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BACKGROUND: Pathogenic variants in several genes have been linked to genetic forms of isolated or combined dystonia. The phenotypic and genetic spectrum and the frequency of pathogenic variants in these genes have not yet been fully elucidated, neither in patients with dystonia nor with other, sometimes co-occurring movement disorders such as Parkinson's disease (PD). OBJECTIVES: To screen >2000 patients with dystonia or PD for rare variants in known dystonia-causing genes. METHODS: We screened 1207 dystonia patients from Germany (DysTract consortium), Spain, and South Korea, and 1036 PD patients from Germany for pathogenic variants using a next-generation sequencing gene panel. The impact on DNA methylation of KMT2B variants was evaluated by analyzing the gene's characteristic episignature. RESULTS: We identified 171 carriers (109 with dystonia [9.0%]; 62 with PD [6.0%]) of 131 rare variants (minor allele frequency <0.005). A total of 52 patients (48 dystonia [4.0%]; four PD [0.4%, all with GCH1 variants]) carried 33 different (likely) pathogenic variants, of which 17 were not previously reported. Pathogenic biallelic variants in PRKRA were not found. Episignature analysis of 48 KMT2B variants revealed that only two of these should be considered (likely) pathogenic. CONCLUSION: This study confirms pathogenic variants in GCH1, GNAL, KMT2B, SGCE, THAP1, and TOR1A as relevant causes in dystonia and expands the mutational spectrum. Of note, likely pathogenic variants only in GCH1 were also found among PD patients. For DYT-KMT2B, the recently described episignature served as a reliable readout to determine the functional effect of newly identified variants. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Distonía , Trastornos Distónicos , Enfermedad de Parkinson , Humanos , Distonía/genética , Trastornos Distónicos/genética , Mutación/genética , Frecuencia de los Genes , Enfermedad de Parkinson/genética , Chaperonas Moleculares/genética , Proteínas de Unión al ADN/genética , Proteínas Reguladoras de la Apoptosis/genéticaRESUMEN
Cervical dystonia is a movement disorder characterized by continuous and involuntary muscular contractions that result in aberrant head and neck motions or postures. A recent study indicates that persons with a history of scoliosis may be at a higher risk of acquiring cervical dystonia later in life. Although muscular tension and contraction abnormalities are linked in both illnesses, the pathophysiological pathways linking these two ailments are not entirely understood. A 13-year-old boy previously diagnosed with adolescent idiopathic scoliosis developed symptoms of cervical dystonia, including moderate neck pain, left-sided migraines, and tingling in the neck and shoulders. During the course of three months, the patient attended 16 chiropractic therapy sessions. He reported slow but considerable improvements in his symptoms, such as the recovery of normal cervical range of motion, decreases in neck discomfort and accompanying headaches as well as paresthesia, and enhancements in sleep quality, daily functioning, and learning capacities. The patient's clinical and radiographic improvements show that chiropractic spinal manipulation may assist in reducing pain and improving spine alignment and mobility in these circumstances. To further investigate the efficacy and safety of chiropractic therapy for the treatment of cervical dystonia, particularly in the setting of associated scoliosis, more study with bigger patient populations is required.
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Primary dystonia is thought to emerge through abnormal functional relationships between basal ganglia and cerebellar motor circuits. These interactions may differ across disease subtypes and provide a novel biomarker for diagnosis and treatment. Using a network mapping algorithm based on resting-state functional MRI (rs-fMRI), a method that is readily implemented on conventional MRI scanners, we identified similar disease topographies in hereditary dystonia associated with the DYT1 or DYT6 mutations and in sporadic patients lacking these mutations. Both networks were characterized by contributions from the basal ganglia, cerebellum, thalamus, sensorimotor areas, as well as cortical association regions. Expression levels for the two networks were elevated in hereditary and sporadic dystonia, and in non-manifesting carriers of dystonia mutations. Nonetheless, the distribution of abnormal functional connections differed across groups, as did metrics of network organization and efficiency in key modules. Despite these differences, network expression correlated with dystonia motor ratings, significantly improving the accuracy of predictions based on thalamocortical tract integrity obtained with diffusion tensor MRI (DTI). Thus, in addition to providing unique information regarding the anatomy of abnormal brain circuits, rs-fMRI functional networks may provide a widely accessible method to help in the objective evaluation of new treatments for this disorder.
