Research & Scholarship
Current Research and Scholarly Interests
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Our goal is to investigate the genetic architecture of neurological complex genetic diseases. We focus on restless legs syndrome (RLS) and want to understand how the functional organization of neuronal sensor motor circuits is altered in RLS patients leading to disease manifestation. We aim to identify genetic and environmental factors modifying disease susceptibility; understand the mode of action of current drugs as well as establishing personalized treatment options in the future.
- Targeted Resequencing and Systematic In Vivo Functional Testing Identifies Rare Variants in MEIS1 as Significant Contributors to Restless Legs Syndrome AMERICAN JOURNAL OF HUMAN GENETICS 2014; 95 (1): 85-95
Targeted Resequencing and Systematic In Vivo Functional Testing Identifies Rare Variants in MEIS1 as Significant Contributors to Restless Legs Syndrome.
American journal of human genetics
2014; 95 (1): 85-95
Restless legs syndrome (RLS) is a common neurologic condition characterized by nocturnal dysesthesias and an urge to move, affecting the legs. RLS is a complex trait, for which genome-wide association studies (GWASs) have identified common susceptibility alleles of modest (OR 1.2-1.7) risk at six genomic loci. Among these, variants in MEIS1 have emerged as the largest risk factors for RLS, suggesting that perturbations in this transcription factor might be causally related to RLS susceptibility. To establish this causality, direction of effect, and total genetic burden of MEIS1, we interrogated 188 case subjects and 182 control subjects for rare alleles not captured by previous GWASs, followed by genotyping of ∼3,000 case subjects and 3,000 control subjects, and concluded with systematic functionalization of all discovered variants using a previously established in vivo model of neurogenesis. We observed a significant excess of rare MEIS1 variants in individuals with RLS. Subsequent assessment of all nonsynonymous variants by in vivo complementation revealed an excess of loss-of-function alleles in individuals with RLS. Strikingly, these alleles compromised the function of the canonical MEIS1 splice isoform but were irrelevant to an isoform known to utilize an alternative 3' sequence. Our data link MEIS1 loss of function to the etiopathology of RLS, highlight how combined sequencing and systematic functional annotation of rare variation at GWAS loci can detect risk burden, and offer a plausible explanation for the specificity of phenotypic expressivity of loss-of-function alleles at a locus broadly necessary for neurogenesis and neurodevelopment.
View details for DOI 10.1016/j.ajhg.2014.06.005
View details for PubMedID 24995868
Blood cis-eQTL Analysis Fails to Identify Novel Association Signals among Sub-Threshold Candidates from Genome-Wide Association Studies in Restless Legs Syndrome
2014; 9 (5)
Restless legs syndrome (RLS) is a common neurologic disorder characterized by nightly dysesthesias affecting the legs primarily during periods of rest and relieved by movement. RLS is a complex genetic disease and susceptibility factors in six genomic regions have been identified by means of genome-wide association studies (GWAS). For some complex genetic traits, expression quantitative trait loci (eQTLs) are enriched among trait-associated single nucleotide polymorphisms (SNPs). With the aim of identifying new genetic susceptibility factors for RLS, we assessed the 332 best-associated SNPs from the genome-wide phase of the to date largest RLS GWAS for cis-eQTL effects in peripheral blood from individuals of European descent. In 740 individuals belonging to the KORA general population cohort, 52 cis-eQTLs with pnominal<10-3 were identified, while in 976 individuals belonging to the SHIP-TREND general population study 53 cis-eQTLs with pnominal<10-3 were present. 23 of these cis-eQTLs overlapped between the two cohorts. Subsequently, the twelve of the 23 cis-eQTL SNPs, which were not located at an already published RLS-associated locus, were tested for association in 2449 RLS cases and 1462 controls. The top SNP, located in the DET1 gene, was nominally significant (p<0.05) but did not withstand correction for multiple testing (p = 0.42). Although a similar approach has been used successfully with regard to other complex diseases, we were unable to identify new genetic susceptibility factor for RLS by adding this novel level of functional assessment to RLS GWAS data.
View details for DOI 10.1371/journal.pone.0098092
View details for Web of Science ID 000336790800023
View details for PubMedID 24875634
Restless Legs Syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon
2014; 24 (4): 592-603
Genome-wide association studies (GWAS) identified the MEIS1 locus for Restless Legs Syndrome (RLS), but causal single nucleotide polymorphisms (SNPs) and their functional relevance remain unknown. This locus contains a large number of highly conserved noncoding regions (HCNRs) potentially functioning as cis-regulatory modules. We analyzed these HCNRs for allele-dependent enhancer activity in zebrafish and mice and found that the risk allele of the lead SNP rs12469063 reduces enhancer activity in the Meis1 expression domain of the murine embryonic ganglionic eminences (GE). CREB1 binds this enhancer and rs12469063 affects its binding in vitro. In addition, MEIS1 target genes suggest a role in the specification of neuronal progenitors in the GE, and heterozygous Meis1-deficient mice exhibit hyperactivity, resembling the RLS phenotype. Thus, in vivo and in vitro analysis of a common SNP with small effect size showed allele-dependent function in the prospective basal ganglia representing the first neurodevelopmental region implicated in RLS.
View details for DOI 10.1101/gr.166751.113
View details for Web of Science ID 000334055600006
View details for PubMedID 24642863
Rare variants in LRRK1 and Parkinson's disease.
2014; 15 (1): 49-57
Approximately 20 % of individuals with Parkinson's disease (PD) report a positive family history. Yet, a large portion of causal and disease-modifying variants is still unknown. We used exome sequencing in two affected individuals from a family with late-onset PD to identify 15 potentially causal variants. Segregation analysis and frequency assessment in 862 PD cases and 1,014 ethnically matched controls highlighted variants in EEF1D and LRRK1 as the best candidates. Mutation screening of the coding regions of these genes in 862 cases and 1,014 controls revealed several novel non-synonymous variants in both genes in cases and controls. An in silico multi-model bioinformatics analysis was used to prioritize identified variants in LRRK1 for functional follow-up. However, protein expression, subcellular localization, and cell viability were not affected by the identified variants. Although it has yet to be proven conclusively that variants in LRRK1 are indeed causative of PD, our data strengthen a possible role for LRRK1 in addition to LRRK2 in the genetic underpinnings of PD but, at the same time, highlight the difficulties encountered in the study of rare variants identified by next-generation sequencing in diseases with autosomal dominant or complex patterns of inheritance.
View details for DOI 10.1007/s10048-013-0383-8
View details for PubMedID 24241507
Rare Sequence Variants in ANO(3) and GNAL in a Primary Torsion Dystonia Series and Controls
2014; 29 (1): 143-147
Rare autosomal-dominant mutations in ANO3 and GNAL have been recently shown to represent novel genetic factors underlying primary torsion dystonia (PTD) with predominantly craniocervical involvement.We used high-resolution melting to screen all exons of ANO3 and GNAL for rare sequence variants in a population of 342 German individuals with mainly sporadic PTD and 376 general population controls.We identified 2 novel missense variants in ANO3 (p.Ile833Val and p.Gly973Arg) and 1 novel missense variant in GNAL (p.Val146Met) in three different nonfamilial cases. Variant carriers presented with adult-onset dystonia involving the neck and/or face. In controls, 3 rare ANO3 missense variants (p.Tyr235Cys, p.Asn256Ser, and p.Pro893Leu) but no rare nonsynonymous GNAL variants were present.GNAL variants seem to be a rare cause of PTD in our mainly sporadic German sample. Low frequency missense variants in ANO3 occur in both cases and controls, warranting further assessment of this gene in PTD pathogenesis. © 2013 International Parkinson and Movement Disorder Society.
View details for DOI 10.1002/mds.25715
View details for Web of Science ID 000330009000029
View details for PubMedID 24151159
- "Malignant restless legs syndrome"--a curse or a blessing? Sleep medicine 2014; 15 (1): 155-156
- Niemann-Pick C Disease Gene Mutations and Age-Related Neurodegenerative Disorders PLOS ONE 2013; 8 (12)
Prolonged release oxycodone-naloxone for treatment of severe restless legs syndrome after failure of previous treatment: a double-blind, randomised, placebo-controlled trial with an open-label extension
2013; 12 (12): 1141-1150
Opioids are a potential new treatment for severe restless legs syndrome. We investigated the efficacy and safety of a fixed-dose combination of prolonged release oxycodone-naloxone for patients with severe restless legs syndrome inadequately controlled by previous, mainly dopaminergic, treatment.This multicentre study consisted of a 12-week randomised, double-blind, placebo-controlled trial and 40-week open-label extension phase done at 55 sites in Austria, Germany, Spain, and Sweden. Patients had symptoms for at least 6 months and an International RLS Study Group severity rating scale sum score of at least 15; patients with severe chronic obstructive pulmonary disease or a history of sleep apnoea syndrome were excluded. Patients were randomly assigned (1:1) to either study drug or matched placebo with a validated interactive response technology system in block sizes of four. Study drug was oxycodone 5·0 mg, naloxone 2·5 mg, twice per day, which was up-titrated according to investigator's opinion to a maximum of oxycodone 40 mg, naloxone 20 mg, twice per day; in the extension, all patients started on oxycodone 5·0 mg, naloxone 2·5 mg, twice per day, which was up-titrated to a maximum of oxycodone 40 mg, naloxone 20 mg, twice per day. The primary outcome was mean change in severity of symptoms according to the International RLS Study Group severity rating scale sum score at 12 weeks. This study is registered with ClinicalTrials.gov (number NCT01112644) and with EudraCT (number 2009-011107-23).We screened 495 patients, of whom 306 were randomly assigned and 276 included in the primary analysis (132 to prolonged release oxycodone-naloxone vs 144 to placebo). 197 patients participated in the open-label extension. Mean International RLS Study Group rating scale sum score at randomisation was 31·6 (SD 4·5); mean change after 12 weeks was -16·5 (SD 11·3) in the prolonged release oxycodone-naloxone group and -9·4 (SD 10·9) in the placebo group (mean difference between groups at 12 weeks 8·15, 95% CI 5·46-10·85; p<0·0001). After the extension phase, mean sum score was 9·7 (SD 7·8). Treatment-related adverse events occurred in 109 of 150 (73%) patients in the prolonged release oxycodone-naloxone group and 66 of 154 (43%) in the placebo group during the double-blind phase; during the extension phase, 112 of 197 (57%) had treatment-related adverse events. Five of 306 (2%) patients had serious treatment-related adverse events when taking prolonged release oxycodone-naloxone (vomiting with concurrent duodenal ulcer, constipation, subileus, ileus, acute flank pain).Prolonged release oxycodone-naloxone was efficacious for short-term treatment of patients with severe restless legs syndrome inadequately controlled with previous treatment and the safety profile was as expected. Our study also provides evidence of open-label long-term efficacy of this treatment. Opioids can be used to treat patients with severe restless legs syndrome who have had no benefit with first-line drugs.Mundipharma Research.
View details for DOI 10.1016/S1474-4422(13)70239-4
View details for Web of Science ID 000327924100009
View details for PubMedID 24140442
- Rare Variants in PLXNA4 and Parkinson's Disease PLOS ONE 2013; 8 (11)
Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis
2013; 45 (11): 1353-?
Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
View details for DOI 10.1038/ng.2770
View details for Web of Science ID 000326384100016
View details for PubMedID 24076602
Association Between Variants of PRDM1 and NDP52 and Crohn's Disease, Based on Exome Sequencing and Functional Studies
2013; 145 (2): 339-347
Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies.We sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems.We identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 × 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 × 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor κB activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways.We have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.
View details for DOI 10.1053/j.gastro.2013.04.040
View details for Web of Science ID 000322630600023
View details for PubMedID 23624108
- High-density genotyping study identifies four new susceptibility loci for atopic dermatitis NATURE GENETICS 2013; 45 (7): 808-?
- Network-Based Multiple Sclerosis Pathway Analysis with GWAS Data from 15,000 Cases and 30,000 Controls AMERICAN JOURNAL OF HUMAN GENETICS 2013; 92 (6): 854-865
High-density genotyping study identifies four new susceptibility loci for atopic dermatitis.
2013; 45 (7): 808-812
Atopic dermatitis is a common inflammatory skin disease with a strong heritable component. Pathogenetic models consider keratinocyte differentiation defects and immune alterations as scaffolds, and recent data indicate a role for autoreactivity in at least a subgroup of patients. FLG (encoding filaggrin) has been identified as a major locus causing skin barrier deficiency. To better define risk variants and identify additional susceptibility loci, we densely genotyped 2,425 German individuals with atopic dermatitis (cases) and 5,449 controls using the Immunochip array followed by replication in 7,196 cases and 15,480 controls from Germany, Ireland, Japan and China. We identified four new susceptibility loci for atopic dermatitis and replicated previous associations. This brings the number of atopic dermatitis risk loci reported in individuals of European ancestry to 11. We estimate that these susceptibility loci together account for 14.4% of the heritability for atopic dermatitis.
View details for DOI 10.1038/ng.2642
View details for PubMedID 23727859
Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis
2013; 45 (6): 670-?
Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.
