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Biomedical subjects

C Klein

Publications and source records attributed to C Klein.

At least 19 recordsLinked to original sources
PubMed2006

Herbicide exposure modifies GSTP1 haplotype association to Parkinson onset age: the GenePD Study.

BACKGROUND: Polymorphisms in the glutathione S-transferase pi gene (GSTP1), encoding GSTP1-1, a detoxification enzyme, may increase the risk of Parkinson disease (PD) with exposure to pesticides. Using the GenePD Study sample of familial PD cases, we explored whether GSTP1 polymorphisms were associated with the age at onset of PD symptoms and whether that relation was modified by exposure to herbicides. METHODS: Seven single-nucleotide polymorphisms (SNPs) were genotyped and tested for association with PD onset age in men in three strata: no exposure to herbicides, residential exposure to herbicides, and occupational exposure to herbicides. Haplotypes were similarly evaluated in stratified analyses. RESULTS: Three SNPs were associated with PD onset age in the group of men occupationally exposed to herbicides. Three additional SNPs had significant trends for the association of PD onset age across the herbicide exposure groups. Haplotype results also provided evidence that the relation between GSTP1 and onset age is modified by herbicide exposure. One haplotype was associated with an approximately 8-years-earlier onset in the occupationally exposed group and a 2.8-years-later onset in the nonexposed group. CONCLUSIONS: Herbicide exposure may be an effect modifier of the relation between glutathione S-transferase pi gene polymorphisms and onset age in familial PD.

Disease Susceptibility↗
PubMed2006

Assignment of the gene locus for severe congenital neutropenia to chromosome 1q22 in the original Kostmann family from Northern Sweden.

Autosomal recessive severe congenital neutropenia (SCN) or Kostmann syndrome is characterised by reduced neutrophil counts and subsequent recurrent bacterial infections. The disease was originally described in a large consanguineous pedigree from Northern Sweden. A genome-wide autozygosity scan was initiated on samples from four individuals in the original pedigree using high density single nucleotide polymorphism (SNP) genotyping arrays in order to map the disease locus. Thirty candidate regions were identified and the ascertainment of samples from two additional patients confirmed a single haplotype with significant association to the disorder (p<0.01) on chromosome 1q22. One affected individual from the original Kostmann pedigree was confirmed as a phenocopy. The minimal haplotype shared by affected individuals spans a candidate region of 1.2 Mb, containing several potential candidate genes.

Chromosome Mapping↗
PubMed2006

Distal myoclonus and late onset in a large Dutch family with myoclonus-dystonia.

We report a large myoclonus-dystonia (M-D) pedigree with a two-base pair deletion in Exon 5 of the epsilon-sarcoglycan gene. Three individuals had onset after age 40 years. Distal myoclonus of the arms was present in all 20 symptomatic mutation carriers. These findings expand the known phenotype of M-D and require revision of the current diagnostic criteria. Five of 14 asymptomatic mutation carriers who inherited the mutation from their mother showed minimal axial dystonia, arguing against a maternal imprinting mechanism.

Adolescent↗
PubMed2006

Efficient green-blue-light-emitting cationic iridium complex for light-emitting electrochemical cells.

A highly luminescent novel cationic iridium complex [iridium bis(2-phenylpyridine)(4,4'-(dimethylamino)-2,2'-bipyridine)]PF6 was synthesized and characterized using NMR, UV-visible absorption, and emission spectroscopy and electrochemical methods. This complex displays intense photoluminescence maxima in the green-blue region of the visible spectrum and exhibits unprecedented phosphorescence quantum yields, 80 +/- 10% with an excited-state lifetime of 2.2 mus in a dichloromethane solution at 298 K. Single-layer light-emitting electrochemical cells with the charged complex as conducting and electroluminescent material sandwiched between indium-tin oxide and Ag electrodes were fabricated, which emit green-blue light with an onset voltage as low as 2.5 V. Density functional theory calculations were performed to provide insight into the electronic structure of the [iridium bis(2-phenylpyridine)(4,4'-(dimethylamino)-2,2'-bipyridine)]PF6 complex, comparing these results with those obtained for [iridium bis(2-phenylpyridine)(4,4'-tert-butyl-2,2'-bipyridine)]PF6.

