TY  - JOUR
AB  - Dystonia is a movement disorder characterized by genetic and clinical heterogeneity. A recurring p.(Glu303del)-deletion in TOR1A is a well-established cause for DYT-TOR1A (DYT1), an autosomal dominant early-onset isolated dystonia. TOR1A encodes TorsinA, an AAA + ATPase located in the nuclear envelope. By whole exome analyses of a family with a novel dystonia-hemichorea-/hemiballism phenotype, we identified a TOR1AIP2 NM_001199260.2 c.1234A > G p.(Arg412Gly) variant. The variant is very rare in databases and was absent from whole exome data from >1000 dystonia patients. TOR1AIP2 encodes LULL1, a transmembrane protein that activates TorsinA, and correct interaction between TorsinA and LULL1 is essential for proper nuclear envelope architecture. The p.(Arg412Gly) variant disrupts the binding interface between TorsinA and LULL1 around p.Arg412; this same interface is also impaired in DYT1. Functional analyses via a co-purification assay revealed that interaction between TorsinA-LULL1Arg412Gly is weaker than the wild-type interaction, and that it resembles the situation in DYT1 (TorsinAΔE303-LULL1). A second family with milder dystonia, hemichorea, and stereotypic leg flexion during gait and a TOR1AIP2 p.(Gln338His) variant was identified. The clinical phenotype of both families shared proximal arm movements, and flutter in facial musculature. Expressivity of the movement disorder symptoms was variable. Several proteins in the nuclear envelope have been implicated in various forms of neurodevelopmental disorders with dystonia. Taken together, our findings suggest TOR1AIP2 as a new candidate gene implicated in a complex hereditary movement disorder with dystonia and hemichorea/hemiballism.
AU  - Kafantari, E.*
AU  - Hernandez, V.J.*
AU  - Necpál, J.*
AU  - Leonidou, M.*
AU  - Baureder, R.*
AU  - Hedberg-Oldfors, C.*
AU  - Jech, R.*
AU  - Zech, M.
AU  - Schwartz, T.U.*
AU  - Puschmann, A.*
C1  - 73683
C2  - 57172
CY  - 125 London Wall, London, England
TI  - TOR1AIP2 as a candidate gene for dystonia-hemichorea/hemiballism.
JO  - Parkinsonism Relat. Disord.
VL  - 134
PB  - Elsevier Sci Ltd
PY  - 2025
SN  - 1353-8020
ER  - 

TY  - JOUR
AU  - Krygier, M.*
AU  - Limanówka, M.*
AU  - Pietruszka, M.*
AU  - Chylińska, M.*
AU  - Mazurkiewicz-Bełdzińska, M.*
AU  - Zech, M.
C1  - 73398
C2  - 57047
CY  - 125 London Wall, London, England
TI  - TAOK1-related neurodevelopmental disorder: A new differential diagnosis for childhood-onset tremor!
JO  - Parkinsonism Relat. Disord.
VL  - 133
PB  - Elsevier Sci Ltd
PY  - 2025
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - BACKGROUND: ADCY5-related movement disorders are typically paroxysmal dyskinesia (PxDs) and/or static hyperkinetic movement disorders. Nocturnal paroxysmal dyskinesia (PxD), facial or perioral dyskinesia are suggestive of this genetic diagnosis. Next generation sequencing has enabled an expansion of the ADCY5- related phenotype. OBJECTIVE: The aim of our study was to report atypical phenotypes. RESULTS: We describe 13 patients from 8 different families, of which 10 had adolescent/adult-onset head and upper limb tremor followed by static cervical dystonia without PxD. We report three novel ADCY5 variants in these patients, located in the catalytic domains, close to previously reported variants. Caffeine was ineffective for the 3 patients who tried the treatment, and botulinum toxin therapy seemed to be the most effective treatment. We also describe 2 patients with spontaneous remission of pediatric-onset PxD before adulthood. CONCLUSION: We highlight an adolescent/adult-onset phenotype with head tremor and cervical dystonia, widening the genetic spectrum of cervical dystonia. Moreover, we broaden the pediatric ADCY5-PxD phenotype, highlighting previously unreported cases of spontaneous remission.
AU  - Quazza, F.*
AU  - Riant, F.*
AU  - Patera, M.*
AU  - Suppa, A.*
AU  - Satolli, S.*
AU  - Burglen, L.*
AU  - Zech, M.
AU  - Boesch, S.*
AU  - Indelicato, E.*
AU  - Hainque, E.*
AU  - Apartis, E.*
AU  - Rodriguez, D.*
AU  - Doummar, D.*
AU  - Méneret, A.*
AU  - Ravelli, C.*
C1  - 73313
C2  - 57006
CY  - 125 London Wall, London, England
TI  - Atypical ADCY5-related movement disorders: Highlighting adolescent/adult-onset cervical dystonia.
JO  - Parkinsonism Relat. Disord.
VL  - 132
PB  - Elsevier Sci Ltd
PY  - 2025
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - The current era of high-throughput analysis-driven research offers invaluable insights into disease etiologies, accurate diagnostics, pathogenesis, and personalized therapy. In the field of movement disorders, investigators are facing an increasing growth in the volume of produced patient-derived datasets, providing substantial opportunities for precision medicine approaches based on extensive information accessibility and advanced annotation practices. Integrating data from multiple sources, including phenomics, genomics, and multi-omics, is crucial for comprehensively understanding different types of movement disorders. Here, we explore formats and analytics of big data generated for patients with movement disorders, including strategies to meaningfully share the data for optimized patient benefit. We review computational methods that are essential to accelerate the process of evaluating the increasing amounts of specialized data collected. Based on concrete examples, we highlight how bioinformatic approaches facilitate the translation of multidimensional biological information into clinically relevant knowledge. Moreover, we outline the feasibility of computer-aided therapeutic target evaluation, and we discuss the importance of expanding the focus of big data research to understudied phenotypes such as dystonia.
AU  - Saparov, A.
AU  - Zech, M.
C1  - 73349
C2  - 57026
CY  - 125 London Wall, London, England
TI  - Big data and transformative bioinformatics in genomic diagnostics and beyond.
JO  - Parkinsonism Relat. Disord.
