497 results on '"Combarros, O"'
Search Results
202. CMT1A duplication: refining the minimal adult phenotype.
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Berciano J, Gallardo E, García A, Ramón C, Mateo I, Infante J, Rodríguez-Rodríguez E, and Combarros O
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- Action Potentials, Charcot-Marie-Tooth Disease complications, Electrophysiology, Female, Foot pathology, Foot Deformities pathology, Humans, Magnetic Resonance Imaging, Middle Aged, Charcot-Marie-Tooth Disease pathology, Charcot-Marie-Tooth Disease physiopathology, Foot Deformities etiology, Phenotype
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- 2008
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203. No association of genetic variants of liver X receptor-beta with Alzheimer's disease risk.
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Rodríguez-Rodríguez E, Llorca J, Mateo I, Infante J, Sánchez-Quintana C, García-Gorostiaga I, Fernández-Viadero C, Peña N, Berciano J, and Combarros O
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- Aged, Aged, 80 and over, Alzheimer Disease epidemiology, Apolipoprotein E4 genetics, Apolipoprotein E4 metabolism, Case-Control Studies, DNA-Binding Proteins physiology, Female, Genotype, Haplotypes, Humans, Liver X Receptors, Male, Middle Aged, Orphan Nuclear Receptors, Receptors, Cytoplasmic and Nuclear physiology, Risk Factors, Spain epidemiology, Alzheimer Disease genetics, DNA-Binding Proteins genetics, Genetic Predisposition to Disease, Genetic Variation, Receptors, Cytoplasmic and Nuclear genetics
- Abstract
Apolipoprotein E (APOE) epsilon4 allele is the strongest hitherto known risk factor for sporadic Alzheimer's disease (AD). Liver X receptor-beta (LXRbeta) is a transcription factor that controls expression of genes involved in brain cholesterol metabolism, and one of the main LXRbeta targets is APOE. To evaluate the relationship between LXRbeta genetic variants and AD, independently or in concert with the APOE epsilon4 allele, we examined three LXRbeta polymorphisms located in introns 2 (rs 2695121), 5 (rs 1052533), and 7 (rs 1405655), in 414 Spanish AD patients and 447 controls. The current study does not demonstrate an association between LXRbeta genotypes or haplotypes and AD, neither in the total sample nor when the populations were stratified for the presence or absence of the APOE epsilon4 allele., (Copyright 2007 Wiley-Liss, Inc.)
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- 2008
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204. Magnetic resonance imaging findings of leg musculature in Charcot-Marie-Tooth disease type 2 due to dynamin 2 mutation.
- Author
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Gallardo E, Claeys KG, Nelis E, García A, Canga A, Combarros O, Timmerman V, De Jonghe P, and Berciano J
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- Adult, Charcot-Marie-Tooth Disease genetics, Dynamin II genetics, Female, Humans, Middle Aged, Mutation, Charcot-Marie-Tooth Disease pathology, Family Health, Leg, Magnetic Resonance Imaging methods, Muscle, Skeletal pathology
- Abstract
The purpose of the study was to prospectively assess magnetic resonance (MR) imaging findings of lower limb musculature in an axonal Charcot-Marie-Tooth disease (CMT2) pedigree due to mutation in the dynamin 2 gene (DNM2). The series comprises a proband patient aged 55 years and her two affected daughters aged 32 and 23. MR imaging study included T1- and fat suppressed T2-weighted spin-echo sequences. MR imaging study showed extensive fatty infiltration of all calf muscle compartments with relative preservation of the deep posterior one. Fatty muscle infiltration increased distally in 19 out of 66 (23%) visualized calf muscles in the three patients, but this percentage increased to 64% in the youngest and least severe patient. Muscle edema without contrast enhancement was present in 23% of calf muscles. There was massive fatty atrophy of foot musculature. We conclude that MR imaging study accurately depicts lower limb muscle involvement in CMT2 caused by DNM2 mutation.
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- 2008
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205. Aromatase and interleukin-10 genetic variants interactively modulate Alzheimer's disease risk.
