Motor assessment of X-linked dystonia parkinsonism via machine-learning-based analysis of wearable sensor data.

X-linked dystonia parkinsonism (XDP) is a neurogenetic combined movement disorder involving both parkinsonism and dystonia. Complex, overlapping phenotypes result in difficulties in clinical rating scale assessment. We performed wearable sensor-based analyses in XDP participants to quantitatively characterize disease phenomenology as a potential clinical trial endpoint. Wearable sensor data was collected from 10 symptomatic XDP patients and 3 healthy controls during a standardized examination. Disease severity was assessed with the Unified Parkinson's Disease Rating Scale Part 3 (MDS-UPDRS) and Burke-Fahn-Marsden dystonia scale (BFM). We collected sensor data during the performance of specific MDS-UPDRS/BFM upper- and lower-limb motor tasks, and derived data features suitable to estimate clinical scores using machine learning (ML). XDP patients were at varying stages of disease and clinical severity. ML-based algorithms estimated MDS-UPDRS scores (parkinsonism) and dystonia-specific data features with a high degree of accuracy. Gait spatio-temporal parameters had high discriminatory power in differentiating XDP patients with different MDS-UPDRS scores from controls, XDP freezing of gait, and dystonic/non-dystonic gait. These analyses suggest the feasibility of using wearable sensor data for deriving reliable clinical score estimates associated with both parkinsonian and dystonic features in a complex, combined movement disorder and the utility of motion sensors in quantifying clinical examination.

Machine learning models for diagnosis of essential tremor and dystonic tremor using grey matter morphological networks.

BACKGROUND: Essential tremor (ET) and dystonic tremor (DT) are the two most common tremor disorders, and misdiagnoses are very common due to similar tremor symptoms. In this study, we explore the structural network mechanisms of ET and DT using brain grey matter (GM) morphological networks and combine those with machine learning models. METHODS: 3D-T1 structural images of 75 ET patients, 71 DT patients, and 79 healthy controls (HCs) were acquired. We used voxel-based morphometry to obtain GM images and constructed GM morphological networks based on the Kullback-Leibler divergence-based similarity (KLS) method. We used the GM volumes, morphological relations, and global topological properties of GM-KLS morphological networks as input features. We employed three classifiers to perform the classification tasks. Moreover, we conducted correlation analysis between discriminative features and clinical characteristics. RESULTS: 16 morphological relations features and 1 global topological metric were identified as the discriminative features, and mainly involved the cerebello-thalamo-cortical circuits and the basal ganglia area. The Random Forest (RF) classifier achieved the best classification performance in the three-classification task, achieving a mean accuracy (mACC) of 78.7%, and was subsequently used for binary classification tasks. Specifically, the RF classifier demonstrated strong classification performance in distinguishing ET vs. HCs, ET vs. DT, and DT vs. HCs, with mACCs of 83.0 %, 95.2 %, and 89.3 %, respectively. Correlation analysis demonstrated that four discriminative features were significantly associated with the clinical characteristics. CONCLUSION: This study offers new insights into the structural network mechanisms of ET and DT. It demonstrates the effectiveness of combining GM-KLS morphological networks with machine learning models in distinguishing between ET, DT, and HCs.

Pyruvate dehydrogenase-E1α deficiency presenting as generalized dystonia: A genetic diagnosis with important clinical implications.

Pyruvate dehydrogenase complex (PDC) deficiency is a genetic mitochondrial disease mostly associated with severe lactic acidosis, rapid progression of neurological symptoms and death during childhood. We present a 33-year-old male with PDC deficiency caused by a Val262Leu mutation in PDHA1gene. He demonstrated generalized dystonia affecting trunk and upper extremities and paraparesis as the most significant features, with onset of symptoms at age 8. Brain MRI showed bilaterally increased signal within the globus pallidus, typical of Leigh syndrome. A periodic lactate increase in serum and cerebrospinal fluid was detected. We describe a case of pyruvate dehydrogenase deficiency being diagnosed only 25 years after the onset of symptoms and highlight PDHC deficiency as a possible cause of treatable dystonia in childhood, which may respond well to thiamine and levodopa treatment.

Genome sequencing reanalysis increases the diagnostic yield in dystonia.