VL  - 134
PB  - Elsevier Sci Ltd
PY  - 2025
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - INTRODUCTION: Variable expressivity is an emerging characteristic of KMT2B-related dystonia. However, it remains poorly understood whether variants reoccurring at specific sites of lysine-specific methlytransferase-2B (KMT2B) can drive intra- and interfamilial clinical heterogeneity. Our goal was to ascertain independent families with variants affecting residue Arg2565 of KMT2B. METHODS: Whole-exome/genome sequencing, multi-site recruitment, genotype-phenotype correlations, and DNA methylation episignature analysis were performed. RESULTS: We report four individuals from two families harboring the variant c.7693C > G, p.Arg2565Gly. In an additional patient, a de-novo c.7693C > T, p.Arg2565Cys variant was identified. The observed phenotypic spectrum ranged from childhood-onset dystonia (N = 2) over unspecific intellectual disability syndromes (N = 2) to undiagnosed behavioral symptoms in adulthood (N = 1). Samples bearing p.Arg2565Gly had a KMT2B-typical episignature, although the effect on methylation was less pronounced than in carriers of loss-of-function KMT2B variants. CONCLUSIONS: We established the existence of a KMT2B missense-mutation hotspot associated with varying degrees of disease severity and expression, providing information for patient counseling and elucidation of pathomechanisms.
AU  - Stehr, A.M.*
AU  - Fischer, J.*
AU  - Mirza-Schreiber, N.
AU  - Bernardi, K.*
AU  - Porrmann, J.*
AU  - Harrer, P.
AU  - Kaiser, F.*
AU  - Jamra, R.A.*
AU  - Winkelmann, J.
AU  - Jech, R.*
AU  - Koy, A.*
AU  - Oexle, K.
AU  - Zech, M.
C1  - 73375
C2  - 57021
CY  - 125 London Wall, London, England
TI  - Variable expressivity of KMT2B variants at codon 2565 in patients with dystonia and developmental disorders.
JO  - Parkinsonism Relat. Disord.
VL  - 133
PB  - Elsevier Sci Ltd
PY  - 2025
SN  - 1353-8020
ER  - 

TY  - JOUR
AU  - Stehr, A.M.*
AU  - Fischer, J.*
AU  - Mirza-Schreiber, N.
AU  - Bernardi, K.*
AU  - Porrmann, J.*
AU  - Harrer, P.
AU  - Kaiser, F.*
AU  - Jamra, R.A.*
AU  - Winkelmann, J.
AU  - Jech, R.*
AU  - Koy, A.*
AU  - Oexle, K.
AU  - Zech, M.
C1  - 73737
C2  - 57204
CY  - 125 London Wall, London, England
TI  - Corrigendum to "Variable expressivity of KMT2B variants at codon 2565 in patients with dystonia and developmental disorders" [Parkinson. Relat. Disord. (2025) 133 107319].
JO  - Parkinsonism Relat. Disord.
VL  - 134
PB  - Elsevier Sci Ltd
PY  - 2025
SN  - 1353-8020
ER  - 

TY  - JOUR
AU  - Stretavská, P.*
AU  - Necpál, J.*
AU  - Trúsiková, E.*
AU  - Okáľová, K.*
AU  - Latka, S.*
AU  - Jech, R.*
AU  - Zech, M.
C1  - 73550
C2  - 57093
CY  - 125 London Wall, London, England
TI  - Paroxysmal nocturnal dystonia in DNM1L-related syndrome.
JO  - Parkinsonism Relat. Disord.
VL  - 133
PB  - Elsevier Sci Ltd
PY  - 2025
SN  - 1353-8020
ER  - 

TY  - JOUR
AU  - Blaschek, A.*
AU  - Sitzberger, A.*
AU  - Brugger, M.*
AU  - Graf, E.*
AU  - Berutti, R.
AU  - Zech, M.
AU  - Vill, K.
C1  - 67517
C2  - 54082
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
TI  - TAOK1-related neurodevelopmental disorder: A new differential diagnosis for childhood-onset tremor?
JO  - Parkinsonism Relat. Disord.
VL  - 109
PB  - Elsevier Sci Ltd
PY  - 2023
SN  - 1353-8020
ER  - 

TY  - JOUR
AU  - Indelicato, E.
AU  - Boesch, S.*
AU  - Havránková, P.*
AU  - Příhodová, I.*
AU  - Winkelmann, J.
AU  - Jech, R.*
AU  - Zech, M.
C1  - 69038
C2  - 53889
CY  - 125 London Wall, London, England
TI  - SOXopathies and dystonia: Consolidation of a recurrent association.
JO  - Parkinsonism Relat. Disord.
VL  - 119
PB  - Elsevier Sci Ltd
PY  - 2023
SN  - 1353-8020
ER  - 

TY  - JOUR
AU  - Necpál, J.*
AU  - Winkelmann, J.
AU  - Zech, M.
AU  - Jech, R.*
C1  - 67813
C2  - 54291
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
TI  - A de novo GRIA3 variant with complex hyperkinetic movement disorder in a girl with developmental delay and self-limited epilepsy.
JO  - Parkinsonism Relat. Disord.
VL  - 111
PB  - Elsevier Sci Ltd
PY  - 2023
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - INTRODUCTION: Cerebral palsy (CP) is a group of permanent disorders attributed to non-progressive disturbances that occurred in the developing fetal or infant brain. Cerebral palsy-like (CP-like) disorders may clinically resemble CP but do not fulfill CP criteria and have often a progressive course and/or neurodevelopmental regression. To assess which patients with dystonic CP and dystonic CP-like disorder should undergo Whole Exome Sequencing (WES), we compared the rate of likely causative variants in individuals regarding their clinical picture, co-morbidities, and environmental risk factors. METHOD: Individuals with early onset neurodevelopmental disorder (ND) manifesting with dystonia as a core feature were divided into CP or CP-like cohorts based on their clinical picture and disease course. Detailed clinical picture, co-morbidities, and environmental risk factors including prematurity, asphyxia, SIRS, IRDS, and cerebral bleeding were evaluated. RESULTS: A total of 122 patients were included and divided into the CP group with 70 subjects (30 males; mean age 18y5m±16y6m, mean GMFCS score 3.3 ± 1.4), and the CP-like group with 52 subjects (29 males; mean age 17y7m±1y,6 m, mean GMFCS score 2,6 ± 1,5). The WES-based diagnosis was present in 19 (27.1%) CP patients and 30 CP-like patients (57.7%) with genetic conditions overlap in both groups. We found significant differences in diagnostic rate in CP individuals with vs. without risk factors (13.9% vs. 43.3%); Fisher's exact p = 0.0065. We did not observe the same tendency in CP-like (45.5% vs 58.5%); Fisher's exact p = 0.5. CONCLUSION: WES is a useful diagnostic method for patients with dystonic ND, regardless of their presentation as a CP or CP-like phenotype.
AU  - Pavelekova, P.*
AU  - Necpál, J.*
AU  - Jech, R.*
AU  - Havránková, P.*
AU  - Švantnerová, J.*
AU  - Jurkova, V.*
AU  - Gdovinova, Z.*
AU  - Lackova, A.*
AU  - Han, V.*
AU  - Winkelmann, J.
AU  - Zech, M.
AU  - Škorvánek, M.*
C1  - 67643
C2  - 53950
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
TI  - Predictors of whole exome sequencing in dystonic cerebral palsy and cerebral palsy-like disorders.