View details for DOI 10.1038/ng.2616
View details for Web of Science ID 000319563900015
View details for PubMedID 23603763
When restless legs syndrome turns malignant
2013; 14 (6): 575-577
Usually symptoms of restless legs syndrome (RLS) respond well to treatment with dopaminergic drugs, opiates, or anticonvulsant medications. Yet sometimes symptoms can be severe and become refractory, even to high-dose combination therapy. Here we present two cases of familial RLS with rigorous and unusual motor and sensory symptoms in the form of episodes of myoclonic hyperkinesias and painful sensations in addition to more characteristic features of RLS. Stepwise reduction of all RLS-and antidepressant medication down to opiate monotherapy-and subsequent opiate rotation led to an improvement of symptoms. Yet in both cases, reintroduction of low-dose dopaminergic drugs was necessary to achieve satisfactory treatment effect. We have termed this form of RLS refractory to multiple combinations of all classes of commonly used drugs malignant RLS. Therapeutically simplification and reduction of the drug scheme and opiate rotation should be considered in malignant RLS.
View details for DOI 10.1016/j.sleep.2013.02.012
View details for Web of Science ID 000319502300016
View details for PubMedID 23643657
The role of SCARB2 as susceptibility factor in Parkinson's disease
2013; 28 (4): 538-540
Genetic variation in the glucocerebrosidase (GBA) gene is strongly associated with Parkinson's disease (PD). Transport of glucocerebrosidase to the lysosome involves the protein encoded by the SCARB2 gene. An association between the common SNP rs6812193, upstream of SCARB2, and PD has been reported previously. The role of exonic variants in the SCARB2 gene in PD has not been examined.We studied the role of exonic variants in SCARB2 and tried to replicate the association between the SNP rs6812193 and PD in a German and Austrian sample. Screening of all SCARB2 exons by high-resolution melting curve analysis was performed in 376 German PD patients. The SNP rs6812193 was analyzed in 984 PD patients and 1014 general population controls.We identified no novel exonic variants in SCARB2 but confirmed the association between SNP rs6812193 and PD (OR, 0.86; P=.02).
View details for DOI 10.1002/mds.25349
View details for Web of Science ID 000317366100026
Dilution of candidates: the case of iron-related genes in restless legs syndrome
EUROPEAN JOURNAL OF HUMAN GENETICS
2013; 21 (4): 410-414
Restless legs syndrome (RLS) is a common multifactorial disease. Some genetic risk factors have been identified. RLS susceptibility also has been related to iron. We therefore asked whether known iron-related genes are candidates for association with RLS and, vice versa, whether known RLS-associated loci influence iron parameters in serum. RLS/control samples (n = 954/1814 in the discovery step, 735/736 in replication 1, and 736/735 in replication 2) were tested for association with SNPs located within 4 Mb intervals surrounding each gene from a list of 111 iron-related genes using a discovery threshold of P = 5 × 10(-4). Two population cohorts (KORA F3 and F4 with together n = 3447) were tested for association of six known RLS loci with iron, ferritin, transferrin, transferrin-saturation, and soluble transferrin receptor. Results were negative. None of the candidate SNPs at the iron-related gene loci was confirmed significantly. An intronic SNP, rs2576036, of KATNAL2 at 18q21.1 was significant in the first (P = 0.00085) but not in the second replication step (joint nominal P-value = 0.044). Especially, rs1800652 (C282Y) in the HFE gene did not associate with RLS. Moreover, SNPs at the known RLS loci did not significantly affect serum iron parameters in the KORA cohorts. In conclusion, the correlation between RLS and iron parameters in serum may be weaker than assumed. Moreover, in a general power analysis, we show that genetic effects are diluted if they are transmitted via an intermediate trait to an end-phenotype. Sample size formulas are provided for small effect sizes.
View details for DOI 10.1038/ejhg.2012.193
View details for Web of Science ID 000317089300011
Mitochondrial membrane protein associated neurodegenration: A novel variant of neurodegeneration with brain iron accumulation
2013; 28 (2): 224-227
Recently, mutations in an open-reading frame on chromosome 19 (C19orf12) were identified as a novel genetic factor in neurodegeneration with brain iron accumulation (NBIA). Because of the mitochondrial localization of the derived protein, this variant is referred to as mitochondrial membrane protein-associated neurodegeneration with brain iron accumulation (MPAN).We describe the clinical phenotype and MRI of 3 newly identified individuals with MPAN due to either previously reported or novel homozygous or compound heterozygous genetic alterations in C19orf12.MPAN is characterized by a juvenile-onset, slowly progressive phenotype with predominant lower limb spasticity, generalized dystonia, and cognitive impairment. Typical additional features include axonal motor neuropathy and atrophy of the optic nerve. MRI showed iron deposition in the globus pallidus and substantia nigra without the eye-of-the-tiger sign, which is typical for PKAN, the most frequent form of NBIA.
View details for DOI 10.1002/mds.25256
View details for Web of Science ID 000315399300019
- ImmunoChip Study Implicates Antigen Presentation to T Cells in Narcolepsy PLOS GENETICS 2013; 9 (2)
Genetic Variants in the Immunoglobulin Heavy Chain Locus are Associated with the IgG Index in Multiple Sclerosis
ANNALS OF NEUROLOGY
2013; 73 (1): 86-94
Intrathecal synthesis of immunoglobulin gamma (IgG) synthesis is frequently observed in patients with multiple sclerosis (MS). Whereas the extent of intrathecal IgG synthesis varies largely between patients, it remains rather constant in the individual patient over time. The aim of this study was to identify common genetic variants associated with the IgG index as a marker of intrathecal IgG synthesis in MS.We performed a genome-wide association study of the IgG index in a discovery series of 229 patients. For confirmation we performed a replication in 2 independent series comprising 256 and 153 patients, respectively. The impact of associated single nucleotide polymorphisms (SNPs) on MS susceptibility was analyzed in an additional 1,854 cases and 5,175 controls.Significant association between the IgG index and 5 SNPs was detected in the discovery and confirmed in both replication series reaching combined p values of p = 6.5 × 10(-11) to p = 7.5 × 10(-16) . All identified SNPs are clustered around the immunoglobulin heavy chain (IGHC) locus on chromosome 14q32.33 and are in linkage disequilibrium (r(2) range, 0.71-0.95). The best associated SNP is located in an intronic region of the immunoglobulin gamma3 heavy chain gene. Additional sequencing identified the GM21* haplotype to be associated with a high IgG index. Further evaluation of the IGHC SNPs revealed no association with susceptibility to MS in our data set.The extent of intrathecal IgG in MS is influenced by the IGHC locus. No association with susceptibility to MS was found. Therefore GM haplotypes might affect intrathecal IgG synthesis independently of the underlying disease.
View details for DOI 10.1002/ana.23749
View details for Web of Science ID 000314660800014
View details for PubMedID 23225573
Niemann-Pick C disease gene mutations and age-related neurodegenerative disorders.
2013; 8 (12)
Niemann-Pick type C (NPC) disease is a rare autosomal-recessively inherited lysosomal storage disorder caused by mutations in NPC1 (95%) or NPC2. Given the highly variable phenotype, diagnosis is challenging and particularly late-onset forms with predominantly neuropsychiatric presentations are likely underdiagnosed. Pathophysiologically, genetic alterations compromising the endosomal/lysosomal system are linked with age-related neurodegenerative disorders. We sought to examine a possible association of rare sequence variants in NPC1 and NPC2 with Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD) and progressive supranuclear palsy (PSP), and to genetically determine the proportion of potentially misdiagnosed NPC patients in these neurodegenerative conditions. By means of high-resolution melting, we screened the coding regions of NPC1 and NPC2 for rare genetic variation in a homogenous German sample of patients clinically diagnosed with PD (n = 563), FTLD (n = 133) and PSP (n = 94), and 846 population-based controls. The frequencies of rare sequence variants in NPC1/2 did not differ significantly between patients and controls. Disease-associated NPC1/2 mutations were found in six PD patients (1.1%) and seven control subjects (0.8%), but not in FTLD or PSP. All rare variation was detected in the heterozygous state and no compound heterozygotes were observed. Our data do not support the hypothesis that rare NPC1/2 variants confer susceptibility for PD, FTLD, or PSP in the German population. Misdiagnosed NPC patients were not present in our samples. However, further assessment of NPC disease genes in age-related neurodegeneration is warranted.
View details for DOI 10.1371/journal.pone.0082879
View details for PubMedID 24386122
Rare Variants in PLXNA4 and Parkinson's Disease.
2013; 8 (11)
Approximately 20% of individuals with Parkinson's disease (PD) report a positive family history. Yet, a large portion of causal and disease-modifying variants is still unknown. We used exome sequencing in two affected individuals from a family with late-onset familial PD followed by frequency assessment in 975 PD cases and 1014 ethnically-matched controls and linkage analysis to identify potentially causal variants. Based on the predicted penetrance and the frequencies, a variant in PLXNA4 proved to be the best candidate and PLXNA4 was screened for additional variants in 862 PD cases and 940 controls, revealing an excess of rare non-synonymous coding variants in PLXNA4 in individuals with PD. Although we cannot conclude that the variant in PLXNA4 is indeed the causative variant, these findings are interesting in the light of a surfacing role of axonal guidance mechanisms in neurodegenerative disorders but, at the same time, highlight the difficulties encountered in the study of rare variants identified by next-generation sequencing in diseases with autosomal dominant or complex patterns of inheritance.
View details for DOI 10.1371/journal.pone.0079145
View details for PubMedID 24244438
ImmunoChip study implicates antigen presentation to T cells in narcolepsy.
2013; 9 (2)
Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease.
View details for DOI 10.1371/journal.pgen.1003270
View details for PubMedID 23459209
Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
2012; 44 (12): 1341-1348
To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.
View details for DOI 10.1038/ng.2467
View details for PubMedID 23143594
Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease
2012; 491 (7422): 119-124
Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.
View details for DOI 10.1038/nature11582
View details for Web of Science ID 000310434500042
View details for PubMedID 23128233
- [Crowned dens syndrome: a rare differential diagnosis of acute neck pain]. Der Nervenarzt 2012; 83 (10): 1308-1311
- Crowned Dens Syndrome A Rare Differential Diagnosis Occurred Acute Neck Pain NERVENARZT 2012; 83 (10): 1308-?
Network-based SNP meta-analysis identifies joint and disjoint genetic features across common human diseases
Genome-wide association studies (GWAS) have provided a large set of genetic loci influencing the risk for many common diseases. Association studies typically analyze one specific trait in single populations in an isolated fashion without taking into account the potential phenotypic and genetic correlation between traits. However, GWA data can be efficiently used to identify overlapping loci with analogous or contrasting effects on different diseases.Here, we describe a new approach to systematically prioritize and interpret available GWA data. We focus on the analysis of joint and disjoint genetic determinants across diseases. Using network analysis, we show that variant-based approaches are superior to locus-based analyses. In addition, we provide a prioritization of disease loci based on network properties and discuss the roles of hub loci across several diseases. We demonstrate that, in general, agonistic associations appear to reflect current disease classifications, and present the potential use of effect sizes in refining and revising these agonistic signals. We further identify potential branching points in disease etiologies based on antagonistic variants and describe plausible small-scale models of the underlying molecular switches.The observation that a surprisingly high fraction (>15%) of the SNPs considered in our study are associated both agonistically and antagonistically with related as well as unrelated disorders indicates that the molecular mechanisms influencing causes and progress of human diseases are in part interrelated. Genetic overlaps between two diseases also suggest the importance of the affected entities in the specific pathogenic pathways and should be investigated further.
View details for DOI 10.1186/1471-2164-13-490
View details for Web of Science ID 000312149400001
View details for PubMedID 22988944
Variants in eukaryotic translation initiation factor 4G1 in sporadic Parkinson's disease
2012; 13 (3): 281-285
Recently, mutations in eukaryotic translation initiation factor 4G1 (EIF4G1) were reported as a rare cause of familial Parkinson's disease (PD). We screened the 33 exons of EIF4G1 by high-resolution melting curve analysis for variants in our Central European cohort of 376 PD cases. Variant frequency was assessed in a total of 975 PD cases and 1,014 general population controls. Eight novel nonsynonymous and four synonymous variants were identified. In our cohort, novel and previously identified nonsynonymous variants were very rare. Although it is possible that our general population controls also comprise individuals who have or could develop PD in the future, the presence of the original mutation (EIF4G1 p.Arg1205 His) in three controls only, raises questions about the causality of this variant with regard to PD.
View details for DOI 10.1007/s10048-012-0334-9
View details for Web of Science ID 000307520500012
Restless legs syndrome in Czech patients with multiple sclerosis: An epidemiological and genetic study
2012; 13 (7): 848-851
Restless legs syndrome (RLS) is a frequent neurological disorder which is presented in idiopathic and secondary form. Idiopathic RLS is associated with common genetic variants in four chromosomal regions. Recently, multiple sclerosis (MS) was identified as a common cause for secondary RLS. The aim of our study was to evaluate the prevalence of RLS among Czech patients with MS and to further analyze the impact of known genetic risk factors for RLS in patients with MS.Each patient underwent a semi-structured interview. A patient was considered to be affected by RLS if all four standard criteria had ever been met in their lifetime. The sample was genotyped using 12 single nucleotide polymorphisms within the four genomic regions, which were selected according to the results of previous genome-wide association studies.A total of 765 subjects with MS were included in the study and the diagnosis of RLS was confirmed in 245 subjects (32.1%, 95%CI 28.7-35.4%). The genetic association study included 642 subjects; 203 MS patients with RLS were compared to 438 MS patients without RLS. No significant association with MEIS 1, BTBD9, and PTPRD gene variants was found despite sufficient statistical power for the first two loci. There was a trend for association with the MAP2K5/SCOR1 gene - the best model for the risk allele was the recessive one (p nominal=0.0029, p corrected for four loci and two models=0.023, odds ratio=1.60).We confirmed that RLS prevalence was high in patients with multiple sclerosis, but this form did not share all genetic risk variants with idiopathic RLS.
