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Article ; Online: Expanding the genetics of amyotrophic lateral sclerosis and frontotemporal dementia.

Schymick, Jennifer C / Traynor, Bryan J

2012 Volume 4, Issue 4, Page(s) 30

Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized clinically by rapidly progressive paralysis leading ultimately to death from respiratory failure. It is now recognized that ALS and frontotemporal lobar degeneration ( ... ...

Abstract	Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized clinically by rapidly progressive paralysis leading ultimately to death from respiratory failure. It is now recognized that ALS and frontotemporal lobar degeneration (FTLD) form a clinical spectrum of disease with overlapping clinical, pathological and genetic features. This past year, the genetic causes of ALS have expanded to include mutations in the genes OPTN, VCP, and UBQLN2, and the hexanucleotide repeat expansion in C9ORF72. The C9ORF72 repeat expansion solidifies the notion that ALS and FTLD are phenotypic variations of a disease spectrum with a common molecular etiology. Furthermore, the C9ORF72 expansion is the genetic cause of a substantial portion of apparently sporadic ALS and FTLD cases, showing that genetics plays a clear role in sporadic disease. Here we describe the progress made in the genetics of ALS and FTLD, including a detailed look at how new insights brought about by C9ORF72 have both broadened and unified current concepts in neurodegeneration.
Language	English
Publishing date	2012-07-26
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/alzrt133
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Article ; Online: The effect of treatment package time in head and neck cancer patients treated with adjuvant radiotherapy and concurrent systemic therapy.

Ghanem, Ahmed I / Schymick, Matthew / Bachiri, Souheyla / Mannari, Aniruddh / Sheqwara, Jawad / Burmeister, Charlotte / Chang, Steven / Ghanem, Tamer / Siddiqui, Farzan

World journal of otorhinolaryngology - head and neck surgery

2019 Volume 5, Issue 3, Page(s) 160–167

Abstract: Objectives: In patients with head and neck carcinoma, "treatment package time" (TPT) was proven to impact outcomes in cases receiving adjuvant radiotherapy alone. Its impact in patients receiving radiotherapy with concurrent systemic therapy has not ... ...

Abstract	Objectives: In patients with head and neck carcinoma, "treatment package time" (TPT) was proven to impact outcomes in cases receiving adjuvant radiotherapy alone. Its impact in patients receiving radiotherapy with concurrent systemic therapy has not been studied previously. The TPT influence on survival endpoints for patients treated with surgery followed by radiation and concurrent systemic therapy was analyzed. Methods: Institutional database to identify head and neck carcinoma cases treated with definitive surgery followed by concomitant chemo(bio) radiotherapy (CRT) was used. TPT was the number of days elapsed between surgery and the last day of radiation. %FINDCUT SAS macro tool was used to search for the cutoff TPT that was associated with significant survival benefit. Kaplan-Meier curves, log-rank tests as well as univariate and multivariate analyses were used to assess overall survival (OS) and recurrence free survival (RFS). Results: One hundred and three cases with a median follow up of 37 months were included in the study. Oropharyngeal tumors were 43%, oral cavity 40% and laryngeal 17% of cases. Concurrent systemic therapy included platinum and cetuximab in 72% and 28%, respectively. Optimal TPT was found to be < 100 days with significantly better OS ( Conclusions: Addition of concomitant systemic therapy to adjuvant radiotherapy did not compensate for longer TPT in head and neck squamous cell carcinoma. Multidisciplinary coordinated care must be provided to ensure the early start of CRT with minimal treatment breaks.
Language	English
Publishing date	2019-01-11
Publishing country	United States
Document type	Journal Article
ISSN	2589-1081
ISSN (online)	2589-1081
DOI	10.1016/j.wjorl.2018.09.005
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Article ; Online: Variable clinical severity in TANGO2 deficiency: Case series and literature review.

Schymick, Jennifer / Leahy, Peter / Cowan, Tina / Ruzhnikov, Maura R Z / Gates, Ryan / Fernandez, Liliana / Pramanik, Gopal / Yarlagadda, Vamsi / Wheeler, Matthew / Bernstein, Jonathan A / Enns, Gregory M / Lee, Chung

American journal of medical genetics. Part A

2021 Volume 188, Issue 2, Page(s) 473–487

Abstract: Biallelic pathogenic variants in the TANGO2 (transport and Golgi organization 2 homolog) gene have been identified as causing a rare metabolic disorder characterized by susceptibility to recurrent rhabdomyolysis, lactic acidosis, encephalopathy, and life- ...