JO  - Parkinsonism Relat. Disord.
VL  - 111
PB  - Elsevier Sci Ltd
PY  - 2023
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - INTRODUCTION: Many patients with Parkinson's disease suffer from REM sleep behavior disorder, potentially preceding the onset of motor symptoms. Phospho-alpha-synuclein is detectable in skin biopsies of patients with isolated REM sleep behavior disorder several years prior to the onset of manifest PD, but information on the association between dermal phospho-alpha-synuclein deposition and REM sleep behavior disorder in patients with manifest PD is limited. We therefore aimed to investigate the alpha-synuclein burden in dermal peripheral nerve fibers in patients with Parkinson's disease with and without REM sleep behavior disorder. METHODS: Patients with Parkinson's disease (n = 43) who had undergone skin biopsy for the immunohistochemical detection of phosphorylated alpha-synuclein were screened for REM sleep behavior disorder using RBDSQ and Mayo Sleep Questionnaire. Skin biopsies from 43 patients with isolated polysomnography-confirmed REM sleep behavior disorder were used as comparators. RESULTS: Dermal alpha-synuclein deposition was more frequently found (81.8% vs. 52.4%, p = 0.05) and was more abundant (p = 0.01) in patients with Parkinson's disease suffering from probable REM sleep behavior disorder compared to patients without REM sleep behavior disorder and was similar to patients with isolated REM sleep behavior disorder (79.1%). CONCLUSION: The phenotype of REM sleep behavior disorder is associated with high amounts of dermal alpha-synuclein deposition, demonstrating a strong involvement of peripheral nerves in patients with this non-motor symptom and may argue in favor of REM sleep behavior disorder as an indicator of a "body-predominant" subtype of Parkinson's disease.
AU  - Doppler, K.*
AU  - Mammadova, S.*
AU  - Kuzkina, A.*
AU  - Reetz, K.*
AU  - Michels, J.*
AU  - Hermann, W.*
AU  - Sommerauer, M.*
AU  - Volkmann, J.*
AU  - Oertel, W.H.
AU  - Janzen, A.*
AU  - Sommer, C.*
C1  - 65067
C2  - 52657
SP  - 58-61
TI  - Association between probable REM sleep behavior disorder and increased dermal alpha-synuclein deposition in Parkinson's disease.
JO  - Parkinsonism Relat. Disord.
VL  - 99
PY  - 2022
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - INTRODUCTION: Although shared genetic factors have been previously reported between dystonia and other neurologic conditions, no sequencing study exploring such links is available. In a large dystonic cohort, we aimed at analyzing the proportions of causative variants in genes associated with disease categories other than dystonia. METHODS: Gene findings related to whole-exome sequencing-derived diagnoses in 1100 dystonia index cases were compared with expert-curated molecular testing panels for ataxia, parkinsonism, spastic paraplegia, neuropathy, epilepsy, and intellectual disability. RESULTS: Among 220 diagnosed patients, 21% had variants in ataxia-linked genes; 15% in parkinsonism-linked genes; 15% in spastic-paraplegia-linked genes; 12% in neuropathy-linked genes; 32% in epilepsy-linked genes; and 65% in intellectual-disability-linked genes. Most diagnosed presentations (80%) were related to genes listed in ≥1 studied panel; 71% of the involved loci were found in the non-dystonia panels but not in an expert-curated gene list for dystonia. CONCLUSIONS: Our study indicates a convergence in the genetics of dystonia and other neurologic phenotypes, informing diagnostic evaluation strategies and pathophysiological considerations.
AU  - Dzinovic, I.
AU  - Boesch, S.*
AU  - Škorvánek, M.*
AU  - Necpál, J.*
AU  - Švantnerová, J.*
AU  - Pavelekova, P.*
AU  - Havránková, P.*
AU  - Tsoma, E.*
AU  - Indelicato, E.*
AU  - Runkel, E.*
AU  - Held, V.*
AU  - Weise, D.*
AU  - Janzarik, W.G.*
AU  - Eckenweiler, M.*
AU  - Berweck, S.*
AU  - Mall, V.*
AU  - Haslinger, B.*
AU  - Jech, R.*
AU  - Winkelmann, J.
AU  - Zech, M.
C1  - 65755
C2  - 52898
SP  - 1-6
TI  - Genetic overlap between dystonia and other neurologic disorders: A study of 1,100 exomes.
JO  - Parkinsonism Relat. Disord.
VL  - 102
PY  - 2022
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - Animal and human brain-imaging studies have suggested a role for neurodevelopmental abnormalities in the pathophysiology of dystonia. Variants in neurodevelopmental genes have also been sporadically implicated, although no systematic investigation has been undertaken before the more widespread availability of genome-wide sequencing techniques. Here, we review findings from recent whole-exome and whole-genome sequencing approaches in individuals with dystonic conditions, indicating that more than 50% of molecularly diagnosed cases may have variants in neurodevelopmental disorder-associated genes. We describe how genomic sequencing has contributed to phenotypic expansions of several known hereditary forms of dystonia to include classical neurodevelopmental features. Moreover, we demonstrate that many of the newly reported monogenic neurodevelopmental disorders can manifest with prominent dystonic presentations, including isolated generalized dystonia, paroxysmal dystonia, and dopa-responsive dystonia-parkinsonism. Considering the published evidence, we argue that the clinical feature dystonia might be regarded as an expression of developmental brain dysfunction, a status referring to the common etiological basis of many neurodevelopmental disease traits. Finally, we provide a view into clinical implications, including the necessity to integrate the interrogation of neurodevelopmental disorder-associated genes into the molecular analysis process of patients with dystonia. Recognizing the relationship between dystonia and neurodevelopmental disorders is important to improve patient counseling and management and develop novel therapeutic strategies.
AU  - Dzinovic, I.
AU  - Winkelmann, J.
AU  - Zech, M.
C1  - 66212
C2  - 52626
SP  - 131-140
TI  - Genetic intersection between dystonia and neurodevelopmental disorders: Insights from genomic sequencing.
JO  - Parkinsonism Relat. Disord.
VL  - 102
PY  - 2022
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - INTRODUCTION: The genetic basis of autosomal-recessive dystonia remains poorly understood. Our objective was to report identification of additional individuals with variants in AOPEP, a recently described gene for recessively inherited dystonic disorders (OMIM:619565). METHODS: Ongoing analysis on a high-throughput genetic platform and international case-recruitment efforts were undertaken. RESULTS: Novel biallelic, likely pathogenic loss-of-function alleles were identified in two pedigrees of different ethnic background. Two members of a consanguineous Iranian family shared a homozygous c.1917-1G>A essential splice-site variant and featured presentations of adolescence-onset generalized dystonia. An individual of Chinese descent, homozygous for the nonsense variant c.1909G>T (p.Glu637*), displayed childhood-onset generalized dystonia combined with later-manifesting parkinsonism. One additional Iranian patient with adolescence-onset generalized dystonia carried an ultrarare, likely protein-damaging homozygous missense variant (c.1201C>T [p.Arg401Trp]). CONCLUSIONS: These findings support the implication of AOPEP in recessive forms of generalized dystonia and dystonia-parkinsonism. Biallelic AOPEP variants represent a worldwide cause of dystonic movement-disorder phenotypes and should be considered in dystonia molecular testing approaches.