View details for DOI 10.1016/j.sleep.2012.03.012
View details for Web of Science ID 000307747000013
View details for PubMedID 22609020
Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy
HUMAN MOLECULAR GENETICS
2012; 21 (10): 2205-2210
Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30-40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy-cataplexy and dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT1 as the only gene with mutations found in all five affected individuals. Sanger sequencing confirmed the de novo mutation p.Ala570Val in one family, and showed co-segregation of p.Val606Phe and p.Ala570Val, with the ADCA-DN phenotype, in two other kindreds. An additional ADCA-DN kindred with a p.GLY605Ala mutation was subsequently identified. Narcolepsy and deafness were the first symptoms to appear in all pedigrees, followed by ataxia. DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding to HDAC2. It is also highly expressed in immune cells and required for the differentiation of CD4+ into T regulatory cells. Mutations in exon 20 of this gene were recently reported to cause hereditary sensory neuropathy with dementia and hearing loss (HSAN1). Our mutations are all located in exon 21 and in very close spatial proximity, suggesting distinct phenotypes depending on mutation location within this gene.
View details for DOI 10.1093/hmg/dds035
View details for Web of Science ID 000303333700006
View details for PubMedID 22328086
PSEA: Phenotype Set Enrichment Analysis-A New Method for Analysis of Multiple Phenotypes
2012; 36 (3): 244-252
Most genome-wide association studies (GWAS) are restricted to one phenotype, even if multiple related or unrelated phenotypes are available. However, an integrated analysis of multiple phenotypes can provide insight into their shared genetic basis and may improve the power of association studies. We present a new method, called "phenotype set enrichment analysis" (PSEA), which uses ideas of gene set enrichment analysis for the investigation of phenotype sets. PSEA combines statistics of univariate phenotype analyses and tests by permutation. It does not only allow analyzing predefined phenotype sets, but also to identify new phenotype sets. Apart from the application to situations where phenotypes and genotypes are available for each person, the method was adjusted to the analysis of GWAS summary statistics. PSEA was applied to data from the population-based cohort KORA F4 (N = 1,814) using iron-related and blood count traits. By confirming associations previously found in large meta-analyses on these traits, PSEA was shown to be a reliable tool. Many of these associations were not detectable by GWAS on single phenotypes in KORA F4. Therefore, the results suggest that PSEA can be more powerful than a single phenotype GWAS for the identification of association with multiple phenotypes. PSEA is a valuable method for analysis of multiple phenotypes, which can help to understand phenotype networks. Its flexible design enables both the use of prior knowledge and the generation of new knowledge on connection of multiple phenotypes. A software program for PSEA based on GWAS results is available upon request.
View details for DOI 10.1002/gepi.21617
View details for Web of Science ID 000303319700008
View details for PubMedID 22714936
- Variation within the Huntington's Disease Gene Influences Normal Brain Structure PLOS ONE 2012; 7 (1)
Variation within the Huntington's disease gene influences normal brain structure.
2012; 7 (1)
Genetics of the variability of normal and diseased brain structure largely remains to be elucidated. Expansions of certain trinucleotide repeats cause neurodegenerative disorders of which Huntington's disease constitutes the most common example. Here, we test the hypothesis that variation within the IT15 gene on chromosome 4, whose expansion causes Huntington's disease, influences normal human brain structure. In 278 normal subjects, we determined CAG repeat length within the IT15 gene on chromosome 4 and analyzed high-resolution T1-weighted magnetic resonance images by the use of voxel-based morphometry. We found an increase of GM with increasing long CAG repeat and its interaction with age within the pallidum, which is involved in Huntington's disease. Our study demonstrates that a certain trinucleotide repeat influences normal brain structure in humans. This result may have important implications for the understanding of both the healthy and diseased brain.
View details for DOI 10.1371/journal.pone.0029809
View details for PubMedID 22235343
- Mutational screening of THAP1 in a German population with primary dystonia PARKINSONISM & RELATED DISORDERS 2012; 18 (1): 104-106
- Novel SCARB2 mutation in Action Myoclonus-Renal Failure syndrome and evaluation of SCARB2 mutations in isolated AMRF features BMC NEUROLOGY 2011; 11
Absence of an Orphan Mitochondrial Protein, C19orf12, Causes a Distinct Clinical Subtype of Neurodegeneration with Brain Iron Accumulation
AMERICAN JOURNAL OF HUMAN GENETICS
2011; 89 (4): 543-550
The disease classification neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of progressive neurodegenerative disorders characterized by brain iron deposits in the basal ganglia. For about half of the cases, the molecular basis is currently unknown. We used homozygosity mapping followed by candidate gene sequencing to identify a homozygous 11 bp deletion in the orphan gene C19orf12. Mutation screening of 23 ideopathic NBIA index cases revealed two mutated alleles in 18 of them, and one loss-of-function mutation is the most prevalent. We also identified compound heterozygous missense mutations in a case initially diagnosed with Parkinson disease at age 49. Psychiatric signs, optic atrophy, and motor axonal neuropathy were common findings. Compared to the most prevalent NBIA subtype, pantothenate kinase associated neurodegeneration (PKAN), individuals with two C19orf12 mutations were older at age of onset and the disease progressed more slowly. A polyclonal antibody against the predicted membrane spanning protein showed a mitochondrial localization. A histopathological examination in a single autopsy case detected Lewy bodies, tangles, spheroids, and tau pathology. The mitochondrial localization together with the immunohistopathological findings suggests a pathomechanistic overlap with common forms of neurodegenerative disorders.
View details for Web of Science ID 000295951300008
View details for PubMedID 21981780
Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
2011; 476 (7359): 214-219
Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
View details for DOI 10.1038/nature10251
View details for Web of Science ID 000293731900038
View details for PubMedID 21833088
Restless legs syndrome and cardiovascular risk
2011; 82 (8): 1006-1011
Large epidemiological studies have repeatedly suggested a possible association between restless legs syndrome (RLS) and common cardiovascular diseases and cardiovascular risk factors. Patients complaining of symptoms of RLS were also more likely to suffer from coronary artery disease, stroke, or, in some instances, hypertension. The underlying pathogenesis of the disease association depicted above has not been elucidated conclusively. Increased activation of the sympathetic nervous system - due to the RLS itself and the frequently accompanying periodic limb movements - has been linked to increased cardiovascular stress in patients with RLS.
View details for DOI 10.1007/s00115-010-3185-3
View details for Web of Science ID 000293968500008
View details for PubMedID 21174071
A Mutation in VPS35, Encoding a Subunit of the Retromer Complex, Causes Late-Onset Parkinson Disease
AMERICAN JOURNAL OF HUMAN GENETICS
2011; 89 (1): 168-175
To identify rare causal variants in late-onset Parkinson disease (PD), we investigated an Austrian family with 16 affected individuals by exome sequencing. We found a missense mutation, c.1858G>A (p.Asp620Asn), in the VPS35 gene in all seven affected family members who are alive. By screening additional PD cases, we saw the same variant cosegregating with the disease in an autosomal-dominant mode with high but incomplete penetrance in two further families with five and ten affected members, respectively. The mean age of onset in the affected individuals was 53 years. Genotyping showed that the shared haplotype extends across 65 kilobases around VPS35. Screening the entire VPS35 coding sequence in an additional 860 cases and 1014 controls revealed six further nonsynonymous missense variants. Three were only present in cases, two were only present in controls, and one was present in cases and controls. The familial mutation p.Asp620Asn and a further variant, c.1570C>T (p.Arg524Trp), detected in a sporadic PD case were predicted to be damaging by sequence-based and molecular-dynamics analyses. VPS35 is a component of the retromer complex and mediates retrograde transport between endosomes and the trans-Golgi network, and it has recently been found to be involved in Alzheimer disease.
View details for DOI 10.1016/j.ajhg.2011.06.008
View details for Web of Science ID 000293041700016
View details for PubMedID 21763483
MEIS1 and BTBD9: genetic association with restless leg syndrome in end stage renal disease
JOURNAL OF MEDICAL GENETICS
2011; 48 (7): 462-466
Restless legs syndrome (RLS) is a sleep related movement disorder that occurs both in an idiopathic form and in symptomatic varieties. RLS is a frequent and distressing comorbidity in end stage renal disease (ESRD). For idiopathic RLS (iRLS), genetic risk factors have been identified, but their role in RLS in ESRD has not been investigated yet. Therefore, a case-control association study of these variants in ESRD patients was performed.The study genotyped 10 iRLS associated variants at four loci encompassing the genes MEIS1, BTBD9, MAP2K5/SKOR1, and PTPRD, in two independent case-control samples from Germany and Greece using multiplex PCR and MALDI-TOF (matrix assisted laser desorption/ionisation time-of-flight) mass spectrometry. Statistical analysis was performed as logistic regression with age and gender as covariates. For the combined analysis a Cochran-Mantel-Haenszel test was applied.The study included 200 RLS-positive and 443 RLS-negative ESRD patients in the German sample, and 141 and 393 patients, respectively, in the Greek sample. In the German sample, variants in MEIS1 and BTBD9 were associated with RLS in ESRD (P(nom)?0.004, ORs 1.52 and 1.55), whereas, in the Greek sample, there was a trend for association to MAP2K5/SKOR1 and BTBD9 (P(nom)?0.08, ORs 1.41 and 1.33). In the combined analysis including all samples, BTBD9 was associated after correction for multiple testing (P(corrected)=0.0013, OR 1.47).This is the first demonstration of a genetic influence on RLS in ESRD patients with BTBD9 being significantly associated. The extent of the genetic predisposition could vary between different subgroups of RLS in ESRD.
View details for DOI 10.1136/jmg.2010.087858
View details for Web of Science ID 000291926800006
View details for PubMedID 21572129
Genome-Wide Association Study Identifies Novel Restless Legs Syndrome Susceptibility Loci on 2p14 and 16q12.1
2011; 7 (7)
Restless legs syndrome (RLS) is a sensorimotor disorder with an age-dependent prevalence of up to 10% in the general population above 65 years of age. Affected individuals suffer from uncomfortable sensations and an urge to move in the lower limbs that occurs mainly in resting situations during the evening or at night. Moving the legs or walking leads to an improvement of symptoms. Concomitantly, patients report sleep disturbances with consequences such as reduced daytime functioning. We conducted a genome-wide association study (GWA) for RLS in 922 cases and 1,526 controls (using 301,406 SNPs) followed by a replication of 76 candidate SNPs in 3,935 cases and 5,754 controls, all of European ancestry. Herein, we identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972, P?=?9.03 × 10(-11), OR?=?1.23) and a locus on 16q12.1 (rs3104767, P?=?9.4 × 10(-19), OR?=?1.35) in a linkage disequilibrium block of 140 kb containing the 5'-end of TOX3 and the adjacent non-coding RNA BC034767.
View details for DOI 10.1371/journal.pgen.1002171
View details for Web of Science ID 000293338600020
View details for PubMedID 21779176
[Treatment of secondary restless legs syndrome].
MMW Fortschritte der Medizin
2011; 153 (21): 45-48
View details for PubMedID 21736066
Parkinson's disease risk score: moving to a premotor diagnosis.
Journal of neurology
2011; 258: S311-5
Early pre-motor symptoms (also frequently termed "non-motor" symptoms) in Parkinson's disease (PD), which precede the onset of motor symptoms, are being increasingly recognized by clinicians. Non-motor symptoms in the pre-motor phase of PD include impaired olfaction (hyposmia), sleep disturbances (i.e., radid eye movement sleep behavior disorder, daytime sleepiness), behavioral/emotional dysfunction (i.e., change of personality or change of core personal characteristics), dysautonomia (i.e., constipation, urinary dysfunction, orthostatic hypotension), depressive symptoms (i.e., fatigue, apathy, anxiety), and chronic pain (joint and muscle). The pre-motor phase of PD is based on current pathophysiological concepts that relate these symptoms to early structural changes within lower brainstem nuclei and the peripheral nervous system including the autonomic and enteric ganglia. The perspective to identify these symptoms as early as possible will enable neurologists to make a diagnosis at the pre-motor stage of PD. Thus, the development of a PD risk score will be the first means to identify individuals at risk who are most likely to develop the prototypical motor symptoms of PD later in life. More importantly, these individuals at risk will be the first to benefit from disease-modifying strategies. In this workshop report, the elements of a PD risk score are proposed, including the stepwise sequence of escalating diagnostic measures to diagnose the pre-motor stage in PD.
View details for DOI 10.1007/s00415-011-5952-x
View details for PubMedID 21560061
When Parkinson's disease patients go to sleep: specific sleep disturbances related to Parkinson's disease.
