References of "Klein, Christine 50002100"
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See detailThe DRD2 TaqIA polymorphism and demand of dopaminergic medication in Parkinson's disease.
Paus, Sebastian; Grünewald, Anne UL; Klein, Christine UL et al

in Movement disorders : official journal of the Movement Disorder Society (2008), 23(4), 599-602

Previous studies have demonstrated that the TaqIA polymorphism of the D2 dopamine receptor gene (DRD2) is associated with response to dopaminergic and antidopaminergic treatment in Parkinson's disease (PD ... [more ▼]

Previous studies have demonstrated that the TaqIA polymorphism of the D2 dopamine receptor gene (DRD2) is associated with response to dopaminergic and antidopaminergic treatment in Parkinson's disease (PD) and schizophrenia, respectively. We tested whether the TaqIA genotype in PD is responsible for demand of dopaminergic medication, measured in total dopaminergic load per year of disease, in a large scale association study based on the gene bank of the German Competence Network on Parkinson's disease. Regression analysis yielded no significant differences between the TaqIA genotypes. We conclude that the DRD2 TaqIA polymorphism alone has no pivotal role for interindividual variability of dopaminergic requirement in PD. We propose a practicable system of measuring dopaminergic treatment for future pharmacogenetic studies in PD. [less ▲]

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See detailMyoclonus-dystonia: significance of large SGCE deletions.
Grünewald, Anne UL; Djarmati, A.; Lohmann-Hedrich, K. et al

in Human mutation (2008), 29(2), 331-2

Myoclonus-dystonia (M-D) is an autosomal-dominant movement disorder caused by mutations in SGCE. We investigated the frequency and type of SGCE mutations with emphasis on gene dosage alterations and ... [more ▼]

Myoclonus-dystonia (M-D) is an autosomal-dominant movement disorder caused by mutations in SGCE. We investigated the frequency and type of SGCE mutations with emphasis on gene dosage alterations and explored the associated phenotypes. We tested 35 M-D index patients by multiplex ligation-dependent probe amplification (MLPA) and genomic sequencing. Mutations were found in 26% (9/35) of the cases, all but three with definite M-D. Two heterozygous deletions of the entire SGCE gene and flanking DNA and a heterozygous deletion of exon 2 only were detected, accounting for 33% (3/9) of the mutations found. Both large deletions contained COL1A2 and were additionally associated with joint problems. Further, we discovered one novel small deletion (c.771_772delAT, p.C258X) and four recurrent point mutations (c.289C>T, p.R97X; c.304C>T, p.R102X; c.709C>T, p.R237X; c.1114C>T, p.R372X). A Medline search identified 22 articles on SGCE mutational screening. Sixty-four unrelated M-D patients were described with 41 different mutations. No genotype-phenotype association was found, except in patients with deletions encompassing additional genes. In conclusion, a rigorous clinical preselection of patients and careful accounting for non-motor signs should precede mutational tests. Gene dosage studies should be included in routine SGCE genetic testing. [less ▲]

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See detailRe: Alpha-synuclein gene duplication is present in sporadic Parkinson disease.
Brueggemann, N.; Odin, P.; Gruenewald, Anne UL et al

in Neurology (2008), 71(16), 12941294

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See detailRapid and reliable detection of exon rearrangements in various movement disorders genes by multiplex ligation-dependent probe amplification.
Djarmati, Ana; Guzvic, Miodrag; Grünewald, Anne UL et al

in Movement disorders : official journal of the Movement Disorder Society (2007), 22(12), 1708-14

Because of the occurrence of different types of mutations, comprehensive genetic testing for Parkinson's disease (PD), dopa-responsive dystonia (DRD), and myoclonus-dystonia (M-D) should include screening ... [more ▼]

Because of the occurrence of different types of mutations, comprehensive genetic testing for Parkinson's disease (PD), dopa-responsive dystonia (DRD), and myoclonus-dystonia (M-D) should include screening for small sequence changes and for large exonic rearrangements in disease-associated genes. In diagnostic and research settings, the latter is frequently omitted or performed by laborious and expensive quantitative real-time PCR (qPCR). Our study aimed to evaluate the utility of a novel method, multiplex ligation-dependent probe amplification (MLPA), in molecular diagnostics of movement disorders. We have analyzed, by MLPA, genomic DNA from 21 patients affected with PD, DRD, or M-D, in which the presence of exon rearrangement(s) (n = 20) or of a specific point mutation (detectable by MLPA, n = 1) had been established previously by qPCR or sequencing. In parallel, we have studied, in a blinded fashion, DNA from 49 patients with an unknown mutational status. Exon rearrangements were evident in 20 samples with previously established mutations; in the 21st sample the known specific point mutation was detected. We conclude that MLPA represents a reliable method for large-scale and cost-effective gene dosage screening of various movement disorders genes. This finding reaches far beyond a simple technical advancement and has two major implications: (1) By improving the availability of comprehensive genetic testing, it supports clinicians in the establishment of a genetically defined diagnosis; (2) By enabling gene dosage testing of several genes simultaneously, it significantly facilitates the mutational analysis of large patient and control populations and thereby constitutes the prerequisite for meaningful phenotype-genotype correlations. [less ▲]

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See detailBiological effects of the PINK1 c.1366C>T mutation: implications in Parkinson disease pathogenesis.
Grünewald, Anne UL; Breedveld, Guido J.; Lohmann-Hedrich, Katja et al

in Neurogenetics (2007), 8(2), 103-9

PINK1 gene mutations are a cause of recessively inherited, early-onset Parkinson's disease. In some patients, a single heterozygous mutation has been identified, including the recurrent c.1366C>T ... [more ▼]

