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See detailEffective thalamic deep brain stimulation for neuropathic tremor in a patient with severe demyelinating neuropathy.
Breit, S.; Wachter, T.; Schols, L. et al

in Journal of neurology, neurosurgery, and psychiatry (2009), 80(2), 235-6

Postural and action tremor in peripheral neuropathy is characteristic of Roussy-Levy syndrome. A patient with a severe demyelinating neuropathy and disabling neuropathic tremor successfully treated by ... [more ▼]

Postural and action tremor in peripheral neuropathy is characteristic of Roussy-Levy syndrome. A patient with a severe demyelinating neuropathy and disabling neuropathic tremor successfully treated by deep brain stimulation (DBS) is reported. Disease onset was at age 63 years with sensory symptoms and slight action tremor. Within the following 9 years a severe, drug resistant, postural and action tremor developed rendering the patient unable to feed himself. At age 72 years the patient was treated by bilateral DBS of the ventral intermediate thalamic nucleus, with a useful 30% reduction in tremor. The clinical benefit of the stimulation remained stable over a 1 year postoperative observation period. [less ▲]

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See detailPolymorphisms of the alpha-synuclein promoter: expression analyses and association studies in Parkinson's disease.
Holzmann, C.; Krüger, Rejko UL; Saecker, A. M. M. Vieira et al

in Journal of neural transmission (Vienna, Austria : 1996) (2003), 110(1), 67-76

Mutations of the alpha-synuclein gene have shown to be relevant in some rare families with autosomal dominant Parkinson's disease (PD). Furthermore, alpha-synuclein protein is a major component of the ... [more ▼]

Mutations of the alpha-synuclein gene have shown to be relevant in some rare families with autosomal dominant Parkinson's disease (PD). Furthermore, alpha-synuclein protein is a major component of the Lewy bodies also in sporadic PD patients. Increased levels of wildtype alpha-synuclein in the cell leads to increased intracellular hydrogen peroxide levels and causes death of dopaminergic neurons in rat primary culture. Subsequently, oxidative stress has been directly linked with alpha-synuclein aggregation in vitro. This raises the question whether increased alpha-synuclein expression might be linked to higher susceptibility to PD and whether alpha-synuclein promoter polymorphisms are associated with PD. Here, two polymorphisms (-116C>G and -668T>C) of the alpha-synuclein promoter defining four haplotypes have been characterized in 315 German PD patients. The influence of the four haplotypes on gene expression was studied by CAT reporter gene assays in neuronal SK-N-AS cells. The -668C/-116G haplotype revealed significant higher CAT expression than the -668T/-116G or the -668T/-116C haplotype, respectively. Although the -668C/-116G haplotype was more common in PD patients, this difference was not significant. [less ▲]

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See detailModulation of disease risk according to a cathepsin D / apolipoprotein E genotype in Parkinson's disease.
Schulte, T.; Bohringer, S.; Schols, L. et al

in Journal of neural transmission (Vienna, Austria : 1996) (2003), 110(7), 749-55

Aspartyl protease Cathepsin D (CTSD) has been suggested to play a role in the pathogenesis of sporadic Alzheimer's disease (AD) due to interference with protein degradation mechanisms. A C224T (A38V ... [more ▼]

Aspartyl protease Cathepsin D (CTSD) has been suggested to play a role in the pathogenesis of sporadic Alzheimer's disease (AD) due to interference with protein degradation mechanisms. A C224T (A38V) polymorphism in exon 2 of the CTSD gene is reported to be associated with an increased risk for AD. The partially overlapping pathology between AD and Parkinson's disease (PD) led us to investigate the role of this polymorphism in PD. Using association studies in 457 German PD patients and 340 controls we found no evidence for direct association between the CTSD genotype and PD. However, stratification for the apolipoprotein E (APOE) epsilon4 allele suggests a protective effect of the CTSD T-allele in PD (OR = 0.24, p = 0.002). Our findings suggest interference of CTSD and APOE polymorphisms in the pathogenesis of PD, in the sense of modulating disease risk. [less ▲]

