Search

INTRODUCTION: In dystonia, dopaminergic alterations are considered to be responsible for the motor symptoms. Recent attention for the highly prevalent non-motor symptoms suggest also a role for serotonin in the pathophysiology. In this study we investigated the dopaminergic, serotonergic and noradrenergic metabolism in blood samples of dystonia patients and its relation with (non-)motor manifestations.METHODS: Concentrations of metabolites of dopaminergic, serotonergic and noradrenergic pathways were measured in platelet-rich plasma in 41 myoclonus-dystonia (M-D), 25 dopa-responsive dystonia (DRD), 50 cervical dystonia (CD) patients and 55 healthy individuals. (Non-)motor symptoms were assessed using validated instruments, and correlated with concentrations of metabolites.RESULTS: A significantly higher concentration of 3-methoxytyramine (0.03 vs. 0.02 nmol/L, p < 0.01), a metabolite of dopamine, and a reduced concentration of tryptophan (50 vs. 53 μmol/L, p = 0.03), the precursor of serotonin was found in dystonia patients compared to controls. The dopamine/levodopa ratio was higher in CD patients compared to other dystonia groups (p < 0.01). Surprisingly, relatively high concentrations of levodopa were found in the untreated DRD patients. Low concentrations of levodopa were associated with severity of dystonia (rs = -0.3, p < 0.01), depression (rs = -0.3, p < 0.01) and fatigue (rs = -0.2, p = 0.04).CONCLUSION: This study shows alterations in the dopaminergic and serotonergic metabolism of patients with dystonia, with dystonia subtype specific changes. Low concentrations of levodopa, but not of serotonergic metabolites, were associated with both motor and non-motor symptoms. Further insight into the dopaminergic and serotonergic systems in dystonia with a special attention to the kinetics of enzymes involved in these pathways, might lead to better treatment options.

Background Dystonia is a rare movement disorder, in which patients suffer from involuntary twisting movements or abnormal posturing. Next to these motor symptoms, patients have a high prevalence of psychiatric comorbidity, suggesting a role for serotonin in its pathophysiology. This study investigates the percentage of DNA methylation of the gene encoding for the serotonin reuptake transporter (SLC6A4) in dystonia patients and the associations between methylation levels and presence and severity of psychiatric symptoms. Methods Patients with cervical dystonia (n = 49), myoclonus dystonia (n = 41) and dopa-responsive dystonia (DRD) (n = 27) and a group of healthy controls (n = 56) were included. Psychiatric comorbidity was evaluated with validated questionnaires. Methylation levels of 20 CpG sites situated 69 to 213 base pairs upstream of the start codon of SLC6A4 were investigated. Methylation in dystonia patients was compared to healthy controls, correcting for age, and correlated with psychiatric comorbidity. Results Bootstrapped quantile regression analysis showed that being a dystonia patient compared to a healthy control significantly explains the methylation level at two CpG sites (CpG 24: pseudo-R2 = 0.05, p = 0.04, CpG 32: pseudo-R2 = 0.14, p = 0.03). Subgroup analysis revealed that being a DRD patient significantly explained a part of the variance of methylation levels at two CpG sites (CpG 21: pseudo-R2 = 0.03, p = 0.00, CpG 24: pseudo-R2 = 0.06, p = 0.03). Regression analysis showed that methylation level at CpG 38 significantly explained a small proportion of the variance of severity score for anxiety (R2 = 0.07, p = 0.04) and having a diagnosis of depression (Nagelkerke R2: 0.11, p = 0.00). Genotype of the 5-HTTLPR polymorphism had no additional effect on these associations. Conclusions This study showed an association between percentage of methylation at several specific sites of the promoter region of SLCA64 and (dopa-responsive) dystonia patients compared to healthy controls. Furthermore, methylation levels were associated with severity of anxiety and presence of a depressive disorder in the dystonia group. This study suggests alterations in the serotonergic metabolism in dystonia patients, and its relation with the non-motor symptoms.

