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Movement Disorders : Official Journal... Nov 2022The objective of this study was to better delineate the genetic landscape and key clinical characteristics of complex, early-onset, monogenic hyperkinetic movement...
BACKGROUND AND OBJECTIVE
The objective of this study was to better delineate the genetic landscape and key clinical characteristics of complex, early-onset, monogenic hyperkinetic movement disorders.
METHODS
Patients were recruited from 14 international centers. Participating clinicians completed standardized proformas capturing demographic, clinical, and genetic data. Two pediatric movement disorder experts reviewed available video footage, classifying hyperkinetic movements according to published criteria.
RESULTS
One hundred forty patients with pathogenic variants in 17 different genes (ADCY5, ATP1A3, DDC, DHPR, FOXG1, GCH1, GNAO1, KMT2B, MICU1, NKX2.1, PDE10A, PTPS, SGCE, SLC2A1, SLC6A3, SPR, and TH) were identified. In the majority, hyperkinetic movements were generalized (77%), with most patients (69%) manifesting combined motor semiologies. Parkinsonism-dystonia was characteristic of primary neurotransmitter disorders (DDC, DHPR, PTPS, SLC6A3, SPR, TH); chorea predominated in ADCY5-, ATP1A3-, FOXG1-, NKX2.1-, SLC2A1-, GNAO1-, and PDE10A-related disorders; and stereotypies were a prominent feature in FOXG1- and GNAO1-related disease. Those with generalized hyperkinetic movements had an earlier disease onset than those with focal/segmental distribution (2.5 ± 0.3 vs. 4.7 ± 0.7 years; P = 0.007). Patients with developmental delay also presented with hyperkinetic movements earlier than those with normal neurodevelopment (1.5 ± 2.9 vs. 4.7 ± 3.8 years; P < 0.001). Effective disease-specific therapies included dopaminergic agents for neurotransmitters disorders, ketogenic diet for glucose transporter deficiency, and deep brain stimulation for SGCE-, KMT2B-, and GNAO1-related hyperkinesia.
CONCLUSIONS
This study highlights the complex phenotypes observed in children with genetic hyperkinetic movement disorders that can lead to diagnostic difficulty. We provide a comprehensive analysis of motor semiology to guide physicians in the genetic investigation of these patients, to facilitate early diagnosis, precision medicine treatments, and genetic counseling. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Child; Humans; Hyperkinesis; Movement Disorders; Dystonic Disorders; Chorea; Dystonia; Nerve Tissue Proteins; Forkhead Transcription Factors; Phosphoric Diester Hydrolases; Sodium-Potassium-Exchanging ATPase; GTP-Binding Protein alpha Subunits, Gi-Go
PubMed: 36054588
DOI: 10.1002/mds.29182 -
Neurology India 2020Deep brain stimulation (DBS) is currently the preferred surgical treatment for various movement disorders. Pallidotomy is an effective procedure for patients with...
BACKGROUND
Deep brain stimulation (DBS) is currently the preferred surgical treatment for various movement disorders. Pallidotomy is an effective procedure for patients with dystonia and Parkinson's disease and was the surgical treatment of choice before the advent of DBS. However, it can be the preferred modality in immunocompromised patients and those patients who cannot afford DBS due to financial constraints. Hypophonia, dysarthria and dysphagia are the most significant complications of bilateral pallidotomy.
OBJECTIVE
The aim of this study was to present the surgical technique and nuances involved in bilateral simultaneous pallidotomy in a patient with generalized dystonia.
PROCEDURE
A 30-year male with primary generalized dystonia presented to us with preoperative Burke-Fahn-Marsden (BFM) Dystonia Rating Scale of 24. After acquiring preoperative volumetric 3T MRI and stereotactic CT, bilateral pallidotomy was done under general anesthesia. There were no procedure related complications.
RESULTS
At two months of follow-up, his BFM dystonia score improved from 24 to 4.5.
CONCLUSION
Appropriately acquired volumetric MRI, meticulous planning and meticulously performed surgical procedure can help in achieving good outcome and minimize the complications.