Abstract	Biallelic pathogenic variants in the TANGO2 (transport and Golgi organization 2 homolog) gene have been identified as causing a rare metabolic disorder characterized by susceptibility to recurrent rhabdomyolysis, lactic acidosis, encephalopathy, and life-threatening tachyarrhythmias. Recently published reports suggest variable clinical severity and phenotypes. This study details five new patients from two families with biallelic pathogenic variants in the TANGO2 gene identified by whole exome sequencing and includes the largest number of affected individuals from a single family reported to date. We document significant intrafamilial variability and highlight that milder phenotypes may be underrecognized. We present biochemical and clinical data to help highlight the features that aid in consideration of this condition in the differential with disorders of fatty acid oxidation. We also present a comprehensive literature review summarizing the molecular, clinical, and biochemical findings for 92 individuals across 13 publications. Of the 27 pathogenic variants reported to date, the recurrent exons 3-9 deletion represents the most common variant seen in 42% of individuals with TANGO2 deficiency. Common clinical features seen in >70% of all individuals include acute metabolic crisis, rhabdomyolysis, neurologic abnormalities, developmental delay, and intellectual disability. Findings such as elevated creatine kinase, hypothyroidism, ketotic hypoglycemia, QT prolongation, or abnormalities of long-chain acylcarnitines and urine dicarboxylic acids should raise clinical suspicion for this life-threatening condition.
MeSH term(s)	Exons ; Humans ; Intellectual Disability/genetics ; Phenotype ; Rhabdomyolysis/diagnosis ; Rhabdomyolysis/genetics ; Whole Exome Sequencing
Language	English
Publishing date	2021-10-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2108614-X
ISSN	1552-4833 ; 0148-7299 ; 1552-4825
ISSN (online)	1552-4833
ISSN	0148-7299 ; 1552-4825
DOI	10.1002/ajmg.a.62543
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Article ; Online: Influence of Treatment Package Time on outcomes in High-Risk Oral Cavity Carcinoma in patients receiving Adjuvant Radiation and Concurrent Systemic Therapy: A Multi-Institutional Oral Cavity Collaborative study.

I Ghanem, Ahmed / Woody, Neil M / Schymick, Mathew A / Joshi, Nikhil P / Geiger, Jessica L / Jillian Tsai, Chiaojung / Dunlap, Neal E / Liu, Howard Y / Burkey, Brian B / Lamarre, Eric D / Ku, Jamie A / Scharpf, Joseph / Caudell, Jimmy J / V Porceddu, Sandro / Lee, Nancy Y / Adelstein, David J / Koyfman, Shlomo A / Siddiqui, Farzan

Oral oncology

2022 Volume 126, Page(s) 105781

Abstract: Objectives: To explore the influence of treatment package time(TPT) in high-risk oral cavity squamous cell carcinoma(OCSCC) receiving adjuvant radiotherapy with concurrent chemotherapy(CRT).: Materials and methods: We queried our multi-institutional ... ...

Abstract	Objectives: To explore the influence of treatment package time(TPT) in high-risk oral cavity squamous cell carcinoma(OCSCC) receiving adjuvant radiotherapy with concurrent chemotherapy(CRT). Materials and methods: We queried our multi-institutional OCSCC collaborative database for cases diagnosed between 2005 and 2015 who underwent surgery followed by adjuvant CRT. All patients had high-risk features: extranodal extension(ENE) and/or positive surgical margin(PM). TPT was days between surgery to last radiotherapy fraction. Kaplan-Meier curves, log-rank p-values and multivariate analysis(MVA) were used to investigate the impact of TPT on overall(OS), disease-free(DFS), locoregional failure-free(LRFS) and distant metastases-free(DMFS) survival. Results: We identified 187 cases: median age 58 (range, 24-87 years), males 66%, and ever smokers 69%. ENE and PM were detected in 85% and 32%, and oral tongue and floor of the mouth constituted 49% and 18%, respectively. Median radiotherapy and cisplatin doses received were 66 Gy and 200 mg/m2. Overall, median TPT was 98 (range, 63-162 days). OS was worse for TPT > 90-days (n = 134) than TPT ≤ 90 (n = 53) at two-(65% vs. 71%) and five-years (45% vs. 62%); p = 0.05, with similar results for DFS. No influence on LRFS or DMFS was noted. More lymph nodes(LN) dissected(P = 0.039), T3-4 disease(P = 0.017), and unplanned reoperations(P = 0.037) occurred with TPT > 90-days. On MVA, TPT in 10-day increments was independently detrimental for OS (Hazard Ratio: 1.14; 95 %Confidence Interval [1-1.28]; P = 0.043), perineural invasion, age and positive LN (p < 0.05 for all). Conclusion: In one of the largest multi-institutional cohorts, TPT > 90-days predicted worse OS for high-risk OCSCC receiving adjuvant CRT. All efforts are needed to optimize perioperative care and baseline conditions for favorable outcomes.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Carcinoma, Squamous Cell/drug therapy ; Carcinoma, Squamous Cell/radiotherapy ; Female ; Head and Neck Neoplasms ; Humans ; Male ; Middle Aged ; Mouth Neoplasms/drug therapy ; Mouth Neoplasms/radiotherapy ; Radiotherapy, Adjuvant ; Young Adult
Language	English
Publishing date	2022-02-17
Publishing country	England
Document type	Journal Article ; Multicenter Study
ZDB-ID	1120465-5
ISSN	1879-0593 ; 0964-1955 ; 1368-8375
ISSN (online)	1879-0593
ISSN	0964-1955 ; 1368-8375
DOI	10.1016/j.oraloncology.2022.105781
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Zs.A 4869: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.A 456: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)

