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Katja Lohmann,
Robert A Wilcox,
Susen Winkler,
Alfredo Ramirez,
Aleksandar Rakovic,
Jin-Sung Park,
Björn Arns,
Thora Lohnau,
Justus Groen,
Meike Kasten, [......],
Anthony E Lang,
Alexander Münchau,
Vladimir Kostic,
Kristina Simonyan,
Marc Agzarian,
Laurie J Ozelius,
Antonius P M Langeveld,
Carolyn M Sue,
Marina A J Tijssen,
Christine Klein
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ABSTRACT: OBJECTIVE: A study was undertaken to identify the gene underlying DYT4 dystonia, a dominantly inherited form of spasmodic dysphonia combined with other focal or generalized dystonia and a characteristic facies and body habitus, in an Australian family. METHODS: Genome-wide linkage analysis was carried out in 14 family members followed by genome sequencing in 2 individuals. The index patient underwent a detailed neurological follow-up examination, including electrophysiological studies and magnetic resonance imaging scanning. Biopsies of the skin and olfactory mucosa were obtained, and expression levels of TUBB4 mRNA were determined by quantitative real-time polymerase chain reaction in 3 different cell types. All exons of TUBB4 were screened for mutations in 394 unrelated dystonia patients. RESULTS: The disease-causing gene was mapped to a 23cM region on chromosome 19p13.3-p13.2 with a maximum multipoint LOD score of 5.338 at markers D9S427 and D9S1034. Genome sequencing revealed a missense variant in the TUBB4 (tubulin beta-4; Arg2Gly) gene as the likely cause of disease. Sequencing of TUBB4 in 394 unrelated dystonia patients revealed another missense variant (Ala271Thr) in a familial case of segmental dystonia with spasmodic dysphonia. mRNA expression studies demonstrated significantly reduced levels of mutant TUBB4 mRNA in different cell types from a heterozygous Arg2Gly mutation carrier compared to controls. INTERPRETATION: A mutation in TUBB4 causes DYT4 dystonia in this Australian family with so-called whispering dysphonia, and other mutations in TUBB4 may contribute to spasmodic dysphonia. Given that TUBB4 is a neuronally expressed tubulin, our results imply abnormal microtubule function as a novel mechanism in the pathophysiology of dystonia. Ann Neurol 2012.
Annals of Neurology 12/2012; · 11.09 Impact Factor
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Anne Weissbach,
Katharina Siegesmund,
Norbert Brüggemann, Alexander Schmidt,
Meike Kasten,
Irene Pichler,
Hiltrud Muhle,
Ebba Lohmann,
Thora Lohnau,
Eberhard Schwinger,
Johann Hagenah,
Ulrich Stephani,
Peter P Pramstaller,
Christine Klein,
Katja Lohmann
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ABSTRACT: Restless legs syndrome (RLS) has a high familial aggregation. To date, several loci and genetic risk factors have been identified, but no causative gene mutation has been found.
We evaluated a German family with autosomal dominantly inherited RLS in 7 definitely and 2 possibly affected members by genome-wide linkage analysis and exome sequencing.
We identified three novel missense and one splice site variant in the PCDHA3, WWC2, ATRN, and FAT2 genes that segregated with RLS in the family. All four exons of the PCDHA3 gene, the most plausible candidate, were sequenced in 64 unrelated RLS cases and 250 controls. This revealed three additional rare missense variants (frequency <1%) of unknown pathogenicity in 2 patients and 1 control.
We present the first next-generation sequencing study on RLS and suggest PCDHA3 as a candidate gene for RLS. © 2012 Movement Disorder Society.