Journal of neurology
2011; 258: S328-35
Nonmotor symptoms of Parkinson's disease can be as disabling as the much better studied motor symptoms. Among the nonmotor manifestations are numerous forms of alterations of physiologic sleep patterns that may present at different stages during the course of disease. These include changes believed to be primarily related to the underlying neurodegenerative process of the disease as well as those brought about secondarily, for example, by pharmacologic treatment. Also, sleep disturbances seen in Parkinson's disease can range from temporarily increased daytime sleepiness after introduction of a dopamine agonist to the therapeutic regime to specific sleep-related diagnoses such as restless legs syndrome, rapid eye movement sleep behavior disorder, periodic limb movements in sleep, and sleep-related breathing disorders such as obstructive sleep apnea. In this review, we discuss the different specific sleep disturbances that arise in the context of Parkinson's disease with a special emphasis on epidemiology, pathophysiology, and diagnosis.
View details for DOI 10.1007/s00415-011-5933-0
View details for PubMedID 21560064
- VARIANT SCREENING OF THE CODING REGIONS OF MEIS1 IN PATIENTS WITH RESTLESS LEGS SYNDROME NEUROLOGY 2011; 76 (12): 1106-1108
Novel association to the proprotein convertase PCSK7 gene locus revealed by analysing soluble transferrin receptor (sTfR) levels
HUMAN MOLECULAR GENETICS
2011; 20 (5): 1042-1047
The level of body iron storage and the erythropoietic need for iron are indicated by the serum levels of ferritin and soluble transferrin receptor (sTfR), respectively. A meta-analysis of five genome-wide association studies on sTfR and ferritin revealed novel association to the PCSK7 and TMPRSS6 loci for sTfR and the HFE locus for both parameters. The PCSK7 association was the most significant (rs236918, P = 1.1 × 10E-27) suggesting that proprotein convertase 7, the gene product of PCSK7, may be involved in sTfR generation and/or iron homeostasis. Conditioning the sTfR analyses on transferrin saturation abolished the HFE signal and substantially diminished the TMPRSS6 signal while the PCSK7 association was unaffected, suggesting that the former may be mediated by transferrin saturation whereas the PCSK7-associated effect on sTfR generation appears to be more direct.
View details for DOI 10.1093/hmg/ddq538
View details for Web of Science ID 000286993500018
View details for PubMedID 21149283
- Myoclonus-Dystonia in 18p Deletion Syndrome MOVEMENT DISORDERS 2011; 26 (3): 560-561
- Genetics of sleep disorders. Handbook of clinical neurology 2011; 99: 681-693
Novel SCARB2 mutation in action myoclonus-renal failure syndrome and evaluation of SCARB2 mutations in isolated AMRF features.
2011; 11: 134-?
Action myoclonus-renal failure syndrome is a hereditary form of progressive myoclonus epilepsy associated with renal failure. It is considered to be an autosomal-recessive disease related to loss-of-function mutations in SCARB2. We studied a German AMRF family, additionally showing signs of demyelinating polyneuropathy and dilated cardiomyopathy. To test the hypothesis whether isolated appearance of individual AMRF syndrome features could be related to heterozygote SCARB2 mutations, we screened for SCARB2 mutations in unrelated patients showing isolated AMRF features.In the AMRF family all exons of SCARB2 were analyzed by Sanger sequencing. The mutation screening of unrelated patients with isolated AMRF features affected by either epilepsy (n = 103, progressive myoclonus epilepsy or generalized epilepsy), demyelinating polyneuropathy (n = 103), renal failure (n = 192) or dilated cardiomyopathy (n = 85) was performed as high resolution melting curve analysis of the SCARB2 exons.A novel homozygous 1 bp deletion (c.111delC) in SCARB2 was found by sequencing three affected homozygous siblings of the affected family. A heterozygous sister showed generalized seizures and reduction of nerve conduction velocity in her legs. No mutations were found in the epilepsy, renal failure or dilated cardiomyopathy samples. In the polyneuropathy sample two individuals with demyelinating disease were found to be carriers of a SCARB2 frameshift mutation (c.666delCCTTA).Our findings indicate that demyelinating polyneuropathy and dilated cardiomyopathy are part of the action myoclonus-renal failure syndrome. Moreover, they raise the possibility that in rare cases heterozygous SCARB2 mutations may be associated with PNP features.
View details for DOI 10.1186/1471-2377-11-134
View details for PubMedID 22032306
Common variants in P2RY11 are associated with narcolepsy
2011; 43 (1): 66-U90
Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3' untranslated region of P2RY11, the purinergic receptor subtype P2Y?? gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10?¹?, odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8(+) T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.
View details for DOI 10.1038/ng.734
View details for Web of Science ID 000285683500018
View details for PubMedID 21170044
Common Variants at 10 Genomic Loci Influence Hemoglobin A(1C) Levels via Glycemic and Nonglycemic Pathways
2010; 59 (12): 3229-3239
Glycated hemoglobin (HbA?(c)), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA?(c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA?(c) levels.We studied associations with HbA?(c) in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA?(c) loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening.Ten loci reached genome-wide significant association with HbA(1c), including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 × 10?²?), HFE (rs1800562/P = 2.6 × 10?²?), TMPRSS6 (rs855791/P = 2.7 × 10?¹?), ANK1 (rs4737009/P = 6.1 × 10?¹²), SPTA1 (rs2779116/P = 2.8 × 10??) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 × 10??), and four known HbA?(c) loci: HK1 (rs16926246/P = 3.1 × 10???), MTNR1B (rs1387153/P = 4.0 × 10?¹¹), GCK (rs1799884/P = 1.5 × 10?²?) and G6PC2/ABCB11 (rs552976/P = 8.2 × 10?¹?). We show that associations with HbA?(c) are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA?(c)) difference between the extreme 10% tails of the risk score, and would reclassify ?2% of a general white population screened for diabetes with HbA?(c).GWAS identified 10 genetic loci reproducibly associated with HbA?(c). Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA?(c) levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA?(c).
View details for DOI 10.2337/db10-0502
View details for Web of Science ID 000285988200032
View details for PubMedID 20858683
Short-Term Attention and Verbal Fluency is Decreased in Restless Legs Syndrome Patients
2010; 25 (15): 2641-2648
Restless legs syndrome (RLS) is a frequent sleep-related movement disorder with disturbed sleep and quality of life. RLS patients complain about increased daytime sleepiness, but there are only few and inconsistent reports about cognitive functioning in this group. We compared cognitive performance of 23 unmedicated RLS patients to that of 23 healthy controls matched individually for age, gender, and educational level. Cognitive tasks were chosen to assess short-term attention, working memory, learning and memory, verbal fluency, and executive functioning. RLS patients performed worse than controls in the area of attention and verbal fluency, and performance in these tasks was associated with RLS severity, sleep quality, depression scores, and memory. There was no difference for working memory, memory, learning, cognitive flexibility, and abstract reasoning. We conclude that there is evidence for deficits in short-term attention and verbal fluency in RLS patients.
View details for DOI 10.1002/mds.23353
View details for Web of Science ID 000284060600023
View details for PubMedID 20836134
- IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci GENES AND IMMUNITY 2010; 11 (5): 397-405
Low-Level Expression of a Folding-Incompetent Protein in Escherichia coli: Search for the Molecular Determinants of Protein Aggregation In Vivo
JOURNAL OF MOLECULAR BIOLOGY
2010; 398 (4): 600-613
Aggregation of peptides and proteins into insoluble amyloid fibrils or related intracellular inclusions is the hallmark of many degenerative diseases, including Alzheimer's disease, Parkinson's disease, and various forms of amyloidosis. In spite of the considerable progress carried out in vitro in elucidating the molecular determinants of the conversion of purified and isolated proteins into amyloid fibrils, very little is known on factors governing this process in the complex environment of living organisms. Taking advantage of increasing evidence that bacterial inclusion bodies consist of amyloid-like aggregates, we have expressed in Escherichia coli both wild type and 21 single-point mutants of the N-terminal domain of the E. coli protein HypF. All variants were expressed as folding-incompetent units in a controlled manner, at low and comparable levels. Their solubilities were measured by quantifying the protein amount contained in the soluble and insoluble fractions by Western blot analysis. A significant negative correlation was found between the solubility of the variants in E. coli and their intrinsic propensity to form amyloid fibrils, predicted using an algorithm previously validated experimentally in vitro on a number of unfolded peptides and proteins, and considering hydrophobicity, beta-sheet propensity, and charge as major sequence determinants of the aggregation process. These findings show that the physicochemical parameters previously recognized to govern amyloid formation by fully or partially unfolded proteins are largely applicable in vivo and pave the way for the molecular exploration of a process as complex as protein aggregation in living organisms.
View details for DOI 10.1016/j.jmb.2010.03.030
View details for Web of Science ID 000277895500012
View details for PubMedID 20346957
Narcolepsy is strongly associated with the T-cell receptor alpha locus
2009; 41 (6): 708-711
Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals. Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1*0602 (ref. 4). Following studies in dogs and mice, a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported. Using genome-wide association (GWA) in Caucasians with replication in three ethnic groups, we found association between narcolepsy and polymorphisms in the TRA@ (T-cell receptor alpha) locus, with highest significance at rs1154155 (average allelic odds ratio 1.69, genotypic odds ratios 1.94 and 2.55, P < 10(-21), 1,830 cases, 2,164 controls). This is the first documented genetic involvement of the TRA@ locus, encoding the major receptor for HLA-peptide presentation, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders; thus, narcolepsy will provide new insights on how HLA-TCR interactions contribute to organ-specific autoimmune targeting and may serve as a model for over 100 other HLA-associated disorders.
View details for DOI 10.1038/ng.372
View details for Web of Science ID 000266411700020
View details for PubMedID 19412176
Replication of restless legs syndrome loci in three European populations
JOURNAL OF MEDICAL GENETICS
2009; 46 (5): 315-318
Restless legs syndrome (RLS) is associated with common variants in three intronic and intergenic regions in MEIS1, BTBD9, and MAP2K5/LBXCOR1 on chromosomes 2p, 6p and 15q.Our study investigated these variants in 649 RLS patients and 1230 controls from the Czech Republic (290 cases and 450 controls), Austria (269 cases and 611 controls) and Finland (90 cases and 169 controls). Ten single nucleotide polymorphisms (SNPs) within the three genomic regions were selected according to the results of previous genome-wide scans. Samples were genotyped using Sequenom platforms.We replicated associations for all loci in the combined samples set (rs2300478 in MEIS1, p = 1.26 x 10(-5), odds ratio (OR) = 1.47, rs3923809 in BTBD9, p = 4.11 x 10(-5), OR = 1.58 and rs6494696 in MAP2K5/LBXCOR1, p = 0.04764, OR = 1.27). Analysing only familial cases against all controls, all three loci were significantly associated. Using sporadic cases only, we could confirm the association only with BTBD9.Our study shows that variants in these three loci confer consistent disease risks in patients of European descent. Among the known loci, BTBD9 seems to be the most consistent in its effect on RLS across populations and is also most independent of familial clustering.
View details for DOI 10.1136/jmg.2008.062992
View details for Web of Science ID 000265665200004
View details for PubMedID 19279021
Recent advances in the diagnosis, genetics and treatment of restless legs syndrome
JOURNAL OF NEUROLOGY
2009; 256 (4): 539-553
Knowledge of restless legs syndrome (RLS) has greatly increased in recent years due to the many advances that have been made in diagnosis, management and genetics. Tools have been developed that facilitate the diagnosis and treatment of RLS, in particular the essential diagnostic criteria for RLS have been refined, severity scales (IRLS, RLS-6, JHSS) have been developed, as have instruments that improve diagnostic accuracy and assess for specific aspects of RLS such as augmentation. These newly developed tools have been used in recent population-based studies, which have provided a greater understanding of the epidemiology of RLS, and also within patient-based trials. As far as the genetics of RLS is concerned, linkage studies in RLS families have revealed eight loci but no causally related sequence variant has yet been identified using this approach. Recent genome-wide association studies have identified variants within intronic or intergenic regions of MEIS1, BTBD9, and MAP2K5/LBXCOR1, and PTPRD, raising new pathological hypotheses for RLS. An overview on therapeutic options and recent trials is given based on evidence-based management strategies for this common disorder.
View details for DOI 10.1007/s00415-009-0134-9
View details for Web of Science ID 000266091300003
View details for PubMedID 19444530
Heritability of sleep electroencephalogram
2008; 64 (4): 344-348
Understanding the basis of sleep-related endophenotypes might help to pinpoint factors modulating susceptibility to psychiatric disorders. However, the genetic underpinnings of sleep microarchitecture in humans remain largely unknown. Here we report on the results of a classical twin study in monozygotic (MZ) and dizygotic (DZ) twin pairs examining the genetic effect on sleep electroencephalogram (EEG) composition.Polysomnographic recordings were obtained in 35 pairs of MZ (26.4 +/- 5.4 years, 17-43 years, 17 male pairs, 18 female pairs) and 14 same-gender pairs of DZ twins (22.1 +/- 2.7 years, 18-26 years, 7 male pairs, 7 female pairs). The EEG power spectra were generated on the basis of Fast Fourier transformations combined with conventional sleep parameters, according to standardized criteria.We tested the genetic variance contributing to the observed overall variance of the sleep measures and found that the relative contributions of the delta, theta, alpha, and sigma frequency bands at central derivations were significantly correlated to the genetic background. In these frequency bands, MZ twins also showed within-pair concordance in spectral power that was significantly higher than that of DZ twins.The broad overlap of EEG frequencies during non-REM sleep and wakefulness, which shows a significant genetic variance, supports the hypothesis of common neuronal mechanisms generating EEG oscillations in humans. Our findings strongly support the suitability of the spectral composition of non-REM sleep for defining endophenotypes.
