ANO10-Related Spinocerebellar Ataxia: MDSGene Systematic Literature Review and a Romani Case Series.

BACKGROUND: Biallelic pathogenic variants in the ANO10 gene cause autosomal recessive progressive ataxia (ATX-ANO10). METHODS: Following the MDSGene protocol, we systematically investigated genotype-phenotype relationships in ATX-ANO10 based on the clinical and genetic data from 82 published and 12 newly identified patients. RESULTS: Most patients (>80%) had loss-of-function (LOF) variants. The most common variant was c.1150_1151del, found in all 29 patients of Romani ancestry, who had a 14-year earlier mean age at onset than patients homozygous for other LOF variants. We identified previously undescribed clinical features of ATX-ANO10 (e.g., facial muscle involvement and strabismus) suggesting the involvement of brainstem pathology, and we propose a diagnostic algorithm that may aid clinical ATX-ANO10 diagnosis. CONCLUSIONS: The early disease onset in patients with c.1150_1151del may indicate the existence of genetic/environmental disease-modifying factors in the Romani population. Our findings will inform patient counseling and may improve our understanding of the disease mechanism. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Genotype-Phenotype Correlations for ATX-TBP (SCA17): MDSGene Systematic Review.

Spinocerebellar ataxia type 17 or ATX-TBP is a CAG/CAA repeat expansion disorder characterized by marked clinical heterogeneity. Reports of affected carriers with subthreshold repeat expansions and of patients with Parkinson's disease (PD) with expanded repeats have cast doubt on the established cutoff values of the expansions and the phenotypic spectrum of this disorder. The objective of this systematic review was to explore the genotype-phenotype relationships for repeat expansions in TBP to delineate the ATX-TBP phenotype and reevaluate the pathological range of repeat expansions. The International Parkinson and Movement Disorder Society Genetic Mutation Database (MDSGene) standardized data extraction protocol was followed. Clinically affected carriers of reported ATX-TBP expansions were included. Publications that contained repeat sizes in screened cohorts of patients with PD and/or healthy individuals were included for a separate evaluation of cutoff values. Phenotypic and genotypic data for 346 ATX-TBP patients were curated. Overall, 97.7% of the patients had ≥41 repeats, while 99.6% of patients with PD and 99.9% of healthy individuals had ≤42 repeats, with a gray zone of reduced penetrance between 41 and 45 repeats. Pure parkinsonism was more common in ATX-TBP patients with 41 to 45 repeats than in the group with ≥46 repeats, which conversely more often presented with a complex phenotype with mixed movement disorders. An updated genotype-phenotype assessment for ATX-TBP is provided, and new repeat expansion cutoff values of reduced penetrance (41-45 expanded repeats) and full penetrance (46-66 expanded repeats) are proposed. These adjusted cutoff values will have diagnostic and counseling implications and may guide future clinical trial protocol. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Genotype-phenotype relations for episodic ataxia genes: MDSGene systematic review.

BACKGROUND: Most episodic ataxias (EA) are autosomal dominantly inherited and characterized by recurrent attacks of ataxia and other paroxysmal and non-paroxysmal features. EA is often caused by pathogenic variants in the CACNA1A, KCNA1, PDHA1, and SLC1A3 genes, listed as paroxysmal movement disorders (PxMD) by the MDS Task Force on the Nomenclature of Genetic Movement Disorders. Little is known about the genotype-phenotype correlation of the different genetic EA forms. METHODS: We performed a systematic review of the literature to identify individuals affected by an episodic movement disorder harboring pathogenic variants in one of the four genes. We applied the standardized MDSGene literature search and data extraction protocol to summarize the clinical and genetic features. All data are available via the MDSGene protocol and platform on the MDSGene website (https://www.mdsgene.org/). RESULTS: Information on 717 patients (CACNA1A: 491, KCNA1: 125, PDHA1: 90, and SLC1A3: 11) carrying 287 different pathogenic variants from 229 papers was identified and summarized. We show the profound phenotypic variability and overlap leading to the absence of frank genotype-phenotype correlation aside from a few key 'red flags'. CONCLUSION: Given this overlap, a broad approach to genetic testing using a panel or whole exome or genome approach is most practical in most circumstances.

Rapid Eye Movement Sleep Behavior Disorder in Parkinson's Disease: A Survey-Based Study.