Movement Disorders 11/2012; 27(13):1686-9. · 4.51 Impact Factor
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Katja Lohmann,
Nils Uflacker,
Alev Erogullari,
Thora Lohnau,
Susen Winkler,
Andreas Dendorfer,
Susanne A Schneider,
Alma Osmanovic,
Marina Svetel,
Andreas Ferbert, [......],
Alexander Münchau,
Christoph Kamm,
Matthias Wittstock,
Andreas Kupsch,
Elena Moro,
Jens Volkmann,
Vladimir Kostic,
Frank J Kaiser,
Christine Klein,
Norbert Brüggemann
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ABSTRACT: Mutations in THAP1 have been associated with dystonia 6 (DYT6). THAP1 encodes a transcription factor that represses the expression of DYT1. To further evaluate the mutational spectrum of THAP1 and its associated phenotype, we sequenced THAP1 in 567 patients with focal (n = 461), segmental (n = 68), or generalized dystonia (n = 38). We identified 10 novel variants, including six missense substitutions within the DNA-binding Thanatos-associated protein domain (Arg13His, Lys16Glu, His23Pro, Lys24Glu, Pro26Leu, Ile80Val), a 1bp-deletion downstream of the nuclear localization signal (Asp191Thrfs*9), and three alterations in the untranslated regions. The effect of the missense variants was assessed using prediction tools and luciferase reporter gene assays. This indicated the Ile80Val substitution as a benign variant. The subcellular localization of Asp191Thrfs*9 suggests a disturbed nuclear import for this mutation. Thus, we consider six of the 10 novel variants as pathogenic mutations accounting for a mutation frequency of 1.1%. Mutation carriers presented mainly with early onset dystonia (<12 years in five of six patients). Symptoms started in an arm or neck and spread to become generalized in three patients or segmental in two patients. Speech was affected in four mutation carriers. In conclusion, THAP1 mutations are rare in unselected dystonia patients and functional analysis is necessary to distinguish between benign variants and pathogenic mutations.
European journal of human genetics: EJHG 08/2011; 20(2):171-5. · 3.56 Impact Factor
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ABSTRACT: The classification of arm tremor in cervical dystonia is a controversial issue. There have been many, at times passionate disputes in the movement disorder community about whether it should be classified as a manifestation of dystonia or essential tremor associated with dystonia. There are arguments in favor of both views. Settling the issue might be relevant to the understanding of the etiological, presumably genetic, background because phenomenological grouping is the starting point for genetic analyses. From this point of view, we outline this tremor debate and add some new clinical data.
Movement Disorders 07/2011; 26(10):1789-92. · 4.51 Impact Factor
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ABSTRACT: Psychological abnormalities, including anxiety, have been observed in patients with musician's dystonia (MD). It is unclear if these conditions develop prior to MD or if they are psychoreactive phenomena.
Psychological conditions were studied in 44 professional musicians with MD, 45 healthy musicians, and 44 healthy nonmusicians using the State-Trait Anxiety Inventory (STAI) and NEO Five-Factor Inventory (NEO-FFI).
Musicians with MD had significantly higher STAI state and trait anxiety scores than healthy musicians (P = .009 and P = .012, respectively) and nonmusicians (P = .013 and P = .001, respectively) and significantly higher NEO-FFI neuroticism scores than healthy musicians (P = .018) and nonmusicians (P = .001). Duration of dystonia did not correlate with anxiety or neuroticism scores.
Musicians with MD display increased levels of anxiety and neuroticism. The lack of correlation between anxiety and the duration of dystonia suggests that anxiety may not be a psychoreactive phenomenon and is consistent with the hypothesis that anxiety and MD share a common pathophysiological mechanism.
Movement Disorders 03/2011; 26(3):539-42. · 4.51 Impact Factor
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ABSTRACT: Musician's dystonia (MD) is traditionally considered a sporadic and task-specific movement disorder.
The phenotypic spectrum of the disorder was studied in 116 patients suffering from MD including videotaping.
Based on the movement disorders observed, we categorized our patients into two different groups: (i) 65 patients with isolated MD, that is only present when playing the instrument and (ii) 51 patients with MD and one or more additional features of primary dystonia independent of MD (complex MD). Patients with a positive family history of movement disorders had an increased risk to develop complex MD [odds ratio = 4.80; 95% confidence interval: 1.94-11.92; P = 0.001].
In previous studies, we recently identified 22 relatives with different types of movement disorders in the families of 28 MD patients. Taken together, our results further support a genetic contribution to MD with a broad individual and familial phenotypic spectrum consisting of MD, other dystonias and even other, non-dystonic movement disorders.