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Distonía , Trastornos Distónicos , Humanos , Distonía/diagnóstico por imagen , Distonía/genética , Distonía/patología , Vías Nerviosas , Trastornos Distónicos/diagnóstico por imagen , Trastornos Distónicos/genética , Trastornos Distónicos/patología , Cerebelo , Ganglios Basales , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: Primary dystonia is conventionally considered as a motor disorder, though an emerging literature reports associated cognitive dysfunction. OBJECTIVES: Here, we conducted meta-analyses on studies comparing clinical measures of cognition in persons with primary dystonia and healthy controls (HCs). METHODS: We searched PubMed, Embase, Cochrane Library, Scopus, and PsycINFO (January 2000-October 2020). Analyses were modeled under random effects. We used Hedge's g as a bias-corrected estimate of effect size, where negative values indicate lower performance in dystonia versus controls. Between-study heterogeneity and bias were primarily assessed with Cochran's Q, I2 , and Egger's regression. RESULTS: From 866 initial results, 20 studies met criteria for analysis (dystonia n = 739, controls n = 643; 254 effect sizes extracted). Meta-analysis showed a significant combined effect size of primary dystonia across all studies (g = -0.56, P < 0.001), with low heterogeneity (Q = 25.26, P = 0.15, I2 = 24.78). Within-domain effects of primary dystonia were motor speed = -0.84, nonmotor speed = -0.83, global cognition = -0.65, language = -0.54, executive functioning = -0.53, learning/memory = -0.46, visuospatial/construction = -0.44, and simple/complex attention = -0.37 (P-values <0.01). High heterogeneity was observed in the motor/nonmotor speed and learning/memory domains. There was no evidence of publication bias. Moderator analyses were mostly negative but possibly underpowered. Blepharospasm samples showed worse performance than other focal/cervical dystonias. Those with inherited (ie, genetic) disease etiology demonstrated worse performance than acquired. CONCLUSIONS: Dystonia patients consistently demonstrated lower performances on neuropsychological tests versus HCs. Effect sizes were generally moderate in strength, clustering around -0.50 SD units. Within the speed domain, results suggested cognitive slowing beyond effects from motor symptoms. Overall, findings indicate dystonia patients experience multidomain cognitive difficulties, as detected by neuropsychological tests. © 2022 International Parkinson and Movement Disorder Society.
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Distonía , Trastornos Distónicos , Cognición , Función Ejecutiva , Humanos , Pruebas NeuropsicológicasRESUMEN
DYT6 dystonia is caused by mutations in the transcription factor THAP1. THAP1 knock-out or knock-in mouse models revealed complex gene expression changes, which are potentially responsible for the pathogenesis of DYT6 dystonia. However, how THAP1 mutations lead to these gene expression alterations and whether the gene expression changes are also reflected in the brain of THAP1 patients are still unclear. In this study we used epigenetic and transcriptomic approaches combined with multiple model systems [THAP1 patients' frontal cortex, THAP1 patients' induced pluripotent stem cell (iPSC)-derived midbrain dopaminergic neurons, THAP1 heterozygous knock-out rat model, and THAP1 heterozygous knock-out SH-SY5Y cell lines] to uncover a novel function of THAP1 and the potential pathogenesis of DYT6 dystonia. We observed that THAP1 targeted only a minority of differentially expressed genes caused by its mutation. THAP1 mutations lead to dysregulation of genes mainly through regulation of SP1 family members, SP1 and SP4, in a cell type dependent manner. Comparing global differentially expressed genes detected in THAP1 patients' iPSC-derived midbrain dopaminergic neurons and THAP1 heterozygous knock-out rat striatum, we observed many common dysregulated genes and 61 of them were involved in dystonic syndrome-related pathways, like synaptic transmission, nervous system development, and locomotor behaviour. Further behavioural and electrophysiological studies confirmed the involvement of these pathways in THAP1 knock-out rats. Taken together, our study characterized the function of THAP1 and contributes to the understanding of the pathogenesis of primary dystonia in humans and rats. As SP1 family members were dysregulated in some neurodegenerative diseases, our data may link THAP1 dystonia to multiple neurological diseases and may thus provide common treatment targets.