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See detailMutation analysis and association studies of nuclear factor-kappaB1 in sporadic Parkinson's disease patients.
Wintermeyer, P.; Riess, O.; Schols, L. et al

in Journal of neural transmission (Vienna, Austria : 1996) (2002), 109(9), 1181-8

Biochemical and morphological studies revealed that oxidative stress and apoptosis play a role in neurodegeneration in Parkinson's disease (PD). Reactive oxygen species may be directly involved in ... [more ▼]

Biochemical and morphological studies revealed that oxidative stress and apoptosis play a role in neurodegeneration in Parkinson's disease (PD). Reactive oxygen species may be directly involved in apoptosis or via upregulation of toxic cytokines, i.e. tumor necrosis factor alpha (TNFalpha). We recently demonstrated that the TNFalpha pathway contributes to the pathogenesis of sporadic PD using a genetic approach. These signalling pathways converge to the transcription factor nuclear factor kappaB (NF-kappaB), which has been found activated in affected neurons in PD. We performed a detailed mutation analysis of the p50 subunit of NF-kappaB (NFKB1 gene) in 96 sporadic PD patients. Previously, positive association was demonstrated in this cohort to chromosome 4q21-23 containing the NFKB1 gene. We identified three base exchanges not affecting the amino acid sequence, which were found at similar frequencies in controls. Our study does not support a genetically definable role of NFKB1 in the pathogenesis of sporadic PD. [less ▲]

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See detailFamilial parkinsonism with synuclein pathology: clinical and PET studies of A30P mutation carriers.
Krüger, Rejko UL; Kuhn, W.; Leenders, K. L. et al

in Neurology (2001), 56(10), 1355-62

BACKGROUND: The authors identified the second known mutation in the alpha-synuclein(SNCA) gene, an alanine-to-proline exchange in amino acid position 30 (A30P), that cosegregates with the disease in one ... [more ▼]

BACKGROUND: The authors identified the second known mutation in the alpha-synuclein(SNCA) gene, an alanine-to-proline exchange in amino acid position 30 (A30P), that cosegregates with the disease in one German family with autosomal dominantly inherited parkinsonism (ADP). The authors studied carriers of the A30P mutation to compare the phenotype of this mutation with idiopathic PD (IPD) and to assess nigrostriatal dopaminergic function in symptomatic and preclinical mutation carriers. METHODS: The pedigree of the A30P family spans five generations with five affected individuals. The authors performed detailed neurologic examinations followed by mutation analysis in 11 living individuals. In three mutation carriers, two individuals with definite PD and one person at risk for PD, they used L-[18]F-fluoro-3,4-dihydroxyphenylalanine (F-DOPA), [11]C-raclopride (RAC), and [18]F-fluorodeoxyglucose (FDG) PET to investigate presynaptic dopaminergic function, dopamine D2 receptors, and cerebral energy metabolism. The authors studied the cognitive functions of carriers of the A30P mutation using neuropsychological screening. RESULTS: PET studies revealed striatal presynaptic dopaminergic alterations consistent with sporadic IPD in two affected family members and no evidence for nigrostriatal dopaminergic dysfunction in one presymptomatic mutation carrier. Neuropsychological testing in four mutation carriers provided evidence for cognitive impairment as a frequent and early symptom of the A30P mutation; this is also supported by regional cerebral energy metabolism alterations in the clinically presymptomatic subject. CONCLUSIONS: The phenotype of the A30P mutation in the SNCA gene is similar to that of sporadic IPD, including a high variability of the age at disease onset, ranging from 54 to 76 years. The follow-up of presymptomatic carriers of the A30P mutation may give insight into preclinical disease stages and early manifestations of PD. [less ▲]

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See detailEvaluation of the gamma-synuclein gene in German Parkinson's disease patients.
Krüger, Rejko UL; Schols, L.; Muller, T. et al

in Neuroscience letters (2001), 310(2-3), 191-3

Mutations in the alpha-synuclein gene are responsible for an autosomal-dominantly inherited form of Parkinson's disease (PD) and alpha-synuclein was found to be the major component of Lewy bodies in PD ... [more ▼]