PURPOSE: We investigated the contribution of genomic data reanalysis to the diagnostic yield of dystonia patients who remained undiagnosed after prior genome sequencing. METHODS: Probands with heterogeneous dystonia phenotypes who underwent initial genome sequencing (GS) analysis in 2019 were included in the reanalysis, which was performed through gene-specific discovery collaborations and systematic genomic data reanalysis. RESULTS: Initial GS analysis in 2019 (n = 111) identified a molecular diagnosis in 11.7 % (13/111) of cases. Reanalysis between 2020 and 2023 increased the diagnostic yield by 7.2 % (8/111); 3.6 % (4/111) through focused gene-specific clinical correlation collaborative efforts [VPS16 (two probands), AOPEP and POLG], and 3.6 % (4/111) by systematic reanalysis completed in 2023 [NUS1 (two probands) and DDX3X variants, and a microdeletion encompassing VPS16]. Seven of these patients had a high phenotype-based dystonia score ≥3. Notable unverified findings in four additional cases included suspicious variants of uncertain significance in FBXL4 and EIF2AK2, and potential phenotypic expansion associated with SLC2A1 and TREX1 variants. CONCLUSION: GS data reanalysis increased the diagnostic yield from 11.7 % to 18.9 %, with potential extension up to 22.5 %. While optimal timing for diagnostic reanalysis remains to be determined, this study demonstrates that periodic re-interrogation of dystonia GS datasets can provide additional genetic diagnoses, which may have significant implications for patients and their families.

Dystonic Tremor: Time to Change.

BACKGROUND: The term dystonic tremor is being increasingly used in neurological publications despite uncertainties about its meaning. We provide here a historical reconstruction from its original introduction in 1984 to help distinguish dystonia from essential tremor. METHODS: A comprehensive Pubmed search of MeSH terms "dystonia", "tremor", and "essential tremor" provided the information base for reconstructing historical usage of the term "dystonic tremor". RESULTS: Over the years, this expression was enriched of additional meanings and sided by companion descriptors, such as tremor associated with dystonia. Dystonic tremor has been considered characteristically coarse, jerky, irregular, directional and asymmetrical. These characteristics, however, are not included in the most recent definitions of tremor. The relationship between tremor and dystonia is not easy to untangle, as the two phenomena are often recognized in association. Tremor and dystonia experts have developed different visions of dystonic tremor that have been variably implemented. There are currently two independent consensus definitions, which are not coincident and imply different pathophysiological interpretations. CONCLUSIONS: This historical reappraisal highlights that usage of the expression dystonic tremor has evolved over time to lose its original meaning. Notwithstanding inconsistencies of current definitions, its usage has steadily increased and it is time now to agree on an updated terminology.

Blood-Based Proteomics for Adult-Onset Focal Dystonias.

OBJECTIVES: The adult-onset focal dystonias are characterized by over-active muscles leading to abnormal movements. For most cases, the etiology and pathogenesis remain unknown. In the current study, unbiased proteomics methods were used to identify potential changes in blood plasma proteins. METHODS: A large-scale unbiased proteomics screen was used to compare proteins (N = 6,345) in blood plasma of normal healthy controls (N = 49) with adult-onset focal dystonia (N = 143) consisting of specific subpopulations of cervical dystonia (N = 45), laryngeal dystonia (N = 49), and blepharospasm (N = 49). Pathway analyses were conducted to identify relevant biological pathways. Finally, protein changes were used to build a prediction model for dystonia. RESULTS: After correction for multiple comparisons, 15 proteins were associated with adult-onset focal dystonia. Subgroup analyses revealed some proteins were shared across the dystonia subgroups while others were unique to 1 subgroup. The top biological pathways involved changes in the immune system, metal ion transport, and reactive oxygen species. A 4-protein model showed high accuracy in discriminating control individuals from dystonia cases [average area under the curve (AUC) = 0.89]. INTERPRETATION: These studies provide novel insights into the etiopathogenesis of dystonia, as well as novel potential biomarkers. ANN NEUROL 2024;96:110-120.

Posterior Interosseous Neuropathy with Peripheral Dystonia: A Case Report.

Background: Posterior interosseous neuropathy is an uncommon cause of peripheral dystonia. Case Report: A 62-year-old man awakened and noticed right finger drop. A neurological examination revealed posterior interosseous neuropathy with dystonia-like finger movements. Abnormal movements were predominantly observed in the right thumb, ring finger, and little finger. Within 2 weeks, the muscle weakness in the right fingers had completely improved. However, a brief abnormal posture of the right thumb was persistent. Discussion: The residual abnormal posture of the right thumb may reflect pre-existing motor control abnormalities, which may have contributed to the onset of posterior interosseous neuropathy-associated peripheral dystonia.

Oromandibular dystonia: from onset to spread a multicenter italian study.