AU  - Garavaglia, B.*
AU  - Vallian, S.*
AU  - Romito, L.M.*
AU  - Straccia, G.*
AU  - Capecci, M.*
AU  - Invernizzi, F.*
AU  - Andrenelli, E.*
AU  - Kazemi, A.*
AU  - Boesch, S.*
AU  - Kopajtich, R.
AU  - Olfati, N.*
AU  - Shariati, M.*
AU  - Shoeibi, A.*
AU  - Sadr-Nabavi, A.*
AU  - Prokisch, H.
AU  - Winkelmann, J.
AU  - Zech, M.
C1  - 64626
C2  - 52357
SP  - 52-56
TI  - AOPEP variants as a novel cause of recessive dystonia: Generalized dystonia and dystonia-parkinsonism.
JO  - Parkinsonism Relat. Disord.
VL  - 97
PY  - 2022
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - INTRODUCTION: Sixteen subjects with biallelic WARS2 variants encoding the tryptophanyl mitochondrial aminoacyl-tRNA synthetase, presenting with a neonatal- or infantile-onset mitochondrial disease, have been reported to date. Here we present six novel cases with WARS2-related diseases and expand the spectrum to later onset phenotypes including dopa-responsive early-onset parkinsonism and progressive myoclonus-ataxia. METHODS: Six individuals from four families underwent whole-exome sequencing within research and diagnostic settings. Following the identification of a genetic defect, in-depth phenotyping and protein expression studies were performed. RESULTS: A relatively common (gnomAD MAF = 0.0033) pathogenic p.(Trp13Gly) missense variant in WARS2 was detected in trans in all six affected individuals in combination with different pathogenic alleles (exon 2 deletion in family 1; p.(Leu100del) in family 2; p.(Gly50Asp) in family 3; and p.(Glu208*) in family 4). Two subjects presented with action tremor around age 10-12 years and developed tremor-dominant parkinsonism with prominent neuropsychiatric features later in their 20s. Two subjects presented with a progressive myoclonus-ataxia dominant phenotype. One subject presented with spasticity, choreo-dystonia, myoclonus, and speech problems. One subject presented with speech problems, ataxia, and tremor. Western blotting analyses in patient-derived fibroblasts showed a markedly decreased expression of the full-length WARS2 protein in both subjects carrying p.(Trp13Gly) and an exon-2 deletion in compound heterozygosity. CONCLUSIONS: This study expands the spectrum of the disease to later onset phenotypes of early-onset tremor-dominant parkinsonism and progressive myoclonus-ataxia phenotypes.
AU  - Škorvánek, M.*
AU  - Rektorová, I.*
AU  - Mandemakers, W.*
AU  - Wagner, M.
AU  - Steinfeld, R.*
AU  - Orec, L.*
AU  - Han, V.*
AU  - Pavelekova, P.*
AU  - Lackova, A.*
AU  - Kulcsarová, K.*
AU  - Ostrozovičová, M.*
AU  - Gdovinova, Z.*
AU  - Plecko, B.*
AU  - Brunet, T.*
AU  - Berutti, R.
AU  - Kuipers, D.J.S.*
AU  - Boumeester, V.*
AU  - Havránková, P.*
AU  - Tijssen, M.A.J.*
AU  - Kaiyrzhanov, R.*
AU  - Rizig, M.*
AU  - Houlden, H.*
AU  - Winkelmann, J.*
AU  - Bonifati, V.*
AU  - Zech, M.
AU  - Jech, R.*
C1  - 63780
C2  - 51755
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
SP  - 54-61
TI  - WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia.
JO  - Parkinsonism Relat. Disord.
VL  - 94
PB  - Elsevier Sci Ltd
PY  - 2022
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - We report a Dystonia-Deafness syndrome patient treated by pallidal Deep Brain Stimulation with significant long-term benefits. Our study expands and confirms the complex phenotypic spectrum of ACTB gene-related disorders and supports the effectiveness of pallidal stimulation on motor outcomes and quality of life in dystonia due to ACTB p.Arg183Trp heterozygosity.
AU  - Straccia, G.*
AU  - Reale, C.*
AU  - Castellani, M.*
AU  - Colangelo, I.*
AU  - Orunesu, E.*
AU  - Meoni, S.*
AU  - Moro, E.*
AU  - Krack, P.*
AU  - Prokisch, H.
AU  - Zech, M.
AU  - Romito, L.M.*
AU  - Garavaglia, B.*
C1  - 66365
C2  - 53152
SP  - 3-6
TI  - ACTB gene mutation in combined Dystonia-Deafness syndrome with parkinsonism: Expanding the phenotype and highlighting the long-term GPi DBS outcome.
JO  - Parkinsonism Relat. Disord.
VL  - 104
PY  - 2022
SN  - 1353-8020
ER  - 

TY  - JOUR
AU  - Svorenova, T.*
AU  - Romito, L.M.*
AU  - Colangelo, I.*
AU  - Han, V.*
AU  - Jech, R.*
AU  - Prokisch, H.
AU  - Škorvánek, M.*
AU  - Garavaglia, B.*
AU  - Zech, M.
C1  - 65920
C2  - 52989
SP  - 89-91
TI  - Dystonia as a prominent feature of TCF20-associated neurodevelopmental disorder: Expanding the phenotype.
JO  - Parkinsonism Relat. Disord.
VL  - 102
PY  - 2022
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - Dentatorubral-pallidoluysian atrophy (DRPLA) is a CAG trinucleotide repeat expansion disorder with an autosomal-dominant mode of inheritance and very low prevalence in Europe. We herein report the clinical characteristics of the first Austrian DRPLA family. Genetic analysis revealed the presence of a common European haplotype, suggesting a founder mutation in Europe.
AU  - Amprosi, M.*
AU  - Zech, M.
AU  - Lichtner, P.
AU  - Eckstein, G.N.
AU  - Unterberger, I.*
AU  - Eigentler, A.*
AU  - Indelicato, E.*
AU  - Puttinger, G.*
AU  - Nachbauer, W.*
AU  - Boesch, S.*
C1  - 62083
C2  - 50638
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
SP  - 119-121
TI  - The rare and the common: An Austrian DRPLA family harboring the European haplotype.
JO  - Parkinsonism Relat. Disord.
