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Search Results: 1 - 10 of 139638 matches for " Zbigniew K. Wszolek "
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Autosomal dominant cerebellar ataxia type I: A review of the phenotypic and genotypic characteristics
Nathaniel Whaley, Shinsuke Fujioka, Zbigniew K Wszolek
Orphanet Journal of Rare Diseases , 2011, DOI: 10.1186/1750-1172-6-33
Abstract: Autosomal Dominant Cerebellar Ataxias, Spinocerebellar ataxias.The definition of spinal cerebellar ataxias (SCAs) despite significant progress in their understanding is still imprecise. They can be divided by the mode of inheritance to autosomal dominant, autosomal recessive, or sporadic conditions, Harding proposed a classification of autosomal dominant cerebellar ataxias (ADCA) into three categories, Type I, Type II and Type III. ADCA Type I comprises syndromes such as SCA1- SCA4, SCA8, SCA10, SCA12 - SCA23, SCA25, SCA27, SCA28 and DRPLA. ADCA Type II comprises syndromes associated with pigmentary maculopathies and includes SCA7. ADCA Type III comprises pure cerebellar syndromes and includes SCA5, SCA6, SCA11, SCA26, SCA29, SCA30 and SCA31 [1].The ADCA Type I are the subject of this review. ADCA Type I contain at the time of this writing a group of 22 disorders. There are no fully validated diagnostic criteria for ADCA Type I. The diagnosis is based on clinical history, physical examination and genetic testing.Phenotypes of ADCA Type I are complex and include ataxia plus other neurological signs. The clinical spectrum ranges from just "pure" cerebellar signs to constellations including spinal cord syndromes, peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmologic signs, psychiatric problems, and seizure disorders. The ataxia in ADCA Type I is characterized as disordered voluntary movement in (1) the rate of initiation and cessation called dyschronometria, (2) the amplitude known as dysmetria, (3) the coordination of single movements termed dyssynergia, (4) the speed of alternating movements called dysdiadochokinesia, and (5) the continuity resulting in action tremors [2]. Cerebellar ataxia can affect virtually any body part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most evident cerebellar findings though nystagmus, saccadic abnormalities, and dysarthria are usually associated. Table 1 lists clini
Autosomal dominant cerebellar ataxia type III: a review of the phenotypic and genotypic characteristics
Fujioka Shinsuke,Sundal Christina,Wszolek Zbigniew K
Orphanet Journal of Rare Diseases , 2013, DOI: 10.1186/1750-1172-8-14
Abstract: Autosomal Dominant Cerebellar Ataxia (ADCA) Type III is a type of spinocerebellar ataxia (SCA) classically characterized by pure cerebellar ataxia and occasionally by non-cerebellar signs such as pyramidal signs, ophthalmoplegia, and tremor. The onset of symptoms typically occurs in adulthood; however, a minority of patients develop clinical features in adolescence. The incidence of ADCA Type III is unknown. ADCA Type III consists of six subtypes, SCA5, SCA6, SCA11, SCA26, SCA30, and SCA31. The subtype SCA6 is the most common. These subtypes are associated with four causative genes and two loci. The severity of symptoms and age of onset can vary between each SCA subtype and even between families with the same subtype. SCA5 and SCA11 are caused by specific gene mutations such as missense, inframe deletions, and frameshift insertions or deletions. SCA6 is caused by trinucleotide CAG repeat expansions encoding large uninterrupted glutamine tracts. SCA31 is caused by repeat expansions that fall outside of the protein-coding region of the disease gene. Currently, there are no specific gene mutations associated with SCA26 or SCA30, though there is a confirmed locus for each subtype. This disease is mainly diagnosed via genetic testing; however, differential diagnoses include pure cerebellar ataxia and non-cerebellar features in addition to ataxia. Although not fatal, ADCA Type III may cause dysphagia and falls, which reduce the quality of life of the patients and may in turn shorten the lifespan. The therapy for ADCA Type III is supportive and includes occupational and speech modalities. There is no cure for ADCA Type III, but a number of recent studies have highlighted novel therapies, which bring hope for future curative treatments.
Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)
Zbigniew K Wszolek, Yoshio Tsuboi, Bernardino Ghetti, Stuart Pickering-Brown, Yasuhiko Baba, William P Cheshire
Orphanet Journal of Rare Diseases , 2006, DOI: 10.1186/1750-1172-1-30
Abstract: Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).The term frontotemporal dementia and parkinsonism linked to chromosome 17 was defined during the International Consensus Conference in Ann Arbor, Michigan, in 1996 [1]. At the time, affected individuals with frontotemporal dementia and parkinsonism linked to the wld locus on chromosome 17 had been identified within 13 families. This syndrome is a familial disorder with autosomal dominant inheritance. The three major clinical features include behavioral disturbances, cognitive impairment, and parkinsonism. There are no strict diagnostic criteria for FTDP-17. Nevertheless, FTDP-17 should be considered in the differential diagnosis in the presence of one or more of the following [2]:? Age of onset of neurological symptoms between the third and fifth decades;? Progressive neuropsychiatric syndrome including personality and behavioral abnormalities and/or frontotemporal dementia;? Parkinsonism-plus syndrome (bradykinesia, rigidity, postural instability, paucity of resting tremor, and poor or no response to dopaminergic therapy) frequently associated with falls and supranuclear gaze palsy and less commonly associated with apraxia, dystonia, and lateralization;? Progressive speech difficulties from the onset of the illness;? Seizure disorder poorly controlled by standard anticonvulsant therapy;? Positive family history suggestive of autosomal dominant inheritance of a neurodegenerative disorder, even if there has been variability in clinical presentations.FTDP-17 is an extremely rare condition. Its prevalence and incidence remain unknown. Over 100 families with FTDP-17 have been reported to date in numerous countries (USA, Great Britain, Japan, Netherlands, France, Canada, Australia, Italy, Germany, Israel, Ireland, Spain and Sweden). Some of these families share a common founder [3]. We estimate that there have been about 50–600 patients described, with fewer than 70 individuals still living. Molec
Evaluation of the Role of SNCA Variants in Survival without Neurological Disease
Michael G. Heckman, Alexandra I. Soto-Ortolaza, Nancy N. Diehl, Minerva M. Carrasquillo, Ryan J. Uitti, Zbigniew K. Wszolek, Neill R. Graff-Radford, Owen A. Ross
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042877
Abstract: Background A variety of definitions of successful aging have been proposed, many of which relate to longevity, freedom from disease and disability, or preservation of high physical and cognitive function. Many behavioral, biomedical, and psychological factors have been linked with these various measures of successful aging, however genetic predictors are less understood. Parkinson's disease (PD) is an age-related neurodegenerative disorder, and variants in the α-synuclein gene (SNCA) affect susceptibility to PD. This exploratory study examined whether SNCA variants may also promote successful aging as defined by survival without neurological disease. Methods We utilized 769 controls without neurological disease (Mean age: 79 years, Range: 33–99 years) and examined the frequency of 20 different SNCA variants across age groups using logistic regression models. We also included 426 PD cases to assess the effect of these variants on PD risk. Results There was a significant decline in the proportion of carriers of the minor allele of rs10014396 as age increased (P = 0.021), from 30% in controls younger than 60 to 14% in controls 90 years of age or older. Findings were similar for rs3775439, where the proportion of carriers of the minor allele declined from 32% in controls less than 60 years old to 19% in those 90 or older (P = 0.025). A number of SNCA variants, not including rs10014396 or rs3775439, were significantly associated with susceptibility to PD. Conclusions In addition to its documented roles in PD and α-synucleinopathies, our results suggest that SNCA has a role in survival free of neurological disease. Acknowledging that our findings would not have withstood correction for multiple testing, validation in an independent series of aged neurologically normal controls is needed.