View details for DOI 10.1016/j.biopsych.2008.03.002
View details for Web of Science ID 000258357200012
View details for PubMedID 18405882
PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome
2008; 40 (8): 946-948
We identified association of restless legs syndrome (RLS) with PTPRD at 9p23-24 in 2,458 affected individuals and 4,749 controls from Germany, Austria, Czechia and Canada. Two independent SNPs in the 5' UTR of splice variants expressed predominantly in the central nervous system showed highly significant P values (rs4626664, P(nominal/lambda corrected) = 5.91 x 10(-10), odds ratio (OR) = 1.44; rs1975197, P(nominal/lambda corrected) = 5.81 x 10(-9), OR = 1.31). This work identifies PTPRD as the fourth genome-wide significant locus for RLS.
View details for DOI 10.1038/ng.190
View details for Web of Science ID 000258026900008
View details for PubMedID 18660810
Genetics of restless legs syndrome
CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS
2008; 8 (3): 211-216
Restless legs syndrome (RLS) is a highly familial trait with heritability estimates of about 50%. It is a polygenetic disorder in which a number of variants contribute to the phenotype. Linkage studies in families with RLS revealed several loci but have not yet led to the identification of disease-causing sequence variants. Phenocopies, nonpenetrance, and possible intrafamilial heterogeneity make it difficult to define the exact candidate region. Genome-wide association studies identified variants within intronic or intergenic regions of MEIS1, BTBD9, and MAP2K5/LBOXCOR1. Carriers of one risk allele had a 50% increased risk of developing RLS. MEIS1 and LBXCOR1 are developmental factors and raise new pathophysiologic questions for RLS. These variants have weak and moderate effects and increase the risk of developing RLS. It is still possible that strong effects explain the occurrence of RLS in families. Therefore, linkage and association studies should be used congruently to dissect the complete genetic architecture of RLS.
View details for Web of Science ID 000256319400005
View details for PubMedID 18541116
Suggestive evidence for linkage for restless legs syndrome on chromosome 19p13
2008; 9 (2): 75-82
Five loci for restless legs syndrome (RLS) on chromosomes 12q, 14q, 9p, 2q, and 20p (RLS1-RLS5) have been mapped in RLS families, with a recessive in the first and autosomal-dominant mode of inheritance in the latter cases. Investigations of further RLS families showed evidence for genetic locus heterogeneity. We have conducted a genome-wide linkage analysis in a large RLS family of Italian origin with 12 affected members in 3 generations using 5,861 single nucleotide polymorphisms (SNP, 6K Illumina). Linkage analysis was performed under an autosomal-dominant model with a complete penetrance, an allele frequency of 0.003 and a phenocopy rate of 0.005. The genome-wide scan resulted in suggestive evidence for linkage on chromosome 19p with maximum multipoint logarithm of the odds score of 2.61 between markers rs754292 and rs273265. The locus was replicated in a family-based association study in a set of 159 trios of European origin. This study provides evidence for a further RLS locus, thus supporting the picture of RLS as a genetically heterogenous complex trait.
View details for DOI 10.1007/s10048-007-0113-1
View details for Web of Science ID 000255034000001
View details for PubMedID 18193462
- Genetics of restless legs syndrome - A burning urge to move NEUROLOGY 2008; 70 (9): 664-665
Variants in the neuronal nitric oxide synthase (nNOS, NOS1) gene are associated with restless legs syndrome
2008; 23 (3): 350-358
Sixty percent of the patients with restless legs syndrome (RLS) report a positive family history. To date five loci have been mapped on chromosome 12q, 14q, 9p, 2q, and 20p (RLS1-5) but no gene has been identified so far. To identify genes related to RLS, we performed a three-stage association study (explorative study, replication study, high-density mapping) in two Caucasian RLS case-control samples of altogether 918 independent cases and controls. In the explorative study (367 cases and controls, respectively), we screened 1536 SNPs in 366 genes in a 21 Mb region encompassing the RLS1 critical region on chromosome 12. Armitage trend test revealed three genomic regions that were significant (P < 0.05). In the replication study (551 cases and controls, respectively) we genotyped the most significant SNPs of Stage 1. After correction for multiple testing, association was observed with SNP rs7977109 (P(nominal) = 0.00175, P(Westfall-Young) = 0.04895, OR = 0.76228, 95% CI = 0.64310-0.90355), which is in the neuronal nitric oxide synthase (NOS1) gene. High-density mapping using altogether 34 tagging and coding SNPs of the NOS1 gene in both case-control samples further confirmed the significant association results to NOS1. Ten more SNPs revealed significance with nominal P-values from 0.0001 to 0.0482 (genotypic test and Armitage test). Altogether, this study provides evidence for an association of variants in the NOS1 gene and RLS, and suggests the involvement of the NO/arginine pathway in the pathogenesis of RLS. Potential usage of NO modulating agents as new treatment options for RLS have become a challenging aspect for future research of this disorder.
View details for DOI 10.1002/mds.21647
View details for Web of Science ID 000253925700004
View details for PubMedID 18058820
Diagnostic standards for dopaminergic augmentation of restless legs syndrome: Report from a World Association of Sleep Medicine - International Restless Legs Syndrome Study Group consensus conference at the Max Planck Institute
2007; 8 (5): 520-530
Augmentation of symptom severity is the main complication of dopaminergic treatment of restless legs syndrome (RLS). The current article reports on the considerations of augmentation that were made during a European Restless Legs Syndrome Study Group (EURLSSG)-sponsored Consensus Conference in April 2006 at the Max Planck Institute (MPI) in Munich, Germany, the conclusions of which were endorsed by the International RLS Study Group (IRLSSG) and the World Association of Sleep Medicine (WASM). The Consensus Conference sought to develop a better understanding of augmentation and generate a better operational definition for its clinical identification.Current concepts of the pathophysiology, clinical features, and therapy of RLS augmentation were evaluated by subgroups who presented a summary of their findings for general consideration and discussion. Recent data indicating sensitivity and specificity of augmentation features for identification of augmentation were also evaluated. The diagnostic criteria of augmentation developed at the National Institutes of Health (NIH) conference in 2002 were reviewed in light of current data and theoretical understanding of augmentation. The diagnostic value and criteria for each of the accepted features of augmentation were considered by the group. A consensus was then developed for a revised statement of the diagnostic criteria for augmentation.Five major diagnostic features of augmentation were identified: usual time of RLS symptom onset each day, number of body parts with RLS symptoms, latency to symptoms at rest, severity of the symptoms when they occur, and effects of dopaminergic medication on symptoms. The quantitative data available relating the time of RLS onset and the presence of other features indicated optimal augmentation criteria of either a 4-h advance in usual starting time for RLS symptoms or a combination of the occurrence of other features. A paradoxical response to changes in medication dose also indicates augmentation. Clinical significance of augmentation is defined.The Consensus Conference agreed upon new operational criteria for the clinical diagnosis of RLS augmentation: the MPI diagnostic criteria for augmentation. Areas needing further consideration for validating these criteria and for understanding the underlying biology of RLS augmentation are indicated.
View details for DOI 10.1016/j.sleep.2007.03.022
View details for Web of Science ID 000248955800012
View details for PubMedID 17544323
Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions
2007; 39 (8): 1000-1006
Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene encoding a BTB(POZ) domain as well as variants in a third locus containing the genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p and 15q, respectively. Two independent replications confirmed these association signals. Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder.
View details for DOI 10.1038/ng2099
View details for Web of Science ID 000248446900018
View details for PubMedID 17637780
Genetics of sleep and sleep disorders
CELLULAR AND MOLECULAR LIFE SCIENCES
2007; 64 (10): 1216-1226
Genetic factors affect sleep. Studies in twin pairs demonstrate that the strong hereditary influences on sleep architecture and some sleep disorders are transmitted through families. Evidence like this strongly suggests that sleep regulation receives significant influence from genetic factors. Although recent molecular technologies have revealed evidence that genetic traits or gene products trigger particular changes in sleep electroencephalogram activity, we are still far from finding candidate genes or multiple mutations responsible for individual sleep disorders. Sleep is a very complex phenotype. Genetic susceptibility and environmental factors should be also considered as contributors to sleep phenotype. The aim of this review is to present a current summary and future prospects for genetic studies on sleep and selected sleep-associated disorders.
View details for DOI 10.1007/s00018-007-6532-1
View details for Web of Science ID 000246617400005
View details for PubMedID 17370036
Family-based association study of the loci 2 and 3 in a European restless legs syndrome population
2007; 22 (2): 207-212
Three loci for the restless legs syndrome (RLS) on chromosomes 12q, 14q, and 9p (RLS1, RLS2, and RLS3) have been mapped, but no gene has been identified as yet. RLS1 has been confirmed in families from three different populations. We conducted a family-based association study of 159 European RLS trios. The subjects were genotyped using microsatellite markers evenly covering the candidate regions on chromosomes 14q and 9p with an average intermarker distance of 1.1 cM. Transmission disequilibrium tests were used to analyze the data, and empirical P values were estimated by permutation testing. On chromosome 14q, a significant association (empirical P = 0.0033) was found with a haplotype formed by markers D14S1014 and D14S1017 when analyzing all families. On chromosome 9p, no significant association in the sample of all families and only marginally significant associations were detected, with a haplotype involving markers D9S1846-D9S171 in a subset of South European trios and with a haplotype at D9S156-D9S157 in a subset of Central European trios (P = 0.0086 and 0.0077, respectively). These results represent the first confirmation of these loci in a mixed European population. Variable results observed in families of different ethnic groups further corroborate the genetic complexity of RLS.
View details for DOI 10.1002/mds.21254
View details for Web of Science ID 000243944800010
View details for PubMedID 17133505
Animal studies in restless legs syndrome
2007; 22: S459-S465
Although restless legs syndrome (RLS) is a common disorder that has been studied thoroughly in the past decades, the underlying pathophysiology is still not fully understood. However, some attractive hypotheses on the pathogenesis of the disorder have been forwarded. Animal models are an important tool to verify hypotheses and to dissect out the details of pathophysiological mechanisms. Ideally they might serve the development of future treatment strategies. This review discusses the general and specific prerequisites necessary for the establishment of animal models for RLS and summarizes the approaches that have been made.
View details for DOI 10.1002/mds.21605
View details for Web of Science ID 000251605200011
View details for PubMedID 17595041
Genetics of restless legs syndrome (RLS): State-of-the-art and future directions
2007; 22: S449-S458
Several studies demonstrated that 60% of restless legs syndrome (RLS) patients have a positive family history and it has been suggested that RLS is a highly hereditary trait. To date, several loci have been mapped but no gene has been identified yet. Phenocopies and possible nonpenetrants made it difficult to detect a common segregating haplotype within the families. Defining the exact candidate region is hampered by possible intrafamilial, allelic, and nonallelic heterogeneity. One important prerequisite for future successful genetic studies in RLS is the availability of large and thoroughly phenotyped patients and family samples for linkage as well as association studies.
View details for DOI 10.1002/mds.21587
View details for Web of Science ID 000251605200010
View details for PubMedID 17557342
Clinical trials in restless legs syndrome - Recommendations of the European RLS study group (EURLSSG)
2007; 22: S495-S504
The European Restless Legs Syndrome (RLS) Study Group (EURLSSG) is an association of European RLS experts who are actively involved in RLS research. A major aim of the Study Group is the development and continuous improvement of standards for diagnosis and treatment of RLS. Several members developed study designs and evaluation methods in investigator-initiated trials early in the 1990s, and all members have since contributed to many pivotal and nonpivotal drug trials for the treatment of RLS. The recommendations on clinical investigations of pharmacological treatment of RLS patients summarize the group's expertise and knowledge acquired through clinical trials. The recommendations primarily address how to plan and conduct confirmatory, randomized clinical studies in patients with idiopathic RLS. Advice is presented for the diagnosis of RLS and clinical and polysomnographic inclusion and exclusion criteria. Primary and secondary endpoints for an evaluation of efficacy are based on a critical description of validated methods for both short- and long-term trials, also in special populations (children, pregnant women, elderly patients). The recommendations include the assessment of augmentation. Finally, general issues including the evaluation of safety and tolerability, as well as specific neurological and cardiovascular risks and sleep attacks/daytime somnolence, are discussed. The aim of these recommendations is to support research groups or pharmaceutical companies in the design of optimized study protocols.
View details for DOI 10.1002/mds.21538
View details for Web of Science ID 000251605200015
View details for PubMedID 17530666
Augmentation as a treatment complication of restless legs syndrome: Concept and management
2007; 22: S476-S484
Augmentation constitutes the main complication of long-term dopaminergic treatment in restless legs syndrome (RLS). Although this condition was first described in 1996, and is characterized by an overall increase in severity of RLS symptoms (including earlier onset of symptoms during the day, faster onset of symptoms when at rest, expansion to the upper limbs and trunk, and shorter duration of the treatment effect), precise diagnostic criteria were not established until 2003. These criteria have recently been updated to form a new definition of augmentation based on multicentric studies. The present article reviews our current knowledge on clinical diagnosis, evaluation, pathophysiology, and treatment recommendations for this condition.