Journal Article↗
PubMed2006

Dominantly transmitted focal dystonia in families of patients with musician's cramp.

Musician's dystonia is generally considered a sporadic disorder. We present three families with the index patient affected by musician's dystonia, but other forms of upper limb focal task-specific dystonia (FTSD), mainly writer's cramp, in seven relatives. Our results suggest a genetic contribution to FTSD with phenotypic variability, including musician's dystonia.

Adult↗
PubMed2006

Blink amplitude but not saccadic hypometria indicates carriers of Parkin mutations.

We investigated saccades, eyelid blinks, and their interaction in symptomatic (n = 22) and asymptomatic (n = 31) subjects with (n = 19) and without (n = 34) Parkin mutations. Saccadic hypometria was correlated with clinical symptoms of Parkinson's disease, irrespective of mutational status. By contrast, blink amplitude was increased in carriers of Parkin mutations independent of their clinical status. Saccade main sequence and blink effects on saccades were normal. We propose that increased blink amplitude may serve as an endophenotype in carriers of Parkin mutations.

Adult↗
PubMed2006

Morphological basis for the spectrum of clinical deficits in spinocerebellar ataxia 17 (SCA17).

Spinocerebellar ataxia 17 (SCA17) is a rare genetic disorder characterized by cerebellar, extrapyramidal, pyramidal as well as psychiatric signs. The pathoanatomical basis of this disorder is still not well known. A total of 12 patients and 12 age- and sex-matched controls were examined by in vivo MRI voxel-based morphometry (VBM). Besides general patterns of disease-related brain atrophy, characteristic syndrome-related morphological changes in SCA17 patients were studied. In comparison with normal controls, SCA17 patients showed a pattern of degeneration of the grey matter centred around mesial cerebellar structures, occipito-parietal structures, the anterior putamen bilaterally, the thalamus and other parts of the motor network, reflecting the cerebellar, pyramidal and extrapyramidal signs. A correlation analysis revealed a clear association between the clinical cerebellar, extrapyramidal and psychiatric scores and degeneration in specific areas. Two degeneration patterns were found as follows: regarding motor dysfunction, atrophy of the grey matter involved mainly the cerebellum and other motor networks, in particular the basal ganglia. In contrast, correlations with psychiatric scores revealed grey matter degeneration patterns in the frontal and temporal lobe, the cuneus and cingulum. Most interestingly, there was a highly significant correlation between the clinical Mini-Mental State Examination scores and atrophy of the nucleus accumbens, probably accounting for the leading psychiatric signs.

Adult↗
PubMed2006

QN1/KIAA1009: a new essential protein for chromosome segregation and mitotic spindle assembly.

We previously reported the involvement of QN1 (quail neuroretina 1) protein in cell cycle control during retinal development. We show here that QN1 is an ATPase conserved through evolution, from fugu to humans. We show that chicken/quail QN1 protein is orthologous to the KIAA1009 protein in humans, the function of which was not known. We demonstrate here for the first time that QN1/KIAA1009 protein is located at the spindle poles of the mitotic apparatus and at centrosomes during mitosis. The siRNA-mediated depletion of KIAA1009 led to abnormal mitosis with chromosome segregation defects and abnormal centrosome separation leading to the death of PC12 and MCF7 cells. Thus, QN1/KIAA1009 is a new microtubule-associated ATPase involved in cell division.

Adenosine Triphosphatases↗
PubMed2006

Phenotype-genotype correlation in Dutch patients with myoclonus-dystonia.

The epsilon-sarcoglycan (SGCE) gene is an important cause of myoclonus-dystonia (M-D), although the majority of cases with an M-D phenotype test negative. Seven of 31 patients with the M-D phenotype carried a mutation in the SGCE gene. Positive family history and truncal myoclonus were independent prognostic factors. Early disease onset, onset with both myoclonus and dystonia, and axial dystonia were detected significantly more often in the mutation carriers.