VL  - 87
PB  - Elsevier Sci Ltd
PY  - 2021
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - Objective/methods: Phosphorylated alpha-synuclein (p-syn) in dermal nerves of patients with isolated REM sleep behavior disorder (iRBD) is detectable by immunofluorescence-labeling. Skin-biopsy-p-syn-positivity was recently postulated to be a prodromal marker of Parkinson's disease (PD) or related synucleinopathies. Here, we provide two-to four-year clinical and skin biopsy follow-up data of 33 iRBD patients, whose skin biopsy findings at baseline were reported in 2017. Results: Follow-up biopsies were available from 25 patients (18 positive at baseline) and showed consistent findings over time in 24 patients. One patient converted from skin-biopsy-negativity to -positivity. P-syn-positivity was observed in iRBD patients who still had a normal FP-CIT-SPECT two years later. Clinically, five of the 23 at baseline skin-biopsy-positive patients (21.7%) had converted to PD or dementia with Lewy bodies at follow-up, but none of the skin-biopsy-negative patients. Conclusions: Dermal p-syn in iRBD is most probably an early consistent marker of synucleinopathy and may support other indicators of conversion to manifest disease state.
AU  - Doppler, K.*
AU  - Antelmi, E.*
AU  - Kuzkina, A.*
AU  - Donadio, V.*
AU  - Incensi, A.*
AU  - Plazzi, G.*
AU  - Pizza, F.*
AU  - Marelli, S.*
AU  - Ferini-Strambi, L.*
AU  - Tinazzi, M.*
AU  - Mayer, G.*
AU  - Sittig, E.*
AU  - Booij, J.*
AU  - Sedghi, A.*
AU  - Oertel, W.H.
AU  - Volkmann, J.*
AU  - Sommer, C.*
AU  - Janzen, A.*
AU  - Liguori, R.*
C1  - 62366
C2  - 50704
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
SP  - 108-113
TI  - Consistent skin alpha-synuclein positivity in REM sleep behavior disorder-A two center two-to-four-year follow-up study.
JO  - Parkinsonism Relat. Disord.
VL  - 86
PB  - Elsevier Sci Ltd
PY  - 2021
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - Introduction: Although there has been increasing recognition of the occurrence of non-epileptic involuntary movements in developmental and epileptic encephalopathies (DEEs), the spectrum of dystonic presentations associated with these conditions remains poorly described. We sought to expand the catalogue of dystonia-predominant phenotypes in monogenic DEEs, building on the recently introduced concept of an epilepsy-movement disorder spectrum. Methods: Cases were identified from a whole-exome-sequenced cohort of 45 pediatric index patients with complex dystonia (67% sequenced as parent-child trios). Review of molecular findings in DEE-associated genes was performed. For five individuals with identified DEE-causing variants, detailed information about presenting phenotypic features and the natural history of disease was obtained. Results: De-novo pathogenic and likely pathogenic missense variants in GABRA1, GABBR2, GNAO1, and FOXG1 gave rise to infantile-onset persistent and paroxysmal dystonic manifestations, beginning in the limb or truncal musculature and progressing gradually to a generalized state. Coexisting, less prominent movement-disorder symptoms were observed and included myoclonic, ballistic, and stereotypic abnormal movements as well as choreoathetosis. Dystonia dominated over epileptic neurodevelopmental comorbidities in all four subjects and represented the primary indication for molecular genetic analysis. We also report the unusual case of an adult female patient with dystonia, tremor, and mild learning disability who was found to harbor a pathogenic frameshift variant in MECP2. Conclusions: Dystonia can be a leading clinical manifestation in different DEEs. A monogenic basis of disease should be considered on the association of dystonia and developmental delay-epilepsy presentations, justifying a molecular screening for variants in DEE-associated genes.
AU  - Dzinovic, I.
AU  - Škorvánek, M.*
AU  - Necpál, J.*
AU  - Boesch, S.*
AU  - Švantnerová, J.*
AU  - Wagner, M.
AU  - Havránková, P.*
AU  - Pavelekova, P.*
AU  - Han, V.*
AU  - Janzarik, W.G.*
AU  - Berweck, S.*
AU  - Diebold, I.*
AU  - Kuster, A.*
AU  - Jech, R.*
AU  - Winkelmann, J.
AU  - Zech, M.
C1  - 62808
C2  - 51075
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
SP  - 73-78
TI  - Dystonia as a prominent presenting feature in developmental and epileptic encephalopathies: A case series.
JO  - Parkinsonism Relat. Disord.
VL  - 90
PB  - Elsevier Sci Ltd
PY  - 2021
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - DYT1 gene mutations lead to early-onset dystonia that begins with focal limb onset and spreads to other body regions within 5 years, with typical sparing of the oromandibular muscles. In the present study, we describe two patients with an unusual presentation of the disease.
AU  - Pavelekova, P.*
AU  - Jech, R.*
AU  - Zech, M.
AU  - Krepelova, A.*
AU  - Han, V.*
AU  - Mosejova, A.*
AU  - Liba, Z.*
AU  - Urgošík, D.*
AU  - Gdovinova, Z.*
AU  - Havránková, P.*
AU  - Fečíková, A.*
AU  - Winkelmann, J.
AU  - Škorvánek, M.*
C1  - 61072
C2  - 49692
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
SP  - 54-55
TI  - Atypical presentations of DYT1 dystonia with acute craniocervical onset.
JO  - Parkinsonism Relat. Disord.
VL  - 83
PB  - Elsevier Sci Ltd
PY  - 2021
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - Introduction: Next-generation sequencing is now used on a routine basis for molecular testing but studies on copy-number variant (CNV) detection from next-generation sequencing data are underrepresented. Utilizing an existing whole-exome sequencing (WES) dataset, we sought to investigate the contribution of rare CNVs to the genetic causality of dystonia. Methods: The CNV read-depth analysis tool ExomeDepth was applied to the exome sequences of 953 unrelated patients with dystonia (600 with isolated dystonia and 353 with combined dystonia; 33% with additional neurological involvement). We prioritized rare CNVs that affected known disease genes and/or were known to be associated with defined microdeletion/microduplication syndromes. Pathogenicity assessment of CNVs was based on recently published standards of the American College of Medical Genetics and Genomics and the Clinical Genome Resource. Results: We identified pathogenic or likely pathogenic CNVs in 14 of 953 patients (1.5%). Of the 14 different CNVs, 12 were deletions and 2 were duplications, ranging in predicted size from 124bp to 17 Mb. Within the deletion intervals, BRPF1, CHD8, DJ1, EFTUD2, FGF14, GCH1, PANK2, SGCE, UBE3A, VPS16, WARS2, and WDR45 were determined as the most clinically relevant genes. The duplications involved chromosomal regions 6q21-q22 and 15q11-q13. CNV analysis increased the diagnostic yield in the total cohort from 18.4% to 19.8%, as compared to the assessment of single-nucleotide variants and small insertions and deletions alone. Conclusions: WES-based CNV analysis in dystonia is feasible, increases the diagnostic yield, and should be combined with the assessment of single-nucleotide variants and small insertions and deletions.
