TY  - JOUR
AB  - BACKGROUND: Through the agnostic screening of patients with uncharacterised disease phenotypes for an upregulation of type I interferon (IFN) signalling, we identified a cohort of individuals heterozygous for mutations in PTPN1, encoding the protein-tyrosine phosphatase 1B (PTP1B). We aimed to describe the clinical phenotype and molecular and cellular pathology of this new disease. METHODS: In this case series, we identified patients and collected clinical and neuroradiological data through collaboration with paediatric neurology and clinical genetics colleagues across Europe (Czechia, France, Germany, Italy, Slovenia, and the UK) and Israel. Variants in PTPN1 were identified by exome and directed Sanger sequencing. The expression of IFN-stimulated genes was determined by quantitative (q) PCR or NanoString technology. Experiments to assess RNA and protein expression and to investigate type 1 IFN signalling were undertaken in patient fibroblasts, hTERT-immortalised BJ-5ta fibroblasts, and RPE-1 cells using CRISPR-Cas9 editing and standard cell biology techniques. FINDINGS: Between Dec 20, 2013, and Jan 11, 2023, we identified 12 patients from 11 families who were heterozygous for mutations in PTPN1. We found ten novel or very rare variants in PTPN1 (frequency on gnomAD version 4.1.0 of <1·25 × 10:sup>-6). Six variants were predicted as STOP mutations, two involved canonical splice-site nucleotides, and two were missense substitutions. In three patients, the variant occurred de novo, whereas in nine affected individuals, the variant was inherited from an asymptomatic parent. The clinical phenotype was characterised by the subacute onset (age range 1-8 years) of loss of motor and language skills in the absence of seizures after initially normal development, leading to spastic dystonia and bulbar involvement. Neuroimaging variably demonstrated cerebral atrophy (sometimes unilateral initially) or high T2 white matter signal. Neopterin in CSF was elevated in all ten patients who were tested, and all probands demonstrated an upregulation of IFN-stimulated genes in whole blood. Although clinical stabilisation and neuroradiological improvement was seen in both treated and untreated patients, in six of eight treated patients, high-dose corticosteroids were judged clinically to result in an improvement in neurological status. Of the four asymptomatic parents tested, IFN signalling in blood was normal (three patients) or minimally elevated (one patient). Analysis of patient blood and fibroblasts showed that tested PTPN1 variants led to reduced levels of PTPN1 mRNA and PTP1B protein, and in-vitro assays demonstrated that loss of PTP1B function was associated with impaired negative regulation of type 1 IFN signalling. INTERPRETATION: PTPN1 haploinsufficiency causes a type 1 IFN-driven autoinflammatory encephalopathy. Notably, some patients demonstrated stabilisation, and even recovery, of neurological function in the absence of treatment, whereas in others, the disease appeared to be responsive to immune suppression. Prospective studies are needed to investigate the safety and efficacy of specific immune suppression approaches in this disease population. FUNDING: The UK Medical Research Council, the European Research Council, and the Agence Nationale de la Recherche.
AU  - Zhu, G.*
AU  - Didry-Barca, B.*
AU  - Seabra, L.*
AU  - Rice, G.I.*
AU  - Uggenti, C.*
AU  - Touimy, M.*
AU  - Rodero, M.P.*
AU  - Trapero, R.H.*
AU  - Bondet, V.*
AU  - Duffy, D.L.*
AU  - Gautier, P.*
AU  - Livingstone, K.*
AU  - Sutherland, F.J.H.*
AU  - Lebon, P.*
AU  - Parisot, M.*
AU  - Bole-Feysot, C.*
AU  - Masson, C.*
AU  - Cagnard, N.*
AU  - Nitschke, P.*
AU  - Anderson, G.*
AU  - Assmann, B.*
AU  - Barth, M.*
AU  - Boespflug-Tanguy, O.*
AU  - D'Arco, F.*
AU  - Dorboz, I.*
AU  - Giese, T.*
AU  - Hacohen, Y.*
AU  - Hančárová, M.*
AU  - Husson, M.*
AU  - Lepine, A.*
AU  - Lim, M.*
AU  - Mancardi, M.M.*
AU  - Melki, I.*
AU  - Neubauer, D.*
AU  - Sa, M.*
AU  - Sedláček, Z.*
AU  - Seitz, A.*
AU  - Rottman, M.S.*
AU  - Sanquer, S.*
AU  - Straussberg, R.*
AU  - Vlčková, M.*
AU  - Villéga, F.*
AU  - Wagner, M.
AU  - Zerem, A.*
AU  - Marsh, J.A.*
AU  - Frémond, M.L.*
AU  - Kaliakatsos, M.*
AU  - Crow, Y.J.*
AU  - El-Daher, M.T.*
AU  - Lepelley, A.*
C1  - 73444
C2  - 57066
SP  - 218-229
TI  - Autoinflammatory encephalopathy due to PTPN1 haploinsufficiency: A case series.