Topics: Deep Brain Stimulation; Dystonia; Dystonic Disorders; Globus Pallidus; Humans; Male; Movement Disorders; Pallidotomy; Treatment Outcome
PubMed: 33318369
DOI: 10.4103/0028-3886.302460 -
Current Neurology and Neuroscience... Nov 2022To review recent literature evaluating psychiatric and cognitive symptoms in dystonia, the two non-motor symptom groups most frequently evaluated in dystonia research... (Review)
Review
PURPOSE OF REVIEW
To review recent literature evaluating psychiatric and cognitive symptoms in dystonia, the two non-motor symptom groups most frequently evaluated in dystonia research and recognised in clinical practice.
RECENT FINDINGS
Recent work has embedded clinical recognition of psychiatric symptoms in dystonia, with depressive and anxiety-related symptoms routinely observed to be the most common. Less explored symptoms, such as self-harm, suicidal ideation, and substance abuse, represent newer areas of investigation, with initial work suggesting higher rates than the background population. Investigation of cognitive function has provided less consistent results, both within individual dystonia subtypes and across the spectrum of dystonias, partly reflecting the heterogeneity in approaches to assessment. However, recent work indicates impairments of higher cognitive function, e.g. social cognition, and disrupted visual and auditory sensory processing. Dystonia demonstrates psychiatric and cognitive symptom heterogeneity, with further work needed to recognise endophenotypes and improve diagnostic accuracy, symptom recognition, and management.
Topics: Humans; Dystonia; Dystonic Disorders; Mental Disorders; Cognition
PubMed: 36201146
DOI: 10.1007/s11910-022-01233-3 -
Current Opinion in Neurology Aug 2019Our understanding of X-Linked Dystonia-Parkinsonism (XDP) has advanced considerably in recent years because of a wealth of new data describing its genetic basis,... (Review)
Review
PURPOSE OF REVIEW
Our understanding of X-Linked Dystonia-Parkinsonism (XDP) has advanced considerably in recent years because of a wealth of new data describing its genetic basis, cellular phenotypes, neuroimaging features, and response to deep brain stimulation (DBS). This review provides a concise summary of these studies.
RECENT FINDINGS
XDP is associated with a SINE-VNTR-Alu (SVA)-type retrotransposon insertion within the TAF1 gene. This element includes a hexameric DNA repeat expansion, (CCCTCT)n, the length of which varies among patients and is inversely correlated to age of disease onset. In cell models, the SVA alters TAF1 splicing and reduces levels of full-length transcript. Neuroimaging data have confirmed previous neuropathology studies that XDP involves a progressive striatal atrophy, while further detecting functional alterations in additional brain regions. In patients exhibiting features of both dystonia and parkinsonism, pallidal DBS has resulted in rapid improvement of hyperkinetic movements, but effects on hypokinetic features have been inconsistent.
SUMMARY
The discovery that XDP is linked to a polymorphic hexameric sequence suggests that it could share mechanisms with other DNA repeat disorders, whereas the transcriptional defect in cell models raises the possibility that strategies to correct TAF1 splicing could provide therapeutic benefit.
Topics: Brain; DNA Repeat Expansion; Deep Brain Stimulation; Dystonic Disorders; Genetic Diseases, X-Linked; Humans
PubMed: 31116117
DOI: 10.1097/WCO.0000000000000708 -
Journal of Neural Transmission (Vienna,... Apr 2021Rehabilitation for isolated forms of dystonia, such as cervical or focal hand dystonia, is usually targeted towards the affected body part and focuses on sensorimotor... (Review)
Review
Rehabilitation for isolated forms of dystonia, such as cervical or focal hand dystonia, is usually targeted towards the affected body part and focuses on sensorimotor control and motor retraining of affected muscles. Recent evidence, has revealed people who live with dystonia experience a range of functional and non-motor deficits that reduce engagement in daily activities and health-related quality of life, which should be addressed with therapeutic interventions. These findings support the need for a holistic approach to the rehabilitation of dystonia, where assessment and treatments involve non-motor signs and symptoms, and not just the dystonic body part. Most studies have investigated Cervical Dystonia, and in this population, it is evident there is reduced postural control and walking speed, high fear of falling and actual falls, visual compensation for the impaired neck posture, and a myriad of non-motor symptoms including pain, fatigue, sleep disorders and anxiety and depression. In other populations of dystonia, there is also emerging evidence of falls and reduced vision-related quality of life, along with the inability to participate in physical activity due to worsening of dystonic symptoms during or after exercise. A holistic approach to dystonia would support the management of a wide range of symptoms and signs, that if properly addressed could meaningfully reduce disability and improve quality of life in people living with dystonia.