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Distonía , Trastornos Distónicos , Neuroblastoma , Humanos , Ratones , Animales , Ratas , Distonía/genética , Proteínas Nucleares/genética , Proteínas de Unión al ADN/metabolismo , Proteínas Reguladoras de la Apoptosis/genética , Trastornos Distónicos/genética , Mutación/genética , Factor de Transcripción Sp1/genéticaRESUMEN
BACKGROUND: Deep brain stimulation (DBS) is an effective treatment for motor disturbance in people with primary dystonia (PWD). Numerous factors are considered by an interdisciplinary consensus conference before deciding candidacy for DBS surgery (e.g., demographic, medical, cognitive, and behavioral factors). However, little is known about which of these factors are associated with PWD DBS surgery consensus conference decisions. OBJECTIVE: Our goal was to examine whether pre-operative demographic, medical, and cognitive/behavioral variables are associated DBS consensus conference decisions in patients with dystonia. METHODS: Thirty-two PWD completed comprehensive presurgery workup included neurological and neuropsychological exams, and neuroimaging in consideration for DBS surgery. An interdisciplinary conference committee either recommended or did not recommend DBS surgery based upon these data. Demographic and medical data (e.g., dystonia disease characteristics, medical comorbidities, medications) were also collected. We also examined impact from cardiovascular disease factors, using a Revised Cardiac Risk Index. PWD were grouped based on DBS conference decision (eligible: n = 21, ineligible: n = 11) and compared across demographic, medical, and cognitive/behavioral variables. RESULTS: Across clinical variables, PWD who were deemed ineligible for DBS surgery had a higher Revised Cardiac Risk Index. PWD who were classified as ineligible displayed lower global cognitive functioning, working memory, phonemic fluency, memory retrieval, and cognitive flexibility. CONCLUSIONS: Consensus decision making regarding DBS surgery eligibility involves a multifactorial process. We found that deficits in executive functioning were associated with the DBS consensus committee decision. We also observed elevated cardiac risk among these individuals, likely reflecting the relation between vascular health and cognition. Implications, and clinical and scientific applications of these findings are discussed.
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Toma de Decisiones Clínicas/métodos , Consenso , Estimulación Encefálica Profunda/métodos , Trastornos Distónicos/cirugía , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
When considering Deep Brain Stimulation (DBS) surgical treatment of dystonia syndromes, it is important to consider multiple aspects of the disease and its presentation. It is crucial to know if the dystonia is idiopathic, inherited or acquired as well as focal, segmental or generalised. Careful phenotyping of idiopathic as well as inherited dystonias and accurate diagnosis of acquired dystonias informs the decision-making process for patients and clinicians by providing them with useful predictors of outcomes of the proposed surgery. Here, we provided a review of the current literature, highlighted the areas where evidence is scarce and suggested future directions for research.
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Estimulación Encefálica Profunda , Distonía , Distonía/terapia , Globo Pálido , Humanos , Resultado del TratamientoRESUMEN
BACKGROUND: Still, the genetic basis of a large number of cases of early-onset isolated dystonia continues to be a mystery. In recent years, many new candidate genes are being identified as putative pathogenic factors in children with isolated dystonia due to the easy availability of whole-exome sequencing. Recently biallelic mutations in the COL6A3 gene were identified as a cause of rare dystonia (DYT)-27 syndrome. Till date, only six cases of DYT27 have been reported in the literature. METHODS: We report a new case of COL6A3 mutation associated early-onset isolated dystonia-DYT27. We did a review of the previously published cases of DYT27. Citations were identified through PubMed, Embase, Web of Science and Google scholar searches using the search terms (including variations), "Dystonia-27 or DYT27" or/and "COL6A3 mutation associated early-onset isolated dystonia", combined with study filters for original research, case reports and case series. RESULTS: Next-generation sequencing in the index patient revealed two pathogenic compound heterozygous loss of function mutations in exon 10 and exon 12 of the COL6A3 gene coding for the alpha(α)3(VI) chain of type VI collagen. Together with the presented case, seven cases (five males) were available for analysis. The median age at onset was 22 years (range: 6-61). Dystonic symptoms were started from hands in five and from the neck in the remaining two patients. Five patients had favorable outcomes with trihexyphenidyl and botulinum toxin while tetrabenazine and levodopa were ineffective. CONCLUSIONS: Although it is a new entity that is only recently discovered, in future years many more new cases suffering from this particular entity are likely to be reported and the already heterogeneous clinical spectrum is likely to be further widespread in years to come.
