ABSTRACT
INTRODUCTION: Deep brain stimulation (DBS) is widely used for treatment of advanced, medication-refractory Parkinson's disease (PD). However, a significant proportion of patients may suffer adverse effects; up to 10% will present one or more transient or permanent neurobehavioral events. PATIENT AND METHODS: In our case study, a 44-year-old woman diagnosed with PD 6 years previously who was suffering from motor fluctuations, dyskinesia, and freezing of gait episodes was submitted for DBS and implanted with directional electrodes. Intraoperative local field potentials (LFPs) were recorded. After surgery, conventional monopolar revision was performed. Preoperative 3T MRI studies and postoperative 3D and X-ray data were integrated using the Guide DTI software application (Brainlab), and diffusion tensor imaging tractography traced from cortical areas to each subthalamic nucleus (STN) using Elements software (Brainlab). RESULTS: We observed that left STN stimulation in the ring mode significantly improved motor symptoms, but the patient presented uncontrollable mirthful laughter. Stimulation was then switched to the directional mode; laughter remained when using the more posteromedial contact (3-C+) but not 2-C+ or 4-C+ at the same parameters. Interestingly, LFP recordings showed the highest beta-band activity over contacts 4 and 2, and very scarce beta power over contact 3. The orientation of the directional leads was selected based on the 3D postoperative X-rays. Associative fibers showed the shortest distance to contact number 3. CONCLUSION: Stimulation of the STN can affect motor and associative loops. The use of directional electrodes is a good option to avoid not only undesirable capsular or lemniscal effects, but also limbic/associative events. Oscillatory activity in the beta range that preferentially takes place over the somatomotor STN region and is closely related to motor improvement, provides a reliable guide for optimizing the DBS programming. The importance of the exact location of electrical stimulation to determine the non-motor symptoms such as mood, apathy, attention, and memory, as well as the usefulness of biological markers such as LFP for optimal programming, is discussed in relation to this case.
ABSTRACT
OBJECTIVE: We aimed to investigate the prevalence of TOR1A, GNAL and THAP1 variants as the cause of dystonia in a cohort of Spanish patients with isolated dystonia and in the literature. METHODS: A population of 2028 subjects (including 1053 patients with different subtypes of isolated dystonia and 975 healthy controls) from southern and central Spain was included. The genes TOR1A, THAP1 and GNAL were screened using a combination of high-resolution melting analysis and direct DNA resequencing. In addition, an extensive literature search to identify original articles (published before 10 August 2020) reporting mutations in TOR1A, THAP1 or GNAL associated to dystonia was performed. RESULTS: Pathogenic or likely pathogenic variants in TOR1A, THAP1 and GNAL were identified in 0.48%, 0.57% and 0.29% of our patients, respectively. Five patients carried the variation p.Glu303del in TOR1A. A very rare variant in GNAL (p.Ser238Asn) was found as a putative risk factor for dystonia. In the literature, variations in TOR1A, THAP1 and GNAL accounted for about 6%, 1.8% and 1.1% of published dystonia patients, respectively. CONCLUSIONS: There is a different genetic contribution to dystonia of these three genes in our patients (about 1.3% of patients) and in the literature (about 3.6% of patients), probably due the high proportion of adult-onset cases in our cohort. As regards age at onset, site of dystonia onset, and final distribution, in our population there is a clear differentiation between DYT-TOR1A and DYT-GNAL, with DYT-THAP1 likely to be an intermediate phenotype.
Subject(s)
Dystonia , Dystonic Disorders , Adult , Apoptosis Regulatory Proteins/genetics , DNA-Binding Proteins/genetics , Dystonia/epidemiology , Dystonia/genetics , Dystonic Disorders/epidemiology , Dystonic Disorders/genetics , Humans , Molecular Chaperones/genetics , Mutation , Spain/epidemiologyABSTRACT
BACKGROUND: A polymorphism in brain-derived neurotrophic factor (BDNF) (Val66Met) has been reported as a risk factor in primary dystonia. However, overall the results have been inconclusive. Our aim was to clarify the association of Val66Met with primary dystonia, and with the most prevalent clinical subtypes, cervical dystonia and blepharospasm. METHODS: We conducted a Spanish multicenter case-control study (including 680 primary dystonia patients and 788 healthy controls) and performed a meta-analysis integrating our study and six previously published studies (including a total of 1,936 primary dystonia patients and 2,519 healthy controls). RESULTS: We found no allelic or genotypic association with primary dystonia, cervical dystonia, or blepharospasm risks, for the allele A (Met) from a BDNF Val66Met polymorphism in our case-control study. This was confirmed by results from our meta-analysis in white and mixed ethnic populations in any genetic model. CONCLUSION: We did not find any evidence supporting the association of the BDNF Val66Met polymorphism with primary dystonia.
Subject(s)
Brain-Derived Neurotrophic Factor/genetics , Dystonic Disorders/genetics , Genetic Predisposition to Disease/genetics , Polymorphism, Single Nucleotide/genetics , Adult , Aged , Case-Control Studies , Female , Gene Frequency , Genetic Association Studies , Genotype , Humans , Male , Methionine/genetics , Middle Aged , Valine/geneticsABSTRACT
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