Topics: Accidental Falls; Dystonic Disorders; Fear; Humans; Neurological Rehabilitation; Quality of Life; Torticollis
PubMed: 33099684
DOI: 10.1007/s00702-020-02265-0 -
Movement Disorders : Official Journal... Jul 2022Most reported patients carrying GNAO1 mutations showed a severe phenotype characterized by early-onset epileptic encephalopathy and/or chorea.
BACKGROUND
Most reported patients carrying GNAO1 mutations showed a severe phenotype characterized by early-onset epileptic encephalopathy and/or chorea.
OBJECTIVE
The aim was to characterize the clinical and genetic features of patients with mild GNAO1-related phenotype with prominent movement disorders.
METHODS
We included patients diagnosed with GNAO1-related movement disorders of delayed onset (>2 years). Patients experiencing either severe or profound intellectual disability or early-onset epileptic encephalopathy were excluded.
RESULTS
Twenty-four patients and 1 asymptomatic subject were included. All patients showed dystonia as prominent movement disorder. Dystonia was focal in 1, segmental in 6, multifocal in 4, and generalized in 13. Six patients showed adolescence or adulthood-onset dystonia. Seven patients presented with parkinsonism and 3 with myoclonus. Dysarthria was observed in 19 patients. Mild and moderate ID were present in 10 and 2 patients, respectively.
CONCLUSION
We highlighted a mild GNAO1-related phenotype, including adolescent-onset dystonia, broadening the clinical spectrum of this condition. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Dystonia; Dystonic Disorders; GTP-Binding Protein alpha Subunits, Gi-Go; Humans; Movement Disorders; Parkinsonian Disorders; Phenotype
PubMed: 35722775
DOI: 10.1002/mds.29074 -
Neurology Mar 2020Dystonia is a complex movement disorder. Research progress has been difficult, particularly in developing widely effective therapies. This is a review of the current... (Review)
Review
OBJECTIVE
Dystonia is a complex movement disorder. Research progress has been difficult, particularly in developing widely effective therapies. This is a review of the current state of knowledge, research gaps, and proposed research priorities.
METHODS
The NIH convened leaders in the field for a 2-day workshop. The participants addressed the natural history of the disease, the underlying etiology, the pathophysiology, relevant research technologies, research resources, and therapeutic approaches and attempted to prioritize dystonia research recommendations.
RESULTS
The heterogeneity of dystonia poses challenges to research and therapy development. Much can be learned from specific genetic subtypes, and the disorder can be conceptualized along clinical, etiology, and pathophysiology axes. Advances in research technology and pooled resources can accelerate progress. Although etiologically based therapies would be optimal, a focus on circuit abnormalities can provide a convergent common target for symptomatic therapies across dystonia subtypes. The discussions have been integrated into a comprehensive review of all aspects of dystonia.
CONCLUSION
Overall research priorities include the generation and integration of high-quality phenotypic and genotypic data, reproducing key features in cellular and animal models, both of basic cellular mechanisms and phenotypes, leveraging new research technologies, and targeting circuit-level dysfunction with therapeutic interventions. Collaboration is necessary both for collection of large data sets and integration of different research methods.