JO  - Lancet Neurol.
VL  - 24
IS  - 3
PY  - 2025
SN  - 1474-4422
ER  - 

TY  - JOUR
AB  - BACKGROUND: Up-to-date estimates of stroke burden and attributable risks and their trends at global, regional, and national levels are essential for evidence-based health care, prevention, and resource allocation planning. We aimed to provide such estimates for the period 1990-2021. METHODS: We estimated incidence, prevalence, death, and disability-adjusted life-year (DALY) counts and age-standardised rates per 100 000 people per year for overall stroke, ischaemic stroke, intracerebral haemorrhage, and subarachnoid haemorrhage, for 204 countries and territories from 1990 to 2021. We also calculated burden of stroke attributable to 23 risk factors and six risk clusters (air pollution, tobacco smoking, behavioural, dietary, environmental, and metabolic risks) at the global and regional levels (21 GBD regions and Socio-demographic Index [SDI] quintiles), using the standard GBD methodology. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. FINDINGS: In 2021, stroke was the third most common GBD level 3 cause of death (7·3 million [95% UI 6·6-7·8] deaths; 10·7% [9·8-11·3] of all deaths) after ischaemic heart disease and COVID-19, and the fourth most common cause of DALYs (160·5 million [147·8-171·6] DALYs; 5·6% [5·0-6·1] of all DALYs). In 2021, there were 93·8 million (89·0-99·3) prevalent and 11·9 million (10·7-13·2) incident strokes. We found disparities in stroke burden and risk factors by GBD region, country or territory, and SDI, as well as a stagnation in the reduction of incidence from 2015 onwards, and even some increases in the stroke incidence, death, prevalence, and DALY rates in southeast Asia, east Asia, and Oceania, countries with lower SDI, and people younger than 70 years. Globally, ischaemic stroke constituted 65·3% (62·4-67·7), intracerebral haemorrhage constituted 28·8% (28·3-28·8), and subarachnoid haemorrhage constituted 5·8% (5·7-6·0) of incident strokes. There were substantial increases in DALYs attributable to high BMI (88·2% [53·4-117·7]), high ambient temperature (72·4% [51·1 to 179·5]), high fasting plasma glucose (32·1% [26·7-38·1]), diet high in sugar-sweetened beverages (23·4% [12·7-35·7]), low physical activity (11·3% [1·8-34·9]), high systolic blood pressure (6·7% [2·5-11·6]), lead exposure (6·5% [4·5-11·2]), and diet low in omega-6 polyunsaturated fatty acids (5·3% [0·5-10·5]). INTERPRETATION: Stroke burden has increased from 1990 to 2021, and the contribution of several risk factors has also increased. Effective, accessible, and affordable measures to improve stroke surveillance, prevention (with the emphasis on blood pressure, lifestyle, and environmental factors), acute care, and rehabilitation need to be urgently implemented across all countries to reduce stroke burden. FUNDING: Bill & Melinda Gates Foundation.
AU  - GBD 2021 Stroke Risk Factor Collaborators (Breitner-Busch, S.)
C1  - 72330
C2  - 56598
SP  - 973-1003
TI  - Global, regional, and national burden of stroke and its risk factors, 1990-2021: A systematic analysis for the Global Burden of Disease Study 2021.
JO  - Lancet Neurol.
VL  - 23
IS  - 10
PY  - 2024
SN  - 1474-4422
ER  - 

TY  - JOUR
AB  - Background: Therapeutic modulation of TREM2-dependent microglial function might provide an additional strategy to slow the progression of Alzheimer's disease. Although studies in animal models suggest that TREM2 is protective against Alzheimer's pathology, its effect on tau pathology and its potential beneficial role in people with Alzheimer's disease is still unclear. Our aim was to study associations between the dynamics of soluble TREM2, as a biomarker of TREM2 signalling, and amyloid β (Aβ) deposition, tau-related pathology, neuroimaging markers, and cognitive decline, during the progression of autosomal dominant Alzheimer's disease. Methods: We did a longitudinal analysis of data from the Dominantly Inherited Alzheimer Network (DIAN) observational study, which includes families with a history of autosomal dominant Alzheimer's disease. Participants aged over 18 years who were enrolled in DIAN between Jan 1, 2009, and July 31, 2019, were categorised as either carriers of pathogenic variants in PSEN1, PSEN2, and APP genes (n=155) or non-carriers (n=93). We measured amounts of cleaved soluble TREM2 using a novel immunoassay in CSF samples obtained every 2 years from participants who were asymptomatic (Clinical Dementia Rating [CDR]=0) and annually for