Polymorphic genes of detoxification and mitochondrial enzymes and risk for progressive supranuclear palsy: a case control study
Lisa F Potts, Alex C Cambon, Owen A Ross, Rosa Rademakers, Dennis W Dickson, Ryan J Uitti, Zbigniew K Wszolek, Shesh N Rai, Matthew J Farrer, David W Hein, Irene Litvan
BMC Medical Genetics , 2012, DOI: 10.1186/1471-2350-13-16
Abstract: DNA from 553 autopsy-confirmed Caucasian PSP cases (266 females, 279 males; age at onset 68 ± 8 years; age at death 75 ± 8) from the Society for PSP Brain Bank and 425 clinical control samples (197 females, 226 males; age at draw 72 ± 11 years) from healthy volunteers were genotyped using Taqman PCR and the SequenomiPLEX Gold assay.The proportion of NAT2 rapid acetylators compared to intermediate and slow acetylators was larger in cases than in controls (OR = 1.82, p < 0.05). There were no allelic or genotypic associations with PSP for any other SNPs tested with the exception of MAPT (p < 0.001).Our results show that NAT2 rapid acetylator phenotype is associated with PSP, suggesting that NAT2 may be responsible for activation of a xenobiotic whose metabolite is neurotoxic. Although our results need to be further confirmed in an independent sample, NAT2 acetylation status should be considered in future genetic and epidemiological studies of PSP.Progressive supranuclear palsy (PSP) is the most common atypical parkinsonian disorder. Classically, patients present with progressive postural instability and falls followed by slow and hypometric vertical saccades and eventually vertical supranuclear gaze palsy.Neuropathologically, PSP is characterized by deposits of four-repeat microtubule associated protein tau (encoded by the MAPT gene) aggregates in neurons and glia of the basal ganglia and brain-stem [1]. Additionally, there is mitochondrial dysfunction, decreased ATP levels and inflammation in the brains of PSP patients [2-4]. The MAPT H1 haplotype has been consistently reported to be associated with PSP; however, it is also common in the general population, suggesting that gene-gene or gene-environment interactions are likely required for the development of this disease [5,6]. Recently, MAPT H1 was also associated with risk of Parkinson's disease (PD) suggesting shared pathways of disease [7]. Early-onset PD and PSP can present with a similar phenotype and be misdiagn
High-throughput mutational analysis of TOR1A in primary dystonia
Jianfeng Xiao, Robert W Bastian, Joel S Perlmutter, Brad A Racette, Samer D Tabbal, Morvarid Karimi, Randal C Paniello, Andrew Blitzer, Sat Batish, Zbigniew K Wszolek, Ryan J Uitti, Peter Hedera, David K Simon, Daniel Tarsy, Daniel D Truong, Karen P Frei, Ronald F Pfeiffer, Suzhen Gong, Yu Zhao, Mark S LeDoux
BMC Medical Genetics , 2009, DOI: 10.1186/1471-2350-10-24
Abstract: High resolution melting (HRM) was used to examine the entire TOR1A Exon 5 coding sequence in 1014 subjects with primary dystonia (422 spasmodic dysphonia, 285 cervical dystonia, 67 blepharospasm, 41 writer's cramp, 16 oromandibular dystonia, 38 other primary focal dystonia, 112 segmental dystonia, 16 multifocal dystonia, and 17 generalized dystonia) and 250 controls (150 neurologically normal and 100 with other movement disorders). Diagnostic sensitivity and specificity were evaluated in an additional 8 subjects with known ΔGAG DYT1 dystonia and 88 subjects with ΔGAG-negative dystonia.HRM of TOR1A Exon 5 showed high (100%) diagnostic sensitivity and specificity. HRM was rapid and economical. HRM reliably differentiated the TOR1A ΔGAG and c.863G>A mutations. Melting curves were normal in 250/250 controls and 1012/1014 subjects with primary dystonia. The two subjects with shifted melting curves were found to harbor the classic ΔGAG deletion: 1) a non-Jewish Caucasian female with childhood-onset multifocal dystonia and 2) an Ashkenazi Jewish female with adolescent-onset spasmodic dysphonia.First, HRM is an inexpensive, diagnostically sensitive and specific, high-throughput method for mutation discovery. Second, Exon 5 mutations in TOR1A are rarely associated with non-generalized primary dystonia.Dystonia is a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements, or abnormal postures [1]. Dystonia can be classified by etiology (primary or secondary), age of onset (childhood-onset [0–12 yrs], adolescent-onset [13–20 yrs], or late-onset [>20 yrs]), and anatomical distribution (focal, segmental, multifocal, hemidystonia, or generalized) [1-4]. Primary generalized dystonias usually begin in childhood or adolescence, whereas focal dystonias typically present during adult life. Primary dystonia includes syndromes in which dystonia is the sole phenotypic manifestation, with the exception that tremor may be present as well.In most neur
Replication of EPHA1 and CD33 associations with late-onset Alzheimer's disease: a multi-centre case-control study