Movement Disorders 02/2011; 26(3):546-9. · 4.51 Impact Factor
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Lena Kertelge,
Norbert Brüggemann, Alexander Schmidt,
Vera Tadic,
Claudia Wisse,
Sylwia Dankert,
Laura Drude,
Joyce van der Vegt,
Hartwig Siebner,
Heike Pawlack,
Peter P Pramstaller,
Maria Isabel Behrens,
Alfredo Ramirez,
Dirk Reichel,
Carsten Buhmann,
Johann Hagenah,
Christine Klein,
Katja Lohmann,
Meike Kasten
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ABSTRACT: Olfaction is typically impaired in idiopathic Parkinson's disease (IPD), but its role is uncertain in monogenic PD. Diminished color discrimination has been suggested as another early sign of dopaminergic dysfunction but not been systematically studied. Furthermore, it is unknown whether both deficits are linked. We examined 100 patients with IPD, 27 manifesting mutation carriers (MC), 20 nonmanifesting mutation carriers (NMC), and 110 controls. Participants underwent a standardized neurological examination, the University of Pennsylvania Smell Identification Test (UPSIT), the Farnsworth-Munsell (FM) color discrimination test, and mutation testing in known PD genes. The monogenic group consisted of 15 Parkin (6MC/9NMC), 17 PINK1 (10MC/7NMC), 8 LRRK2 (4MC/4NMC), 3 SNCA (MC), and 4 ATP13A2 (MC) carriers. Olfaction was most impaired in IPD (UPSIT percentiles 10.1 ± 13.5) compared with all other groups (MC 13.8 ± 11.9, NMC 19.6 ± 13.0, controls 33.8 ± 22.4). Within MC, carriers of two mutations in Parkin and PINK1 showed higher UPSIT percentiles than LRRK2 and SNCA carriers. Color discrimination was reduced in IPD (FM total error score 134.8 ± 92.7). In MC (122.4 ± 142.4), the reduction was most pronounced in LRRK2, NMC (80.0 ± 38.8) were comparable with controls (97.2 ± 61.1). UPSIT and FM scores were correlated in the control (r = -0.305; P = 0.002) and the IPD group (r = -0.303; P = 0.006) but not among mutation carriers. First, we confirmed olfaction and color discrimination to be impaired in IPD and suggest olfaction to be a premotor sign. Second, olfaction differed between carriers with one and two mutations in Parkin/PINK1-associated PD. Third, olfaction and color discrimination impairment do not necessarily evolve in parallel.
Movement Disorders 11/2010; 25(15):2665-9. · 4.51 Impact Factor
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Norbert Brüggemann,
Johann Hagenah,
Kathrin Reetz, Alexander Schmidt,
Meike Kasten,
Inga Buchmann,
Susanne Eckerle,
Manfred Bähre,
Alexander Münchau,
Ana Djarmati,
Joyce van der Vegt,
Hartwig Siebner,
Ferdinand Binkofski,
Alfredo Ramirez,
Maria I Behrens,
Christine Klein
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ABSTRACT: To determine clinical features and to identify changes in brain structure and function in compound heterozygous and heterozygous ATP13A2 mutation carriers.
Prospective multimodal clinical and neuroimaging study.
University of Lübeck, Lübeck, Germany.
Eight family members of a large Chilean pedigree with Kufor-Rakeb syndrome (KRS).
Clinical characterization, dopamine transporter (DAT) imaging, voxel-based morphometry (VBM), and transcranial sonography (TCS).
Frequency of parkinsonian signs, brain structure, and functional alterations.
The only available patient with compound heterozygous KRS showed a markedly reduced striatal DAT density bilaterally. Magnetic resonance imaging revealed severe global brain atrophy as well as iron deposition in the basal ganglia. The heterozygous mother had definite parkinsonism with reduced DAT density in both putamina. While all asymptomatic heterozygous siblings displayed subtle extrapyramidal signs, DAT imaging revealed striatal tracer uptake within physiological levels. Voxel-based morphometry revealed an increase in gray matter volume in the right putamen and a decrease in the cerebellum of the heterozygous carriers. In all mutation carriers, the substantia nigra had a normal appearance on TCS.
Single ATP13A2 heterozygous mutations may be associated with clinical signs of parkinsonism and contribute to structural and functional brain changes. Lack of hyperechogenicity in the substantia nigra may be a distinctive feature of this form of genetic parkinsonism. This, along with the finding of iron in the basal ganglia in our patient with KRS, implies a different underlying pathophysiology compared with other monogenic forms of parkinsonism and idiopathic PD and may place KRS among the syndromes of neurodegeneration with brain iron accumulation (NBIA).