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Colágeno Tipo VI/genética , Distonía/genética , Adolescente , Adulto , Niño , Femenino , Humanos , Mutación con Pérdida de Función , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Next Generation Sequencing (NGS), has now become a very powerful tool for decoding variants of genes involved in pathogenesis of number of human disorders. One of the challenges of this method is to decipher the real pathogenic variants from a number of identified, not related to the disorder in analyzed case. Another issue is recognition of new phenotypes previously unrecognized but related to new variants combinations' in known genes. The other aspect is the HGMD or ClinVar mutation databases usage in data interpretation. The aim of this paper is to discuss pathogenicity of p.(Glu121Lys) missense mutation in the TOR1A gene previously described as dystonia causing variant. The patient diagnosed with typical Parkinson disease and positive family history was included into analysis. Also the internal whole exome sequencing (WES) database containing 600 subjects who has performed WES due to different causes was searched. All subjects had WES performed on SureSelect Human All Exon v.6 enrichment, Illumina NovaSeq 6000 platform, (annotations according to internal Institute Mother and Child's pipeline). The TOR1A p.(Glu121Lys) heterozygous mutation was revealed in 1 patient diagnosed with PD and 2 healthy subjects who has no dystonia symptoms. To conclude the TOR1A p.Glu121Lys variant should not be recognized as clearly pathogenic now.
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Trastornos Distónicos/genética , Chaperonas Moleculares/genética , Enfermedad de Parkinson/genética , Adulto , Niño , Exones , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Mutación , Fenotipo , Secuenciación del ExomaRESUMEN
BACKGROUND: Primary dystonia has been traditionally viewed as a motor disorder. However, non-motor symptoms are frequently present and significantly quality of life. Neuropsychiatric and cognitive symptoms have been identified, but prior studies have been limited in sample size and lack of control groups. This study examined the neurocognitive profile of a sample of persons with primary dystonia (PWD) as compared to demographically matched healthy control group. METHODS: A cognitive test battery was administered to 25 PWD who presented for pre-surgical candidacy evaluation for deep brain stimulation surgery. The test battery domains included global cognitive function, attention, expressive language, visuospatial skills, memory, and executive functioning. Twenty-five age, gender, education-matched healthy control participants were compared to the PWD. RESULTS: Compared to demographically matched healthy controls, PWD performed worse on measures of global cognitive function, attention, memory, and conceptualization. Based on normative comparison, a large portion of PWD were impaired on tasks of executive functioning and expressive language. Over 80% of the PWD showed impairment on at least one neurocognitive measure and over 60% showed impairment on 3 or more tests. CONCLUSIONS: Neurocognitive deficits were prevalent among our PWD sample. These impairments were present across a broad range of cognitive domains. Given the degree of cognitive impairment found in this study, our results have implications for health care providers with providing interventions to PWD.
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Trastornos Distónicos/psicología , Trastornos Neurocognitivos/diagnóstico , Pruebas Neuropsicológicas , Adulto , Atención , Estudios de Casos y Controles , Cognición , Trastornos Distónicos/fisiopatología , Función Ejecutiva , Femenino , Humanos , Lenguaje , Masculino , Memoria , Persona de Mediana Edad , Calidad de VidaRESUMEN
OBJECTIVE: To determine the effects of globus pallidus interna (GPi) deep brain stimulation (DBS) on speech and voice quality of patients with primary, medically refractory dystonia. METHODS: Voices of 14 patients aged ≥18 years (malesâ¯=â¯7 and femalesâ¯=â¯7) with primary dystonia (DYT1 gene mutation dystoniaâ¯=â¯4, cervical dystoniaâ¯=â¯6, and generalized dystoniaâ¯=â¯4) with bilateral GPi DBS were assessed. Five blinded raters (two fellowship-trained laryngologists and three speech/language pathologists) evaluated audio recordings of each patient pre- and post-DBS. Perceptual voice quality was rated using the Grade, Roughness, Breathiness, Asthenia, and Strain scale and changes in speech intelligibility were assessed with the Clinical Global Impression scale of Severity instrument. Inter-rater and intrarater reliability rates for perceptual voice ratings were assessed using the kappa coefficient. RESULTS: Voice quality parameters showed mean improvements in Grade (P < 0.0001), Roughness (Pâ¯=â¯0.0043), and Strain (P < 0.0001) 12 months post-DBS. Asthenia increased from baseline to 6 months (Pâ¯=â¯0.0022) and declined significantly from 6 to 12 months (Pâ¯=â¯0.0170). Breathiness did not change significantly over time. Speech intelligibility also improved from 6 to 12 months (Pâ¯=â¯0.0202) and from pre-DBS to 12 months post-DBS (Pâ¯=â¯0.0022). Grade and Strain ratings had nearly perfect and substantial inter-rater agreement (0.84 and 0.71, respectively). CONCLUSIONS: Voice and speech intelligibility improved after bilateral GPi DBS for dystonia. GPi DBS may emerge as a potential treatment option for patients with medically refractory laryngeal dystonia.