AU  - Zech, M.
AU  - Boesch, S.*
AU  - Škorvánek, M.*
AU  - Necpál, J.*
AU  - Švantnerová, J.*
AU  - Wagner, M.
AU  - Dincer, Y.*
AU  - Sadr-Nabavi, A.*
AU  - Serranová, T.*
AU  - Rektorová, I.*
AU  - Havránková, P.*
AU  - Ganai, S.*
AU  - Mosejová, A.*
AU  - Příhodová, I.*
AU  - Šarláková, J.*
AU  - Kulcsarová, K.*
AU  - Ulmanová, O.*
AU  - Bechyně, K.*
AU  - Ostrozovičová, M.*
AU  - Haň, V.*
AU  - Ventosa, J.R.*
AU  - Shariati, M.*
AU  - Shoeibi, A.*
AU  - Weber, S.
AU  - Mollenhauer, B.*
AU  - Trenkwalder, C.*
AU  - Berutti, R.
AU  - Strom, T.M.*
AU  - Ceballos-Baumann, A.*
AU  - Mall, V.*
AU  - Haslinger, B.*
AU  - Jech, R.*
AU  - Winkelmann, J.
C1  - 61391
C2  - 50205
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
SP  - 129-134
TI  - Clinically relevant copy-number variants in exome sequencing data of patients with dystonia.
JO  - Parkinsonism Relat. Disord.
VL  - 84
PB  - Elsevier Sci Ltd
PY  - 2021
SN  - 1353-8020
ER  - 

TY  - JOUR
AU  - Hopfner, F.*
AU  - Mueller, S.H.*
AU  - Szymczak, S.*
AU  - Junge, O.*
AU  - Tittmann, L.*
AU  - May, S.*
AU  - Lohmann, K.*
AU  - Grallert, H.
AU  - Lieb, W.*
AU  - Strauch, K.
AU  - Müller-Nurasyid, M.
AU  - Berger, K.*
AU  - Schormair, B.
AU  - Winkelmann, J.
AU  - Mollenhauer, B.*
AU  - Trenkwalder, C.*
AU  - Maetzler, W.*
AU  - Berg, D.*
AU  - Kasten, M.*
AU  - Klein, C.*
AU  - Höglinger, G.U.*
AU  - Gasser, T.*
AU  - Deuschl, G.*
AU  - Franke, A.*
AU  - Krawczak, M.*
AU  - Dempfle, A.*
AU  - Kuhlenbäumer, G.*
C1  - 59195
C2  - 48670
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
SP  - 24-26
TI  - Private variants in PRKN are associated with late-onset Parkinson's disease.
JO  - Parkinsonism Relat. Disord.
VL  - 75
PB  - Elsevier Sci Ltd
PY  - 2020
SN  - 1353-8020
ER  - 

TY  - JOUR
AU  - Necpál, J.*
AU  - Zech, M.
AU  - Valachová, A.*
AU  - Sedláček, Z.*
AU  - Bendová, Š.*
AU  - Hančárová, M.*
AU  - Okáľová, K.*
AU  - Winkelmann, J.
AU  - Jech, R.*
C1  - 59683
C2  - 48911
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
SP  - 87-88
TI  - Severe paroxysmal dyskinesias without epilepsy in a RHOBTB2 mutation carrier.
JO  - Parkinsonism Relat. Disord.
VL  - 77
PB  - Elsevier Sci Ltd
PY  - 2020
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - Introduction:The gene encoding myelin-associated glycoprotein (MAG) has been implicated in autosomal-recessive spastic paraplegia type 75. To date, only four families with biallelic missense variants in MAG have been reported. The genotypic and phenotypic spectrum of MAG-associated disease awaits further elucidation.Methods: Four unrelated patients with complex neurologic conditions underwent whole-exome sequencing within research or diagnostic settings. Following determination of the underlying genetic defects, in-depth phenotyping and literature review were performed.Results: In all case subjects, we detected ultra-rare homozygous or compound heterozygous variants in MAG. The observed nonsense (c.693C > A [p.Tyr231*], c.980G > A [p.Trp327*], c.1126C > T [p.Gln376*], and 1522C > T [p.Arg508*]) and frameshift (c.517_521dupAGCTG [p.Trp174*]) alleles were predicted to result in premature termination of protein translation. Affected patients presented with variable combinations of psychomotor delay, ataxia, eye movement abnormalities, spasticity, dystonia, and neuropathic symptoms. Cerebellar signs, nystagmus, and pyramidal tract dysfunction emerged as unifying features in the majority of MAG-mutated individuals identified to date.Conclusions: Our study is the first to describe biallelic null variants in MAG, confirming that loss of myelin associated glycoprotein causes severe infancy-onset disease with central and peripheral nervous system involvement.
AU  - Zech, M.
AU  - Brunet, T.*
AU  - Škorvánek, M.*
AU  - Blaschek, A.*
AU  - Vill, K.*
AU  - Hanker, B.*
AU  - Hüning, I.*
AU  - Haň, V.*
AU  - Došekova, P.*
AU  - Gdovinová, Z.*
AU  - Alhaddad, B.*
AU  - Berutti, R.
AU  - Strom, T.M.*
AU  - Růžička, E.*
AU  - Kamsteeg, E.J.*
AU  - van der Smagt, J.J.*
AU  - Wagner, M.
AU  - Jech, R.*
AU  - Winkelmann, J.
C1  - 59610
C2  - 48923
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
SP  - 70-75
TI  - Recessive null-allele variants in MAG associated with spastic ataxia, nystagmus, neuropathy, and dystonia.
JO  - Parkinsonism Relat. Disord.
VL  - 77
PB  - Elsevier Sci Ltd
PY  - 2020
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - Parkinson's disease (PD) is an etiologically heterogeneous disorder. Experimental, clinical 'and epidemiological data suggest that intestinal inflammation contributes to the pathogenesis of PD. This article reviews recent literature on gut microbiota and intestinal inflammation in PD. We propose that intestinal inflammation links environmental factors (e.g. an altered gut microbiota composition) to neurodegeneration in (genetically susceptible) PD patients. In addition, there is an epidemiological and genetic overlap between PD and inflammatory bowel disease. This overlap provides an opportunity to develop new treatment strategies for at least a subgroup of PD patients.
AU  - Becker, A.*
AU  - Faßbender, K.*
AU  - Oertel, W.H.
AU  - Unger, M.M.*
C1  - 54478
C2  - 45623
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
SP  - 43-45
TI  - A punch in the gut - Intestinal inflammation links environmental factors to neurodegeneration in Parkinson's disease.