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Combarros O, Sánchez-Juan P, Riancho JA, Mateo I, Rodríguez-Rodríguez E, Infante J, García-Gorostiaga I, Vázquez-Higuera JL, and Berciano J
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- 5' Untranslated Regions genetics, Aged, Aged, 80 and over, Alzheimer Disease enzymology, Brain enzymology, Brain physiopathology, Brain Chemistry genetics, Case-Control Studies, DNA Mutational Analysis, Female, Gene Frequency, Genetic Testing, Genetic Variation genetics, Genotype, Humans, Male, Middle Aged, Odds Ratio, Alzheimer Disease genetics, Aromatase genetics, Estrogens biosynthesis, Genetic Predisposition to Disease genetics, Interleukin-10 genetics, Polymorphism, Genetic genetics
- Abstract
A chronic inflammatory process with activation of microglial cells contribute to the neurodegeneration associated with Alzheimer's disease (AD). Estrogen could protect the brain from neurodegeneration by augmenting the secretion of the anti-inflammatory interleukin (IL)-10 from microglial cells. In a case-control study in 231 AD patients and 194 healthy controls, we examined whether the combined effects between the genes coding for aromatase (a critical enzyme in the peripheral synthesis of estrogens) and IL-10 might be responsible for susceptibility to AD. Subjects carrying both the aromatase (5 -UTR) GG and the IL-10 (-1082) GG genotypes had a six times lower risk of developing AD than subjects without these risk genotypes (OR = 0.17, 95% CI = 0.04-0.77, P = 0.02).
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- 2008
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206. Inflammation-related genes and the risk of Parkinson's disease: a multilocus approach.
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Infante J, García-Gorostiaga I, Sánchez-Juan P, Sánchez-Quintana C, Gurpegui JL, Rodríguez-Rodríguez E, Mateo I, Berciano J, and Combarros O
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- Adult, Aged, Aged, 80 and over, Brain metabolism, Female, Genotype, Humans, Inflammation complications, Inflammation metabolism, Interleukin-10 genetics, Interleukin-1alpha genetics, Interleukin-6 genetics, Interleukin-8 genetics, Male, Middle Aged, Parkinson Disease metabolism, Parkinson Disease pathology, Spain epidemiology, Tumor Necrosis Factor-alpha genetics, Inflammation genetics, Parkinson Disease etiology, Parkinson Disease genetics, Polymorphism, Single Nucleotide genetics
- Abstract
For the first time, the multilocus approach by the set-association method has been applied for the analysis of a cluster of five genes [tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), IL-8, IL-1alpha and IL-10] involved in the brain neuroinflammatory pathway in Parkinson's disease (PD), in a well-defined group of 197 PD patients and 173 control subjects from Spain. Set-association analysis did not reveal an independent or an interactive effect of these inflammatory genes on the PD risk.
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- 2008
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207. Gene-gene interaction between 14-3-3 zeta and butyrylcholinesterase modulates Alzheimer's disease risk.
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Mateo I, Llorca J, Infante J, Rodríguez-Rodríguez E, Berciano J, and Combarros O
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- 14-3-3 Proteins metabolism, Aged, Aged, 80 and over, Butyrylcholinesterase metabolism, Case-Control Studies, Female, Gene Frequency, Genotype, Humans, Male, Middle Aged, 14-3-3 Proteins genetics, Alzheimer Disease genetics, Butyrylcholinesterase genetics, Genetic Predisposition to Disease, Polymorphism, Genetic, Risk
- Abstract
A loss in the regulatory mechanism that controls tau phosphorylation in normal brain is suggested to cause tau hyperphosphorylation in Alzheimer's disease (AD) brain and the development of neurofibrillary tangles (NFT). 14-3-3 zeta protein and butyrylcholinesterase (BCHE) are associated with NFT in AD brain and stimulate tau phosphorylation. In a case-control study in 231 AD patients and 221 healthy controls, we examined whether the combined effects between 14-3-3 zeta (rs964917 and rs983583) and BCHE (K variant) polymorphisms might be responsible for susceptibility to AD. Subjects carrying both the BCHE K allele and the 14-3-3 zeta rs964917 G/G genotype (OR = 0.44, 95% CI = 0.20-0.95, P = 0.03), or 14-3-3 zeta rs983583 G/G genotype (OR = 0.46, 95% CI = 0.21-1.00, P = 0.05) had a lower risk of developing AD than subjects without these risk genotypes. Considering synergistic effects between polymorphisms in tau phosphorylation relate-genes may help in determining the risk profile for AD.