Minerva M Carrasquillo, Olivia Belbin, Talisha A Hunter, Li Ma, Gina D Bisceglio, Fanggeng Zou, Julia E Crook, V Pankratz, Sigrid B Sando, Jan O Aasly, Maria Barcikowska, Zbigniew K Wszolek, Dennis W Dickson, Neill R Graff-Radford, Ronald C Petersen, Peter Passmore, Kevin Morgan, for the Alzheimer's Research UK (ARUK) consortium, Steven G Younkin
Molecular Neurodegeneration , 2011, DOI: 10.1186/1750-1326-6-54
Abstract: We found no significant evidence of series heterogeneity. Associations with LOAD were successfully replicated for EPHA1 (rs11767557; OR = 0.87, p = 5 × 10-4) and CD33 (rs3865444; OR = 0.92, p = 0.049), with odds ratios comparable to those previously reported. Although the two ARID5B variants (rs2588969 and rs494288) showed significant association with LOAD in meta-analysis of our dataset (p = 0.046 and 0.008, respectively), the associations did not survive adjustment for covariates (p = 0.30 and 0.11, respectively). We had insufficient evidence in our data to support the association of the CD2AP variant (rs9349407, p = 0.56).Our data overwhelmingly support the association of EPHA1 and CD33 variants with LOAD risk: addition of our data to the results previously reported (total n > 42,000) increased the strength of evidence for these variants, providing impressive p-values of 2.1 × 10-15 (EPHA1) and 1.8 × 10-13 (CD33).Following the identification of the APOE ε4 allele as a risk factor for late-onset Alzheimer's disease (LOAD) in 1993 [1], consistent replication of subsequently identified candidates was not achieved until 2009, when two genome-wide association studies (GWAS) [2,3] identified associations of variants in or near CLU, PICALM , and CR1 with LOAD, which were consistently replicated in multiple large, independent case-control studies [4-17]. Subsequently, a variant near BIN1 was reported [4] to achieve genome-wide significant association in a later GWAS published in 2010 that also replicated well in follow-up studies [14-19]. These results demonstrate the utility of the hypothesis-free GWAS approach for identifying loci that associate with LOAD and the necessity of pooling samples and data from multiple centers to obtain resources with sufficient statistical power (GWAS typically > 14,000, follow-up typically total > 28,000) to detect the modest ORs (e.g. 0.8/1.2) associated with these variants in GWAS and follow-up studies.Two recently published companion s
NOTCH3 Variants and Risk of Ischemic Stroke
Owen A. Ross, Alexandra I. Soto-Ortolaza, Michael G. Heckman, Christophe Verbeeck, Daniel J. Serie, Sruti Rayaprolu, Stephen S. Rich, Michael A. Nalls, Andrew Singleton, Rita Guerreiro, Emma Kinsella, Zbigniew K. Wszolek, Thomas G. Brott, Robert D. Brown, Bradford B. Worrall, James F. Meschia
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0075035
Abstract: Background Mutations within the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL mutations appear to be restricted to the first twenty-four exons, resulting in the gain or loss of a cysteine amino acid. The role of other exonic NOTCH3 variation not involving cysteine residues and mutations in exons 25-33 in ischemic stroke remains unresolved. Methods All 33 exons of NOTCH3 were sequenced in 269 Caucasian probands from the Siblings With Ischemic Stroke Study (SWISS), a 70-center North American affected sibling pair study and 95 healthy Caucasian control subjects. Variants identified by sequencing in the SWISS probands were then tested for association with ischemic stroke using US Caucasian controls collected at the Mayo Clinic (n=654), and further assessed in a Caucasian (n=802) and African American (n=298) patient-control series collected through the Ischemic Stroke Genetics Study (ISGS). Results Sequencing of the 269 SWISS probands identified one (0.4%) with small vessel type stroke carrying a known CADASIL mutation (p.R558C; Exon 11). Of the 19 common NOTCH3 variants identified, the only variant significantly associated with ischemic stroke after multiple testing adjustment was p.R1560P (rs78501403; Exon 25) in the combined SWISS and ISGS Caucasian series (Odds Ratio [OR] 0.50, P=0.0022) where presence of the minor allele was protective against ischemic stroke. Although only significant prior to adjustment for multiple testing, p.T101T (rs3815188; Exon 3) was associated with an increased risk of small-vessel stroke (OR: 1.56, P=0.008) and p.P380P (rs61749020; Exon 7) was associated with decreased risk of large-vessel stroke (OR: 0.35, P=0.047) in Caucasians. No significant associations were observed in the small African American series. Conclusion Cysteine-affecting NOTCH3 mutations are rare in patients with typical ischemic stroke, however our observation that common NOTCH3 variants may be associated with risk of ischemic stroke warrants further study.