those who were symptomatic (CDR>0). CSF concentrations of Aβ40, Aβ42, total tau (t-tau), and tau phosphorylated on threonine 181 (p-tau) were measured by validated immunoassays. Predefined neuroimaging measurements were total cortical uptake of Pittsburgh compound B PET (PiB-PET), cortical thickness in the precuneus ascertained by MRI, and hippocampal volume determined by MRI. Cognition was measured using a validated cognitive composite (including DIAN word list test, logical memory delayed recall, digit symbol coding test [total score], and minimental status examination). We based our statistical analysis on univariate and bivariate linear mixed effects models. Findings: In carriers of pathogenic variants, a high amyloid burden at baseline, represented by low CSF Aβ42 (β=–4·28 × 10–2 [SE 0·013], p=0·0012), but not high cortical uptake in PiB-PET (β=–5·51 × 10–3 [0·011], p=0·63), was the only predictor of an augmented annual rate of subsequent increase in soluble TREM2. Augmented annual rates of increase in soluble TREM2 were associated with a diminished rate of decrease in amyloid deposition, as measured by Aβ42 in CSF (r=0·56 [0·22], p=0·011), in presymptomatic carriers of pathogenic variants, and with diminished annual rate of increase in PiB-PET (r=–0·67 [0·25], p=0·0060) in symptomatic carriers of pathogenic variants. Presymptomatic carriers of pathogenic variants with annual rates of increase in soluble TREM2 lower than the median showed a correlation between enhanced annual rates of increase in p-tau in CSF and augmented annual rates of increase in PiB-PET signal (r=0·45 [0·21], p=0·035), that was not observed in those with rates of increase in soluble TREM2 higher than the median. Furthermore, presymptomatic carriers of pathogenic variants with rates of increase in soluble TREM2 above or below the median had opposite associations between Aβ42 in CSF and PiB-PET uptake when assessed longitudinally. Augmented annual rates of increase in soluble TREM2 in presymptomatic carriers of pathogenic variants correlated with decreased cortical shrinkage in the precuneus (r=0·46 [0·22]), p=0·040) and diminished cognitive decline (r=0·67 [0·22], p=0·0020). Interpretation: Our findings in autosomal dominant Alzheimer's disease position the TREM2 response within the amyloid cascade immediately after the first pathological changes in Aβ aggregation and further support the role of TREM2 on Aβ plaque deposition and compaction. Furthermore, these findings underpin a beneficial effect of TREM2 on Aβ deposition, Aβ-dependent tau pathology, cortical shrinkage, and cognitive decline. Soluble TREM2 could, therefore, be a key marker for clinical trial design and interpretation. Efforts to develop TREM2-boosting therapies are ongoing. Funding: German Research Foundation, US National Institutes of Health.
AU  - Morenas-Rodríguez, E.*
AU  - Li, Y.*
AU  - Nuscher, B.*
AU  - Franzmeier, N.*
AU  - Xiong, C.*
AU  - Suárez-Calvet, M.*
AU  - Fagan, A.M.*
AU  - Schultz, S.*
AU  - Gordon, B.A.*
AU  - Benzinger, T.L.S.*
AU  - Hassenstab, J.*
AU  - McDade, E.*
AU  - Feederle, R.
AU  - Karch, C.M.*
AU  - Schlepckow, K.*
AU  - Morris, J.C.*
AU  - Kleinberger, G.*
AU  - Nellgard, B.*
AU  - Vöglein, J.*
AU  - Blennow, K.*
AU  - Ewers, M.*
AU  - Jucker, M.*
AU  - Levin, J.*
AU  - Bateman, R.J.*
AU  - Haass, C.*
C1  - 64613
C2  - 51898
SP  - 329-341
TI  - Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer's disease: A longitudinal observational study.
JO  - Lancet Neurol.
VL  - 21
IS  - 4
PY  - 2022
SN  - 1474-4422
ER  - 

TY  - JOUR
AB  - Patients with isolated rapid-eye-movement sleep behaviour disorder (RBD) are commonly regarded as being in the early stages of a progressive neurodegenerative disease involving alpha-synuclein pathology, such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. Abnormal alpha-synuclein deposition occurs early in the neurodegenerative process across the central and peripheral nervous systems and might precede the appearance of motor symptoms and cognitive decline by several decades. These findings provide the rationale to develop reliable biomarkers that can better predict conversion to clinically manifest alpha-synucleinopathies. In addition, biomarkers of disease progression will be essential to monitor treatment response once disease-modifying therapies become available, and biomarkers of disease subtype will be essential to enable prediction of which subtype of alpha-synucleinopathy patients with isolated RBD might develop.
