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Biochimica Et Biophysica Acta.... Jun 2024Recessive mutations in the Parkin gene (PRKN) are the most common cause of young-onset inherited parkinsonism. Parkin is a multifunctional E3 ubiquitin ligase that plays...
Recessive mutations in the Parkin gene (PRKN) are the most common cause of young-onset inherited parkinsonism. Parkin is a multifunctional E3 ubiquitin ligase that plays a variety of roles in the cell including the degradation of proteins and the maintenance of mitochondrial homeostasis, integrity, and biogenesis. In 2001, the R275W mutation in the PRKN gene was identified in two unrelated families with a multigenerational history of postural tremor, dystonia and parkinsonism. Drosophila models of Parkin R275W showed selective and progressive degeneration of dopaminergic neuronal clusters, mitochondrial abnormalities, and prominent climbing defects. In the Prkn mouse orthologue, the amino acid R274 corresponds to human R275. Here we described an age-related motor impairment and a muscle phenotype in R274W +/+ mice. In vitro, Parkin R274W mutation correlates with abnormal myoblast differentiation, mitochondrial defects, and alteration in mitochondrial mRNA and protein levels. Our data suggest that the Parkin R274W mutation may impact mitochondrial physiology and eventually myoblast proliferation and differentiation.
PubMed: 38878834
DOI: 10.1016/j.bbadis.2024.167302 -
Frontiers in Neurology 2024Laryngeal dystonia is a task-specific focal dystonia of laryngeal muscles that impairs speech and voice production. At present, there is no cure for LD. The most common...
BACKGROUND
Laryngeal dystonia is a task-specific focal dystonia of laryngeal muscles that impairs speech and voice production. At present, there is no cure for LD. The most common therapeutic option for patients with LD involves Botulinum neurotoxin injections.
OBJECTIVE
Provide empirical evidence that non-invasive vibro-tactile stimulation (VTS) of the skin over the voice box can provide symptom relief to those affected by LD.
METHODS
Single-group 11-week randomized controlled trial with a crossover between two dosages (20 min of VTS once or 3 times per week) self-administered in-home in two 4-week blocks. Acute effects of VTS on voice and speech were assessed in-lab at weeks 1, 6 and 11. Participants were randomized to receive either 40 Hz or 100 Hz VTS.
MAIN OUTCOME MEASURES
Primary: (CPPS) of the voice signal to quantify voice and speech abnormalities, and (PSE) ranked by participants as a measure of voice effort (scale 1-10). Secondary: during continuous speech, the (CAPE-V) inventory as a measure of overall disease severity and the 30-item self report.
RESULTS
Thirty-nine people with a confirmed diagnosis of adductor-type LD (mean [SD] age, 60.3 [11.3] years; 18 women and 21 men) completed the study. A single application of VTS improved voice quality (median CPPS increase: 0.41 dB, 95% CI [0.20, 0.61]) and/or reduced voice effort (PSE) by at least 30% in up to 57% of participants across the three study visits. Effects lasted from less than 30 min to several days. There was no effect of dosage and no evidence that the acute therapeutic effects of VTS increased or decreased longitudinally over the 11-week study period. Both 100 and 40 Hz VTS induced measurable improvements in voice quality and speech effort. VTS induced an additional benefit to those receiving Botulinum toxin. Participants, not receiving Botulinum treatment also responded to VTS.
CONCLUSION
This study provides the first systematic empirical evidence that the prolonged use of laryngeal VTS can induce repeatable acute improvements in voice quality and reductions of voice effort in LD.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov ID: NCT03746509.
PubMed: 38872829
DOI: 10.3389/fneur.2024.1403050 -
The Journal of Pharmacology and... Jun 2024Mutations in the gene, which encodes the abundant brain G-protein Gα, result in neurologic disorders characterized by developmental delay, epilepsy, and movement...
