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Brain : a Journal of Neurology Aug 2023In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later...
In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with foetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71%, with higher mortality in males. Death occurred at a median age of 1.2 months (1 week-9 years), due to respiratory failure, cardiac arrest or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival.
Topics: Male; Humans; Cross-Sectional Studies; Mutation; Phenotype; Dystonia; Dystonic Disorders; Nervous System Malformations; Molecular Chaperones
PubMed: 36757831
DOI: 10.1093/brain/awad039 -
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 -
BMJ Clinical Evidence Jun 2011Dystonia is usually a lifelong condition with persistent pain and disability. Focal dystonia affects a single part of the body; generalised dystonia can affect most or... (Review)
Review
INTRODUCTION
Dystonia is usually a lifelong condition with persistent pain and disability. Focal dystonia affects a single part of the body; generalised dystonia can affect most or all of the body. It is more common in women, and some types of dystonia are more common in people of European Ashkenazi Jewish descent.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments, surgical treatments, and physical treatments for focal, and for generalised dystonia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 15 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acetylcholine release inhibitors (botulinum toxin), acupuncture, anticholinergic/antihistaminic drugs, anticonvulsants, atypical antipsychotic drugs, benzodiazepines, biofeedback, chiropractic manipulation, deep brain stimulation of thalamus and globus pallidus, dopaminergic agonists and antagonists, gamma-aminobutyric acid (GABA) analogues, microvascular decompression, muscle relaxants, myectomy, occupational therapy, osteopathy, pallidotomy, physiotherapy, selective peripheral denervation, serotonergic agonists and antagonists, speech therapy, and thalamotomy.
Topics: Botulinum Toxins; Dystonia; Dystonia Musculorum Deformans; Dystonic Disorders; GABA Antagonists; Globus Pallidus; Humans
PubMed: 21663705
DOI: No ID Found -
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 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 -
BMJ Clinical Evidence Sep 2008Dystonia is usually a lifelong condition with persistent pain and disability. Focal dystonia affects a single part of the body; generalised dystonia can affect most or... (Review)
Review
INTRODUCTION
Dystonia is usually a lifelong condition with persistent pain and disability. Focal dystonia affects a single part of the body; generalised dystonia can affect most or all of the body. It is more common in women, and some types of dystonia are more common in people of European Ashkenazi Jewish descent.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments, surgical treatments, and physical treatments for focal, and for generalised dystonia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 13 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review we present information relating to the effectiveness and safety of the following interventions: acetylcholine receptor inhibitors, acupuncture, anticholinergic drugs, anticonvulsants, atypical antipsychotic drugs, benzodiazepines, biofeedback, botulinum toxin, chiropractic manipulation, deep brain stimulation of thalamus and globus pallidus, dopaminergic agonists and antagonists, gamma-aminobutyric acid (GABA) inhibitors, microvascular decompression, myectomy, occupational therapy, osteopathy, pallidotomy, physiotherapy, selective peripheral denervation, serotonergic agonists and antagonists, speech therapy, and thalamotomy.
Topics: Botulinum Toxins; Deep Brain Stimulation; Dystonia; Dystonia Musculorum Deformans; Dystonic Disorders; Follow-Up Studies; GABA Antagonists; Globus Pallidus; Humans
PubMed: 19445800
DOI: No ID Found -
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 -
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 -
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