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Estimulación Encefálica Profunda , Disfonía/terapia , Distonía/terapia , Globo Pálido/fisiopatología , Acústica del Lenguaje , Calidad de la Voz , Adulto , Anciano , Anciano de 80 o más Años , Disfonía/diagnóstico , Disfonía/fisiopatología , Distonía/diagnóstico , Distonía/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recuperación de la Función , Estudios Retrospectivos , Inteligibilidad del Habla , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Dystonia is one kind of dyskinesia characterized by abnormal movement and/or posture caused by persistent or intermittent muscle contraction. It also has distinguished features of repeatability and modeling, and can be induced or aggravated by random movements. Dystonia caused by hereditary factors is named as primary dystonia. Currently, 28 phenotypes have already been found in primary dystonia. Development of genetic technology has largely promoted the discovery of genetic mechanisms. Even so, many patients still have different genetic and clinical features from these phenotypes. Diagnosis of primary dystonia is quite challenging. Clinical manifestations, imaging examinations, electromyography, gene testing and other examinations should be taken into account for systematic diagnosis. This article reviews the genetic progress and diagnostic strategies of primary dystonia, aimed at providing help for further clinical practice and scientific research.
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A recent report of autosomal-recessive primary isolated dystonia (DYT2 dystonia) identified mutations in HPCA, a gene encoding a neuronal calcium sensor protein, hippocalcin (HPCA), as the cause of this disease. However, how mutant HPCA leads to neuronal dysfunction remains unknown. Using a multidisciplinary approach, we demonstrated the failure of dystonic N75K HPCA mutant to decode short bursts of action potentials and theta rhythms in hippocampal neurons by its Ca2+-dependent translocation to the plasma membrane. This translocation suppresses neuronal activity via slow afterhyperpolarization (sAHP) and we found that the N75K mutant could not control sAHP during physiologically relevant neuronal activation. Simulations based on the obtained experimental results directly demonstrated an increased excitability in neurons expressing N75K mutant instead of wild type (WT) HPCA. In conclusion, our study identifies sAHP as a downstream cellular target perturbed by N75K mutation in DYT2 dystonia, demonstrates its impact on neuronal excitability, and suggests a potential therapeutic strategy to efficiently treat DYT2.
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Potenciales de Acción/fisiología , Señalización del Calcio/fisiología , Distonía Muscular Deformante/genética , Distonía Muscular Deformante/fisiopatología , Hipocalcina/genética , Mutación/fisiología , Animales , Animales Recién Nacidos , Células Cultivadas , Distonía Muscular Deformante/metabolismo , Femenino , Células HEK293 , Hipocalcina/metabolismo , Hipocampo/citología , Hipocampo/fisiología , Humanos , Masculino , Ratas , Ratas WistarRESUMEN
OBJECTIVE: To compare the efficacy and side effects of bilateral globus pallidus internus (GPi) and subthalamic nucleus (STN) deep brain stimulation (DBS) in the same patient with primary dystonia. METHODS: Patients with primary dystonia from the department of functional neurosurgery in Beijing Tiantan Hospital were recruited for the study. Four electrodes were bilaterally implanted in the GPi and STN. A trial stimulation was applied to determine the preliminary therapeutic effects. Five evaluations were conducted: preoperative, postoperative (before stimulation), after sham stimulation, and after stimulation for 24 hours of GPi and STN using optimal parameters, judged by the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). RESULTS: The BFMDRS movement score decreased after both short-term GPi stimulation (from 15.3 ± 6.9 to 7.6 ± 4.2, P < 0.05) and short-term STN stimulation (from 15.3 ± 6.9 to 8.6 ± 5.0, P < 0.05). There were significant reductions in facial (eyes and mouth) movement scores after short-term GPi and STN DBS compared with baseline (P < 0.05), but not in cervical symptoms (P > 0.05). The cervical symptoms of tonic dystonia had an improvement after long-term DBS treatment (P < 0.05). There were more adverse events with STN DBS; however, most side effects could be ameliorated by adjusting stimulation parameters. CONCLUSIONS: Both short-term GPi and STN stimulation improved the motor symptoms of dystonia, but there was no significant difference between GPi DBS and STN DBS. There were more side effects associated with STN stimulation.