JO  - Parkinsonism Relat. Disord.
VL  - 60
PB  - Elsevier Sci Ltd
PY  - 2019
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - The terms "on" and "off" were used by Marsden and his contemporaries over 40 years ago to describe times when Parkinson's disease patients experienced good motor function ("on") and immobility ("off"). Yet there remains no published consensus definition of "off", leading clinicians and patients to develop individualized impressions of "off" determinations. In this paper, we first discuss the evolution of the terminology and understanding of "off" states since Marsden's time, which now include non-motor as well as motor symptoms. We then review pathophysiology and risk factors for the development of "off' states as well as tools to detect the "off" state, before proposing a practical definition of "off" for consideration. A common, practical definition of the "off" state could improve clinical recognition of "off' symptoms and lead to significant benefit for patients.
AU  - Chou, K.L.*
AU  - Stacy, M.*
AU  - Simuni, T.*
AU  - Miyasaki, J.*
AU  - Oertel, W.H.
AU  - Sethi, K.*
AU  - Fernandez, H.H.*
AU  - Stocchi, F.*
C1  - 53001
C2  - 44719
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
SP  - 9-16
TI  - The spectrum of "off" in Parkinson's disease: What have we learned over 40 years?
JO  - Parkinsonism Relat. Disord.
VL  - 51
PB  - Elsevier Sci Ltd
PY  - 2018
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - Introduction: Recently, mutations in the collagen gene COL6A3 have been reported in patients with autosomal-recessive, isolated dystonia (DYT27). Zebrafish models of COL6A3 mutations showed deficits in axonal targeting mechanisms. Therefore, COL6A3 mutations have been considered to contribute to irregular sensorimotor circuit formation. To test this hypothesis, we examined structural abnormalities in cerebral fiber tracts of dystonia patients with COL6A3 mutations using diffusion tensor imaging. Methods: We performed a voxel-wise statistical analysis to compare fractional anisotropy within whole-brain white matter in four of the previously reported dystonia patients with COL6A3 mutations and 12 healthy controls. Region of interests-based probabilistic tractography was performed as a post-hoc-analysis. Results: Dystonia patients with COL6A3 mutations showed significantly decreased fractional anisotropy bilaterally in midbrain, pons, cerebellar peduncles, thalamus, internal capsule and in frontal and parietal subcortical regions compared to healthy controls. Tractography revealed a decreased fractional anisotropy in patients with COL6A3-associated dystonia between bilateral dentate nucleus and thalamus. Conclusion: Diffusion tensor imaging demonstrates an altered white matter structure especially in various parts of the cerebello-thalamo-cortical network in dystonia patients with COL6A3 mutations. This suggests that COL6A3 mutations could contribute to abnormal circuit formation as potential basis of dystonia.
AU  - Jochim, A.*
AU  - Li, Y.*
AU  - Zech, M.
AU  - Lam, D.D.
AU  - Gross, N.*
AU  - Koch, K.W.*
AU  - Zimmer, C.*
AU  - Winkelmann, J.
AU  - Haslinger, B.*
C1  - 52212
C2  - 43809
SP  - 74-78
TI  - Microstructural white matter abnormalities in patients with COL6A3 mutations (DYT27 dystonia).
JO  - Parkinsonism Relat. Disord.
VL  - 46
PY  - 2018
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - Background: Individuals with rapid eye movement (REM)-sleep behavior disorder (RBD) are likely to progress to synucleinopathies, mainly Parkinson's disease (PD), dementia with Lewy-bodies (DLB) and multiple system atrophy (MSA). The genetics of RBD only partially overlaps with PD and DLB, and the role of LRRK2 variants in risk for RBD is still not clear.Methods: The full coding sequence, exon-intron boundaries and 5' and 3' untranslated regions of LRRK2 were sequenced using targeted next-generation sequencing. A total of 350 RBD patients and 869 controls were sequenced, and regression and burden models were used to examine the association between LRRK2 variants and RBD.Results: No pathogenic mutations that are known to cause PD were identified in RBD patients. The p.N551K-p.R1398H-p.K1423K haplotype was associated with a reduced risk for RBD (OR = 0.66, 95% CI 0.44-0.98, p = 0.0055 for the tagging p.N551K substitution). A common variant, p.S1647T, was nominally associated with risk for RBD (OR = 1.28, 95% Cl 1.05-1.56, p = 0.029). Burden analysis identified associations with domains and exons that were derived by the variants of the protective haplotype, and no burden of other rare variants was identified.Conclusions: Carriers of the LRRK2 p.N551K-p.R1398H-p.K1423K haplotype have a reduced risk for developing RBD, yet PD-causing mutations probably have minor or no role in RBD. Additional work is needed to confirm these results and to identify the mechanism associated with reduced risk for RBD. (C) 2018 Elsevier Ltd. All rights reserved.
AU  - Ouled Amar Bencheikh, B.*
AU  - Ruskey, J.A.*
AU  - Arnulf, I.*
AU  - Dauvilliers, Y.*
AU  - Monaca, C.C.*
AU  - De Cock, V.C.*
AU  - Gagnon, J.F.*
AU  - Spiegelman, D.*
AU  - Hu, M.T.M.*
AU  - Högl, B.*
AU  - Stefani, A.*
AU  - Ferini-Strambi, L.*
AU  - Plazzi, G.*
AU  - Antelmi, E.*
AU  - Young, P.*
AU  - Heidbreder, A.*
AU  - Mollenhauer, B.*
AU  - Sixel-Döring, F.*
AU  - Trenkwalder, C.*
AU  - Oertel, W.H.
AU  - Montplaisir, J.Y.*
AU  - Postuma, R.B.*
AU  - Rouleau, G.A.*
AU  - Gan-Or, Z.*
C1  - 53323
C2  - 44800
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
SP  - 98-101
TI  - LRRK2 protective haplotype and full sequencing study in REM sleep behavior disorder.
JO  - Parkinsonism Relat. Disord.
VL  - 52
PB  - Elsevier Sci Ltd
PY  - 2018
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - Introduction: RLS is a common movement disorders with a strong genetic component in its pathophysiology, but, up to now, no causative mutation has been reported. Methods: We re-evaluated the previously described RLS2 family by exome sequencing. Results: We identified fifteen variations in the 14q critical region. The c.485G > A transition of the TRAPPC6B gene segregates with the RLS2 haplotype, is absent in 200 local controls and is extremely rare in 12988 exomes from the Exome Variant Server (EVS). This variant alters a splicing site and hampers the normal transcript processing by promoting exon 3-skipping as demonstrated by minigene transfection and by patient transcripts. Conclusions: We identified a TRAPPC6B gene mutation associated to the RLS locus on chromosome 14.
AU  - Aridon, P.*
AU  - De Fusco, M.*
AU  - Winkelmann, J.