OBJECTIVE: To characterize Parkinson's disease (PD) symptoms based on the presence, onset time, and severity of rapid eye movement sleep behavior disorder (RBD) and their association with impulse control disorders (ICD). BACKGROUND: RBD is a frequent non-motor symptom in PD, usually described as prodromal. The severity of RBD according to the start time and its relationship with ICD in PD needs further clarification. METHODS: A survey-based study was performed to determine the presence of RBD symptoms, their severity, and the temporal relationship with the PD onset. The survey included RBD1Q, the Mayo Sleep, and the RBDQ-HK questionnaires and questions about clinical characteristics, including ICD. Only PD patients with care partners spending night hours in the same room were included. RESULTS: 410 PD patients were included: 206 with RBD (50.2%) and 204 non-RBD (49.8%). The PD-RBD patients were younger and their daily levodopa dose was higher than the non-RBD group. Most of these patients developed RBD symptoms after the onset of clinical PD were younger at motor symptom onset and had higher scores in the hallucinations and psychosis subsection of MDS-UPDRS-I. RBD group had a more severe non-motor phenotype, including more ICD than those without RBD, mainly due to higher compulsive eating. CONCLUSIONS: In our study, most patients recognized RBD symptoms after the onset of the PD motor symptoms and the clinical features of PD with and without RBD were distinctive, supporting the hypothesis that PD-RBD might represent a variant pattern of neurodegeneration.

Nomenclature of Genetic Movement Disorders: Recommendations of the International Parkinson and Movement Disorder Society Task Force - An Update.

In 2016, the Movement Disorder Society Task Force for the Nomenclature of Genetic Movement Disorders presented a new system for naming genetically determined movement disorders and provided a criterion-based list of confirmed monogenic movement disorders. Since then, a substantial number of novel disease-causing genes have been described, which warrant classification using this system. In addition, with this update, we further refined the system and propose dissolving the imaging-based categories of Primary Familial Brain Calcification and Neurodegeneration with Brain Iron Accumulation and reclassifying these genetic conditions according to their predominant phenotype. We also introduce the novel category of Mixed Movement Disorders (MxMD), which includes conditions linked to multiple equally prominent movement disorder phenotypes. In this article, we present updated lists of newly confirmed monogenic causes of movement disorders. We found a total of 89 different newly identified genes that warrant a prefix based on our criteria; 6 genes for parkinsonism, 21 for dystonia, 38 for dominant and recessive ataxia, 5 for chorea, 7 for myoclonus, 13 for spastic paraplegia, 3 for paroxysmal movement disorders, and 6 for mixed movement disorder phenotypes; 10 genes were linked to combined phenotypes and have been assigned two new prefixes. The updated lists represent a resource for clinicians and researchers alike and they have also been published on the website of the Task Force for the Nomenclature of Genetic Movement Disorders on the homepage of the International Parkinson and Movement Disorder Society (https://www.movementdisorders.org/MDS/About/Committees--Other-Groups/MDS-Task-Forces/Task-Force-on-Nomenclature-in-Movement-Disorders.htm). © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Punding in Parkinson's Disease: An Update.

Background: Punding is a stereotyped behavior characterized by an intense fascination with a complex, excessive, non-goal oriented, repetitive activity affecting individuals with Parkinson's disease (PD) on dopamine replacement therapy (DRT). Objectives: In 2010, we published the first review focused on the pathophysiology of punding. This study aims to systematically review the literature of the past decade on punding in PD, particularly focusing on the clinical features, underlying pathophysiological mechanisms, and treatment. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched PubMed, Embase, and APA PsycInfo for articles published between July 1, 2010 and March 19, 2022. The search strategy included: (punding) AND (parkinson*). Results: Of 256 studies identified, 29 were eligible for inclusion with 19 original research articles and 10 case reports. This review confirmed that predictors of punding in PD are higher doses of DRT, younger age, male sex, and increasing disease severity. We also found an association between punding and psychiatric and/or cognitive symptoms. Neuroimaging studies have showed that punding in PD is associated with a disconnection between midbrain, limbic and white matter tracts projecting to the frontal cortices and a breakdown of the connectivity among the crucial nodes of the reward circuit. Low-frequency repetitive transcranial magnetic stimulation on the dorsolateral prefrontal cortex has been shown to produce a transient beneficial effect in PD patients with punding. Conclusion: In conclusion, although the clinical features of punding have been established, in the past 12 years, we gained a better understanding of the pathophysiological mechanisms of punding, mainly thanks to magnetic resonance imaging techniques.

Gait Analysis in Idiopathic Normal Pressure Hydrocephalus: A Meta-Analysis.