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Estimulación Encefálica Profunda/métodos , Trastornos Distónicos/terapia , Adulto , Anciano , Estimulación Encefálica Profunda/efectos adversos , Trastornos Distónicos/fisiopatología , Femenino , Globo Pálido/diagnóstico por imagen , Globo Pálido/fisiopatología , Globo Pálido/cirugía , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Núcleo Subtalámico/diagnóstico por imagen , Núcleo Subtalámico/fisiopatología , Núcleo Subtalámico/cirugíaRESUMEN
@# DYT1 and DYT6 dystonias are the two most common genetic primary dystonias. However, they are rare in the Asian population and have never been reported in Thailand. DYT6 dystonia typically presents with craniosegmental dystonia with speech involvement, whereas DYT1 dystonia typically presents with lower limb dystonia, which tends to become generalized over time. Methods: Blood samples were collected from 14 patients with primary dystonia evaluated in five tertiary hospitals in Thailand. Genotyping of the TOR1A and THAP1 gene was performed. Results: Two patients were found to have a missense mutation, p.M143V (c.427A>G), in exon 3 of the THAP1 gene confirming the diagnosis of DYT6 dystonia. One patient was a woman who developed blepharospasm and lower cranial dystonia at the age of 38 years. Her dystonia spread to the neck and arm six months later. The other patient developed focal hand dystonia at the age of 34 years. The TOR1A mutation was not identified in any of these 14 patients.
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Primary dystonia's prolonged muscle contractions and the associated abnormal postures and twisting movements remain incurable. Genetic mutation/deletion of GAG from TorsonA's gene resulting in ΔE303 (which weakens the binding between TorsinA and its activator, such as LULL1) primarily cause this neurodegenerative disorder. We studied TorsinA-LULL1 (or TorsinAΔE303-LULL1) bindings and interactions. For the first time, we show the atomic details of TorsinA-LULL1 dynamic interactions and TorsinAΔE303-LULL1 dynamic interactions and their binding affinities. Our results show extensive effects of ΔE303 on TorsinAΔE303-LULL1 interactions, and suggest that the differences between TorsinA-LULL1 interactions and TorsinAΔE303-LULL1 interactions are non-subtle. ΔE303 significantly weakens TorsinAΔE303-LULL1's binding affinity. We present pieces of evidence proving that the effects of ΔE303 (on the differences between TorsinA-LULL1 interactions and TorsinAΔE303-LULL1 interactions) are more pronounced than previously suggested, and that the nanobody used for achieving the X-ray crystallization in the previous study attenuated the differences between TorsinA-LULL1 and TorsinAΔE303-LULL1 interactions. Our accounts of the dynamic interactions between "TorsinA and LULL1" and between "TorsinAΔE303 and LULL1" and the detailed effects of ΔE303 on TorsinA-/TorsinAΔE303-LULL1 build on previous findings and offer new insights for a better understanding of the molecular basis of Primary Dystonia. Our results have long-term potentials of guiding the development of medications for the disease.