Age of Onset↗
PubMed2006

Dendritic cell deficiencies in pediatric acute lymphoblastic leukemia patients.

Acute lymphoblastic leukemia (ALL) cells are particularly poor at generating anti-leukemia immunity, despite residing in lymphoid organs. To assess a potential role of dendritic cells (DC) in poor anti-leukemia immunity, we analyzed peripheral blood DC in 55 pediatric ALL patients at the time of initial diagnosis and 19 age-matched healthy controls. Dendritic cells were identified by their expression of HLA-DR, lack of B, T, NK, and monocyte markers, and expression of CD11c (myeloid DC(mDC)) or BDCA-2 (plasmacytoid DC(pDC)) using flow cytometry. We found that in children with B-lineage ALL, numbers of both mDC and pDC were significantly reduced (P = 0.0001). In contrast, T-lineage ALL patients showed normal pDC and significantly elevated mDC (P = 0.003) levels, with normal expression of HLA-DR and co-stimulatory molecules. A decrease in DC could not be explained by general impairment of myelopoiesis, as we could not demonstrate a correlation of DC numbers with granulocyte/monocyte numbers in patients with B-lineage ALL. However, aberrant expression of myeloid surface markers on leukemic blasts was frequent in patients lacking myeloid DC indicating a potential block of DC differentiation. Thus, depletion of DC in B-lineage ALL patients may contribute to poor anti-leukemia immune responses.

Adolescent↗
PubMed2006

Generation and characterization of a novel hematopoietic progenitor cell line with DC differentiation potential.

Studies of hematopoietic stem cell (HSC)-derived dendritic cells (DCs) are often limited by the rarity of HSC. To facilitate the study of DCs, we have generated a novel cell line (CR1) by retroviral Notch(IC) gene transfer into Sca1(+)ckit(+)lin- HSC. CR1 cells proliferated in vitro in the presence of recombinant interleukin-3. They maintained an immature progenitor cell phenotype and an intact karyotype. In the presence of granulocyte-macrophage colony-stimulating factor or Flt3L, CR1 cells differentiated into myeloid and plasmacytoid DCs, respectively. Functionally, CR1 cells were comparable to primary bone-marrow-derived DCs with respect to Toll-like-receptor-mediated maturation, cytokine release and capacity to induce effective antitumor immunity. CR1 cells thus provide an elegant new cellular tool to study DC development, function and preclinical DC-based immunotherapies.

Cell Differentiation↗
PubMed2006

Functional MRI reveals activation of a subcortical network in a 5-year-old girl with genetically confirmed myoclonus-dystonia.

We investigated a five-year-old girl suffering from genetically confirmed, action-induced myoclonus-dystonia (M-D) with functional magnetic resonance imaging (MRI). We compared the activation pattern by movements of her right hand as if drawing a picture, which elicited M-D, with simple snapping movements (without overt M-D). The drawing and snapping conditions resulted in activation of a motor network including the motor cortex, the putamen, and the cerebellar hemispheres. The direct comparison of the drawing condition with snapping as control revealed specific activations within the thalamus and the dentate nucleus. An age matched healthy control did not show significant activation within the thalamus or dentate nucleus.

Brain↗
PubMed2006

Jacobsen syndrome and Beckwith-Wiedemann syndrome caused by a parental pericentric inversion inv(11)(p15q24).