AU  - Miglis, M.G.*
AU  - Adler, C.H.*
AU  - Antelmi, E.*
AU  - Arnaldi, D.*
AU  - Baldelli, L.*
AU  - Boeve, B.F.*
AU  - Cesari, M.*
AU  - Dall'Antonia, I.*
AU  - Diederich, N.J.*
AU  - Doppler, K.*
AU  - Dušek, P.*
AU  - Ferri, R.*
AU  - Gagnon, J.F.*
AU  - Gan-Or, Z.*
AU  - Hermann, W.*
AU  - Hoegl, B.*
AU  - Hu, M.T.*
AU  - Iranzo, A.*
AU  - Janzen, A.*
AU  - Kuzkina, A.*
AU  - Lee, J.*
AU  - Leenders, K.L.*
AU  - Lewis, S.J.G.*
AU  - Liguori, C.*
AU  - Liu, J.*
AU  - Lo, C.*
AU  - Martens, K.A.E*
AU  - Nepozitek, J.*
AU  - Plazzi, G.*
AU  - Provini, F.*
AU  - Puligheddu, M.*
AU  - Rolinski, M.*
AU  - Rusz, J.*
AU  - Stefani, A.*
AU  - Summers, R.L.S.*
AU  - Yoo, D.*
AU  - Zitser, J.*
AU  - Oertel, W.H.
C1  - 62815
C2  - 50998
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 671-684
TI  - Biomarkers of conversion to α-synucleinopathy in isolated rapid-eye-movement sleep behaviour disorder.
JO  - Lancet Neurol.
VL  - 20
IS  - 8
PB  - Elsevier Science Inc
PY  - 2021
SN  - 1474-4422
ER  - 

TY  - JOUR
AB  - Background Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia.Methods For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow.Findings We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism.Interpretation In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations.
AU  - Zech, M.
AU  - Jech, R.*
AU  - Boesch, S.*
AU  - Škorvánek, M.*
AU  - Weber, S.
AU  - Wagner, M.
AU  - Zhao, C.
AU  - Jochim, A.*
AU  - Necpál, J.*
AU  - Dincer, Y.*
AU  - Vill, K.*
AU  - Disteimaier, F.*
AU  - Stoklosa, M.*
AU  - Krenn, M.*
AU  - Grunwald, S.*
AU  - Bock-Bierbaum, T.*
AU  - Fečíková, A.*
AU  - Havránková, P.*
AU  - Roth, J.*
AU  - Příhodová, I.*
AU  - Adamovičová, M.*
AU  - Ulmanová, O.*
AU  - Bechyně, K.*
AU  - Danhofer, P.*
AU  - Veselý, B.*
AU  - Han, V.*
AU  - Pavelekova, P.*
AU  - Gdovinova, Z.*
AU  - Mantel, T.*
AU  - Meindl, T.*
AU  - Sitzberger, A.*
AU  - Schroeder, S.*
AU  - Blaschek, A.*
AU  - Roser, T.*
AU  - Bonfert, M.*
AU  - Haberlandt, E.*
AU  - Plecko, B.*
AU  - Leineweber, B.*
AU  - Berweck, S.*
AU  - Herberhold, T.*
AU  - Langguth, B.*
AU  - Švantnerová, J.*
AU  - Minár, M.*
AU  - Ramos-Rivera, G.A.*
AU  - Wojcik, M.H.*
AU  - Pajusalu, S.*
AU  - Ounap, K.*
AU  - Schatz, U.A.*
AU  - Poelsler, L.*
AU  - Milenkovic, I.*
AU  - Laccone, F.*
AU  - Pilhofer, V.*
AU  - Colombo, R.*
AU  - Patzer, S.*
AU  - Iuso, A.
AU  - Vera, J.*
AU  - Troncoso, M.*
AU  - Fang, F.*
AU  - Prokisch, H.
AU  - Wilbert, F.*
AU  - Eckenweiler, M.*
AU  - Graf, E.*
AU  - Westphal, D.S.*
AU  - Riedhammer, K.M.*
AU  - Brunet, T.*
AU  - Alhaddad, B.*
AU  - Berutti, R.*
AU  - Strom, T.M.*
AU  - Hecht, M.*
AU  - Baumann, M.*
AU  - Wolf, M.*
AU  - Telegrafi, A.*
AU  - Person, R.E.*
AU  - Zamora, F.M.*
AU  - Henderson, L.B.*
AU  - Weise, D.*
AU  - Musacchio, T.*
AU  - Volkmann, J.*
AU  - Szuto, A.*
AU  - Becker, J.*
AU  - Cremer, K.*
AU  - Sycha, T.*
AU  - Zimprich, F.*
AU  - Kraus, V.*
AU  - Makowski, C.*
AU  - Gonzalez-Alegre, P.*
AU  - Bardakjian, T.M.*
AU  - Ozelius, L.J.*
AU  - Vetro, A.*
AU  - Guerrini, R.*
AU  - Maier, E.*
AU  - Borggraefe, I.*
AU  - Kuster, A.*
AU  - Wortmann, S.B.*
AU  - Hackenberg, A.*
AU  - Steinfeld, R.*
AU  - Assmann, B.*
AU  - Staufner, C.*
AU  - Opladen, T.*
AU  - Ruzicka, E.*
AU  - Cohn, R.D.*
AU  - Dyment, D.*
AU  - Chung, W.K.*
AU  - Engels, H.*
AU  - Ceballos-Baumann, A.*
AU  - Ploski, R.*
AU  - Daumke, O.*
AU  - Haslinger, B.*
AU  - Mall, V.*
AU  - Oexle, K.