PINK1 gene mutations are a cause of recessively inherited, early-onset Parkinson's disease. In some patients, a single heterozygous mutation has been identified, including the recurrent c.1366C>T transition. The interpretation of this finding remains controversial. Furthermore, the c.1366C>T mutation is associated with lower levels of PINK1 transcript, raising the question of whether mRNA levels correlate with the clinical status. We sequenced genomic DNA and copy DNA (cDNA) from 20 subjects carrying the c.1366C>T mutation in the homozygous (n = 5) or heterozygous (n = 15) state. In 17 mutation carriers, messenger RNA (mRNA) was quantified by real-time PCR using four different assays (PINK1 exon 5-6 or exon 7-8 relative to control genes SDHA or YWHAZ). Genomic sequencing confirmed the presence and zygosity of PINK1 mutations. cDNA sequencing in heterozygous mutation carriers revealed a strong wild-type and a much weaker or almost absent mutant signal, whereas in the homozygous patients, only the mutant signal was detected. Homozygous and heterozygous carriers showed PINK1 mRNA levels relative to a reference gene in the range of 0.1-0.2 and 0.5-0.6, respectively, compared with values of 0.9-1.0 in mutation-negative individuals. Treatment of lymphoblasts from a heterozygous mutation carrier with cycloheximide markedly increased the mutant transcript signal. We conclude that the recurrent PINK1 c.1366C>T mutation exerts a major effect at the mRNA level (80-90% reduction), most likely via nonsense-mediated mRNA decay. The absence of correlation between PINK1 mRNA levels and clinical status in heterozygous mutation carriers suggests that other genetic or environmental factors play a role in determining the phenotypic variability associated with the c.1366C>T mutation. [less ▲]

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See detailAutosomal dominant myoclonus-dystonia and Tourette syndrome in a family without linkage to the SGCE gene.
Orth, Michael; Djarmati, Ana; Baumer, Tobias et al

in Movement disorders : official journal of the Movement Disorder Society (2007), 22(14), 2090-6

The objective of this study was to report clinical details and results of genetic testing for mutations in the epsilon-sarcoglycan (SGCE) gene, the Slit and Trk-like 1 (SLITRK1) gene and for linkage to ... [more ▼]

The objective of this study was to report clinical details and results of genetic testing for mutations in the epsilon-sarcoglycan (SGCE) gene, the Slit and Trk-like 1 (SLITRK1) gene and for linkage to the DYT15, DYT1, and DRD2 gene loci in a family with autosomal dominant myoclonus-dystonia (M-D) and Gilles de la Tourette syndrome (GTS). Fourteen family members, from three generations, underwent a detailed clinical assessment and donated DNA samples. The SGCE and the SLITRK1 gene were sequenced and investigated by gene dosage analysis in selected family members. Linkage to the SGCE, DYT15, DYT1, DRD2, and SLITRK1 loci was also tested. RESULTS: We included three healthy and 11 affected family members with M-D (n = 3), dystonia alone (n = 2), GTS (n = 1), tics (n = 1) or a combination of these with obsessive compulsive disorder (OCD) (M-D + OCD: n = 2; dystonia+OCD: n = 1; M-D + GTS + OCD: n = 1). There was no linkage to the SGCE, DYT15, DYT1 or DRD2 loci. No changes were found in the SLITRK1 gene. The presence of both M-D and GTS in one family, in which all known M-D loci and a recently discovered GTS locus were excluded, suggests a novel susceptibility gene for both M-D and GTS. [less ▲]

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See detailClinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit?
Hedrich, Katja; Hagenah, Johann; Djarmati, Ana et al

in Archives of neurology (2006), 63(6), 833-8

BACKGROUND: Although homozygous mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been unequivocally associated with early-onset Parkinson disease (PD), the role of single heterozygous ... [more ▼]

BACKGROUND: Although homozygous mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been unequivocally associated with early-onset Parkinson disease (PD), the role of single heterozygous PINK1 mutations is less clear. OBJECTIVE: To investigate the role of homozygous and heterozygous PINK1 mutations in a large German pedigree (family W). DESIGN: Mutation analysis of PINK1 and results of standardized neurological and motor examination by 3 independent movement disorder specialists, including blinded video rating. SETTINGS: University of Lubeck. PARTICIPANTS: Twenty family members. MAIN OUTCOME MEASURES: The PINK1 genotype and PD status of all family members. RESULTS: The index patient of family W carried a homozygous nonsense mutation (c.1366C>T; p.Q456X) and presented with a phenotype closely resembling idiopathic PD but with an onset at 39 years of age. The family included a total of 4 affected homozygous members (age, 60-71 years; age at onset, 39-61 years), 6 members with slight or mild signs of PD (affected) and a heterozygous mutation (age, 31-49 years), and 5 unaffected heterozygous mutation carriers (age, 34-44 years). Although none of the heterozygous affected family members was aware of their signs (asymptomatic), the clinical findings were unequivocal and predominantly or exclusively present on their dominant right-hand side, eg, unilaterally reduced or absent arm swing and unilateral rigidity. The heterozygous members were all considerably younger than the affected homozygous mutation carriers. CONCLUSIONS: Heterozygous PINK1 mutations may predispose to PD, as was previously suggested by the presence of dopamine hypometabolism in asymptomatic mutation carriers. Long-term follow-up of our large family W provides an excellent opportunity to further evaluate the role of single heterozygous PINK1 mutations later in life, which will have major implications on genetic counseling. [less ▲]

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See detailEarly-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes.
Klein, Christine UL; Grünewald, Anne UL; Hedrich, Katja

in Neurology (2006), 66(7), 1129-301129-30

Detailed reference viewed: 49 (2 UL)