Mutations in the alpha-synuclein gene are responsible for an autosomal-dominantly inherited form of Parkinson's disease (PD) and alpha-synuclein was found to be the major component of Lewy bodies in PD. Because of the high homology to alpha-synuclein and the abundance in neuronal tissues, we investigated the gamma-synuclein gene in PD. We analyzed 262 German PD patients and 179 healthy German controls via two polymorphisms in the gamma-synuclein gene. No significant differences in the allelic or genotypic distributions of the investigated polymorphisms were observed between patients and controls. In addition no evidence for an increased risk of combined genotypes of polymorphisms in the gamma-synuclein and the alpha-synuclein gene was found. Therefore, our results do not support a major role of the gamma-synuclein gene in PD. [less ▲]

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See detailGenetic analysis of the alpha2-macroglobulin gene in early- and late-onset Parkinson's disease.
Krüger, Rejko UL; Menezes-Saecker, A. M.; Schols, L. et al

in Neuroreport (2000), 11(11), 2439-42

Recent association studies investigating polymorphisms in the alpha2-macroglobulin (A2M) gene provided evidence for an involvement of this protease inhibitor in the pathogenesis of Alzheimer's disease (AD ... [more ▼]

Recent association studies investigating polymorphisms in the alpha2-macroglobulin (A2M) gene provided evidence for an involvement of this protease inhibitor in the pathogenesis of Alzheimer's disease (AD). The partially overlapping pathology between AD and Parkinson's disease (PD) led us to investigate the role of A2M in PD. We performed association studies in a large sample of 328 German PD patients and 322 closely matched healthy controls. Analyzing the Val1000Ile polymorphism and a pentanucleotide deletion in the 5' splice site of exon 18 of the A2M gene we found an excess of homozygosity for the A2M deletion in early-onset PD (EOPD) patients (age at onset < 50 years) compared to late-onset PD (LOPD) patients (age at onset > 50 years; p = 0.008, p(p)c = 0.064, chi2 = 7.017). Therefore our data might indicate an age at onset modulating effect of the homozygous A2M deletion in PD. [less ▲]

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See detailMutation analysis and association studies of the UCHL1 gene in German Parkinson's disease patients.
Wintermeyer, P.; Krüger, Rejko UL; Kuhn, W. et al

in Neuroreport (2000), 11(10), 2079-82

Recently, an Ile93Met substitution has been identified in the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene in a single German PD family with autosomal dominant inheritance. To determine whether ... [more ▼]

Recently, an Ile93Met substitution has been identified in the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene in a single German PD family with autosomal dominant inheritance. To determine whether mutations in the UCHL1 gene are causative for Parkinson's disease (PD) a detailed mutation analysis was performed in a large sample of German sporadic and familial PD patients. We found no disease-causing mutation in the coding region of the UCHL1 gene. Direct sequencing revealed six intronic polymorphisms in the UCHL1 gene. Analysis of an S18Y polymorphism in exon 3 of the UCHL1 gene in sporadic PD patients and controls showed carriers of allele 2 (tyrosine) significantly less frequent in patients with a reduced risk of 0.57 (CI = 0.36-0.88; p = 0.012, p(c) = 0.047, chi2 = 6.31). Our study shows that sequence variations in the coding region of UCHL1 are a rare event. A protective effect of a certain UCHL1 variant in the pathogenesis of sporadic PD is suggested, underlining the relevance of UCHL1 in neurodegeneration. [less ▲]

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See detailExtrapyramidal motor signs in degenerative ataxias.
Schols, L.; Peters, S.; Szymanski, S. et al

in Archives of neurology (2000), 57(10), 1495-500

BACKGROUND: Extrapyramidal motor signs (EPS) are well-known symptoms of degenerative ataxia. However, little is known about frequency and appearance of EPS in subtypes of ataxia. METHODS: We characterized ... [more ▼]