Archives of neurology 11/2010; 67(11):1357-63. · 6.31 Impact Factor
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Maria I Behrens,
Norbert Brüggemann,
Pedro Chana,
Pablo Venegas,
Marianne Kägi,
Teresa Parrao,
Patricia Orellana,
Cristian Garrido,
Cecilia V Rojas,
Jan Hauke, [......],
Rafael González,
Nicolas Seleme,
Verónica Fernández, Alexander Schmidt,
Ferdinand Binkofski,
Detlef Kömpf,
Christian Kubisch,
Johann Hagenah,
Christine Klein,
Alfredo Ramirez
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ABSTRACT: We report the clinical features of the original Chilean family with Kufor-Rakeb syndrome (KRS) that led to the discovery of the ATP13A2 gene at the PARK9 locus. KRS is a rare juvenile-onset autosomal recessive disease characterized by progressive Parkinsonism, pyramidal signs, and cognitive decline in addition to vertical gaze palsy and facial-faucial-finger minimyoclonus. Neurological and neuropsychological examination during a 10-year period, videotaping, neuroimaging, and measurement of DNA methylation of the ATP13A2 promoter region were performed. The youngest 5 of 17 children of nonconsanguineous parents, carrying compound-heterozygous ATP13A2 mutations, had normal development until ages ∼10 to 12 years, when school performance deteriorated and slowness, rigidity, and frequent falls developed. Examination revealed bradykinesia, subtle postural/action tremor, cogwheel rigidity, spasticity, upward gaze palsy, smooth pursuit with saccadic intrusions, and dementia. Additional signs included facial-faucial-finger minimyoclonus, absent postural reflexes, visual/auditory hallucinations, and insomnia. Levodopa response could not be fully judged in this family. T2* magnetic resonance imaging sequences revealed marked diffuse hypointensity of the caudate (head and body) and lenticular nucleus bilaterally. Disease progression was slow including epilepsy, cachexia, and anarthria. Four affected members died after 28.5 ± 5.5 (mean ± SD) years of disease. Two heterozygous carriers, the mother and eldest sibling, showed jerky perioral muscle contractions and clumsiness of hand movements. There was no significant correlation between DNA methylation of the ATP13A2 promoter region and disease progression. The marked caudate and lenticular nucleus T2*-hypointensity suggests that KRS might belong to the family of neurodegenerative diseases associated with brain iron accumulation.
Movement Disorders 09/2010; 25(12):1929-37. · 4.51 Impact Factor
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PhD Maria I. Behrens MD,
Norbert Brüggemann MD,
Pedro Chana MD,
Pablo Venegas MD,
Marianne Kägi MD,
Teresa Parrao BPsych,
Patricia Orellana MD,
Cristian Garrido MRT,
Cecilia V. Rojas PhD,
Jan Hauke MSc, [......],
Rafael González,
Nicolas Seleme,
Verónica Fernández, Alexander Schmidt,
Ferdinand Binkofski,
Detlef Kömpf,
Christian Kubisch,
Johann Hagenah,
Christine Klein,
Alfredo Ramirez
[show abstract]
[hide abstract]
ABSTRACT: We report the clinical features of the original Chilean family with Kufor-Rakeb syndrome (KRS) that led to the discovery of the ATP13A2 gene at the PARK9 locus. KRS is a rare juvenile-onset autosomal recessive disease characterized by progressive Parkinsonism, pyramidal signs, and cognitive decline in addition to vertical gaze palsy and facial-faucial-finger minimyoclonus. Neurological and neuropsychological examination during a 10-year period, videotaping, neuroimaging, and measurement of DNA methylation of the ATP13A2 promoter region were performed. The youngest 5 of 17 children of nonconsanguineous parents, carrying compound-heterozygous ATP13A2 mutations, had normal development until ages ∼10 to 12 years, when school performance deteriorated and slowness, rigidity, and frequent falls developed. Examination revealed bradykinesia, subtle postural/action tremor, cogwheel rigidity, spasticity, upward gaze palsy, smooth pursuit with saccadic intrusions, and dementia. Additional signs included facial-faucial-finger minimyoclonus, absent postural reflexes, visual/auditory hallucinations, and insomnia. Levodopa response could not be fully judged in this family. T2* magnetic resonance imaging sequences revealed marked diffuse hypointensity of the caudate (head and body) and lenticular nucleus bilaterally. Disease progression was slow including epilepsy, cachexia, and anarthria. Four affected members died after 28.5 ± 5.5 (mean ± SD) years of disease. Two heterozygous carriers, the mother and eldest sibling, showed jerky perioral muscle contractions and clumsiness of hand movements. There was no significant correlation between DNA methylation of the ATP13A2 promoter region and disease progression. The marked caudate and lenticular nucleus T2*-hypointensity suggests that KRS might belong to the family of neurodegenerative diseases associated with brain iron accumulation. © 2010 Movement Disorder Society.