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Article: Genetics of sporadic amyotrophic lateral sclerosis.

Schymick, J C / Talbot, K / Traynor, B J

Human molecular genetics

2007 Volume 16 Spec No. 2, Page(s) R233–42

Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized clinically by rapidly progressive paralysis leading ultimately to death from respiratory failure. There is substantial evidence suggesting that ALS is a heritable ... ...

Abstract	Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized clinically by rapidly progressive paralysis leading ultimately to death from respiratory failure. There is substantial evidence suggesting that ALS is a heritable disease, and a number of genes have been identified as being causative in familial ALS. In contrast, the genetics of the much commoner sporadic form of the disease is poorly understood and no single gene has been definitively shown to increase the risk of developing ALS. In this review, we discuss the genetic evidence for each candidate gene that has been putatively associated with increased risk of sporadic ALS. We also review whole genome association studies of ALS and discuss the potential of this methodology for identifying genes relevant to motor neuron degeneration.
MeSH term(s)	Amyotrophic Lateral Sclerosis/genetics ; Aryldialkylphosphatase/genetics ; Cyclic AMP Response Element-Binding Protein/genetics ; DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics ; Dynactin Complex ; Endosomal Sorting Complexes Required for Transport ; Hemochromatosis Protein ; Histocompatibility Antigens Class I/genetics ; Humans ; Intercellular Signaling Peptides and Proteins/genetics ; Intermediate Filament Proteins/genetics ; Membrane Glycoproteins/genetics ; Membrane Proteins/genetics ; Microtubule-Associated Proteins/genetics ; Nerve Degeneration/genetics ; Nerve Tissue Proteins/genetics ; Neurofilament Proteins/genetics ; Peripherins ; RNA-Binding Proteins/genetics ; Ribonuclease, Pancreatic/genetics ; SMN Complex Proteins ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Vascular Endothelial Growth Factor A/genetics
Chemical Substances	CHMP2B protein, human ; Cyclic AMP Response Element-Binding Protein ; Dynactin Complex ; Endosomal Sorting Complexes Required for Transport ; GRN protein, human ; HFE protein, human ; Hemochromatosis Protein ; Histocompatibility Antigens Class I ; Intercellular Signaling Peptides and Proteins ; Intermediate Filament Proteins ; Membrane Glycoproteins ; Membrane Proteins ; Microtubule-Associated Proteins ; Nerve Tissue Proteins ; Neurofilament Proteins ; Peripherins ; RNA-Binding Proteins ; SMN Complex Proteins ; SOD1 protein, human ; VEGFA protein, human ; Vascular Endothelial Growth Factor A ; neurofilament protein L ; Superoxide Dismutase (EC 1.15.1.1) ; Superoxide Dismutase-1 (EC 1.15.1.1) ; angiogenin (EC 3.1.27.-) ; Ribonuclease, Pancreatic (EC 3.1.27.5) ; Aryldialkylphosphatase (EC 3.1.8.1) ; DNA-(Apurinic or Apyrimidinic Site) Lyase (EC 4.2.99.18)
Language	English
Publishing date	2007-10-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Review
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddm215
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Article ; Online: TDP-43 is not a common cause of sporadic amyotrophic lateral sclerosis.