Mutations in the gene, which encodes the abundant brain G-protein Gα, result in neurologic disorders characterized by developmental delay, epilepsy, and movement abnormalities. There are over 50 mutant alleles associated with disorders; the R209H mutation results in dystonia, choreoathetosis, and developmental delay without seizures. Mice heterozygous for the human mutant allele ( ) exhibit hyperactivity in open field tests but no seizures. We developed self-complimentary adeno-associated virus vectors (scAAV9) expressing two splice variants of human Gα isoforms 1 (GA, ) and 2 (GB, ). Bilateral intra-striatal injections of either scAAV9- or scAAV9- significantly reversed mutation-associated hyperactivity in open field tests. overexpression did not increase seizure susceptibility, a potential side-effect of vector treatment. This represents the first report of successful preclinical gene therapy for encephalopathy applied Further studies are needed to uncover the molecular mechanism that results in behavior improvements after scAAV9-mediated Gα expression and to refine the vector design. mutations cause a spectrum of developmental, epilepsy, and movement disorders. Here, we show that intra-striatal delivery of scAAV9- to express the wild-type Gα protein reduces the hyperactivity of the mouse model, which carries one of the most common movement disorder-associated mutations. This is the first report of a gene therapy for encephalopathy applied on a patient-allele model.
PubMed: 38866563
DOI: 10.1124/jpet.124.002117 -
Journal of Psychiatric Research Jun 2024Deep brain stimulation (DBS) has been reported as a therapy option for the motor dysfunction of severe tardive dystonia (TD). The major psychiatric diseases, however,...
BACKGROUND
Deep brain stimulation (DBS) has been reported as a therapy option for the motor dysfunction of severe tardive dystonia (TD). The major psychiatric diseases, however, are contraindications to DBS treatment in TD patients.
METHODS
Six severe, medically refractory TD patients undergoing bilateral anterior capsulotomy combined with bilateral subthalamic nucleus (STN)-DBS treatment were studied retrospectively at two time points: pre-operation, and 1-3 years post-operation. Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) was used to assess the dystonia and disability. Depressive, anxiety, psychiatric symptoms, and Quality of Life (QoL) were evaluated using the 17-item Hamilton Depression Scale (HAMD-17), the 14-item Hamilton Anxiety Scale (HAMA-14), the Positive and Negative Syndrome Scale (PANSS), and 36-item Short-Form Health Survey (SF-36), respectively.
RESULTS
After receiving the combination treatment for 25 ± 11.6 months (range, 12-41 months), significant clinical symptom improvements were reported in TD patients. BFMDRS motor and disability scores were ameliorated by 78.5 ± 32.0% (p = 0.031) and 76.5 ± 38.6% (p = 0.031), respectively. The HAMD-17 and HAMA-14 scores were reduced by 60.3 ± 27.9% (p = 0.007) and 60.0 ± 24.6% (p = 0.009), respectively. Furthermore, the PANSS scores of the comorbidity schizophrenia TD patients decreased by 58.1 ± 6.0% (p = 0.022), and the QoL improved by 59.7 ± 14.1% (SF-36, p = 0.0001). During the research, there were no notable adverse effects or problems.
CONCLUSION
Bilateral anterior capsulotomy combined with bilateral STN-DBS may be an effective and relatively safe treatment option for severe TD comorbid with major psychiatric disorders.
PubMed: 38865864
DOI: 10.1016/j.jpsychires.2024.06.011 -
Frontiers in Network Physiology 2024Abnormal neuronal synchrony is associated with several neurological disorders, including Parkinson's disease (PD), essential tremor, dystonia, and epilepsy. Coordinated...
BACKGROUND
Abnormal neuronal synchrony is associated with several neurological disorders, including Parkinson's disease (PD), essential tremor, dystonia, and epilepsy. Coordinated reset (CR) stimulation was developed computationally to counteract abnormal neuronal synchrony. During CR stimulation, phase-shifted stimuli are delivered to multiple stimulation sites. Computational studies in plastic neural networks reported that CR stimulation drove the networks into an attractor of a stable desynchronized state by down-regulating synaptic connections, which led to long-lasting desynchronization effects that outlasted stimulation. Later, corresponding long-lasting desynchronization and therapeutic effects were found in animal models of PD and PD patients. To date, it is unclear how spatially dependent synaptic connections, as typically observed in the brain, shape CR-induced synaptic downregulation and long-lasting effects.