View details for DOI 10.1002/mds.21610
View details for Web of Science ID 000251605200013
View details for PubMedID 17580331
- Olanzapine-induced oculogyric crisis JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY 2006; 26 (4): 431-431
RLS3: Fine-mapping of an autosomal dominant locus in a family with intrafamilial heterogeneity
2006; 67 (2): 320-321
A new locus for restless legs syndrome (RLS3) was identified on chromosome 9p24-22. The authors analyzed transmission disequilibrium tests (TDTs) and affecteds-only linkage analysis in one large family of Bavarian origin, taking into account age at onset. P values were 0.0054 for marker D9S1810 for TDT and 0.0009 for the affecteds-only linkage analysis, providing a confirmation of RLS3. This study narrows the region containing the autosomal dominant RLS3 locus to 11.1 cM (16.6 Mbp).
View details for Web of Science ID 000239237600029
View details for PubMedID 16864828
Epidemiology of restless legs syndrome: The current status
SLEEP MEDICINE REVIEWS
2006; 10 (3): 153-167
Epidemiological studies in restless legs syndrome (RLS) have often been limited by misdiagnosis and by the fact that affected individuals, even when their symptoms are severe, might not seek medical care. Some of these limitations have been overcome in the last years as population studies based on face to face interviews have been carried out with new standardized diagnostic criteria. According to these studies, and in contrast to earlier views, RLS has been shown to be a common disorder with prevalences ranging between 2.5 and 10% of the population. Although few studies performed outside Europe/North America have shown a low prevalence, a number of methodological issues have been raised that might question these results. Furthermore, once established, RLS usually follows a chronic course, and preliminary evidence shows that it might worsen over time in some patients. Endstage renal disease, increasing age, female gender, pregnancy, frequent blood donations, iron deficiency and neuropathy are considered to be risk factors for this disorder. The association to RLS is less definitely established for other conditions, such as PD or diabetes. In summary, epidemiological evidence suggests that RLS is a common neurological disorder-with high impact on many aspects of the life of those affected.
View details for DOI 10.1016/j.smrv.2006.01.001
View details for Web of Science ID 000238631100002
View details for PubMedID 16762806
Genetics of restless legs syndrome
SLEEP MEDICINE REVIEWS
2006; 10 (3): 179-183
Several studies on restless legs syndrome (RLS) have suggested a substantial genetic contribution in the etiology of this sleep disorder. Clinical surveys of idiopathic RLS patients have shown that 40-90% report a positive family history. The clinical features have been compared between familial and sporadic cases and the only difference found was a younger age-at-onset in familial RLS. Despite several reports suggesting a genetic contribution to the etiology of idiopathic RLS, few molecular genetic studies have been carried out attempting to identify genes that can predispose to this disorder. In particular, genes encoding for the GABA A receptor subunits, the gene for the alpha1 subunit of the glycine receptor, and genes involved in dopaminergic transmission and metabolism have been analyzed, however no significant findings have been reported. Genomewide linkage analysis studies using microsatellite markers have identified three loci for RLS: on chromosome 12q, on chromosome 14q and on chromosome 9p. It is important to investigate whether further RLS families show linkage to one of these loci to discuss the contribution of these loci and to provide a prerequisite of a mutational screening and identification of the RLS genes.
View details for DOI 10.1016/j.smrv.2006.01.003
View details for Web of Science ID 000238631100004
View details for PubMedID 16624598
Evidence for further genetic locus heterogeneity and confirmation of RLS-1 in restless legs syndrome
2006; 21 (1): 28-33
Restless legs syndrome (RLS; MIM 102300) is a common neurological disorder characterized by dysesthesias and an urge to move the lower limbs. The symptoms predominantly occur at rest, in the evening, and improve with movement. There is a high familial aggregation but gene mutations have not yet been found. Three loci for RLS on chromosomes 12q, 14q, and 9p (RLS-1, RLS-2, and RLS-3) have been reported with a recessive (RLS-1) and autosomal dominant (RLS-2, RLS-3) mode of inheritance, respectively. The overall contribution of these loci to this disorder is not known. To evaluate the significance of these loci, we investigated 12 RLS families for possible linkage to these chromosomal regions. Genotyping was carried out in 70 affected family members using 26 polymorphic microsatellite markers (chromosome 12: 7; chromosome 14: 7, chromosome 9: 12). Linkage analysis was carried out using the published parameters applied in the original studies (chromosome 12: q=0.25, f0=0.005, f1=0.005, f2=0.8; chromosome 14: q=0.003, f0=0.005, f1=f2=0.95; chromosome 9: q=0.001, f0=0.005, f1=f2=0.95; affected individuals only). In addition, transmission disequilibrium test (TDT) analyses were done. We found evidence for linkage on chromosome 12 using the TDT. Linkage to RLS-2 and RLS-3 was excluded in 1 of 12 families. This supports the existence of RLS-1 and provides evidence for the likelihood of further genetic locus heterogeneity of RLS. Investigations in additional RLS families are required to confirm the known loci and further genome wide linkage analyses have the potential to identify additional RLS loci.
View details for DOI 10.1002/mds.20627
View details for Web of Science ID 000235113800004
View details for PubMedID 16124010
Paroxetine treatment improves motor symptoms in patients with multiple system atrophy
PARKINSONISM & RELATED DISORDERS
2006; 12 (7): 432-437
In view of the putative role of serotonergic neurotransmission in basal ganglia circuitry we investigated the effects of paroxetine (PXT) as a selective serotonin reuptake inhibitor (SSRI) on the motor performance in n=19 patients clinically diagnosed as MSA using a double-blind placebo-controlled randomized study design. In addition, we assessed the effects on the psychopathological status of the patients.The short-term add-on treatment with PXT up to 30 mg tid for two weeks resulted in a significant improvement of the motor abilities of the upper limbs and speech when compared to placebo. The treatment with PXT was generally well tolerated. The degree of depressive symptoms was not significantly influenced by PXT or placebo during the observation period.Previous observations suggest that serotonergic projections may modulate the neuronal excitability of the mesolimbic system and cerebellar system. The observed effects of PXT on motor performance may therefore be due to a direct action of the drug on the motor system. However, these results should be regarded as preliminary, and further research is suggested to evaluate the long-term outcome and clinical relevance of SSRI co-medication in MSA.
View details for DOI 10.1016/j.parkreldis.2006.04.002
View details for Web of Science ID 000241605700005
View details for PubMedID 16769235
"Anxietas Tibiarum" - Depression and anxiety disorders in patients with restless legs syndrome
JOURNAL OF NEUROLOGY
2005; 252 (1): 67-71
Symptoms of anxiety and depression in patients with restless legs syndrome (RLS) have been observed. However, it is unclear whether rates of threshold depression and anxiety disorders according to DSM-IV criteria in such patients are also elevated.238 RLS patients were assessed with a standardized diagnostic interview (Munich-Composite International Diagnostic Interview for DSM-IV) validated for subjects aged 18-65 years. Rates of anxiety and depressive disorders were compared between 130 RLS patients within this age range and 2265 community respondents from a nationally representative sample with somatic morbidity of other types.RLS patients revealed an increased risk of having 12-month anxiety and depressive disorders with particularly strong associations with panic disorder (OR=4.7; 95% CI=2.1-10.1), generalized anxiety disorder (OR=3.5; 95% CI= 1.7-7.1), and major depression (OR=2.6; 95% CI=1.5-4.4). In addition, lifetime rates of panic disorder and most depressive disorders as well as comorbid depression and anxiety disorders were considerably increased among RLS patients compared with controls.The results suggest that RLS patients are at increased risk of having specific anxiety and depressive disorders. Causal attributions of patients suggest that a considerable proportion of the excess morbidity for depression and panic disorder might be due to RLS symptomatology.
View details for DOI 10.1007/s00415-005-0604-7
View details for Web of Science ID 000226322100011
View details for PubMedID 15654556
High-dose treatment with pergolide in Parkinson's disease patients with motor fluctuations and dyskinesias
PARKINSONISM & RELATED DISORDERS
2005; 11 (6): 393-398
Motor complications arising after long-term treatment with levodopa remain one of the main challenges in the treatment of patients with Parkinson's disease (PD). Monotherapy with dopamine agonists may delay the onset of motor complications or reduce their severity when added to levodopa treatment. Here, we retrospectively analyzed data from 62 patients with advanced PD who presented with moderate to severe response fluctuations in whom we increased the dose of oral treatment with pergolide beyond 4.5mg daily. Patients had been treated with levodopa for 10.7+/-4.8 years. Pergolide was increased to 8.2+/-4.3 mg per day over a median titration period of 13.5 weeks. Mean daily dose of levodopa prior to pergolide high-dose treatment was 733+/-468 mg and decreased to 348+/-186 mg after pergolide titration. The duration of OFF times decreased from 7.3+/-3.8 to 1.7+/-0.9 h per day (p < 0.001) measured by patients' diaries. Dyskinesias, present for 5.0+/-3.3 h per day at baseline, were reduced to 1.4+/-0.8 h per day (p < 0.001) and the total daily duration of motor fluctuations (off-time duration plus dyskinesia duration) decreased from 10.5+/-7.0 to 2.8+/-2.2 h (p < 0.001). There was a significant improvement in parkinsonian symptoms (baseline to endpoint reduction of UPDRS III from a median of 36 to 8; p < 0.001). To reduce gastrointestinal side effects 23 patients required concomitant treatment with domperidone. Seven patients developed hallucinations during the titration period, six patients required treatment with clozapine. Our data indicate that increasing the dose of pergolide above 5mg per day can dramatically reduce the need for levodopa, motor fluctuations and severity of clinical symptoms. Controlled trials are needed to further substantiate the efficacy and safety of this treatment strategy.
View details for DOI 10.1016/j.parkreldis.2005.03.005
View details for Web of Science ID 000232420400009
View details for PubMedID 15993640
Action myoclonus-renal failure syndrome: characterization of a unique cerebro-renal disorder
2004; 127: 2173-2182
Action myoclonus-renal failure syndrome (AMRF) is a distinctive form of progressive myoclonus epilepsy associated with renal dysfunction. The syndrome was not recognized prior to the advent of dialysis and renal transplantation because of its rapidly fatal course if renal failure is untreated. The first and only description of AMRF was in four French Canadian patients in three families (Andermann et al., 1986). We now describe 15 individuals with AMRF from five countries, including a follow-up of the four French Canadian patients, allowing a more complete characterization of this disease. Our 15 patients with AMRF belong to nine different families. Segregation analyses were compatible with autosomal recessive inheritance. In addition, our findings show that AMRF can present with either renal or neurological features. Tremor (onset 17-26 years, mean 19.8 years, median 19 years) and progressively disabling action myoclonus (onset 14-29 years, mean 21.7 years, median 21 years), with infrequent generalized seizures (onset 20-28 years, mean 22.7 years, median 22 years) and cerebellar features are characteristic. Proteinuria, detected between ages 9 and 30 years in all cases, progressed to renal failure in 12 out of 15 patients within 0-8 years after proteinuria detection. Brain autopsy in two patients revealed extraneuronal pigment accumulation. Renal biopsies showed collapsing glomerulopathy, a severe variant of focal glomerulosclerosis. This study extends the AMRF phenotype, and demonstrates a more extensive ethnic and geographic distribution of a syndrome originally believed to be confined to individuals of French Canadian ancestry. The independent progression of neurological and renal disorders in AMRF suggests a unitary molecular lesion with pleiotropic effects. Our results demonstrate that the renal lesion in AMRF is a recessive form of collapsing glomerulopathy. Genes identified for focal segmental glomerulosclerosis and involved with the function of the glomerular basement membrane and related proteins are thus good candidates. Treatment can improve quality of life and extend the lifespan of these patients. Dialysis and renal transplantation are effective for the renal but not the neurological features, which continue to progress even in the presence of normalized renal function; the latter can be managed with anti-myoclonic and anti-epileptic drugs.
View details for DOI 10.1093/brain/awh263
View details for Web of Science ID 000224082400003
View details for PubMedID 15364701
Current treatment options for restless legs syndrome
EXPERT OPINION ON PHARMACOTHERAPY
2003; 4 (10): 1727-1738
Restless legs syndrome (RLS) is a common but often underdiagnosed neurological disorder characterised by an imperative desire to move the extremities associated with paraesthesias, motor restlessness, worsening of symptoms at rest in the evening or at night and, as a consequence, sleep disturbances particulary. Additionally, most patients with RLS have periodic limb movements during sleep and relaxed wakefulness. The aetiology of RLS remains unknown. Treatment of RLS is generally symptomatic, a causal therapy is possible only in the secondary forms. Dopaminergic agents including levodopa and dopamine agonists such as pergolide, pramipexole, cabergoline and ropinirole are regarded as the treatment of choice for idiopathic RLS, however, the development of augmentation of symptoms, especially under levodopa therapy, may be a major problem. Except in special circumstances, opioids and anticonvulsants such as gabapentin or benzodiazepines, are regarded as second-line treatment. In secondary RLS, the underlying illness should first be treated, although dopaminergic drugs may also be helpful.