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BACKGROUND: Subthalamic deep brain stimulation (STN-DBS) is a promising intervention for primary dystonia; however, evidence regarding its efficacy is lacking. Thus, a long-term follow-up is indispensable. OBJECTIVE: This trial was designed to examine the efficacy and consistency of subthalamic deep brain stimulation in patients with primary dystonia over the long term. METHOD: This was a retrospective study involving 14 patients with primary dystonia who underwent STN-DBS and consented to a follow-up of at least 10 years. The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and 36-item Short-Form General Health Survey were employed, at five time points (pre-operation [baseline], 1 month post-operation, 1 year post-operation, 5 years post-operation, and last follow-up), to assess improvement of dystonic symptoms and changes in quality of life. OUTCOMES: All patients gained extensive clinical benefits from STN-DBS therapy, without experiencing serious adverse effects. Improvements of 59.0% at 1 month, 85.0% at 1 year, and 90.8% at 5 years after the operation, and up to 91.4% at the last follow-up, were demonstrated by movement evaluation with the BFMDRS. All patients achieved a substantial improvement in quality of life. CONCLUSION: Subthalamic deep brain stimulation is an effective and persisting alternative to pallidal deep brain stimulation, and importantly, it is very safe even with extremely long-term chronic stimulation.
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Estimulación Encefálica Profunda/métodos , Trastornos Distónicos/terapia , Subtálamo/fisiología , Adolescente , Adulto , Anciano , Niño , Trastornos Distónicos/diagnóstico por imagen , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Subtálamo/diagnóstico por imagen , Resultado del Tratamiento , Adulto JovenAsunto(s)
Afecto , Llanto , Estimulación Encefálica Profunda/efectos adversos , Tortícolis/terapia , Afecto/fisiología , Llanto/fisiología , Estimulación Encefálica Profunda/métodos , Femenino , Globo Pálido/fisiopatología , Humanos , Persona de Mediana Edad , Tortícolis/etiología , Tortícolis/fisiopatología , Resultado del TratamientoRESUMEN
Performance deficits on the Wisconsin Card Sorting Test (WCST) in patients with prefrontal cortex (PFC) lesions are traditionally interpreted as evidence for a role of the PFC in cognitive flexibility. However, WCST deficits do not occur exclusively after PFC lesions, but also in various neurological and psychiatric disorders. We propose a multi-component approach that can accommodate this pattern of omnipresent WCST deficits: the WCST is not a pure test of cognitive flexibility, but relies on the effective functioning of multiple dissociable cognitive components. Our review of recent efforts to decompose WCST performance deficits supports this view by revealing that WCST deficits in different neurological disorders can be attributed to alterations in different components. Frontoparietal changes underlying impaired set shifting seem to give rise to WCST deficits in patients with amyotrophic lateral sclerosis, whereas the WCST deficits associated with primary dystonia and Parkinson's disease are rather related to frontostriatal changes underlying deficient rule inference. Clinical implications of these findings and of a multi-component view of WCST performance are discussed.
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Trastornos del Conocimiento/etiología , Potenciales Evocados/fisiología , Enfermedades del Sistema Nervioso/complicaciones , Electroencefalografía , Humanos , Pruebas NeuropsicológicasRESUMEN
BACKGROUND: Adult onset idiopathic isolated focal dystonia presents with a number of phenotypes. Reported prevalence rates vary considerably; well-characterized cohorts are important to our understanding of this disorder. AIM: To perform a nationwide epidemiological study of adult onset idiopathic isolated focal dystonia in the Republic of Ireland. METHODS: Patients with adult onset idiopathic isolated focal dystonia were recruited from multiple sources. Diagnosis was based on assessment by a neurologist with an expertise in movement disorders. When consent was obtained, a number of clinical features including family history were assessed. RESULTS: On the prevalence date there were 592 individuals in Ireland with adult onset idiopathic isolated focal dystonia, a point prevalence of 17.8 per 100 000 (95% confidence interval 16.4-19.2). Phenotype numbers were cervical dystonia 410 (69.2%), blepharospasm 102 (17.2%), focal hand dystonia 39 (6.6%), spasmodic dysphonia 18 (3.0%), musician's dystonia 17 (2.9%) and oromandibular dystonia six (1.0%). Sixty-two (16.5%) of 375 consenting index cases had a relative with clinically confirmed adult onset idiopathic isolated focal dystonia (18 multiplex and 24 duplex families). Marked variations in the proportions of patients with tremor, segmental spread, sensory tricks, pain and psychiatric symptoms by phenotype were documented. CONCLUSIONS: The prevalence of adult onset idiopathic isolated focal dystonia in Ireland is higher than that recorded in many similar service-based epidemiological studies but is still likely to be an underestimate. The low proportion of individuals with blepharospasm may reflect reduced environmental exposure to sunlight in Ireland. This study will serve as a resource for international comparative studies of environmental and genetic factors in the pathogenesis of the disorder.