Topics: Animals; Dystonia; Dystonic Disorders; Humans; Neurology; Research
PubMed: 32098856
DOI: 10.1212/WNL.0000000000009140 -
Progress in Neurological Surgery 2018Deep brain stimulation (DBS) has markedly changed how we treat movement disorders including Parkinson's disease (PD), dystonia, and essential tremor (ET). However,... (Review)
Review
Deep brain stimulation (DBS) has markedly changed how we treat movement disorders including Parkinson's disease (PD), dystonia, and essential tremor (ET). However, despite its demonstrable clinical benefit, DBS is often limited by side effects and partial efficacy. These limitations may be due in part to the fact that DBS interferes with both pathological and physiological neural activities. DBS could, therefore, be potentially improved were it applied selectively and only at times of enhanced pathological activity. This form of stimulation is known as closed-loop or adaptive DBS (aDBS). An aDBS approach has been shown to be superior to conventional DBS in PD in primates using cortical neuronal spike triggering and in humans employing local field potential biomarkers. Likewise, aDBS studies for essential and Parkinsonian tremor are advancing and show great promise, using both peripheral or central sensing and stimulation. aDBS has not yet been trialed in dystonia and yet exciting and promising biomarkers suggest it could be beneficial here too. In this chapter, we will review the existing literature on aDBS in movement disorders and explore potential biomarkers and stimulation algorithms for applying aDBS in PD, ET, and dystonia.
Topics: Animals; Deep Brain Stimulation; Dystonic Disorders; Essential Tremor; Humans; Parkinson Disease
PubMed: 29332087
DOI: 10.1159/000481107 -
International Journal of Molecular... Mar 2024A neurological condition called dystonia results in abnormal, uncontrollable postures or movements because of sporadic or continuous muscular spasms. Several varieties... (Review)
Review
A neurological condition called dystonia results in abnormal, uncontrollable postures or movements because of sporadic or continuous muscular spasms. Several varieties of dystonia can impact people of all ages, leading to severe impairment and a decreased standard of living. The discovery of genes causing variations of single or mixed dystonia has improved our understanding of the disease's etiology. Genetic dystonias are linked to several genes, including pathogenic variations of VPS16, TOR1A, THAP1, GNAL, and ANO3. Diagnosis of dystonia is primarily based on clinical symptoms, which can be challenging due to overlapping symptoms with other neurological conditions, such as Parkinson's disease. This review aims to summarize recent advances in the genetic origins and management of focal dystonia.
Topics: Humans; Dystonia; Dystonic Disorders; Movement; Parkinson Disease; Molecular Chaperones; DNA-Binding Proteins; Apoptosis Regulatory Proteins; Anoctamins
PubMed: 38612382
DOI: 10.3390/ijms25073571 -
Journal of Neural Transmission (Vienna,... Apr 2021Dystonia is a disabling movement disorder characterized by abnormal postures or patterned and repetitive movements due to co-contraction of muscles in proximity to... (Review)
Review
Dystonia is a disabling movement disorder characterized by abnormal postures or patterned and repetitive movements due to co-contraction of muscles in proximity to muscles desired for a certain movement. Important and well-established pathophysiological concepts are the impairment of sensorimotor integration, a loss of inhibitory control on several levels of the central nervous system and changes in synaptic plasticity. These mechanisms collectively contribute to an impairment of the gating function of the basal ganglia which results in an insufficient suppression of noisy activity and an excessive activation of cortical areas. In addition to this traditional view, a plethora of animal, genetic, imaging and electrophysiological studies highlight the role of the (1) cerebellum, (2) the cerebello-thalamic connection and (3) the functional interplay between basal ganglia and the cerebellum in the pathophysiology of dystonia. Another emerging topic is the better understanding of the microarchitecture of the striatum and its implications for dystonia. The striosomes are of particular interest as they likely control the dopamine release via inhibitory striato-nigral projections. Striosomal dysfunction has been implicated in hyperkinetic movement disorders including dystonia. This review will provide a comprehensive overview about the current understanding of the functional neuroanatomy and pathophysiology of dystonia and aims to move the traditional view of a 'basal ganglia disorder' to a network perspective with a dynamic interplay between cortex, basal ganglia, thalamus, brainstem and cerebellum.
Topics: Animals; Basal Ganglia; Corpus Striatum; Dystonia; Dystonic Disorders; Neuroanatomy
PubMed: 33486625
DOI: 10.1007/s00702-021-02299-y