AU  - Winkelmann, J.
C1  - 60563
C2  - 49389
CY  - Ste 800, 230 Park Ave, New York, Ny 10169 Usa
SP  - 908-918
TI  - Monogenic variants in dystonia: An exome-wide sequencing study.
JO  - Lancet Neurol.
VL  - 19
IS  - 11
PB  - Elsevier Science Inc
PY  - 2020
SN  - 1474-4422
ER  - 

TY  - JOUR
AB  - Background: Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers. Methods: The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p<1 × 10−5) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin. Findings: Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited from 26 sites, 20 of which overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery or replication stages, or in the meta-analysis. However, in the case-control analysis, we replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio [OR] 0·54, 95% CI 0·46–0·63; p=3·54 × 10−16), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (rs36196656 meta-analysis OR 1·49, 95% CI 1·30–1·71; p=1·58 × 10−8). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in cerebellar tissue (p=0·04). No effect of rs36196656 on plasma and CSF progranulin concentrations was detected by ELISA; however, co-immunoprecipitation experiments in HEK293T cells did suggest a direct binding of progranulin and GFRA2. Interpretation: TMEM106B-related and GFRA2-related pathways might be future targets for treatments for FTLD, but the biological interaction between progranulin and these potential disease modifiers requires further study. TMEM106B and GFRA2 might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling, especially for asymptomatic individuals. Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Canadian Institutes of Health Research, Italian Ministry of Health, UK National Institute for Health Research, National Health and Medical Research Council of Australia, and the French National Research Agency.
AU  - Pottier, C.*
AU  - Zhou, X.*
AU  - Perkerson, R.B.*
AU  - Baker, M.*
AU  - Jenkins, G.D.*
AU  - Serie, D.J.*
AU  - Ghidoni, R.*
AU  - Benussi, L.*
AU  - Binetti, G.*
AU  - López de Munain, A.*
AU  - Zulaica, M.*
AU  - Moreno, F.*
AU  - Le Ber, I.*
AU  - Pasquier, F.*
AU  - Hannequin, D.*
AU  - Sánchez-Valle, R.*
AU  - Antonell, A.*
AU  - Lladó, A.*
AU  - Parsons, T.M.*
AU  - Finch, N.C.A.*
AU  - Finger, E.C.*
AU  - Lippa, C.F.*
AU  - Huey, E.D.*
AU  - Neumann, M.*
AU  - Heutink, P.*
AU  - Synofzik, M.*
AU  - Wilke, C.*
AU  - Rissman, R.A.*
AU  - Slawek, J.*
AU  - Sitek, E.*
AU  - Johannsen, P.*
AU  - Nielsen, J.E.*
AU  - Ren, Y.*
AU  - van Blitterswijk, M.*
AU  - DeJesus-Hernandez, M.*
AU  - Christopher, E.*
AU  - Murray, M.E.*
AU  - Bieniek, K.F.*
AU  - Evers, B.M.*
AU  - Ferrari, C.*
AU  - Rollinson, S.*
AU  - Richardson, A.*
AU  - Scarpini, E.*
AU  - Fumagalli, G.G.*
AU  - Padovani, A.*
AU  - Hardy, J.*
AU  - Momeni, P.*
AU  - Ferrari, R.*
AU  - Frangipane, F.*
AU  - Maletta, R.*
AU  - Anfossi, M.*
AU  - Gallo, M.*
AU  - Petrucelli, L.*
AU  - Suh, E.R.*
AU  - Lopez, O.L.*
AU  - Wong, T.H.*
AU  - van Rooij, J.G.J.*
AU  - Seelaar, H.*
AU  - Mead, S.*
AU  - Caselli, R.J.*
AU  - Reiman, E.M.*
AU  - Noel Sabbagh, M.*
AU  - Kjolby, M.*
AU  - Nykjaer, A.*
AU  - Karydas, A.M.*
AU  - Boxer, A.L.*
AU  - Winkelmann, J.
AU  - Rademakers, R.*
AU  - Spina, S.*
AU  - Oblak, A.*
AU  - Mesulam, M.M.*
AU  - Weintraub, S.*
AU  - Geula, C.*
AU  - Hodges, J.R.*
AU  - Piguet, O.*
AU  - Brooks, W.S.*
AU  - Irwin, D.J.*
AU  - Trojanowski, J.Q.*
AU  - Lee, E.B.*
AU  - Biernacka, J.M.*
C1  - 53888
C2  - 45125
SP  - 548-558
TI  - Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: A genome-wide association study.
JO  - Lancet Neurol.