METHODS
We performed numerical simulations of networks of leaky integrate-and-fire neurons with spike-timing-dependent plasticity and spatially dependent synaptic connections to study and further improve acute and long-term responses to CR stimulation.
RESULTS
The characteristic length scale of synaptic connections relative to the distance between stimulation sites plays a key role in CR parameter adjustment. In networks with short synaptic length scales, a substantial synaptic downregulation can be achieved by selecting appropriate stimulus-related parameters, such as the stimulus amplitude and shape, regardless of the employed spatiotemporal pattern of stimulus deliveries. Complex stimulus shapes can induce local connectivity patterns in the vicinity of the stimulation sites. In contrast, in networks with longer synaptic length scales, the spatiotemporal sequence of stimulus deliveries is of major importance for synaptic downregulation. In particular, rapid shuffling of the stimulus sequence is advantageous for synaptic downregulation.
CONCLUSION
Our results suggest that CR stimulation parameters can be adjusted to synaptic connectivity to further improve the long-lasting effects. Furthermore, shuffling of CR sequences is advantageous for long-lasting desynchronization effects. Our work provides important hypotheses on CR parameter selection for future preclinical and clinical studies.
PubMed: 38863734
DOI: 10.3389/fnetp.2024.1351815 -
BMJ Neurology Open 2024A critical first step in managing functional neurological disorder (FND) is a positive diagnosis and clear explanation using an understandable illness model....
BACKGROUND
A critical first step in managing functional neurological disorder (FND) is a positive diagnosis and clear explanation using an understandable illness model. Multidisciplinary group education sessions are one way to achieve this, with some evidence they improve understanding, confidence in diagnosis and outcomes with further treatment. In many conditions, illness perceptions and stigma affect distress, functioning, quality of life and engagement. Exploring relationships between these factors could lead to deeper understanding of the impact of education.
METHODS
Questionnaires assessing illness perceptions, quality of life, mood, anxiety, comorbidities, treatment engagement and stigma (both experienced and anticipated) were completed before, immediately and 1 month after a multidisciplinary online group education session for FND at a regional neurosciences centre. Free-text data on causal attributions and needs were also collected.
RESULTS
166 patients attended online education sessions from January 2022 to July 2023; 61 (37%) completed presession surveys, 42 (25%) completed postsession and 35 (21%) completed 1 month postsession surveys. Patients reported multiple comorbidities, poor quality of life, functioning and high levels of stigma. Illness perception scores indicated FND as threatening, mysterious and unpredictable, with low personal or treatment control over symptoms. Illness coherence/understanding (mean difference 2.27, p<0.01, 95% CI 1.22 to 4.23) and engagement (mean difference 2.42, p<0.01, 95% CI 0.46 to 4.36) increased after the session. There were no significant changes in stigma, distress, sense of control or anticipated discrimination. Free-text analysis revealed stress and trauma as the most common causal attributions, followed by physical illnesses. Patients requested personalised formulations, practical disability advice, help with explaining the condition to others (eg, employers), peer support and treatment.
CONCLUSION
Multidisciplinary group FND education sessions potentially improve patient understanding and engagement. Clinicians should consider the possible benefits of personalised formulations and linking to practical and peer support. Further work assessing illness perceptions is needed, such as adapting measures for FND.
PubMed: 38860228
DOI: 10.1136/bmjno-2024-000633 -
Cureus May 2024Meige syndrome (MS) is a cranial dystonia that involves blepharospasm and oromandibular dystonia. It can also evolve to include other adjacent muscle groups in the...
Meige syndrome (MS) is a cranial dystonia that involves blepharospasm and oromandibular dystonia. It can also evolve to include other adjacent muscle groups in the cervical region. It typically presents in middle-aged females, and while the disorder is relatively uncommon, its exact prevalence varies. Diagnosis is typically made with a thorough history and physical and workup to rule out other causes. Treatment options include medical management with gamma-aminobutyric acid (GABA) antagonists, dopamine antagonists, and anticholinergics for short-term management. Long-term treatment options are Botox and deep brain stimulation. This case report presents a 56-year-old female with a complex presentation of MS; the patient's symptoms progressed from isolated blepharospasms to involve orofacial and cervical musculature. A distinctive aspect of this case was the simultaneous presence of upper motor neuron (UMN) signs in the patient alongside acute to subacute compression fractures of the superior endplate of C7 and T3, as revealed by cervical spine imaging. Treatment with clonazepam led to significant symptomatic improvement, highlighting the importance of a multimodal approach in managing MS. This case underscores the need for careful clinical evaluation, collaboration with movement disorder specialists, and ongoing research efforts to enhance understanding and treatment of MS.