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- 2008
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208. Autosomal-dominant distal myopathy with a myotilin S55F mutation: sorting out the phenotype.
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Berciano J, Gallardo E, Domínguez-Perles R, Gallardo E, García A, García-Barredo R, Combarros O, Infante J, and Illa I
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- Adipose Tissue pathology, Adult, Aged, Amino Acid Substitution genetics, Atrophy, Biopsy, Codon genetics, Connectin, Creatine Kinase blood, Electromyography, Exons genetics, Female, Genetic Carrier Screening, Humans, Leg, Magnetic Resonance Imaging, Male, Microfilament Proteins, Middle Aged, Muscle Weakness diagnosis, Muscle Weakness genetics, Muscle, Skeletal pathology, Muscular Atrophy diagnosis, Muscular Atrophy genetics, Muscular Diseases diagnosis, Muscular Dystrophies, Limb-Girdle diagnosis, Muscular Dystrophies, Limb-Girdle genetics, Mutation, Missense, Neurologic Examination, Pedigree, Chromosome Aberrations, Cytoskeletal Proteins genetics, DNA Mutational Analysis, Genes, Dominant genetics, Muscle Proteins genetics, Muscular Diseases genetics, Phenotype, Phenylalanine genetics, Serine genetics
- Abstract
Objective: To describe the clinical phenotype of an autosomal-dominant pedigree with myotilinopathy., Methods: Two symptomatic patients and six asymptomatic gene mutation carriers were examined. We performed serum chemistry, electrophysiological assessments, magnetic resonance imaging (MRI) of lower limb musculature, histochemical and immunohistochemical studies of a muscle biopsy and mutation analysis of the myotilin gene., Results: Both symptomatic patients, aged 76 and 61 years, presented with late-onset, distal lower-limb weakness involving the ankle and toe flexo-extensor muscles extending up to the thigh muscles; there was mild weakness of the intrinsic hand musculature in the eldest patient. Electromyography revealed a myopathic pattern. Serum creatine kinase levels were slightly elevated. Muscle biopsy revealed myopathic changes with myotilin- and desmin-positive aggregates. Gene sequencing identified a myotilin S55F mutation. In both patients, MRI showed moderate to severe fatty atrophy of all four leg muscle compartments, extending up to the thigh musculature, mainly involving the biceps, femoris, semimembranosus, vasti and glutei muscles; intrinsic foot musculature was involved but to a lesser degree. In all six gene mutation carriers, aged from 21 to 63 years, clinical examinations showed no myopathic signs. MRI was normal in the youngest individual, whereas in the remaining five individuals the outstanding finding was fatty infiltration of the soleus muscles., Conclusions: Myotilin S55F mutations may cause a clinically distinct autosomal-dominant late-onset and lower-limb distal myopathic syndrome involving all four leg muscle compartments. MRI helps to reliably depict the topography of fatty muscle atrophy and to detect early leg muscle changes in asymptomatic gene mutation carriers.
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- 2008
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209. Interaction between CD14 and LXRbeta genes modulates Alzheimer's disease risk.