VL  - 17
IS  - 6
PY  - 2018
SN  - 1474-4422
ER  - 

TY  - JOUR
AB  - Restless legs syndrome, also known as Willis-Ekbom disease, is a common neurological condition whose manifestation is affected by complex environmental and genetic interactions. Restless legs syndrome can occur on its own, mostly at a young age, or with comorbidities such as cardiovascular disease, diabetes, and arterial hypertension, making it a difficult condition to properly diagnose. However, the concept of restless legs syndrome as being two entities, primary or secondary to another condition, has been challenged with genetic data providing further insight into the pathophysiology of the condition. Although dopaminergic treatment was formerly the first-line therapy, prolonged use can result in a serious worsening of symptoms known as augmentation. Clinical studies on pregabalin, gabapentin enacarbil, oxycodone-naloxone, and iron preparations have provided new treatment options, but most patients still report inadequate long-term management of symptoms. Studies of the hypoxic pathway activation and iron deficiency have provided valuable information about the pathophysiology of restless legs syndrome that should now be translated into new, more effective treatments for restless legs syndrome.
AU  - Trenkwalder, C.*
AU  - Allen, R.J.*
AU  - Högl, B.*
AU  - Clemens, S.*
AU  - Patton, S.*
AU  - Schormair, B.
AU  - Winkelmann, J.
C1  - 54393
C2  - 45545
CY  - 360 Park Ave South, New York, Ny 10010-1710 Usa
SP  - 994-1005
TI  - Comorbidities, treatment, and pathophysiology in restless legs syndrome.
JO  - Lancet Neurol.
VL  - 17
IS  - 11
PB  - Elsevier Science Inc
PY  - 2018
SN  - 1474-4422
ER  - 

TY  - JOUR
AB  - Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation. Funding The European Commission FP7 NeurOmics project; CHDI Foundation; the Medical Research Council UK; the Brain Research Trust; and the Guarantors of Brain.
AU  - Moss, D.J.H.*
AU  - Pardiñas, A.F.*
AU  - Langbehn, D.*
AU  - Lo, K.*
AU  - Leavitt, B.R.*
AU  - Roos, R.*
AU  - Dürr, A.*
AU  - Mead, S.*
AU  - REGISTRY investigators (Winkelmann, J.)
AU  - Holmans, P.*
AU  - Jones, L.*
AU  - Tabrizi, S.J.*
C1  - 61156
C2  - 0
SP  - 701-711
TI  - Identification of genetic variants associated with Huntington's disease progression: A genome-wide association study.
JO  - Lancet Neurol.
VL  - 16
IS  - 9
PY  - 2017
SN  - 1474-4422
ER  - 

TY  - JOUR
AB  - Background Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. Methods In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10−8) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest. Findings We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85–1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). Interpretation Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations.  
AU  - Schormair, B.
AU  - Zhao, C.
AU  - Bell, S.*
AU  - Tilch, E.
AU  - Salminen, A.V.
AU  - Pütz, B.*
AU  - Dauvilliers, Y.*
AU  - Stefani, A.*
AU  - Högl, B.*
AU  - Poewe, W.*
AU  - Kemlink, D.*
AU  - Sonka, K.*
AU  - Bachmann, C.G.*
AU  - Paulus, W.*
AU  - Trenkwalder, C.*
AU  - Oertel, W.H.
AU  - Hornyak, M.*
AU  - Teder-Laving, M.*
AU  - Metspalu, A.*
AU  - Hadjigeorgiou, G.M.*
AU  - Polo, O.*
AU  - Fietze, I.*
AU  - Ross, O.A.*
AU  - Wszolek, Z.*
AU  - Butterworth, A.S.*
AU  - Soranzo, N.*
AU  - Ouwehand, W.H.*
AU  - Roberts, D.J.*
AU  - Danesh, J.*
AU  - Allen, R.P.*
AU  - Earley, C.J.*
AU  - Ondo, W.G.*
AU  - Xiong, L.*
AU  - Montplaisir, J.*
AU  - Gan-Or, Z.*
AU  - Perola, M.*
AU  - Vodicka, P.*
AU  - Dina, C.*
AU  - Franke, A.*
AU  - Tittmann, L.*
AU  - Stewart, A.F.R.*
AU  - Shah, S.H.*
AU  - Gieger, C.
AU  - Peters, A.
AU  - Rouleau, G.A.*
AU  - Berger, K.*
AU  - Oexle, K.
AU  - di Angelantonio, E.*
AU  - Hinds, D.A.*
AU  - Müller-Myhsok, B.*
AU  - Winkelmann, J.
C1  - 52064
C2  - 43680
SP  - 898–907
TI  - Identification of novel risk loci for restless legs syndrome: A meta-analysis of genome-wide association studies in individuals of European ancestry: A meta-analysis.
JO  - Lancet Neurol.