BACKGROUND: Detailed information about the epidemiological and phenomenological differences among the aetiological subtypes of oromandibular dystonia (OMD) is lacking. Moreover, the OMD tendency to spread to other body sites has never been investigated. AIM: To compare the main demographic and clinical features of OMD in different aetiological groups and assess the risk of spread. MATERIALS AND METHODS: We retrospectively analysed data from patients contained in the Italian Dystonia Registry. The risk of spread was assessed by Kaplan Meyer curves and Cox regression analysis. RESULTS: The study included 273 patients (175 women) aged 55.7 years (SD 12.7) at OMD onset. Female predominance was observed. Idiopathic dystonia was diagnosed in 241 patients, acquired dystonia in 22. In 50/273 patients, dystonia started in the oromandibular region (focal OMD onset); in 96/273 patients the onset involved the oromandibular region and a neighbouring body site (segmental/multifocal OMD onset); and in 127/273 patients OMD was a site of spread from another body region. Sensory trick (ST) and positive family history predominated in the idiopathic group. No dystonia spread was detected in the acquired group, whereas spread mostly occurred within the first five years of history in 34% of the focal OMD onset idiopathic patients. Cox regression analysis revealed ST as a significant predictor of spread (HR, 12.1; 95% CI, 2.5 - 18.8; P = 0.002). CONCLUSION: This large study provides novel information about the clinical phenomenology of idiopathic and acquired OMD. We pointed out a possible role of oestrogens in favouring dystonia development. Moreover, we described for the first time the association between ST and dystonia spread, revealing possible common pathophysiological mechanisms. Our findings may be suggested as a referral point for future pathophysiological and therapeutic studies on OMD.

Interdisciplinary insights into tremor in dystonia: Navigating clinical controversies, definitional challenges, and pathophysiological complexities.

This review delves into the historical evolution and ongoing controversy surrounding the relationship between tremor and dystonia. The Dystonia Consensus Panel and the International Parkinson's and Movement Disorders Society's Tremor Taskforce have attempted to define these entities, but the complexity arises when patients have a combination of both dystonia and tremor. The term "dystonic tremor" has sparked diverse interpretations, with debates over its clinical features and the need for more objectively defined characteristics. Logistic regression analyses in a large cohort of dystonia patients identified determinants such as body region affected by dystonia, dystonia severity, age, and recruitment site, with unexpected associations emphasizing the subjectivity in detecting and classifying tremor. The study further discovered diverse prevalence of "dystonic tremor" based on different definitions, revealing substantial variability among investigators. The recently convened Dystonia-Tremor panel aimed to address these challenges by proposing a more uniform nomenclature, emphasizing precise and descriptive terms. Despite the complexity, instrumented measures, such as electromyography, temporal discrimination threshold, blink reflex, and trajectory shape analysis, seem to be useful in distinguishing between tremor and dystonia. The pathophysiology debate centers around the involvement of the cerebello-thalamo-cortical and basal ganglia-thalamo-cortical circuits. Evidence supports the role of both circuits in driving the pathophysiology of dystonic tremor, challenging the notion of a clear dichotomy. The review concludes by emphasizing the need for a nuanced understanding, highlighting the intricate interplay between tremor and dystonia, and the potential of instrumental measures in advancing diagnostic accuracy.

CHD8-related disorders redefined: an expanding spectrum of dystonic phenotypes.

BACKGROUND: Heterozygous loss-of-function variants in CHD8 have been associated with a syndromic neurodevelopmental-disease spectrum, collectively referred to as CHD8-related neurodevelopmental disorders. Several different clinical manifestations, affecting neurodevelopmental and systemic domains, have been described, presenting with highly variable expressivity. Some expressions are well established and comprise autism spectrum disorders, psychomotor delay with cognitive impairment, postnatal overgrowth with macrocephaly, structural brain abnormalities, gastrointestinal disturbances, and behavioral and sleep-pattern problems. However, the complete phenotypic spectrum of CHD8-related disorders is still undefined. In 2021, our group described two singular female patients with CHD8-related neurodevelopmental disorder and striking dystonic manifestations, prompting the suggestion that dystonia should be considered a possible component of this condition. CASE SERIES PRESENTATION: We describe three additional unrelated female individuals, each carrying a different CHD8 frameshift variant and whose clinical presentations were primarily characterized by young-onset dystonia. Their dystonic manifestations were remarkably heterogeneous and ranged from focal, exercise-dependent, apparently isolated forms to generalized permanent phenotypes accompanied by spasticity and tremor. Neurocognitive impairment and autistic behaviors, typical of CHD8-related disorders, were virtually absent or at the mild end of the spectrum. CONCLUSIONS: This work validates our previous observation that dystonia is part of the phenotypic spectrum of CHD8-related neurodevelopmental disorders with potential female preponderance, raising new challenges and opportunities in the diagnosis and management of this condition. It also highlights the importance of in-depth neurologic phenotyping of patients carrying variants associated with neurodevelopmental disorders, as the connection between neurodevelopmental and movement disorders is proving closer than previously appreciated.