Guerreiro, Rita J / Schymick, Jennifer C / Crews, Cynthia / Singleton, Andrew / Hardy, John / Traynor, Bryan J

PloS one

2008 Volume 3, Issue 6, Page(s) e2450

Abstract: Background: TAR DNA binding protein, encoded by TARDBP, was shown to be a central component of ubiquitin-positive, tau-negative inclusions in frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). Recently, mutations in ... ...

Abstract	Background: TAR DNA binding protein, encoded by TARDBP, was shown to be a central component of ubiquitin-positive, tau-negative inclusions in frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). Recently, mutations in TARDBP have been linked to familial and sporadic ALS. Methodology/principal findings: To further examine the frequency of mutations in TARDBP in sporadic ALS, 279 ALS cases and 806 neurologically normal control individuals of European descent were screened for sequence variants, copy number variants, genetic and haplotype association with disease. An additional 173 African samples from the Human Gene Diversity Panel were sequenced as this population had the highest likelihood of finding changes. No mutations were found in the ALS cases. Several genetic variants were identified in controls, which were considered as non-pathogenic changes. Furthermore, pathogenic structural variants were not observed in the cases and there was no genetic or haplotype association with disease status across the TARDBP locus. Conclusions: Our data indicate that genetic variation in TARDBP is not a common cause of sporadic ALS in North American.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/physiopathology ; Cohort Studies ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/physiology ; Genotype ; Haplotypes ; Humans ; Likelihood Functions ; Middle Aged ; Mutation ; Polymorphism, Single Nucleotide
Chemical Substances	DNA-Binding Proteins
Language	English
Publishing date	2008-06-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0002450
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Article ; Online: Genome-wide association reveals three SNPs associated with sporadic amyotrophic lateral sclerosis through a two-locus analysis.

Sha, Qiuying / Zhang, Zhaogong / Schymick, Jennifer C / Traynor, Bryan J / Zhang, Shuanglin

BMC medical genetics

2009 Volume 10, Page(s) 86

Abstract: Background: Amyotrophic lateral sclerosis (ALS) is a fatal, degenerative neuromuscular disease characterized by a progressive loss of voluntary motor activity. About 95% of ALS patients are in "sporadic form"-meaning their disease is not associated with ...

Abstract	Background: Amyotrophic lateral sclerosis (ALS) is a fatal, degenerative neuromuscular disease characterized by a progressive loss of voluntary motor activity. About 95% of ALS patients are in "sporadic form"-meaning their disease is not associated with a family history of the disease. To date, the genetic factors of the sporadic form of ALS are poorly understood. Methods: We proposed a two-stage approach based on seventeen biological plausible models to search for two-locus combinations that have significant joint effects to the disease in a genome-wide association study (GWAS). We used a two-stage strategy to reduce the computational burden associated with performing an exhaustive two-locus search across the genome. In the first stage, all SNPs were screened using a single-marker test. In the second stage, all pairs made from the 1000 SNPs with the lowest p-values from the first stage were evaluated under each of the 17 two-locus models. Results: we performed the two-stage approach on a GWAS data set of sporadic ALS from the SNP Database at the NINDS Human Genetics Resource Center DNA and Cell Line Repository http://ccr.coriell.org/ninds/. Our two-locus analysis showed that two two-locus combinations--rs4363506 (SNP1) and rs3733242 (SNP2), and rs4363506 and rs16984239 (SNP3) -- were significantly associated with sporadic ALS. After adjusting for multiple tests and multiple models, the combination of SNP1 and SNP2 had a p-value of 0.032 under the Dom intersection Dom epistatic model; SNP1 and SNP3 had a p-value of 0.042 under the Dom x Dom multiplicative model. Conclusion: The proposed two-stage analytical method can be used to search for joint effects of genes in GWAS. The two-stage strategy decreased the computational time and the multiple testing burdens associated with GWAS. We have also observed that the loci identified by our two-stage strategy can not be detected by single-locus tests.
MeSH term(s)	Alleles ; Amyotrophic Lateral Sclerosis/genetics ; Case-Control Studies ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Likelihood Functions ; Models, Genetic ; Odds Ratio ; Polymorphism, Single Nucleotide
Language	English
Publishing date	2009-09-09
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2041359-2
ISSN	1471-2350 ; 1471-2350
ISSN (online)	1471-2350
ISSN	1471-2350
DOI	10.1186/1471-2350-10-86
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Article ; Online: Genome-wide association reveals three SNPs associated with sporadic amyotrophic lateral sclerosis through a two-locus analysis