Background: Gait analysis objectively quantifies gait impairment in idiopathic normal pressure hydrocephalus (iNPH), may improve diagnosis and evaluation for surgical candidacy. Objectives: This meta-analysis aims to understand which objective gait parameters improve after tap-test (TT) and CSF shunt surgery (CSS), also comparing responders (R) with non-responders (NR) and to assess if gait restores within the range of healthy controls after procedures. Methods: Studies enrolling iNPH with at least one instrumented gait measure were selected. Three time points of gait assessment were defined: PRE, POST-TT, and POST-CSS. Gait velocity, cadence, step length, stride length, and double limb support time were evaluated. Patients were categorized based on responsiveness to CSF diversion procedures. Results: Seventeen studies including 527 patients were selected. iNPH improved significantly in almost all gait parameters POST-TT, and to a greater extent POST-CSS. Gait parameters consistently discriminated iNPH from healthy controls. Despite the aforementioned improvements, iNPH's gait did not completely normalize after CSF diversion procedures. Meta-regression analysis also revealed that TT's effect on gait velocity plateaus after 24-48 hr and returns to baseline in 90-100 hr. Conclusions: Gait analysis is a reliable quantitative instrument to assess gait impairment in iNPH, demarking a net differentiation from healthy controls, according to the notion that the iNPH CSF dynamic alteration also leads to an irreversible damage. Specific gait parameters improve among TT-R, providing an opportunity to select patients that will respond to CSS. Future studies validating a standardized reporting method including criteria of responsiveness, specific gait parameters, and timeframe of assessment are needed.

Gender Differences in the Prevalence of Parkinson's Disease.

Background: Parkinson's disease (PD) affects males more than females. The reasons for the gender differences in PD prevalence remain unclear. Objective: The objective of this systematic review and meta-analysis was to update the overall male/female prevalence ratios (OPR). Methods: We updated previous work by searching MEDLINE, SCOPUS, and OVID for articles reporting PD prevalence for both genders between 2011 and 2021. We calculated OPRs and investigated heterogeneity in effect estimates. Results: We included 19 new articles and 13 articles from a previously published meta-analysis. The OPR was 1.18, 95% CI, [1.03, 1.36]. The OPR was lowest in Asia and appeared to be decreasing over time. Study design, national wealth, and participant age did not explain OPR heterogeneity. Conclusion: Gender differences in PD prevalence may not be as stark as previously thought. Studies are needed to understand the role of other determinants of gender differences in PD prevalence.

Axial Impairment Following Deep Brain Stimulation in Parkinson's Disease: A Surgicogenomic Approach.

BACKGROUND: Postoperative outcome following deep brain stimulation (DBS) of the subthalamic nucleus is variable, particularly with respect to axial motor improvement. We hypothesized a genetic underpinning to the response to surgical intervention, termed "surgicogenomics". OBJECTIVE: We aimed to identify genetic variants associated with clinical heterogeneity in DBS outcome of Parkinson's disease (PD) patients that could then be applied clinically to target selection leading to improved surgical outcome. METHODS: Retrospective clinical data was extracted from 150 patient's charts. Each individual was genotyped using the genome-wide NeuroX array tailored to study neurologic diseases. Genetic data were clustered based on surgical outcome assessed by comparing pre- and post-operative scores of levodopa equivalent daily dose and axial impairment at one and five years post-surgery. Allele frequencies were compared between patients with excellent vs. moderate/poor outcomes grouped using a priori defined cut-offs. We analyzed common variants, burden of rare coding variants, and PD polygenic risk score. RESULTS: NeuroX identified 2,917 polymorphic markers at 113 genes mapped to known PD loci. The gene-burden analyses of 202 rare nonsynonymous variants suggested a nominal association of axial impairment with 14 genes (most consistent with CRHR1, IP6K2, and PRSS3). The strongest association with surgical outcome was detected between a reduction in levodopa equivalent daily dose and common variations tagging two linkage disequilibrium blocks with SH3GL2. CONCLUSION: Once validated in independent populations, our findings may be implemented to improve patient selection for DBS in PD.

Parkinson's Disease Subtypes: Critical Appraisal and Recommendations.