GTP-cyclohydrolase deficiency in dopa-responsive dystonia (DRD) patients impairs the biosynthesis of dopamine, but also of serotonin. The high prevalence of non-motor symptoms suggests involvement of the serotonergic pathway. Our study aimed to investigate the serotonergic system in vivo in the brain of`DRD patients and correlate this to (non-)motor symptoms. Dynamic [11C]DASB PET scans, a marker of serotonin transporter availability, were performed. Ten DRD, 14 cervical dystonia patients and 12 controls were included. Univariate- and network-analysis did not show differences in binding between DRD patients compared to controls. Sleep disturbances were correlated with binding in the dorsal raphe nucleus (all participants: rs = 0.45, p = 0.04; patients: rs = 0.64, p = 0.05) and participants with a psychiatric disorder had a lower binding in the hippocampus (all participants: p = 0.00; patients: p = 0.06). Post-hoc analysis with correction for psychiatric co-morbidity showed a significant difference in binding in the hippocampus between DRD patients and controls (p = 0.00). This suggests that psychiatric symptoms might mask the altered serotonergic metabolism in DRD patients, but definite conclusions are difficult as psychiatry is considered part of the phenotype. We hypothesize that an imbalance between different neurotransmitter systems is responsible for the non-motor symptoms, and further research investigating multiple neurotransmitters and psychiatry in DRD is necessary.

Background: myoclonus-dystonia (M-D) due to a pathogenic variant of SGCE is an autosomal dominant inherited movement disorder. Apart from motor symptoms, psychiatric disorders are highly prevalent in patients with MD. Previous studies suggest, but never tested directly, that the type of psychiatric disorder differs between dystonia syndromes, probably related to disease specific pathology. Little is known about other non-motor symptoms (NMS) in M.D. Here, we systematically study NMS in M-D in direct comparison to other types of dystonia and healthy controls.Methods: Standardized questionnaires were used to assess type and severity of psychiatric co-morbidity, sleep problems, fatigue and quality of life. Results of M-D patients with a pathogenic variant of SGCE were compared to results of idiopathic cervical dystonia (CD) patients, dopa-responsive dystonia (DRD) patients with a pathogenic variant of GCH1 and controls.Results: We included 164 participants: 41 M-D, 51 CD, 19 DRD patients, 53 controls. Dystonia patients (M-D, CD and DRD) had an increased prevalence of psychiatric disorders compared to controls (56-74% vs. 29%). In M-D we found a significantly increased prevalence of obsessive-compulsive disorder (OCD) and psychosis compared to CD and DRD. All dystonia patients had more sleep problems (49-68% vs. 36%) and fatigue (42-73% vs. 15%) than controls. Compared to other dystonia subtypes, M-D patients reported less excessive daytime sleepiness and fatigue.Conclusion: Psychiatric comorbidity is frequent in all dystonia types, but OCD and psychosis are more common in M-D patients. Further research is necessary to elucidate underlying pathways.

GTP-cyclohydrolase deficiency in dopa-responsive dystonia (DRD) patients impairs the biosynthesis of dopamine, but also of serotonin. The high prevalence of non-motor symptoms suggests involvement of the serotonergic pathway. Our study aimed to investigate the serotonergic system in vivo in the brain of`DRD patients and correlate this to (non-)motor symptoms. Dynamic [

Myoclonus‐dystonia (M‐D) is a rare hyperkinetic movement disorder characterized by upper body–predominant myoclonus and dystonia.1 A large proportion of cases are caused by autosomal‐dominant inherited mutations in the SGCE gene. In addition to the motor manifestations, psychiatric disorders are frequently reported.2 Several studies have suggested that they may form a primary component of the M‐D phenotype.3, 4 This study represents the first long‐term follow‐up study of both motor and psychiatric symptomatology in adults with M‐D (SGCE mutation), providing further insights into the natural history of M‐D and enabling more prognostic information.

Background: In patients with GTP-cyclohydrolase deficient dopa-responsive dystonia (DRD) the occurrence of associated non-motor symptoms (NMS) is to be expected. Earlier studies report conflicting results with regard to the nature and severity of NMS. The aim of our study was to investigate the prevalence of psychiatric disorders, sleep problems, fatigue and health-related quality of life (HR-QoL) in a Dutch DRD cohort. Methods: Clinical characteristics, motor symptoms, type and severity of psychiatric co-morbidity, sleep problems, fatigue and HR-QoL were assessed in DRD patients with a confirmed GCH1 mutation and matched controls. Results: Twenty-eight patients were included (18 adults and 10 children), from 10 families. Dystonia symptoms were well-controlled in all patients. According to the DSM IV patients significantly more often met the criteria for a lifetime psychiatric disorder than controls (61% vs. 29%, p