Schymick Jennifer C / Zhang Zhaogong / Sha Qiuying / Traynor Bryan J / Zhang Shuanglin

BMC Medical Genetics, Vol 10, Iss 1, p

2009 Volume 86

Abstract: Abstract Background Amyotrophic lateral sclerosis (ALS) is a fatal, degenerative neuromuscular disease characterized by a progressive loss of voluntary motor activity. About 95% of ALS patients are in "sporadic form"-meaning their disease is not ... ...

Abstract	Abstract Background Amyotrophic lateral sclerosis (ALS) is a fatal, degenerative neuromuscular disease characterized by a progressive loss of voluntary motor activity. About 95% of ALS patients are in "sporadic form"-meaning their disease is not associated with a family history of the disease. To date, the genetic factors of the sporadic form of ALS are poorly understood. Methods We proposed a two-stage approach based on seventeen biological plausible models to search for two-locus combinations that have significant joint effects to the disease in a genome-wide association study (GWAS). We used a two-stage strategy to reduce the computational burden associated with performing an exhaustive two-locus search across the genome. In the first stage, all SNPs were screened using a single-marker test. In the second stage, all pairs made from the 1000 SNPs with the lowest p-values from the first stage were evaluated under each of the 17 two-locus models. Results we performed the two-stage approach on a GWAS data set of sporadic ALS from the SNP Database at the NINDS Human Genetics Resource Center DNA and Cell Line Repository http://ccr.coriell.org/ninds/ . Our two-locus analysis showed that two two-locus combinations--rs4363506 (SNP1) and rs3733242 (SNP2), and rs4363506 and rs16984239 (SNP3) -- were significantly associated with sporadic ALS. After adjusting for multiple tests and multiple models, the combination of SNP1 and SNP2 had a p-value of 0.032 under the Dom∩Dom epistatic model; SNP1 and SNP3 had a p-value of 0.042 under the Dom × Dom multiplicative model. Conclusion The proposed two-stage analytical method can be used to search for joint effects of genes in GWAS. The two-stage strategy decreased the computational time and the multiple testing burdens associated with GWAS. We have also observed that the loci identified by our two-stage strategy can not be detected by single-locus tests.
Keywords	Internal medicine ; RC31-1245 ; Genetics ; QH426-470
Subject code	616
Language	English
Publishing date	2009-09-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
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Article ; Online: Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion.

Xi, Zhengrui / Zinman, Lorne / Moreno, Danielle / Schymick, Jennifer / Liang, Yan / Sato, Christine / Zheng, Yonglan / Ghani, Mahdi / Dib, Samar / Keith, Julia / Robertson, Janice / Rogaeva, Ekaterina

American journal of human genetics

2013 Volume 92, Issue 6, Page(s) 981–989

Abstract: The G4C2 repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We tested the hypothesis that the repeat expansion causes aberrant CpG methylation near the G4C2 ... ...

Abstract	The G4C2 repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We tested the hypothesis that the repeat expansion causes aberrant CpG methylation near the G4C2 repeat, which could be responsible for the downregulation of gene expression. We investigated the CpG methylation profile by two methods using genomic DNA from the blood of individuals with ALS (37 expansion carriers and 64 noncarriers), normal controls (n = 76), and family members of 7 ALS probands with the expansion. We report that hypermethylation of the CpG island 5' of the G4C2 repeat is associated with the presence of the expansion (p < 0.0001). A higher degree of methylation was significantly correlated with a shorter disease duration (p < 0.01), associated with familial ALS (p = 0.009) and segregated with the expansion in 7 investigated families. Notably, we did not detect methylation for either normal or intermediate alleles (up to 43 repeats), bringing to question the current cutoff of 30 repeats for pathological alleles. Our study raises several important questions for the future investigation of large data sets, such as whether the degree of methylation corresponds to clinical presentation (ALS versus FTLD).
MeSH term(s)	Aged ; Amyotrophic Lateral Sclerosis/genetics ; Base Sequence ; Case-Control Studies ; CpG Islands ; DNA Methylation ; DNA Repeat Expansion ; Genetic Association Studies ; Heterozygote ; Humans ; Linear Models ; Membrane Proteins/genetics ; Middle Aged ; Molecular Sequence Data ; Pedigree ; Sequence Analysis, DNA ; Tumor Suppressor Proteins/genetics
Chemical Substances	Membrane Proteins ; TMEM8B protein, human ; Tumor Suppressor Proteins
Language	English
Publishing date	2013-05-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	219384-x
ISSN	1537-6605 ; 0002-9297
ISSN (online)	1537-6605
ISSN	0002-9297
DOI	10.1016/j.ajhg.2013.04.017
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Article ; Online: Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study.