BACKGROUND: In Parkinson's disease (PD), there is heterogeneity in the clinical presentation and underlying biology. Research on PD subtypes aims to understand this heterogeneity with potential contribution for the knowledge of disease pathophysiology, natural history and therapeutic development. There have been many studies of PD subtypes but their impact remains unclear with limited application in research or clinical practice. OBJECTIVE: To critically evaluate PD subtyping systems. METHODS: We conducted a systematic review of PD subtypes, assessing the characteristics of the studies reporting a subtyping system for the first time. We completed a critical appraisal of their methodologic quality and clinical applicability using standardized checklists. RESULTS: We included 38 studies. The majority were cross-sectional (n = 26, 68.4%), used a data-driven approach (n = 25, 65.8%), and non-clinical biomarkers were rarely used (n = 5, 13.1%). Motor characteristics were the domain most commonly reported to differentiate PD subtypes. Most of the studies did not achieve the top rating across items of a Methodologic Quality checklist. In a Clinical Applicability Checklist, the clinical importance of differences between subtypes, potential treatment implications and applicability to the general population were rated poorly, and subtype stability over time and prognostic value were largely unknown. CONCLUSION: Subtyping studies undertaken to date have significant methodologic shortcomings and most have questionable clinical applicability and unknown biological relevance. The clinical and biological signature of PD may be unique to the individual, rendering PD resistant to meaningful cluster solutions. New approaches that acknowledge the individual-level heterogeneity and that are more aligned with personalized medicine are needed.

Atrial cardiopathy in patients with embolic strokes of unknown source and other stroke etiologies.

OBJECTIVE: To investigate the prevalence and clinical determinants of atrial cardiopathy in patients with embolic stroke of unknown source (ESUS) and compare with other established stroke etiologies. METHODS: In a cross-sectional study of 846 consecutive patients with ischemic stroke, we compared the prevalence of atrial cardiopathy (defined by p-wave terminal force in V1 >5,000 µV·ms or severe left atrial enlargement) between ESUS patients and patients with large artery atherosclerosis (LAA) and small vessel disease (SVD) strokes. Baseline characteristics were also compared between ESUS and cardioembolic (CE) patients. RESULTS: Of all, 158 (19%) patients met ESUS diagnostic criteria, while others were classified into LAA (n = 224, 26%), SVD (n = 154, 18%), and CE (n = 310, 37%). The prevalence of atrial cardiopathy was higher in ESUS patients compared to noncardioembolic stroke patients (26.6% vs 12.1% in LAA vs 16.9% in SVD; p = 0.001). ESUS patients were younger, were less hypertensive, and had higher cholesterol and low-density lipoprotein levels, but also had less left ventricular or atrial abnormalities when compared to CE patients. CONCLUSION: The prevalence of atrial cardiopathy was high in ESUS patients compared with patients with nonembolic strokes. Interestingly, ESUS patients were also clinically different from CE patients. While the presence of atrial cardiopathy may reflect a unique mechanism of thromboembolism in ESUS patients, it is still unclear if they may benefit from anticoagulation, or if the presence of atrial cardiopathy in this population could serve as a risk-stratifying marker for stroke recurrence. Further efforts are necessary to provide better characterization of the ESUS population in order to develop better stroke preventive strategies.

The clinical significance of lower limb tremors.

INTRODUCTION: To explore the prevalence, clinical course and associated features of lower limb tremor in the most common tremor syndromes. METHODS: This retrospective chart review studied lower limb tremor patients as defined by a Tremor Rating Scale score ≥1 in either lower limb. We compared and correlated their characteristics, also comparing them with patients without lower limb tremor. RESULTS: Of the 283 patients with lower limb tremor (58.3% males, age: 65.0 ±â€¯16.0 years, tremor duration: 25.6 ±â€¯17.9 years), 255 patients within six tremor syndrome groups were included in the final analysis. Prevalence of patients with lower limb tremor (either rest, postural or kinetic) was lowest (28.6%) in the essential tremor (ET) group and highest (69%) in the parkinsonian tremor (PT) group. Lower limb tremor score was higher in patients classified as having intention tremor (IT) compared to ET and dystonic tremor (DT). Total tremor score was highest in IT and lowest in ET. We found a positive correlation between total lower limb tremor score and total tremor score in most groups. In addition, there was a positive correlation between lower limb tremor score and upper limb tremor score. Finally, compared to patients without lower limb tremor, all diagnostic groups with lower limb tremor, with the exception of functional tremor (FT), had worse total tremor score; and disease duration was longer in ET-plus, DT and PT patients with lower limb tremor compared to those without. CONCLUSIONS: Lower limb tremor is less commonly observed in ET than other tremor syndromes, is a marker of symptom severity of the underlying disease condition in all tremor syndromes except FT, and reflects longer disease duration in ET-plus, DT and PT.