LRRTM3 Interacts with APP and BACE1 and Has Variants Associating with Late-Onset Alzheimer’s Disease (LOAD)
Sarah Lincoln, Mariet Allen, Claire L. Cox, Louise P. Walker, Kimberly Malphrus, Yushi Qiu, Thuy Nguyen, Christopher Rowley, Naomi Kouri, Julia Crook, V. Shane Pankratz, Samuel Younkin, Linda Younkin, Minerva Carrasquillo, Fanggeng Zou, Samer O. Abdul-Hay, Wolfdieter Springer, Sigrid B. Sando, Jan O. Aasly, Maria Barcikowska, Zbigniew K. Wszolek, Jada M. Lewis, Dennis Dickson, Neill R. Graff-Radford, Ronald C. Petersen, Elizabeth Eckman, Steven G. Younkin, Nilüfer Ertekin-Taner
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064164
Abstract: Leucine rich repeat transmembrane protein 3 (LRRTM3) is member of a synaptic protein family. LRRTM3 is a nested gene within α-T catenin (CTNNA3) and resides at the linkage peak for late-onset Alzheimer’s disease (LOAD) risk and plasma amyloid β (Aβ) levels. In-vitro knock-down of LRRTM3 was previously shown to decrease secreted Aβ, although the mechanism of this is unclear. In SH-SY5Y cells overexpressing APP and transiently transfected with LRRTM3 alone or with BACE1, we showed that LRRTM3 co-localizes with both APP and BACE1 in early endosomes, where BACE1 processing of APP occurs. Additionally, LRRTM3 co-localizes with APP in primary neuronal cultures from Tg2576 mice transduced with LRRTM3-expressing adeno-associated virus. Moreover, LRRTM3 co-immunoprecipitates with both endogenous APP and overexpressed BACE1, in HEK293T cells transfected with LRRTM3. SH-SY5Y cells with knock-down of LRRTM3 had lower BACE1 and higher CTNNA3 mRNA levels, but no change in APP. Brain mRNA levels of LRRTM3 showed significant correlations with BACE1, CTNNA3 and APP in ~400 humans, but not in LRRTM3 knock-out mice. Finally, we assessed 69 single nucleotide polymorphisms (SNPs) within and flanking LRRTM3 in 1,567 LOADs and 2,082 controls and identified 8 SNPs within a linkage disequilibrium block encompassing 5′UTR-Intron 1 of LRRTM3 that formed multilocus genotypes (MLG) with suggestive global association with LOAD risk (p = 0.06), and significant individual MLGs. These 8 SNPs were genotyped in an independent series (1,258 LOADs and 718 controls) and had significant global and individual MLG associations in the combined dataset (p = 0.02–0.05). Collectively, these results suggest that protein interactions between LRRTM3, APP and BACE1, as well as complex associations between mRNA levels of LRRTM3, CTNNA3, APP and BACE1 in humans might influence APP metabolism and ultimately risk of AD.
The Nature of a Dusty Ring in Virgo
N. Brosch,E. Almoznino,B. Wszolek,K. Rudnicki
Physics , 1999, DOI: 10.1046/j.1365-8711.1999.02817.x
Abstract: We detected a ring-like distribution of far-infrared emission in the direction of the center of the Virgo cluster. We studied this feature in the FIR, radio, and optical domains, and deduced that the dust within the feature reddens the galaxies in the direction of the Virgo cluster but does not affect stars within the Milky Way. This is likely to be a dusty feature in the foreground of the Virgo cluster, presumably in the galactic halo. The HI distribution follows the morphology of the FIR emission and shows peculiar kinematicbehavior. We propose that a highly supersonic past collision between an HI cloud and the Galactic HI formed a shock that heated the interface gas to soft X-ray temperatures. HI remnants from the projectile and from the shocked Galactic HI rain down onto the disk as intermediate velocity gas. Our finding emphasizes that extragalactic astronomy must consider the possibility ofextinction by dust at high Galactic latitude and far from the Galactic plane, which may show structure on one-degree and smaller scales. This is particularly important for studies of the Virgo cluster, for example in the determination of the Hubble constant from Cepheids in cluster galaxies.
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