BACKGROUND: Extrapyramidal motor signs (EPS) are well-known symptoms of degenerative ataxia. However, little is known about frequency and appearance of EPS in subtypes of ataxia. METHODS: We characterized 311 patients with ataxia clinically and genetically. Course of the disease and EPS were investigated according to a standardized protocol. Diagnostic and prognostic impact of EPS in subtypes of ataxia was analyzed by Kaplan-Meier plots. RESULTS: Extrapyramidal motor signs occurred in all forms of ataxia, but frequency and type of EPS varied between genetically and clinically defined subtypes. Postural tremor in hereditary ataxias was typical for spinocerebellar ataxia type 2 (SCA2). Dystonia was generally rare in ataxias, but, if present, suggested SCA3. We observed a parkinsonian variant of SCA3 in which parkinsonism was present in the beginning of the disease and responded well to levodopa therapy, leading to diagnostic confusion. Parkinsonism in SCA3 was independent of CAG repeat length but ran in families, suggesting modifying genes. In idiopathic sporadic cerebellar ataxia (ISCA), EPS are more frequent in late-onset than in early-onset forms. In 50% of ISCA patients with parkinsonism, the diagnosis of multiple system atrophy remained questionable because of normal autonomic function. CONCLUSIONS: Extrapyramidal motor signs can help to predict the genetic subtype of ataxia. Extrapyramidal motor signs were more frequent in genetic subtypes in which basal ganglia affection has been demonstrated by postmortem studies. However, no type of EPS was specific for an underlying mutation. In ISCA, EPS are an adverse prognostic factor. Parkinsonism is especially associated with a more rapid course of the disease. Arch Neurol. 2000;57:1495-1500 [less ▲]

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See detailGenetic analysis of immunomodulating factors in sporadic Parkinson's disease.
Krüger, Rejko UL; Hardt, C.; Tschentscher, F. et al

in Journal of neural transmission (Vienna, Austria : 1996) (2000), 107(5), 553-62

Immunomodulating factors have been shown to play a role in the pathogenesis of Parkinson's disease (PD) by biochemical methods. In order to investigate functionally important genes of the tumor necrosis ... [more ▼]

Immunomodulating factors have been shown to play a role in the pathogenesis of Parkinson's disease (PD) by biochemical methods. In order to investigate functionally important genes of the tumor necrosis factor alpha (TNFalpha) pathway we studied the frequency of DNA polymorphisms in the interleukin 6 (IL6), the TNFalpha, and the TNFalpha receptor 1 (TNFR1) genes in 264 sporadic German PD patients and in 183 age and sex matched German healthy controls. Analyzing the TNFalpha-308 polymorphism we found heterozygous individuals carrying alleles 1 and 2 more frequently in patients with a relative risk of 1.56 (p = 0.046, p(c) = 0.13, chi2 = 3.98). In contrast, the frequency of the B/2 haplotype described by the TNFR1-609 and TNFRI+36 polymorphisms was significantly decreased in our PD patients group (p = 0.0097, p(c) = 0.048, chi2 = 6.69) with a relative risk reduced to 0.52. Our results suggest an involvement of immunomodulating factors in the pathogenesis of sporadic PD as revealed by a molecular genetic approach. [less ▲]

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See detailIncreased susceptibility to sporadic Parkinson's disease by a certain combined alpha-synuclein/apolipoprotein E genotype.
Krüger, Rejko UL; Vieira-Saecker, A. M.; Kuhn, W. et al

in Annals of neurology (1999), 45(5), 611-7

Parkinson's disease (PD) is one of the most common neurodegenerative disorders affecting about 1% of Western populations older than age 50. The pathological hallmark of PD are Lewy bodies, that is ... [more ▼]

Parkinson's disease (PD) is one of the most common neurodegenerative disorders affecting about 1% of Western populations older than age 50. The pathological hallmark of PD are Lewy bodies, that is, intracytoplasmic inclusion bodies in affected neurons of the substantia nigra. Recently, alpha-synuclein (alpha-SYN) has been identified as the main component of Lewy bodies in sporadic PD, suggesting involvement in neurodegeneration via protein accumulation. The partially overlapping pathology of PD and Alzheimer's disease, as well as striking structural similarities of alpha-SYN and apolipoprotein E, which is a major risk factor for late-onset Alzheimer's disease, prompted us to investigate the influence of different alpha-SYN and apolipoprotein E alleles for developing sporadic PD. We performed association studies in 193 German PD patients and 200 healthy control subjects matched for age, sex, and origin. A polymorphism in the promoter region of the alpha-SYN gene (NACP-Rep1) as well as of the closely linked DNA markers D4S1647 and D4S1628 revealed significant differences in the allelic distributions between PD patients and the control group. Furthermore, the Apo epsilon4 allele but not the Th1/E47 promoter polymorphism of the apolipoprotein E gene was significantly more frequent among early-onset PD patients (age at onset, <50 years) than in late-onset PD. Regarding the combination of the Apo epsilon4 allele and allele 1 of the alpha-SYN promoter polymorphism, a highly significant difference between the group of PD patients and control individuals has been found, suggesting interactions or combined actions of these proteins in the pathogenesis of sporadic PD. PD patients harboring this genotype have a 12.8-fold increased relative risk for developing PD during their lives. [less ▲]