Dissecting genetic architecture of rare dystonia: genetic, molecular and clinical insights.

BACKGROUND: Dystonia is one of the most common movement disorders. To date, the genetic causes of dystonia in populations of European descent have been extensively studied. However, other populations, particularly those from the Middle East, have not been adequately studied. The purpose of this study is to discover the genetic basis of dystonia in a clinically and genetically well-characterised dystonia cohort from Turkey, which harbours poorly studied populations. METHODS: Exome sequencing analysis was performed in 42 Turkish dystonia families. Using co-expression network (CEN) analysis, identified candidate genes were interrogated for the networks including known dystonia-associated genes and genes further associated with the protein-protein interaction, animal model-based characteristics and clinical findings. RESULTS: We identified potentially disease-causing variants in the established dystonia genes (PRKRA, SGCE, KMT2B, SLC2A1, GCH1, THAP1, HPCA, TSPOAP1, AOPEP; n=11 families (26%)), in the uncommon forms of dystonia-associated genes (PCCB, CACNA1A, ALDH5A1, PRKN; n=4 families (10%)) and in the candidate genes prioritised based on the pathogenicity of the variants and CEN-based analyses (n=11 families (21%)). The diagnostic yield was found to be 36%. Several pathways and gene ontologies implicated in immune system, transcription, metabolic pathways, endosomal-lysosomal and neurodevelopmental mechanisms were over-represented in our CEN analysis. CONCLUSIONS: Here, using a structured approach, we have characterised a clinically and genetically well-defined dystonia cohort from Turkey, where dystonia has not been widely studied, and provided an uncovered genetic basis, which will facilitate diagnostic dystonia research.

Axial dystonia as a manifestation of stiff-person syndrome in a paediatric patient.

Stiff-person syndrome (SPS) is a rare neurological condition that frequently affects adults, with the neurologist diagnosing only one or two cases during his or her career. Reports of paediatric SPS are exceedingly rare, with less than 20 cases described in the literature.The patient presented was initially diagnosed with a functional movement disorder then a genetic dystonia, with a poor response to treatment trials and negative genetic testing. Consideration of Wilson's disease was refuted with non-supportive investigations and assessments.We aim to present the long road to diagnosing our first paediatric patient with SPS, who presented in middle childhood.

Are Cognitive Symptoms Part of the Phenotypic Spectrum of Idiopathic Adult-Onset Dystonia? Summary of Evidence from Controlled Studies.

BACKGROUND: Cognitive dysfunction has been reported in idiopathic adult-onset dystonia (IAOD), but whether this is a primary or secondary component of the disorder remains uncertain. OBJECTIVE: Here, we aimed to analyze the key domains of abnormal cognitive performance in IAOD and whether this is associated with motor or mood changes. METHODS: Article selection for our critical review was guided by PRISMA guidelines (mesh terms "dystonia" and "cognitive," publication period: 2000-2022). Only peer-reviewed, English-language original case-control studies involving patients with IAOD who were not exposed to dopamine- or acetylcholine-modulating agents and validated cognitive assessments were included. RESULTS: Abstract screening ultimately yielded 22 articles for full-text review and data extraction. A greater proportion of studies (17 of 22, 82%) reported abnormal cognitive performance in IAOD. Most of these studies focused on blepharospasm (BSP) and cervical dystonia (10 and 14, respectively). Most studies reporting cognitive impairment (11 of 17) identified multidomain impairment in cognition. Executive functions were the domain most frequently explored (14 of 22 studies), 79% of which detected worse performance in people with dystonia. Results related to other domains were inconclusive. Cognitive abnormalities were independent of motor symptoms in most studies (7 of 12) that explored this relationship and independent of mood status in all 8 that investigated this. CONCLUSIONS: Within IAOD, cognitive dysfunction (in particular, executive dysfunction) has been documented mainly in BSP and cervical dystonia. More comprehensive testing is warranted to assess abnormalities in other domains and in other forms of IAOD, as well as to evaluate longitudinal progression of cognitive disturbances in this condition.

Caregiver descriptions of dystonia in cerebral palsy.