Movement Disorders 09/2010; 25(12):1929 - 1937. · 4.51 Impact Factor
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Kathrin Reetz,
Vera Tadic,
Meike Kasten,
Norbert Brüggemann, Alexander Schmidt,
Johann Hagenah,
Peter P Pramstaller,
Alfredo Ramirez,
Maria I Behrens,
Hartwig R Siebner,
Christine Klein,
Ferdinand Binkofski
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[hide abstract]
ABSTRACT: Several genes associated with monogenic forms of Parkinson's disease (PD) have been discovered, opening up new avenues for the investigation of presymptomatic stages of PD. Using voxel-based morphometry in 30 asymptomatic mutation carriers (MC) with mutations in four different genes for PD and 100 healthy controls, we identified an increase in gray matter volume (GMV) in the striatum in asymptomatic Parkin, PINK1, ATP13A2 and, to a much lesser extent, in LRRK2 MC. Moreover, an increase in GMV was found in the parieto-temporo-occipital association cortex in asymptomatic Parkin and ATP13A2 MC. The observed striatal GMV increase might be the common structural correlate of compensatory mechanisms due to the latent dopaminergic deficit, reflecting the different, but probably interrelated pathogenic pathways resulting in nigral cell death. Asymptomatic PINK1 and LRRK2 MC also revealed smaller GMV in the hippocampal region, which might play a role in the observed psychiatric disorders.
Neurobiology of Disease 09/2010; 39(3):402-8. · 5.40 Impact Factor
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Neurology 08/2010; 75(5):478; author reply 478-9. · 8.31 Impact Factor
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Meike Kasten,
Lena Kertelge,
Norbert Brüggemann,
Joyce van der Vegt, Alexander Schmidt,
Vera Tadic,
Carsten Buhmann,
Susanne Steinlechner,
Maria Isabel Behrens,
Alfredo Ramirez,
Ferdinand Binkofski,
Hartwig Siebner,
Heiner Raspe,
Johann Hagenah,
Rebekka Lencer,
Christine Klein
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ABSTRACT: To review current knowledge on nonmotor symptoms (NMS), particularly psychiatric features, in genetic Parkinson disease (PD) and to provide original data for genetic and idiopathic PD.
A MEDLINE search using Parkinson and known PD genes focused on the presence of depression, anxiety, hallucinations, and dementia was performed. Original data from 82 outpatients with idiopathic (n = 55) and genetic (n = 27) PD were obtained.
All studies including information on NMS and patients with genetic PD.
Study methods and clinical and genetic information were summarized.
The literature search yielded 1855 citations; 305 included genetic information on PD patients, of which 119 also contained information on any type of NMS (990 cases). Availability of information varied by gene and type of NMS; studies differed by recruitment and examination method. Literature search and original data showed high frequencies of the following NMS: depression, 8% to 37% (literature) and 33% to 40% (our data); anxiety, 7% to 37% (literature) and 10% to 22% (our data); hallucinations, 3% to 23% (literature) and 23% to 29% (our data); and dementia, 5% to 26% (literature), absent in our own data.
Data on NMS in genetic PD are limited. Specific data needs include a systematic approach to NMS assessment reporting permitting comparability of studies. Overall, the frequency of NMS in genetic PD does not appear to be higher and may even be lower than in idiopathic PD. Nonmotor symptoms have a high impact on the patients' quality of life and caregiver burden and should be considered important and often treatable concomitant features of genetic PD.