VL  - 16
IS  - 11
PY  - 2017
SN  - 1474-4422
ER  - 

TY  - JOUR
AB  - BACKGROUND: Parkinson's disease has been reported in a small number of patients with chromosome 22q11.2 deletion syndrome. In this study, we screened a series of large, independent Parkinson's disease case-control studies for deletions at 22q11.2. METHODS: We used data on deletions spanning the 22q11.2 locus from four independent case-control Parkinson's disease studies (UK Wellcome Trust Case Control Consortium 2, Dutch Parkinson's Disease Genetics Consortium, US National Institute on Aging, and International Parkinson's Disease Genomics Consortium studies), which were independent of the original reports of chromosome 22q11.2 deletion syndrome. We did case-control association analysis to compare the proportion of 22q11.2 deletions found, using the Fisher's exact test for the independent case-control studies and the Mantel-Haenszel test for the meta-analyses. We retrieved clinical details of patients with Parkinson's disease who had 22q11.2 deletions from the medical records of these patients. FINDINGS: We included array-based copy number variation data from 9387 patients with Parkinson's disease and 13 863 controls. Eight patients with Parkinson's disease and none of the controls had 22q11.2 deletions (p=0·00082). In the 8451 patients for whom age at onset data were available, deletions at 22q11.2 were associated with Parkinson's disease age at onset (Mann-Whitney U test p=0·001). Age at onset of Parkinson's disease was lower in patients carrying a 22q11.2 deletion (median 37 years, 95% CI 32·0-55·5; mean 42·1 years [SD 11·9]) than in those who did not carry a deletion (median 61 years, 95% CI 60·5-61·0; mean 60·3 years [SD 12·8]). A 22q11.2 deletion was present in more patients with early-onset (p<0·0001) and late-onset Parkinson's disease (p=0·016) than in controls, and in more patients with early-onset than late-onset Parkinson's disease (p=0·005). INTERPRETATION: Clinicians should be alert to the possibility of 22q11.2 deletions in patients with Parkinson's disease who have early presentation or features associated with the chromosome 22q11.2 deletion syndrome, or both.
AU  - Mok, K.Y.*
AU  - Sheerin, U.*
AU  - Simon-Sanchez, J.*
AU  - Salaka, A.*
AU  - Chester, L.*
AU  - Escott-Price, V.*
AU  - Mantripragada, K.*
AU  - Doherty, K.M.*
AU  - Noyce, A.J.*
AU  - Mencacci, N.E.*
AU  - Lubbe, S.J.*
AU  - International Parkinson's Disease Genomics Consortium (IPDGC) (Illig, T.
AU  - Lichtner, P.)
AU  - Williams-Gray, C.H.*
AU  - Barker, R.A.*
AU  - van Dijk, K.D.*
AU  - Berendse, H.W.*
AU  - Heutink, P.*
AU  - Corvol, J.C.*
AU  - Cormier, F.*
AU  - Lesage, S.*
AU  - Brice, A.*
AU  - Brockmann, K.*
AU  - Schulte, C.*
AU  - Gasser, T.*
AU  - Foltynie, T.*
AU  - Limousin, P.*
AU  - Morrison, K.E.*
AU  - Clarke, C.E.*
AU  - Sawcer, S.*
AU  - Warner, T.T.*
AU  - Lees, A.J.*
AU  - Morris, H.R.*
AU  - Nalls, M.A.*
AU  - Singleton, A.B.*
AU  - Hardy, J.*
AU  - Abramov, A.Y.*
AU  - Plagnol, V.*
AU  - Williams, N.M.*
AU  - Wood, N.W*
C1  - 48428
C2  - 41119
SP  - 585-596
TI  - Deletions at 22q11.2 in idiopathic Parkinson's disease: A combined analysis of genome-wide association data.
JO  - Lancet Neurol.
VL  - 15
PY  - 2016
SN  - 1474-4422
ER  - 

TY  - JOUR
AB  - BACKGROUND: The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes. METHODS: To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16 851 cases with state-of-the-art phenotyping data and 32 473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20 941 cases and 364 736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10 172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis. FINDINGS: We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50 × 10(-8); joint OR 1·19, 1·12-1·26, p=1·30 × 10(-9)). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26 × 10(-19); joint OR 1·37, 1·30-1·45, p=2·79 × 10(-32)) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93 × 10(-7); joint OR 1·17, 1·11-1·23, p=2·29 × 10(-10)) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50 × 10(-8); joint OR 1·24, 1·15-1·33, p=4·52 × 10(-9)) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82 × 10(-8); joint OR 1·17, 1·11-1·23, p=2·92 × 10(-9)). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed. INTERPRETATION: Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke. FUNDING: US National Institute of Neurological Disorders and Stroke, National Institutes of Health.
AU  - International Stroke Genetics Consortium (Pulit, S.L.*
AU  - McArdle, P.F.*
AU  - Wong, Q.*
AU  - Malik, R.*
AU  - Gieger, C.
AU  - Meisinger, C.
AU  - Müller-Nurasyid, M.
AU  - Peters, A.
AU  - Strauch, K.
AU  - Waldenberger, M.
AU  - Rosand, J.*)
C1  - 47856
C2  - 39600
SP  - 174-184
TI  - Loci associated with ischaemic stroke and its subtypes (SiGN): A genome-wide association study.