AU  - Zucconi, M.*
AU  - Arnao, V.*
AU  - Ferini-Strambi, L.*
AU  - Casari, G.*
C1  - 49919
C2  - 41914
CY  - Oxford
SP  - 135-138
TI  - A TRAPPC6B splicing variant associates to restless legs syndrome.
JO  - Parkinsonism Relat. Disord.
VL  - 31
PB  - Elsevier Sci Ltd
PY  - 2016
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - BACKGROUND: An increasing number of rare, functionally relevant non-c.907_909delGAG (non-ΔGAG) variants in TOR1A have been recognized, associated with phenotypic expressions different from classic DYT1 childhood-onset generalized dystonia. Only recently, DYT1 genotype-phenotype correlations have been proposed, awaiting further elucidation in independent cohorts. METHODS: We screened the entire coding sequence and the 5'-UTR region of TOR1A for rare non-ΔGAG sequence variants in a large series of 940 individuals with various forms of isolated dystonia as well as in 376 ancestry-matched controls. The frequency of rare, predicted deleterious non-ΔGAG TOR1A variants was assessed in the European sample of the Exome Aggregation Consortium (ExAC) dataset. RESULTS: In the case cohort, we identified a rare 5'-UTR variant (c.-39G > T), a rare splice-region variant (c.445-8T > C), as well as one novel (p.Ile231Asn) and two rare (p.Ala163Val, p.Thr321Met) missense variants, each in a single patient with adult-onset focal/segmental isolated dystonia. Of these variants, only p.Thr321Met qualified as possibly disease-related according to variant interpretation criteria. One novel, predicted deleterious missense substitution (p.Asn208Ser) was detected in the control cohort. Among European ExAC individuals, the carrier rate of rare, predicted deleterious non-ΔGAG variants was 0.4%. CONCLUSIONS: Our study does not allow the establishment of genotype-specific clinical correlations for DYT1. Further large-scale genetic screening accompanied by comprehensive segregation and functional studies is required to conclusively define the contribution of TOR1A whole-gene variation to the pathogenesis of isolated dystonia.
AU  - Zech, M.
AU  - Jochim, A.*
AU  - Boesch, S.*
AU  - Weber, S.
AU  - Meindl, T.*
AU  - Peters, A.
AU  - Gieger, C.
AU  - Mueller, J.C.*
AU  - Messner, M.*
AU  - Ceballos-Baumann, A.*
AU  - Poewe, W.*
AU  - Haslinger, B.*
AU  - Winkelmann, J.
C1  - 49211
C2  - 40688
CY  - Oxford
SP  - 119-123
TI  - Systematic TOR1A non-c.907_909delGAG variant analysis in isolated dystonia and controls.
JO  - Parkinsonism Relat. Disord.
VL  - 31
PB  - Elsevier Sci Ltd
PY  - 2016
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - INTRODUCTION: Mutations in TUBB4A have recently been implicated in two seemingly different disease entities, namely DYT4-isolated dystonia and hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), a disorder characterized by considerable clinical variability. While several follow-up studies confirmed the importance of TUBB4A mutations in the development of H-ABC, their contribution to isolated dystonia remains uncertain. METHODS: We screened the TUBB4A coding regions in a large population of 709 isolated dystonia patients of German/Austrian ancestry as well as in 376 ancestry-matched control subjects by means of Sanger sequencing and high-resolution melting. In addition, we assessed the overall frequency of rare non-synonymous TUBB4A genetic variation in the huge exome dataset released by the Exome Aggregation Consortium (ExAC). RESULTS: We were unable to identify any possibly pathogenic sequence alteration in either patients or controls. According to ExAC, the overall prevalence of rare missense and loss-of-function alleles in the TUBB4A gene can be estimated at ∼1:706. CONCLUSIONS: In accordance with previous work, our data indicate that TUBB4A coding mutations do not play a critical role in the broad population of isolated dystonia patients. Rather, isolated dystonia as seen in DYT4 might be an exceptional feature occurring in the heterogeneous phenotypic spectrum due to TUBB4A mutations.
AU  - Zech, M.
AU  - Boesch, S.*
AU  - Jochim, A.*
AU  - Graf, S.*
AU  - Lichtner, P.
AU  - Peters, A.
AU  - Gieger, C.
AU  - Müller, J.*
AU  - Poewe, W.*
AU  - Haslinger, B.*
AU  - Winkelmann, J.
C1  - 46691
C2  - 37713
SP  - 1278-1281
TI  - Large-scale TUBB4A mutational screening in isolated dystonia and controls.
JO  - Parkinsonism Relat. Disord.
VL  - 21
IS  - 10
PY  - 2015
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - no Abstract
AU  - Kaffe, M.
AU  - Gross, N.*
AU  - Castrop, F.*
AU  - Dresel, C.*
AU  - Gieger, C.
AU  - Lichtner, P.
AU  - Haslinger, B.*
AU  - Winkelmann, J.
C1  - 7106
C2  - 29477
SP  - 104-106
TI  - Mutational screening of THAP1 in a German population with primary dystonia.
JO  - Parkinsonism Relat. Disord.
VL  - 18
IS  - 1
PB  - Elsevier
PY  - 2012
SN  - 1353-8020
ER  - 

TY  - JOUR
AB  - The GIGYF2 (Grb10-Interacting GYF Protein-2) gene has recently been proposed to be the responsible gene for the PARK11 locus. Ten different putative pathogenic variants were identified in cohorts of Parkinson's disease (PD) patients from Italy and France. Among these variants Asn56Ser and Asn457Thr were found repeatedly. In the present study we screened 669 PD patients (predominantly of central European origin) and 1051 control individuals for the presence of these two variants. Asn56Ser was found in one patient with a positive family history of the disease and in one control individual. The affected sister of the patient did not carry this variant. Asn457Thr was found in one patient, who was exceptional for his Egyptian origin and in three control individuals. This variant was not found in 50 control individuals from Egypt. We conclude that neither of these two variants plays a major role in the pathogenesis of PD in our study population.
AU  - *
AU  - Schulte, C.*
AU  - Reinthaler, E.*
AU  - Haubenberger, D.*
AU  - Balzar, J.*
AU  - Lichtner, P.
AU  - El Tawil, S.*
AU  - Edrise, S.*
AU  - Foki, T.*
AU  - Pirker, W.*
AU  - Katzenschlager, R.*
AU  - Daniel, G.*
AU  - Brücke, T.*
AU  - Auff, E.*
AU  - Gasser, T.*
C1  - 702
C2  - 27146
SP  - 532-534
TI  - PARK11 gene (GIGYF2) variants Asn56Ser and Asn457Thr are not pathogenic for Parkinson's disease.
JO  - Parkinsonism Relat. Disord.
VL  - 15
IS  - 7
PB  - Elsevier
PY  - 2009
SN  - 1353-8020
ER  -