OBJECTIVE: To determine how caregivers describe dystonia in people with cerebral palsy (CP). METHODS: In this prospective cohort study, paper surveys were administered to caregivers between September 7, 2021 and October 28, 2021 during CP Center visits at a large tertiary care center. Caregivers were asked to describe involuntary movements triggered by voluntary movement or triggered by tactile stimulation in the people with CP they cared for. Their CP Center medical provider separately assessed people with CP for dystonia. Movement features described exclusively by caregivers of people with CP and dystonia were determined using conventional content analysis. RESULTS: 113 caregivers responded on behalf of 56 people with and 57 people without dystonia. If caregivers noted that both voluntary movement and tactile stimulation triggered involuntary movements, that had a 92% positive predictive value for a dystonia diagnosis. Movement features exclusively described in people with CP and dystonia included: (1) stiffening, tensing, or tightening (15% of respondents); (2) involvement of the head (10%), torso (5%), or feet (5%); and (3) triggers of stretching (12.5%), excitement (5%), or transfers (5%). INTERPRETATION: In addition to a thorough exam, asking caregivers of people with CP to describe involuntary movements triggered by voluntary movement or tactile stimulation may inform clinical dystonia diagnosis.

Dominant VPS16 Pathogenic Variants: Not Only Isolated Dystonia.

BACKGROUND: VPS16 pathogenic variants have been recently associated with inherited dystonia. Most patients affected by dominant VPS16-related disease display early-onset isolated dystonia with prominent oromandibular, bulbar, cervical, and upper limb involvement, followed by slowly progressive generalization. CASES: We describe six newly reported dystonic patients carrying VPS16 mutations displaying unusual phenotypic features in addition to dystonia, such as myoclonus, choreoathetosis, pharyngospasm and freezing of gait. Response to bilateral Globus Pallidus Internus Deep Brain Stimulation (GPi-DBS) is reported in three of them, associated with significant improvement of dystonia but only minor effect on other hyperkinetic movements. Moreover, five novel pathogenic/likely pathogenic variants are described. CONCLUSIONS: This case collection expands the genetic and clinical spectrum of VPS16-related disease, prompting movement disorder specialists to suspect mutations of this gene not only in patients with isolated dystonia.

Chronic Pallidal Local Field Potentials Are Associated With Dystonic Symptoms in Children.

BACKGROUND: Novel deep brain stimulation devices can record local field potentials (LFPs), which represent the synchronous synaptic activity of neuronal populations. The clinical relevance of LFPs in patients with dystonia remains unclear. OBJECTIVES: We sought to determine whether chronic LFPs recorded from the globus pallidus internus (GPi) were associated with symptoms of dystonia in children. MATERIALS AND METHODS: Ten patients with heterogeneous forms of dystonia (genetic and acquired) were implanted with neurostimulators that recorded LFP spectral snapshots. Spectra were compared across parent-reported asymptomatic and symptomatic periods, with daily narrowband data superimposed in 24 one-hour bins. RESULTS: Spectral power increased during periods of registered dystonic symptoms: mean increase = 102%, CI: (76.7, 132). Circadian rhythms within the LFP narrowband time series correlated with dystonic symptoms: for delta/theta-waves, correlation = 0.33, CI: (0.18, 0.47) and for alpha waves, correlation = 0.27, CI: (0.14, 0.40). CONCLUSIONS: LFP spectra recorded in the GPi indicate a circadian pattern and are associated with the manifestation of dystonic symptoms.

A scoping review on the diagnosis and treatment of X-linked dystonia-parkinsonism.

INTRODUCTION: X-linked dystonia-parkinsonism (XDP) is a progressive neurodegenerative disorder that has been studied well in recent years. OBJECTIVES: This scoping review aimed to describe the current state of knowledge about the diagnosis and treatment of XDP, to provide clinicians with a concise and up-to-date overview. METHODS: We conducted a scoping review of pertinent literature on the diagnosis and treatment of XDP using Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines. RESULTS: There were 24 articles on diagnostic methods and 20 articles on therapeutic interventions for XDP, with 7 review articles describing both. The detection of the SVA retrotransposon insertion within the TAF1 gene is confirmatory for XDP. Oral medications are marginally effective. Chemodenervation with botulinum toxin is an effective treatment. Pallidal deep brain stimulation (DBS) has been shown to provide significant improvement in the dystonia and quality of life of patients with XDP for a longer time. A less invasive surgical option is the transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS), which has shown promising effects with the limited number of case reports available. CONCLUSION: XDP is a geneti disorder characterized by striatal symptoms and pathology on neuroimaging. No effective oral medications are available for the management of XDP. The use of botulinum toxin is limited by its cost and duration of effects. As of now, pallidal DBS is deemed to be the best option. Another promising option is the tcMRgFUS but still has limited studies on its safety and efficacy in XDP.