Hilten, J.J. van

Phenotypes and genetic architecture of focal primary torsion dystonia (Article)

2012-10-01T00:00:00Z

Background: The focal primary torsion dystonias (FPTDs) form a group of clinical heterogeneous syndromes and can be considered a genetic complex disease; it is thought to be primed by genetic variants with variable impact and triggered by non-genetic factors. Thorough clinical description of FPTDs cohorts is sparse but essential for further progress in genetic research. Objective: To establish suggested relations between age at onset (AaO), site and family history in a large focal dystonias cohort and gain more insight into familial clustering for genetic research. Patients and methods: A prospective cohort study between March 2008 and March 2011, including 676 FPTD patients attending the botulinum toxin outpatient clinics of six Dutch movement disorder centres. Results and conclusions: Of all of the FPTD patients, 25% had a familial predisposition; in 2.4% a Mendelian inheritance pattern was noted. With a stronger family history, a significantly lower AaO was seen in all focal dystonias. In both the sporadic and familial focal dystonia groups, AaO had an effect on the distribution of dystonia, with a caudal to cranial tendency. In all focal dystonia forms, women were more frequently affected, except for writer's cramp. Careful clinical characterisation will allow the formation of phenotype subgroups. We suggest that genetic research into FPTDs will benefit from this approach and discuss genetic research strategies to decipher the complex background of focal dystonias.

Catechol-O-methyltransferase Val158Met and the risk of dyskinesias in Parkinson's disease (Article)

2012-01-01T00:00:00Z

Background:: The A-allele of the catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with decreased enzymatic activity and higher dopamine availability. Methods:: We studied 219 patients with PD who were free of dyskinesias at baseline and underwent thorough annual examinations. Results:: The A-allele of the COMT Val158Met polymorphism was related to an increased risk of developing dyskinesias during follow-up, in a dose-dependent manner (adjusted hazard ratios for the AG and AA genotypes [compared to GG]: 2.09 [95% confidence interval (CI), 1.07-4.06] and 2.81 [CI, 1.43-5.54], respectively). Conclusions:: This finding suggests that genetic factors may affect susceptibility to dyskinesias in PD.

Genome-wide association study confirms extant PD risk loci among the Dutch (Article)

2011-06-01T00:00:00Z

In view of the population-specific heterogeneity in reported genetic risk factors for Parkinson's disease (PD), we conducted a genome-wide association study (GWAS) in a large sample of PD cases and controls from the Netherlands. After quality control (QC), a total of 514 799 SNPs genotyped in 772 PD cases and 2024 controls were included in our analyses. Direct replication of SNPs within SNCA and BST1 confirmed these two genes to be associated with PD in the Netherlands (SNCA, rs2736990: P1.63 × 105, OR1.325 and BST1, rs12502586: P1.63 × 103, OR1.337). Within SNCA, two independent signals in two different linkage disequilibrium (LD) blocks in the 3′ and 5′ ends of the gene were detected. Besides, post-hoc analysis confirmed GAK/DGKQ, HLA and MAPT as PD risk loci among the Dutch (GAK/DGKQ, rs2242235: P1.22 × 10 4, OR1.51; HLA, rs4248166: P4.39 × 10 5, OR1.36; and MAPT, rs3785880: P1.9 × 10 3, OR1.19).

Distribution of signs and symptoms of Complex Regional Pain Syndrome type I in patients meeting the diagnostic criteria of the International Association for the Study of Pain (Article)

2011-02-21T00:00:00Z

The aim of the present study was to describe the occurrence of signs and symptoms in CRPS I patients meeting the IASP (Orlando) criteria, assess the occurrence of signs and symptoms in relation to disease duration and compare these to historical data based on a different diagnostic criteria set. Six hundred and ninety-two ambulatory patients meeting the IASP criteria for CRPS I referred to the outpatient clinics of five participating centers were included in this cross-sectional study. Characteristics were recorded in a standardized fashion and categorized according to the factor structure proposed by Bruehl/Harden. Subgroups were classified according to the duration of complaints and compared to historical data as described by Veldman et al. The Chi-square test corrected for multiple comparisons was used for statistical analysis. The prevalence of sensory signs was higher in patients with longer disease duration, especially for the allodynia's and hyperalgesia (all p < 0.001). Signs in vasomotor (color difference; p = 0.0007) and sudomotor (edema; p < 0.0001) subgroups were less frequently present in patients with longer disease duration (i.e. >6 months). Prevalences of signs in the motor subgroup were all higher (p < 0.0001) in patients with longer disease duration, except for limited range of motion. Occurrence of signs was significantly lower (<0.001) than those reported by Veldman et al., except for hyperesthesia and dystonia. Occurrence rates may vary at different time points after onset of CRPS, which may be of influence for diagnosing patients with novel derived diagnostic criteria. We argue for a mechanism based description of CRPS I based on one set of uniform generally accepted diagnostic criteria in future studies.