Laaksovirta, Hannu / Peuralinna, Terhi / Schymick, Jennifer C / Scholz, Sonja W / Lai, Shaoi-Lin / Myllykangas, Liisa / Sulkava, Raimo / Jansson, Lilja / Hernandez, Dena G / Gibbs, J Raphael / Nalls, Michael A / Heckerman, David / Tienari, Pentti J / Traynor, Bryan J

The Lancet. Neurology

2010 Volume 9, Issue 10, Page(s) 978–985

Abstract: Background: The genetic cause of amyotrophic lateral sclerosis (ALS) is not well understood. Finland is a well suited location for a genome-wide association study of ALS because the incidence of the disease is one of the highest in the world, and ... ...

Abstract	Background: The genetic cause of amyotrophic lateral sclerosis (ALS) is not well understood. Finland is a well suited location for a genome-wide association study of ALS because the incidence of the disease is one of the highest in the world, and because the genetic homogeneity of the Finnish population enhances the ability to detect risk loci. We aimed to identify genetic risk factors for ALS in the Finnish population. Methods: We did a genome-wide association study of Finnish patients with ALS and control individuals by use of Illumina genome-wide genotyping arrays. DNA was collected from patients who attended an ALS specialty clinic that receives referrals from neurologists throughout Finland. Control samples were from a population-based study of elderly Finnish individuals. Patients known to carry D90A alleles of the SOD1 gene (n=40) were included in the final analysis as positive controls to assess whether our genome-wide association study was able to detect an association signal at this locus. Findings: We obtained samples from 442 patients with ALS and 521 control individuals. After quality control filters were applied, 318 167 single nucleotide polymorphisms (SNPs) from 405 people with ALS and 497 control individuals were available for analysis. We identified two association peaks that exceeded genome-wide significance. One was located on chromosome 21q22 (rs13048019, p=2·58×10(-8)), which corresponds to the autosomal recessive D90A allele of the SOD1 gene. The other was detected in a 232 kb block of linkage disequilibrium (rs3849942, p=9·11×10(-11)) in a region of chromosome 9p that was previously identified in linkage studies of families with ALS. Within this region, we defined a 42-SNP haplotype that was associated with significantly increased risk of ALS (p=7·47×10(-33) when people with familial ALS were compared with controls, odds ratio 21·0, 95% CI 11·2-39·1) and which overlapped with an association locus recently reported for frontotemporal dementia. For the 93 patients with familial ALS, the population attributable risk for the chromosome 9p21 locus was 37·9% (95% CI 27·7-48·1) and that for D90A homozygosity was 25·5% (16·9-34·1). Interpretation: The chromosome 9p21 locus is a major cause of familial ALS in the Finnish population. Our data suggest the presence of a founder mutation for chromosome 9p21-linked ALS. Furthermore, the overlap with the risk haplotype recently reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases. Funding: National Institutes of Health and National Institute on Aging, Microsoft Research, ALS Association, Helsinki University Central Hospital, Finnish Academy, Finnish Medical Society Duodecim, and Kuopio University.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/enzymology ; Amyotrophic Lateral Sclerosis/epidemiology ; Amyotrophic Lateral Sclerosis/genetics ; Chromosomes, Human, Pair 9/genetics ; Cohort Studies ; Female ; Finland/epidemiology ; Genetic Loci/genetics ; Genetic Predisposition to Disease/epidemiology ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study/methods ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide/genetics ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Young Adult
Chemical Substances	SOD1 protein, human ; Superoxide Dismutase (EC 1.15.1.1) ; Superoxide Dismutase-1 (EC 1.15.1.1)
Language	English
Publishing date	2010-08-30
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2081241-3
ISSN	1474-4465 ; 1474-4422
ISSN (online)	1474-4465
ISSN	1474-4422
DOI	10.1016/S1474-4422(10)70184-8
Database	MEDical Literature Analysis and Retrieval System OnLINE

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