Archives of neurology 06/2010; 67(6):670-6. · 6.31 Impact Factor
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Ana Djarmati,
Susanne A Schneider,
Katja Lohmann,
Susen Winkler,
Heike Pawlack,
Johann Hagenah,
Norbert Brüggemann,
Simone Zittel,
Tania Fuchs,
Aleksandar Raković, Alexander Schmidt,
Hans-Christian Jabusch,
Robert Wilcox,
Vladimir S Kostić,
Hartwig Siebner,
Eckart Altenmüller,
Alexander Münchau,
Laurie J Ozelius,
Christine Klein
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ABSTRACT: DYT6 is a primary, early-onset torsion dystonia; however, unlike in DYT1 dystonia, the symptoms of DYT6 dystonia frequently involve the craniocervical region. Recently, two mutations in THAP1, the gene that encodes THAP (thanatos-associated protein) domain-containing apoptosis-associated protein 1 (THAP1), have been identified as a cause of DYT6 dystonia.
We screened THAP1 by sequence analysis and quantitative real-time polymerase chain reaction (PCR) in 160 white patients of European ancestry who had dystonia with an early age at onset (n=64), generalised dystonia (n=35), a positive family history of dystonia (n=56), or facial or laryngeal dystonia. Another 160 patients with dystonia were screened for reported and novel variants in THAP1. 280 neurologically healthy controls were screened for the newly identified and previously reported changes in THAP1 and these and an additional 75 controls were screened for a rare non-coding mutation.
We identified two mutations in THAP1 (388_389delTC and 474delA), respectively, in two (1%) German patients from the 160 patients with dystonia. Both mutation carriers had laryngeal dystonia that started in childhood and both went on to develop generalised dystonia. Thus, two of three patients with early-onset generalised dystonia with orobulbar involvement had mutations in THAP1. One of the identified patients with DYT6 dystonia had two family members with subtle motor signs who also carried the same mutation. A rare substitution in the 5'untranslated region (-236_235GA-->TT) was found in 20 of 320 patients and in seven of 355 controls (p=0.0054).
Although mutations in THAP1 might have only a minor role in patients with different, but mainly focal, forms of dystonia, they do seem to be associated with early-onset generalised dystonia with spasmodic dysphonia. This combination of symptoms might be a characteristic feature of DYT6 dystonia and could be useful in the differential diagnosis of DYT1, DYT4, DYT12, and DYT17 dystonia. In addition to the identified mutations, a rare non-coding substitution in THAP1 might increase the risk of dystonia.
Deutsche Forschungsgemeinschaft; Volkswagen Foundation; Dystonia Medical Research Foundation; University of Lübeck.
The Lancet Neurology 04/2009; 8(5):447-52. · 23.46 Impact Factor
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Philip Seibler,
Ana Djarmati,
Brigitte Langpap,
Johann Hagenah, Alexander Schmidt,
Norbert Brüggemann,
Hartwig Siebner,
Hans-Christian Jabusch,
Eckart Altenmüller,
Alexander Münchau,
Katja Lohmann,
Christine Klein
The Lancet Neurology 06/2008; 7(5):380-1. · 23.46 Impact Factor
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ABSTRACT: We present the long-term outcome of 144 musicians with focal dystonia after treatment with botulinum toxin (n = 71), trihexiphenidyl (n = 69), pedagogical retraining (n = 24), ergonomic changes (n = 51), or nonspecific exercises on the instrument (n = 78). Outcome was assessed by patients' subjective rating of cumulative treatment response and response to individual therapies. Seventy-seven patients (54%) reported an alleviation of symptoms: 33% of the patients with trihexiphenidyl, 49% with botulinum toxin, 50% with pedagogical retraining, 56% with unmonitored technical exercises, and 63% with ergonomic changes.
Movement Disorders 01/2006; 20(12):1623-6. · 4.51 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: We present the long-term outcome of 144 musicians with focal dystonia after treatment with botulinum toxin (n = 71), trihexiphenidyl (n = 69), pedagogical retraining (n = 24), ergonomic changes (n = 51), or nonspecific exercises on the instrument (n = 78). Outcome was assessed by patients' subjective rating of cumulative treatment response and response to individual therapies. Seventy-seven patients (54%) reported an alleviation of symptoms: 33% of the patients with trihexiphenidyl, 49% with botulinum toxin, 50% with pedagogical retraining, 56% with unmonitored technical exercises, and 63% with ergonomic changes. © 2005 Movement Disorder Society
Movement Disorders 11/2005; 20(12):1623 - 1626. · 4.51 Impact Factor