Spontaneous onset of Complex Regional Pain Syndrome (Article)

2010-05-01T00:00:00Z

Complex Regional Pain Syndrome (CRPS) usually develops after a noxious event, but spontaneous onsets have been described in 3-11% of the cases. The existence of spontaneous-onset CRPS is highly debated and the aim of the present study was therefore to compare the phenotypic characteristics of CRPS patients with a spontaneous onset, with those of patients with a trauma-induced onset. Data of 537 CRPS patients followed up at four departments of anesthesiology were analyzed and comprised 498 (93%) patients with and 39 (7%) patients without a known eliciting event. There where no significant differences between the two groups in gender, or in onset in upper or lower limb or left or right side of the body. Compared to CRPS patients with a trauma-induced onset, spontaneous-onset cases were on average 9 years younger at disease onset and had a 1.4 years longer median disease duration. No significant differences in frequency were found for any of the 34 compared signs and symptoms when the effect of multiple testing was controlled. In conclusion, CRPS may develop both with and without a precipitating noxious event, with both groups exhibiting a largely similar clinical presentation. Spontaneous-onset CRPS patients generally develop the syndrome at a younger age, possibly indicating a susceptibility to develop the condition. The longer disease duration in spontaneous-onset cases may reflect a more gradual disease onset, poorer prognosis, or a delay in diagnosis, possibly as a result of reluctance to make this diagnosis in the absence of a clear initiating event.

Increased Risk of Complex Regional Pain Syndrome in Siblings of Patients? (Article)

2009-12-01T00:00:00Z

An increased risk among siblings of probands with complex regional pain syndrome (CRPS) may be indicative of a genetic contribution. We calculated the sibling recurrence risk ratio (λsibling), a measure of familial aggregation. We surveyed 405 CRPS patients to collect information on the occurrence of CRPS in their siblings and compared this risk with the population risk to develop the syndrome. Information on disease status was collected from 1242 siblings, of which 24 were possibly affected according to their siblings. The diagnosis was confirmed in 16 patients, rejected in 2, and could not be verified in the remaining 6. Age-specific risk ratios were calculated for younger (<50 years) and older (≥50 years) age groups. The strongest effects were seen in the younger age group, with a λsiblingfor possibly affected and confirmed cases of 5.6 (95% CI, 3.0 to 9.8) and 3.4 (95% CI, 1.5 to 6.8), respectively. We concluded that this study yielded no indications for an overall increased risk of developing CRPS for siblings of CRPS patients but that the risk was significantly increased in siblings younger than 50, which may indicate that genetic factors play a more pronounced role in this subgroup. Perspective: We studied the risk of developing CRPS for siblings of patients with this syndrome. Although the overall risk for siblings was not increased compared with the population risk, the risk for younger siblings was elevated. To enhance chances of success, future genetic studies may consider restricting inclusion to younger-onset cases.

Familial occurrence of complex regional pain syndrome (Article)

2009-02-01T00:00:00Z

Genetic factors are suggested to play a role in complex regional pain syndrome (CRPS), but familial occurrence has not been extensively studied. In the present study we evaluated familial occurrence in Dutch patients with CRPS. Families were recruited through the Dutch Association of CRPS patients and through referral by clinicians. The number of affected members per family, the phenotypic expression and inheritance were assessed. Demographic and clinical characteristics of familial CRPS (fCRPS) patients were compared with those of sporadic CRPS (sCRPS) patients from a Dutch population-based study and with a group of sCRPS patients that was proportionally matched for referral center of the fCRPS probandi to control for referral bias. Thirty-one CRPS families with two or more affected relatives were identified, including two families with five, four with four, eight with three and 17 with two affected relatives. In comparison with sCRPS patients, fCRPS patients had a younger age at onset and more often had multiple affected extremities and dystonia. We conclude that CRPS may occur in a familial form, but did not find a clear inheritance pattern. Patients with fCRPS develop the disease at a younger age and have a more severe phenotype than sporadic cases, suggesting a genetic predisposition to develop CRPS.

Analysis of cerebrospinal fluid inflammatory mediators in chronic complex regional pain syndrome related dystonia (Article)

2008-01-01T00:00:00Z

OBJECTIVES: There is compelling evidence of central nervous system involvement in neuropathic pain and movement disorders in patients with complex regional pain syndrome (CRPS). Previously, elevated cerebrospinal fluid (CSF) levels of interleukin-1β and interleukin-6 were found in CRPS patients with and without movement disorders. The aim of the present study was to replicate these findings and to search for additional CSF biomarkers in chronic CRPS patients with dystonia. METHODS: CSF samples of 20 patients and 29 controls who underwent spinal anesthesia for surgical interventions participated. We measured interleukin-1β, interleukin-6, interferon-γ inducible protein-10, RANTES (regulated upon activation, normal T-cell expressed and secreted), complement C3, mannose-binding lectin, complement C1q, soluble intercellular adhesion molecule-1, endothelin-1, nitric oxide, human lactoferrin, and hypocretin-1 levels in these samples. RESULTS: No differences in the CSF levels of these effector mediators between patients and controls were found. CONCLUSION: Our CSF findings do not support a role of a variety of inflammatory mediators or hypocretin-1 in chronic CRPS patients with dystonia.

Suction blister fluid as potential body fluid for biomarker proteins (Article)

2007-10-01T00:00:00Z

Early diagnosis is important for effective disease management. Measurement of biomarkers present at the local level of the skin could be advantageous in facilitating the diagnostic process. The analysis of the proteome of suction blister fluid, representative for the interstitial fluid of the skin, is therefore a desirable first step in the search for potential biomarkers involved in biological pathways of particular diseases. Here, we describe a global analysis of the suction blister fluid proteome as potential body fluid for biomarker proteins. The suction blister fluid proteome was compared with a serum proteome analyzed using identical protocols. By using stringent criteria allowing less than 1% false positive identifications, we were able to detect, using identical experimental conditions and amount of starting material, 401 proteins in suction blister fluid and 240 proteins in serum. As a major result of our analysis we construct a prejudiced list of 34 proteins, relatively highly and uniquely detected in suction blister fluid as compared to serum, with established and putative characteristics as biomarkers. We conclude that suction blister fluid might potentially serve as a good alternative biomarker body fluid for diseases that involve the skin.