Here we report on a male infant presenting the typical pattern of Jacobsen syndrome including trigonocephaly, thrombocytopenia, congenital heart defect, urethral stenosis, and partial agenesis of the corpus callosum. Conventional karyotyping, FISH, SKY and CGH analyses showed that the region distal to the MLL locus on 11q23 was lost and replaced by the distal region of 11p, leading to a partial trisomy of 11p and a partial monosomy of 11q. According to ISCN (1995) the karyotype can be described as 46,XY,add(11)(q2?3). ish 11ptel(D11S2071x3),11qtel(VIJyRM2072x1). Array-CGH analysis allowed us to narrow down the breakpoints to 11p15.1 and 11q24.1. Methylation analyses of genes located on 11p showed an increased level of the non-methylated paternal allele of the KCNQ1OT1 gene, confirming the concomitant presence of Beckwith-Wiedemann syndrome (BWS). The phenotype resulting from the 11q deletion seems to dominate the phenotype due to the distal 11p trisomy. Investigation of the parents revealed that this chromosomal rearrangement was caused by a paternal pericentric inversion inv(11)(p15q24). Since chromosomal aberrations like the one described here can easily be overlooked during routine chromosome analysis, combined FISH analysis using subtelomeric and possibly additional probes should be applied if there is any doubt about the integrity of telomeric regions.

Abnormalities, Multiple↗
PubMed2006

Expanded motor and psychiatric phenotype in autosomal dominant Segawa syndrome due to GTP cyclohydrolase deficiency.

BACKGROUND: Segawa syndrome due to GTP cyclohydrolase deficiency is an autosomal dominant disorder with variable expression, that is clinically characterised by l-dopa responsive, diurnally fluctuating dystonia and parkinsonian symptoms. OBJECTIVE: To delineate the neurological and psychiatric phenotype in all affected individuals of three extended families. METHODS: GTP cyclohydrolase deficiency was documented by biochemical analyses, enzymatic measurements in fibroblasts, and molecular investigations. All affected individuals were examined neurologically, and psychiatric data were systematically reviewed. RESULTS: Eighteen affected patients from three families with proven GTP cyclohydrolase deficiency were identified. Eight patients presenting at less than 20 years of age had typical motor symptoms of dystonia with diurnal variation. Five family members had late-presenting mild dopa-responsive symptoms of rigidity, frequent falls, and tendonitis. Among mutation carriers older than 20 years of age, major depressive disorder, often recurrent, and obsessive-compulsive disorder were strikingly more frequent than observed in the general population. Patients responded well to medication increasing serotonergic neurotransmission and to l-dopa substitution. Sleep disorders including difficulty in sleep onset and maintenance, excessive sleepiness, and frequent disturbing nightmares were present in 55% of patients. CONCLUSION: Physicians should be aware of this expanded phenotype in affected members of families with GTP cyclohydrolase deficiency.

Adolescent↗
PubMed2005

BDNF genetic variants are associated with onset age of familial Parkinson disease: GenePD Study.

Brain-derived neurotrophic factor (BDNF) stimulates neuronal growth and protects nigral dopamine neurons in animal models of Parkinson disease (PD). Therefore, BDNF is a candidate gene for PD. The authors investigated five single-nucleotide polymorphisms in 597 cases of familial PD. Homozygosity for the rare allele of the functional BDNF G196A (Val66Met) variant was associated with a 5.3-year older onset age (p = 0.0001). These findings suggest that BDNF may influence PD onset age.

Age of Onset↗
PubMed2005

The 'essentials' of essential palatal tremor: a reappraisal of the nosology.

Essential palatal tremor (EPT) is an uncommon disorder, distinct from symptomatic palatal tremor (SPT), but characterized by superficially similar rhythmic movements of the soft palate. While the pathophysiology of SPT has been relatively well defined, this is not the case in EPT. Based on an analysis of 103 published cases, we reviewed EPT in the context of other movement disorders with similar features and outline possible pathophysiological mechanisms. Phenomenologically it remains best classified as a tremor. Four major causes, including a central generator, peripheral/mechanical, voluntary/special skill and psychogenic, appear to account for the majority of cases of EPT, although there is considerable overlap in the pathogenic mechanisms underlying these categories. Among the cases reviewed, a large proportion fit into the latter two categories, although there are others where multiple mechanisms are likely at play. Based on our reappraisal, we suggest a change in designation to 'isolated palatal tremor', with primary and secondary subtypes. This retains the distinction from SPT and emphasizes the non-uniform, heterogeneous nature of the disorder.

Adolescent↗