View details for Web of Science ID 000185994400010
View details for PubMedID 14521483
Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome
2003; 4 (2): 121-132
There is a need for an easily administered instrument which can be applied to all patients with restless legs syndrome (RLS) to measure disease severity for clinical assessment, research, or therapeutic trials. The pathophysiology of RLS is not clear and no objective measure so far devised can apply to all patients or accurately reflect severity. Moreover, RLS is primarily a subjective disorder. Therefore, a subjective scale is at present the optimal instrument to meet this need.Twenty centers from six countries participated in an initial reliability and validation study of a rating scale for the severity of RLS designed by the International RLS study group (IRLSSG). A ten-question scale was developed on the basis of repeated expert evaluation of potential items. This scale, the IRLSSG rating scale (IRLS), was administered to 196 RLS patients, most on some medication, and 209 control subjects.The IRLS was found to have high levels of internal consistency, inter-examiner reliability, test-retest reliability over a 2-4 week period, and convergent validity. It also demonstrated criterion validity when tested against the current criterion of a clinical global impression and readily discriminated patient from control groups. The scale was dominated by a single severity factor that explained at least 59% of the pooled item variance.This scale meets performance criteria for a brief, patient completed instrument that can be used to assess RLS severity for purposes of clinical assessment, research, or therapeutic trials. It supports a finding that RLS is a relatively uniform disorder in which the severity of the basic symptoms is strongly related to their impact on the patient's life. In future studies, the IRLS should be tested against objective measures of RLS severity and its sensitivity should be studied as RLS severity is systematically manipulated by therapeutic interventions.
View details for DOI 10.1016/S1389-9457(02)00258-7
View details for Web of Science ID 000188839100005
View details for PubMedID 14592342
- The genetics of restless legs syndrome SLEEP MEDICINE 2002; 3: S9-S12
Long-term course of restless legs syndrome in dialysis patients after kidney transplantation
2002; 17 (5): 1072-1076
Restless legs syndrome (RLS) is a common cause of sleep disturbance and is frequently experienced by hemodialysis patients. Factors triggering the disease in uremia have not yet been identified. To our knowledge, the course of RLS symptoms after kidney transplantation has not been investigated systematically. We investigated the clinical long-term course of RLS in hemodialysis patients who underwent kidney transplantation. Patients were given a standardized questionnaire three times: at baseline, and twice after their kidney transplants. The severity of RLS was rated by the patients (0 =no symptoms, 10 = very severe symptoms). The description of the final outcome was based on the last follow-up visit. Eleven of 64 hemodialysis patients with RLS received a transplant (5 men, 6 women; severity of RLS at baseline, 7.8 +/- 0.7 [mean +/- SEM]). In all patients, RLS symptoms disappeared within 1 to 21 days after transplantation. At follow-up visits, 4 patients whose transplanted kidneys still functioned well were still free of RLS symptoms up to the longest follow-up period of 9 years. In 3 other patients, RLS symptoms gradually reappeared (severity, 1 +/- 0). In 3 of 11 patients, the transplant failed and RLS symptoms reoccurred within 10 days to 2 months (severity, 7.3 +/- 2.6). RLS symptoms reoccurred in 1 patient with failure of the transplant but disappeared again after a second, successful transplant. Kidney transplantation has a strong and positive influence on RLS symptoms in hemodialysis patients. Hemodialysis patients can expect a substantial improvement of RLS symptoms after a successful kidney transplant.
View details for DOI 10.1002/mds.10231
View details for Web of Science ID 000178384400029
View details for PubMedID 12360562
Complex segregation analysis of restless legs syndrome provides evidence for an autosomal dominant mode of inheritance in early age at onset families
ANNALS OF NEUROLOGY
2002; 52 (3): 297-302
A strong familial component of restless legs syndrome (RLS) is known. The objective of this study therefore was to investigate the likely mode of inheritance of RLS. RLS patients and their first-degree relatives were investigated and classified in RLS affected and RLS nonaffected subjects. Assessments were based on direct, personal standardized diagnostic interviews. Complex segregation analysis was performed with the families stratified according to the mean age at onset of the disease within the families. Two hundred thirty-eight RLS patients, 537 first-degree relatives, and 133 spouses were interviewed. Two groups of families were stratified: mean age at onset up to 30 years of age (Group A) and older than 30 years (Group B; p < 0.005). In Group A, segregation analysis strongly favored a single major gene acting autosomal dominant with a multifactorial component. Parameter estimates were 0.003 for the allele frequency, 1.0 for the penetrance, and 0.005 for the phenocopy rate. In Group B, no evidence for a major gene could be elucidated. The segregation pattern found in our families argues for an autosomal allele acting dominantly in RLS families with an early age at onset of symptoms and suggests that RLS is a causative heterogeneous disease.
View details for DOI 10.1002/ana.10282
View details for Web of Science ID 000177820100006
View details for PubMedID 12205641
Assessment of spontaneously occurring periodic limb movements in sleep in the rat
JOURNAL OF THE NEUROLOGICAL SCIENCES
2002; 198 (1-2): 71-77
Periodic limb movements in sleep (PLMS) are often associated with the restless legs syndrome (RLS). Although the dopaminergic system seems to be involved, the pathophysiology of PLMS and RLS is still obscure. The objective of this study is to explore whether a PLMS-like phenomenon can be observed in rodents in order to elucidate the underlying mechanisms.In a group of young and old rats (1.4-1.6 and 16.2-20.5 months, respectively), sleep-wake behavior was recorded and hindlimb movements were detected by means of a magneto-inductive device during two 12-h light periods. Furthermore, in the old rats, recordings were made after administration of the dopamine antagonist haloperidol (HAL) on three consecutive days. Periodic hindlimb movements (PHLM) during nonrapid eye movement sleep (NREM) were identified according to modified human criteria.In the young animals, no PHLM were observed, whereas, 4 out of 10 old rats showed PHLM, two of them have more than 5 PHLM/h. Haloperidol affects neither the sleep pattern nor the number of PHLM. Interestingly, the percentage of old rats spontaneously displaying PHLM resembles the prevalence of PLMS in the elderly.Our study demonstrates for the first time that periodic hindlimb movements (PHLM) in sleep can occur spontaneously in rats. A clear effect of age on this phenomenon was seen, with only old animals displaying PHLM. To validate whether the observed PHLM constitute a good model for human PLMS or even RLS, their pharmacological properties need to be characterized in a large number of PHLM positive animals.
View details for Web of Science ID 000176485300012
View details for PubMedID 12039666
- "Restless legs" in "The wedding proposal" by Anton Chekhov ACTA NEUROLOGICA SCANDINAVICA 2002; 105 (4): 349-350
Pergolide restores sleep maintenance but impairs sleep EEG synchronization in patients with restless legs syndrome
2002; 3 (1): 49-54
The treatment with the long-acting dopamine D1/D2 receptor agonist pergolide has been proven as very effective in lowering the frequency of periodic leg movements (PLM) in patients with restless legs syndrome (RLS). To further investigate the influence of this potent dopaminergic drug on the microstructure of rapid eye movement (REM) and non-REM sleep EEG we established a quantitative analysis of the EEG data.The study group consisted of 15 patients with primary RLS (mean age 57.1+/-10.1 years) who were a subgroup of patients within a double-blind randomized crossover treatment study with pergolide versus placebo. The polysomnographic recordings were analyzed visually and submitted to a quantitative EEG analysis (fast Fourier transformation).The pergolide treatment induced a significant reduction of the spectral power in the delta range (0.78-3.9 Hz; P<0.05; t-test) during SWS, as well as a significant reduction of PLMs. In addition, we observed a decrease in the sigma EEG activity (12.1-14.8 Hz; P<0.03) during non-REM sleep and stage 2 sleep. The visual sleep scoring revealed a significant increase in stage 2 sleep (P<0.005), whereas wakefulness was markedly diminished (P<0.001). The REM sleep parameters including the EEG power spectrum remained unchanged.The treatment with pergolide markedly improved the sleep quality in RLS patients but did not restore SWS including the spectral power in the lower frequencies. Our results suggest that the dopamine agonist pergolide interferes with the subcortical mechanisms regulating the process of EEG synchronization during non-REM sleep.
View details for Web of Science ID 000208301600009
View details for PubMedID 14592254
Sleep and periodic limb movements in corticobasal degeneration
2002; 3 (1): 33-36
Corticobasal degeneration (CBD) exhibits distinct features of akinesia, the 'alien limb' sign and cortical myoclonus. We report a 63-year old woman with a history of CBD for 18 months who was studied twice using all-night polysomnography with an interval of 13 months. Both recordings revealed frequent periodic arm and leg movements predominantly during non-REM sleep. To our knowledge this has not been described in a patient with CBD so far. Similar to a previous report we found REM sleep without atonia (RWA) in all REM episodes. However, the patient showed RWA and some non violent movements that fulfilled the diagnosis of subclinical REM sleep behavior disorder only in the second investigation. These observations may be due to the underlying degenerative process that involves not only cortical but also thalamic and brainstem structures.
View details for Web of Science ID 000208301600006
View details for PubMedID 14592251
Retention of dopamine 2 receptor mRNA and absence of the protein in craniospinal and extracranial metastasis of a malignant prolactinoma: a case report
EUROPEAN JOURNAL OF ENDOCRINOLOGY
2002; 146 (1): 81-88
The case presented here describes the clinical evolution of a malignant prolactinoma with occurrence of intra- and extra-cranial metastases. In this case, the presence of dopamine 2 receptor (D2R) was studied at the mRNA and protein level, in order to understand the pathological background of the resistance to treatment with different dopamine agonists.Together with an extensive description of the clinical history of this case, a combination of in vitro and in vivo techniques was performed to provide the basis of the dopamine resistance developed in the course of the disease.A comparison of the D2R was performed in specimens obtained at presentation of the disease compared with autoptic specimens derived from local invasion and metastasis using in situ hybridization and immunohistochemical techniques.Intact D2R mRNA was found in the primitive tumor and metastatic tissues, whereas protein for the same receptor was present only in the tissues derived from neurosurgical operations and not in the metastases obtained post-mortem.This is the first report of the absence of D2R protein despite the retention of the transcript in an advanced stage of a malignant prolactinoma. The findings of this single case suggest the hypothesis that postranscriptional mechanisms may contribute to the development of dopamine resistance in prolactinomas.
View details for Web of Science ID 000178742700013
View details for PubMedID 11751072
Long-term follow-up on restless legs syndrome patients treated with opioids
2001; 16 (6): 1105-1109
The medical records of 493 patients with restless legs syndrome (RLS) from three major centers were studied to determine the number and outcome of patients who had been treated with opioids as a monotherapy. At one time or another 113 patients (51 men, 62 women; age range, 37-88 years) had been on opioid therapy either alone (36 patients) or with opioids added secondarily to other medications used to treat RLS (77 patients). Twenty-three of the 36 opioid monotherapy patients had failed dopaminergic and other therapeutic agents prior to the initiation of opioid monotherapy. Twenty of the 36 opioid monotherapy patients continue on monotherapy for an average of 5 years 11 months (range, 1-23 years), despite their knowledge of the availability of other therapies. Of the 16 patients who discontinued opioids as a sole therapy, the medication was discontinued in only one case because of problems related to addiction and tolerance. Polysomnography on seven patients performed after an average of 7 years 1 month of opioid monotherapy (range, 1-15 years) showed a tendency toward an improvement in all leg parameters and associated arousals (decrease in PLMS index, PLMS arousal index, and PLM while awake index) as well as all sleep parameters (increase in stages 3 and 4 and REM sleep, total sleep time, sleep efficiency, and decrease in sleep latency). Two of these seven patients developed sleep apnea and a third patient had worsening of preexisting apnea. Opioids seem to have long-term effectiveness in the treatment of RLS and PLMS, but patients on long-term opioid therapy should be clinically or polysomnographically monitored periodically for the development of sleep apnea.
View details for Web of Science ID 000172464700013
View details for PubMedID 11748742
Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome
2001; 29 (1): 66-69
The dystonias are a common clinically and genetically heterogeneous group of movement disorders. More than ten loci for inherited forms of dystonia have been mapped, but only three mutated genes have been identified so far. These are DYT1, encoding torsin A and mutant in the early-onset generalized form, GCH1 (formerly known as DYT5), encoding GTP-cyclohydrolase I and mutant in dominant dopa-responsive dystonia, and TH, encoding tyrosine hydroxylase and mutant in the recessive form of the disease. Myoclonus-dystonia syndrome (MDS; DYT11) is an autosomal dominant disorder characterized by bilateral, alcohol-sensitive myoclonic jerks involving mainly the arms and axial muscles. Dystonia, usually torticollis and/or writer's cramp, occurs in most but not all affected patients and may occasionally be the only symptom of the disease. In addition, patients often show prominent psychiatric abnormalities, including panic attacks and obsessive-compulsive behavior. In most MDS families, the disease is linked to a locus on chromosome 7q21 (refs. 11-13). Using a positional cloning approach, we have identified five different heterozygous loss-of-function mutations in the gene for epsilon-sarcoglycan (SGCE), which we mapped to a refined critical region of about 3.2 Mb. SGCE is expressed in all brain regions examined. Pedigree analysis shows a marked difference in penetrance depending on the parental origin of the disease allele. This is indicative of a maternal imprinting mechanism, which has been demonstrated in the mouse epsilon-sarcoglycan gene.