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See detailAnalysis of the parkin deletion in sporadic and familial Parkinson's disease. Short communication.
Krüger, Rejko UL; Vieira-Sacker, A. M.; Kuhn, W. et al

in Journal of neural transmission (Vienna, Austria : 1996) (1999), 106(2), 159-63

Recently a mutation in the parking gene has been identified as the cause for an autosomal-recessively inherited form of early onset Parkinson's disease (EOPD). The disease causing minimal deletion has ... [more ▼]

Recently a mutation in the parking gene has been identified as the cause for an autosomal-recessively inherited form of early onset Parkinson's disease (EOPD). The disease causing minimal deletion has been defined as a homozygous exon 4 loss in the parkin gene among Japanese patients. We investigated 140 sporadic and familial EOPD patients of German ancestry for the exon 4 deletion in the parkin gene. None of our patients exhibited a homozygous deletion of exon 4, suggesting a minor role of this mutation for EOPD in Caucasians. Nevertheless a detailed mutation analysis is warranted to explore the overall significance of mutations in the parkin gene in EOPD. [less ▲]

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See detailSpinocerebellar ataxia type 6: genotype and phenotype in German kindreds.
Schols, L.; Krüger, Rejko UL; Amoiridis, G. et al

in Journal of neurology, neurosurgery, and psychiatry (1998), 64(1), 67-73

OBJECTIVE: Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant cerebellar ataxia (ADCA) of which the mutation causing the disease has recently been characterised as an expanded CAG trinucleotide ... [more ▼]

OBJECTIVE: Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant cerebellar ataxia (ADCA) of which the mutation causing the disease has recently been characterised as an expanded CAG trinucleotide repeat in the gene coding for the alpha1A-subunit of the voltage dependent calcium channel. The aim was to further characterise the SCA6 phenotype METHODS: The SCA6 mutation was investigated in 69 German families with ADCA and 61 patients with idiopathic sporadic cerebellar ataxia and the CAG repeat length of the expanded allele was correlated with the disease phenotype. RESULTS: Expanded alleles were found in nine of 69 families as well as in four patients with sporadic disease. Disease onset ranged from 30 to 71 years of age and was significantly later than in other forms of ADCA. Age at onset correlated inversely with repeat length. The SCA6 phenotype comprises predominantly cerebellar signs in concordance with isolated cerebellar atrophy on MRI. Non-cerebellar systems were only mildly affected with external ophthalmoplegia, spasticity, peripheral neuropathy, and parkinsonism. Neither these clinical signs nor progression rate correlated with CAG repeat length. CONCLUSIONS: This study provides the first detailed characterisation of the SCA6 phenotype. Clinical features apart from cerebellar signs were highly variable in patients with SCA6. By comparison with SCA1, SCA2, and SCA3 no clinical or electrophysiological finding was specific for SCA6. Therefore, the molecular defect cannot be predicted from clinical investigations. In Germany, SCA6 accounts for about 13% of families with ADCA. However, up to 30% of SCA6 kindreds may be misdiagnosed clinically as sporadic disease due to late manifestation in apparently healthy parents. Genetic testing is therefore recommended for the SCA6 mutation also in patients with putative sporadic ataxia. [less ▲]

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See detailAla30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease.
Krüger, Rejko UL; Kuhn, W.; Muller, T. et al

in Nature genetics (1998), 18(2), 106-8

Detailed reference viewed: 176 (5 UL)