JO  - Lancet Neurol.
VL  - 15
PY  - 2016
SN  - 1474-4422
ER  - 

TY  - JOUR
AU  - Jansen, I.E.*
AU  - Bras, J.M.*
AU  - Lesage, S.*
AU  - Schulte, C.*
AU  - Gibbs, J.R.*
AU  - Nalls, M.A.*
AU  - Brice, A.*
AU  - Wood, N.W.*
AU  - Morris, H.R.*
AU  - Hardy, J.A.*
AU  - Singleton, A.B.*
AU  - Gasser, T.*
AU  - Heutink, P.*
AU  - Sharma, M.*
AU  - International Parkinson's Disease Genomics Consortium (IPDGC) (Illig, T.
AU  - Lichtner, P.)
C1  - 45663
C2  - 37426
CY  - New York
SP  - 678-679
TI  - CHCHD2 and Parkinson's disease.
JO  - Lancet Neurol.
VL  - 14
IS  - 7
PB  - Elsevier Science Inc
PY  - 2015
SN  - 1474-4422
ER  - 

TY  - JOUR
AB  - Background The epilepsies are a clinically heterogeneous group of neurological disorders. Despite strong evidence for heritability, genome-wide association studies have had little success in identification of risk loci associated with epilepsy, probably because of relatively small sample sizes and insufficient power. We aimed to identify risk loci through meta-analyses of genome-wide association studies for all epilepsy and the two largest clinical subtypes (genetic generalised epilepsy and focal epilepsy). Methods We combined genome-wide association data from 12 cohorts of individuals with epilepsy and controls from population-based datasets. Controls were ethnically matched with cases. We phenotyped individuals with epilepsy into categories of genetic generalised epilepsy, focal epilepsy, or unclassified epilepsy. After standardised filtering for quality control and imputation to account for different genotyping platforms across sites, investigators at each site conducted a linear mixed-model association analysis for each dataset. Combining summary statistics, we conducted fixed-effects meta-analyses of all epilepsy, focal epilepsy, and genetic generalised epilepsy. We set the genome-wide significance threshold at p<1.66 x 10(-8). Findings We included 8696 cases and 26157 controls in our analysis. Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3 (p=8.71 x 10(-10), implicating SCN1A, and at 4p15.1 (p=5.44 x 10(-9)), harbouring PCDH7, which encodes a protocadherin molecule not previously implicated in epilepsy. For the cohort of genetic generalised epilepsy, we noted a single signal at 2p16.1 (p=9.99 x 10(-9)), implicating VRK2 or FANCL. No single nucleotide polymorphism achieved genome-wide significance for focal epilepsy. Interpretation This meta-analysis describes a new locus not previously implicated in epilepsy and provides further evidence about the genetic architecture of these disorders, with the ultimate aim of assisting in disease classification and prognosis. The data suggest that specific loci can act pleiotropically raising risk for epilepsy broadly, or can have effects limited to a specific epilepsy subtype. Future genetic analyses might benefit from both lumping (ie, grouping of epilepsy types together) or splitting (ie, analysis of specific clinical subtypes).
AU  - International League Against Epilepsy Consortium on Complex Epilepsies (Gieger, C.
AU  - Grallert, H.
AU  - Heinrich, J.
AU  - Holle, R.
AU  - Leidl, R.
AU  - Meisinger, C.
AU  - Peters, A.
AU  - Strauch, K.)
C1  - 32445
C2  - 35052
SP  - 893-903
TI  - Genetic determinants of common epilepsies: A meta-analysis of genome-wide association studies.
JO  - Lancet Neurol.
VL  - 13
IS  - 9
PY  - 2014
SN  - 1474-4422
ER  - 

TY  - JOUR
AB  - BACKGROUND: 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. METHODS: 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). FINDINGS: 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). INTERPRETATION: 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. FUNDING: Mundipharma Research.
AU  - Trenkwalder, C.*
AU  - Benes, H.*
AU  - Grote, L.*
AU  - García-Borreguero, D.*
AU  - Högl, B.*
AU  - Hopp, M.*
AU  - Bosse, B.*
AU  - Oksche, A.*
AU  - Reimer, K.*
AU  - Winkelmann, J.
AU  - Allen, R.P.*
AU  - Kohnen, R.*
C1  - 28035
C2  - 32913
SP  - 1141-1150
TI  - 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.
JO  - Lancet Neurol.
VL  - 12
IS  - 12
PB  - Elsevier Science
PY  - 2013
SN  - 1474-4422
ER  - 

TY  - JOUR
AU  - Kretzschmar, H.*
AU  - Illig, T.
C1  - 1254
C2  - 26434
SP  - 25-26
TI  - Are further genetic factors associated with the risk of developing variant Creutzfeldt-Jakob disease?
JO  - Lancet Neurol.
VL  - 8
IS  - 1
PB  - Elsevier Science Inc
PY  - 2009
SN  - 1474-4422
ER  -