PubMed: 38860087
DOI: 10.7759/cureus.60101 -
Neurology. Genetics Apr 2024This study investigates atypical late-onset ataxia-telangiectasia (AT) cases in a Korean family, diagnosed via Nanopore long-read sequencing, diverging from the typical...
OBJECTIVES
This study investigates atypical late-onset ataxia-telangiectasia (AT) cases in a Korean family, diagnosed via Nanopore long-read sequencing, diverging from the typical early childhood onset caused by biallelic pathogenic ATM variants.
METHODS
A 52-year-old Korean woman exhibiting dystonia and tremor, with a family history of similar symptoms in her older sister, underwent comprehensive tests including routine laboratory tests, neuropsychological assessments, and neuroimaging. Genetic analysis was conducted through targeted sequencing of 29 dystonia-associated genes and Nanopore long-read sequencing to assess the configuration of 2 gene variants.
RESULTS
Routine blood tests and brain imaging studies returned normal results, except for elevated α-fetoprotein levels. Neurologic examination revealed dystonia in the face, hand, and trunk, along with cervical dystonia in the proband. Her sister exhibited similar symptoms without evident telangiectasia. Genetic testing revealed 2 heterozygous pathogenic gene variants (p.Glu2014Ter and p.Glu2052Lys). Nanopore long-read sequencing confirmed these variants were in configuration, establishing a definite molecular diagnosis in the proband.
DISCUSSION
This report expands the known clinical spectrum of AT, highlighting a familial case of atypical AT. Moreover, it underscores the clinical utility of Nanopore long-read sequencing in phasing variant haplotypes, essential for diagnosing autosomal recessive disorders, especially beneficial for cases without parental samples.
PubMed: 38854973
DOI: 10.1212/NXG.0000000000200141 -
MedRxiv : the Preprint Server For... May 2024Participation is essential to DBS research, yet circumstances that affect diverse participation remain unclear. Here we evaluate factors impacting participation in an...
OBJECTIVES
Participation is essential to DBS research, yet circumstances that affect diverse participation remain unclear. Here we evaluate factors impacting participation in an adaptive DBS study of Parkinson's disease (PD) and dystonia.
METHODS
Twenty participants were implanted with a sensing-enabled DBS device (Medtronic Summit RC+S) that allows neural data streaming in naturalistic settings and encouraged to stream as much as possible for the first five months after surgery. Using standardized baseline data obtained through neuropsychological evaluation, we compared neuropsychological and social variables to streaming hours.
RESULTS
Marital status and irritability significantly impacted streaming hours (estimate=136.7, bootstrapped ( ) =45.0 to 249.0, =0.016, and estimate=-95.1, =-159.9 to -49.2, =0.027, respectively). These variables remained significant after multivariable analysis. Composite scores on verbal memory evaluations predicted the number of hours of data streamed ( =0.284, estimate=67.7, =20.1 to 119.9, =0.019).
DISCUSSION
Verbal memory impairment, irritability, and lack of a caregiver may be associated with decreased participation. Further study of factors that impact research participation is critical to the sustained inclusion of diverse participants.
PubMed: 38854092
DOI: 10.1101/2024.05.29.24308133 -
Scientific Reports Jun 2024X-linked dystonia parkinsonism (XDP) is a neurogenetic combined movement disorder involving both parkinsonism and dystonia. Complex, overlapping phenotypes result in...
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.
Topics: Humans; Machine Learning; Wearable Electronic Devices; Dystonic Disorders; Genetic Diseases, X-Linked; Male; Adult; Middle Aged; Parkinsonian Disorders; Severity of Illness Index; Female; Gait
PubMed: 38853162
DOI: 10.1038/s41598-024-63946-4