View details for Web of Science ID 000170781300019
View details for PubMedID 11528394
Long-term effects of pergolide in the treatment of restless legs syndrome
2001; 56 (10): 1399-1402
An open follow-up of a controlled study in patients with restless legs syndrome (RLS) shows that the beneficial effect of pergolide on RLS symptoms persists throughout at least 1 year. Twenty-two patients of 28 (78.6%) continued to take pergolide. Polysomnographic measurements showed a persistent improvement of PLM index, PLMS arousal index, total sleep time, and sleep efficiency (p = 0.0001). Side effects, in particular nausea, were common but were well controlled by domperidone in most patients.
View details for Web of Science ID 000168738500033
View details for PubMedID 11376198
[Pathophysiology of restless-legs syndrome. Review of current research].
2001; 72 (2): 100-107
The primary pathomechanism of restless legs syndrome is unclear. Neurophysiological, pharmacological, and imaging studies have demonstrated a complex interaction between central and peripheral structures. The degree of integration of central and peripheral mechanisms is not known. Altered excitability at a spinal level modulated by supraspinal rhythms of the brainstem possibly plays an important role. There is no anatomical structural lesion and it is more likely that circadian disturbances of dopaminergic and/or opioidergic neurotransmission are involved.
View details for PubMedID 11256143
Pathophysiology of restless legs syndrome - the present state of research
2001; 72 (2): 100-?
View details for Web of Science ID 000167274700006
Increased growth hormone response to apomorphine in Parkinson disease compared with multiple system atrophy
ARCHIVES OF NEUROLOGY
2001; 58 (2): 241-246
Parkinson disease (PD) is often difficult to distinguish from parkinsonian syndromes of other causes in early stages of the disease. In search of a suitable endocrinologic challenge test, we investigated dopaminergic sensitivity in patients with de novo parkinsonian syndromes.We measured the growth hormone (GH) response to a subthreshold dose of the dopamine 1-dopamine 2 receptor agonist apomorphine hydrochloride to differentiate parkinsonian syndromes from PD.Seventeen patients with a clinical diagnosis of PD, 16 patients with a clinical diagnosis of multiple system atrophy, and 11 healthy controls. The GH response to a subthreshold dosage of apomorphine and to somatorelin (GH-releasing factor) was tested in a randomized order; on the third day the protocol was repeated with a clinically effective dose of apomorphine.The GH response to the low dose of apomorphine was significantly increased in patients with PD when compared with patients with multiple system atrophy or the control subjects (multivariate analyses of covariance; univariate F test, all P<.05). In contrast, there were no significant group differences with use of the higher dose of apomorphine or in the somatorelin-induced GH release.The GH response to a subthreshold dose of apomorphine appears to be a useful tool to identify patients with PD vs multiple system atrophy. The enhanced GH response to a subthreshold dopaminergic stimulus may reflect a hypersensitivity of the extrastriatal dopamine receptors in PD.
View details for Web of Science ID 000166899800010
View details for PubMedID 11176962
Opioid and dopamine antagonist drug challenges in untreated restless legs syndrome patients
2001; 2 (1): 57-61
View details for Web of Science ID 000208300800007
Opioid and dopamine antagonist drug challenges in untreated restless legs syndrome patients.
2001; 2 (1): 57-61
Background: The restless legs syndrome (RLS) is a common sensomotor disorder associated with severe sleep disturbances. Symptoms clearly improve following treatment with dopaminergic or opioidergic agonists.Objective: To further elucidate the involvement of opioidergic and dopaminergic mechanisms in the pathophysiology of RLS, the effects of specific antagonists on motor (periodic leg movements) and subjective (sensory) RLS-symptoms during daytime were assessed.Methods: A modified suggested immobilization test was performed in eight drug-naive RLS-patients. An infusion of either naloxone, metoclopramide or placebo was administered. In addition, the hormonal levels of adrenocorticotropic hormone, cortisol, prolactin and growth hormone were determined, to elucidate a possible involvement of the hypothalamic-pituitary-adrenocortical (HPA) system in RLS.Results: RLS sensory or motor symptoms could not be provoked. Hormonal responses showed no abnormal profiles.Conclusions: Rather than a general alteration of the opioidergic/dopaminergic tone and an involvement of the HPA system, it is more likely that specific neuronal dopaminergic or opioidergic pathways are altered in the pathophysiology of RLS.
View details for PubMedID 11152983
Clinical characteristics and frequency of the hereditary restless legs syndrome in a population of 300 patients
2000; 23 (5): 597-602
There is a genetic contribution to the idiopathic restless legs syndrome (iRLS). An autosomal dominant mode of inheritance is suspected, but as yet no gene has been identified. To assess the frequency and characteristics of the hereditary restless legs syndrome (RLS) in comparison to those of non-hereditary RLS, we analysed the clinical data of 300 RLS patients. All 300 patients diagnosed as RLS according to the criteria of the International RLS Study Group were examined using a standard questionnaire covering demographic data, family history, clinical symptoms, subjective sleep disturbances and course of the disease. In all patients a complete neurological examination was performed, and in selected cases electrophysiological examinations and polysomnographic studies. Family history was rated as definitely positive when at least one first-degree relative was examined and classified as RLS according to the criteria by one of the authors. If it proved impossible to contact family members to verify reports of a family history, the patients were classified as only having a "possible positive family history." 232 of the 300 patients had iRLS and 68 secondary RLS due to uremia (uRLS). 42.3% of the patients with iRLS and 11.7% of those with uRLS were classified as having "definite positive" hereditary RLS, with a further 12.6% of iRLS patients and 5.8% of uRLS patients as having "possible positive" hereditary RLS. Patients with definite hereditary RLS were significantly younger at the age of onset than those with a negative family history (35.45 vs. 47.17 years, p < 0.05). The clinical characteristics of the disease were similar in both groups, except that women with hereditary RLS experienced a worsening of symptoms during pregnancy (19.1% vs. 2.6%, p < 0.05). Our study shows that patients with hereditary RLS may experience an earlier onset of the disease. Hereditary and non-hereditary RLS present with similiar clinical signs and symptoms.
View details for Web of Science ID 000088624200003
View details for PubMedID 10947027
- Periodic limb movements in syringomyelia and syringobulbia MOVEMENT DISORDERS 2000; 15 (4): 752-753
Therapy of restless legs syndrome
2000; 27 (4): 182-186
View details for Web of Science ID 000087183800005
- Restless legs syndrome ARCHIVES OF NEUROLOGY 1999; 56 (12): 1526-1527
Magnetic resonance imaging findings in corticobasal degeneration
1999; 14 (4): 669-673
Two women (patient 1, 77 years old, and patient 2, 63 years old) with strong clinical evidence for corticobasal degeneration (CBD) are presented. Patient 2 was in an early stage of the disease with only a mild disability of her left hand. In addition to the clinical characteristics, both patients presented the typical cortical reflex myoclonus. Magnetic resonance imaging studies for both patients revealed nearly identical hyperintense lesions somatotopic from the left-hand primary motor cortex (M1), extending to the midline and possibly supplementary motor area (SMA) in patient 2. To our knowledge, this has not been previously described in patients with CBD. These lesions may play a role in the etiology and the development of CBD with involvement of the M1 and may correspond to the underlying pathology of demyelination or gliosis.
View details for Web of Science ID 000082999700018
View details for PubMedID 10435506
Aetiology and treatment of restless legs syndrome
1999; 12 (1): 9-20
View details for Web of Science ID 000081424100002
Visual hallucinations, white matter lesions and disease severity in Parkinson's disease
ACTA NEUROLOGICA SCANDINAVICA
1999; 99 (6): 362-367
To determine if visual hallucinations in patients with Parkinson's disease are associated with an increased prevalence of white matter lesions.Fifteen patients with (group 1) and 15 patients without (group 2) a history of visual hallucinations were studied. Both groups were matched for age. Magnetic resonance imaging was performed in all patients using standard T2 weighted Fast-Spin-Echo sequences. Assessment of cerebral white matter changes was performed using a modification of established criteria, with semiquantitative evaluation of periventricular and deep white matter changes.There was no significant group difference with regard to the total amount of white matter changes, nor was a group difference found between the amount or extent of periventricular hyperintensities or deep white matter lesions. Group 1 was significantly (P = 0.001) more disabled as evaluated by Hoehn/Yahr stage controlling for age and duration of disease. Mean increases in Hoehn/Yahr stage were not significantly greater in group 1 compared with group 2 at a 2-year follow-up examination (0.6 vs. 0.3, P = 0.166).Our data suggest that visual hallucinations are an indicator of a more aggressive course of the disease, but are not associated with a higher prevalence of global or occipital white matter lesions.
View details for Web of Science ID 000080642700006
View details for PubMedID 10577270
A randomized controlled study of pergolide in patients with restless legs syndrome
1999; 52 (5): 944-950
Open clinical trials indicate that low doses of pergolide, a long-acting D1 and D2 dopamine agonist, lead to a reduction in the symptoms of restless legs syndrome (RLS) with subjective improvement in sleep quality.To assess the therapeutic efficacy of pergolide in improving sleep and subjective measures of well-being in patients with idiopathic RLS using polysomnography and clinical ratings.In a randomized, double-blind, placebo-controlled crossover design we enrolled 30 patients with idiopathic RLS according to the criteria of the International RLS Study Group. All patients were free of psychoactive drugs for at least 2 weeks before the study. Patients were monitored using polysomnography, clinical ratings, and sleep diaries at baseline and at the end of a 4-week pergolide or placebo treatment period. The initial dosage of 0.05 mg pergolide was increased to the best subjective improvement paralleled by 20 mg domperidone tid.At a mean dosage of 0.51 mg pergolide as a single daily dose 2 hours before bedtime, there were fewer periodic leg movements per hour of time in bed (5.7 versus 54.9, p < 0.0001), and total sleep time was significantly longer (373 versus 261 minutes, p < 0.0001). Ratings of subjective sleep quality, quality of life, and severity of RLS were improved significantly without relevant adverse events.Pergolide given as a single low-to-medium bedtime dose in combination with domperidone provides a well-tolerated and effective treatment of sensorimotor symptoms and sleep disturbances in patients with primary RLS.
View details for Web of Science ID 000079516900009
View details for PubMedID 10102410
[Restless leg syndrome].
Medizinische Monatsschrift für Pharmazeuten
1999; 22 (3): 67-71
View details for PubMedID 10097580
A controlled study of additional sr-L-dopa in L-dopa-responsive restless legs syndrome with late-night symptoms
1999; 52 (2): 285-290
To investigate whether a combination treatment of regular-release levodopa (rr-L-dopa) and sustained-release levodopa (sr-L-dopa) compared with monotherapy of rr-L-dopa improves sleep quality and reduces periodic limb movements (PLM) in patients with restless legs syndrome (RLS) and problems with maintaining sleep.Reappearance of RLS symptoms during the second half of the night while being treated with rr-L-dopa is a common problem in the treatment of sleep disturbances caused by RLS.A randomized, controlled, double-blind crossover trial was undertaken. Eligible patients fulfilled the diagnostic criteria of the International RLS Study Group, and met an actigraphically confirmed higher number of PLM per hour time in bed (PLM index) during the second half compared with the first half of the night under treatment with rr-L-dopa. During the crossover periods the patients received 100 to 200 mg rr-L-dopa plus either placebo or 100 to 200 mg sr-L-dopa at bedtime for 4 weeks each period.Thirty patients with RLS (11 men and 19 women) were assessed by actigraphy and subjective sleep quality, and showed a significant improvement in PLM index (p < 0.0001), in "time in bed without movements" (p < 0.0001), and in subjective sleep quality (p < 0.001). Eight of 30 patients reported an altered pattern of RLS symptoms, characterized by a time shift of RLS symptoms into the afternoon or evening, five of these during monotherapy with rr-L-dopa.A combination therapy of rr-L-dopa and sr-L-dopa is better than monotherapy with rr-L-dopa in reducing the frequency of PLM and problems maintaining sleep, even in patients who are severely affected.
View details for Web of Science ID 000078274200012
View details for PubMedID 9932945
Treatment of restless leg syndrome with pergolide - An open clinical trial
1998; 13 (3): 566-569
Dopaminergic treatment with levodopa (L-dopa) has been proven as the treatment of first choice in patients with restless leg syndrome (RLS). Augmentation of symptoms and end-of-dose rebound phenomena under L-dopa/decarboxylase inhibitor treatment present major problems in some patients. To evaluate the efficacy of pergolide in RLS, we treated 15 patients suffering from severe RLS, who had previously experienced an augmentation of symptoms under long-term treatment with L-dopa, in an open clinical trial with pergolide. All patients reported an improvement of their RLS symptoms. Our study shows that pergolide, if administered at a mean dose of 0.4 mg in combination with domperidone, is a very effective drug in the treatment of sleep disturbances and daytime symptoms associated with RLS, and does not cause any serious side effects during the observation period of 6 months.
View details for Web of Science ID 000074286100032
View details for PubMedID 9613756
- Nonmotor fluctuations in patients with Parkinson's disease NEUROLOGY 1997; 49 (5): 1472-1472