (reduced), and heart rate variability ([HRV] (reduced). METHODS: We compared video-polysomnographic studies of 49 iRSWA subjects with 41 controls. RSWA and PLMS were scored visually. REM density (REM/hour) and HRV were calculated automatically. RESULTS: We found a higher median total (15.90 vs 7.20; p = 0.001), REM (21.80 vs 11.0; p < 0.001) and non-REM (11.75 vs 5.72; p = 0.027) PLMS index, and a higher mean REM density (342.45 vs 275.96; p = 0.010) in the iRSWA group, with a significant positive correlation between RSWA severity and these variables (r = 0.39; p < 0.00, r = 0.48; p < 0.001, r = 0.24; p = 0.021, r = 0.28; p = 0.012). We found no significant difference in HRV between groups. CONCLUSIONS: Our results suggest an association between RWSA and REM density and PLMS, but not HRV. The positive correlation between these variabilities may imply overlapping pathophysiological processes. SIGNIFICANCE: The evidence of higher REM density and normal HRV weakens the hypothesis that iRWSA is a prodromal PD stage. An alternative interpretation is, however, that REM density and HRV change during caudal-rostral neurodegeneration.