- Author
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Rodríguez-Rodríguez E, Sánchez-Juan P, Mateo I, Infante J, Sánchez-Quintana C, García-Gorostiaga I, Berciano J, and Combarros O
- Subjects
- Aged, Aged, 80 and over, Alzheimer Disease immunology, Alzheimer Disease physiopathology, Brain immunology, Brain metabolism, Brain physiopathology, Case-Control Studies, DNA Mutational Analysis, DNA-Binding Proteins immunology, Encephalitis immunology, Encephalitis physiopathology, Female, Genetic Markers genetics, Genetic Markers immunology, Genetic Testing, Genotype, Gliosis immunology, Gliosis physiopathology, Humans, Immunity, Innate genetics, Introns genetics, Lipopolysaccharide Receptors immunology, Liver X Receptors, Male, Microglia immunology, Microglia metabolism, Middle Aged, Monitoring, Immunologic, Orphan Nuclear Receptors, Polymorphism, Genetic genetics, Receptors, Cytoplasmic and Nuclear immunology, Alzheimer Disease genetics, DNA-Binding Proteins genetics, Encephalitis genetics, Genetic Predisposition to Disease genetics, Gliosis genetics, Lipopolysaccharide Receptors genetics, Receptors, Cytoplasmic and Nuclear genetics
- Abstract
A chronic inflammatory process with activation of microglial cells contribute to the neurodegeneration associated with Alzheimer's disease (AD). CD14 and LXRbeta are receptors involved in the regulation of inflammatory responses of microglia in response to bacterial infection or lipopolysaccharide stimulation. In a case-control study in 266 AD patients and 273 healthy controls, we examined whether the combined gene effects between CD14 (-260) polymorphism and LXRbeta (intron 5) polymorphism might be responsible for susceptibility to AD. Subjects carrying both the CD14 (-260) C/C and the LXRbeta (intron 5) G/G genotypes had a six times lower risk of developing AD than subjects without these risk genotypes (OR 0.16, 95% CI 0.04-0.67, p=0.01). These data support a role for innate immune response genes in risk for AD.
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- 2008
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210. Deficiency of CARD8 is associated with increased Alzheimer's disease risk in women.
- Author
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Fontalba A, Gutiérrez O, Llorca J, Mateo I, Berciano J, Fernández-Luna JL, and Combarros O
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- Aged, Aged, 80 and over, Apolipoprotein E4 genetics, CARD Signaling Adaptor Proteins deficiency, Case-Control Studies, Female, Genetic Predisposition to Disease epidemiology, Genotype, Humans, Male, Middle Aged, NF-kappa B metabolism, Neoplasm Proteins deficiency, Polymorphism, Genetic, Risk Factors, Sex Distribution, Alzheimer Disease epidemiology, Alzheimer Disease genetics, CARD Signaling Adaptor Proteins genetics, Neoplasm Proteins genetics
- Abstract
NF-kappaB, a major transcription factor controlling inflammation, is activated in Alzheimer's disease (AD) brains. CARD8 protein has been implicated in the suppression of NF-kappaB activity, but a truncating polymorphism (p.C10X, rs2043211) renders a non-functional CARD8 protein that gives rise to a more active NF-kappaB and an amplification of the inflammatory process. Apolipoprotein E (ApoE) epsilon4 allele, the major genetic risk factor of AD, is associated with hyperactivation of NF-kappaB and enhanced brain inflammation. In a case-control study in 300 AD patients and 300 healthy controls, we examined whether the CARD8 (p.C10X) polymorphism, independently or in concert with the ApoE epsilon4 allele, might predispose to AD. Women, but not men, carrying the CARD8 AA genotype (truncated protein) had a 2.39-fold higher risk of developing AD than subjects with the CARD8 TT genotype (full-length protein). This association with susceptibility to AD was independent of the ApoE epsilon4 allele., (Copyright 2008 S. Karger AG, Basel.)
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- 2008
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211. Meta-analysis of genetic variability in the beta-amyloid production, aggregation and degradation metabolic pathways and the risk of Alzheimer's disease.
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Llorca J, Rodríguez-Rodríguez E, Dierssen-Sotos T, Delgado-Rodríguez M, Berciano J, and Combarros O
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- Alzheimer Disease physiopathology, Amyloid Precursor Protein Secretases genetics, Asian People genetics, Aspartic Acid Endopeptidases genetics, Brain physiopathology, Genotype, Humans, Polymorphism, Genetic genetics, Receptors, LDL genetics, Scavenger Receptors, Class E genetics, Alzheimer Disease genetics, Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Brain metabolism, Genetic Predisposition to Disease genetics, Genetic Variation genetics
- Abstract
Background: Variants in genes encoding enzymes involved in production, aggregation or degradation of beta-amyloid are potential risk factors for sporadic Alzheimer's disease (AD)., Methods: Meta-analyses on AD association with BACE1 exon 5, BACE1 intron 5, FE65 intron 13, CYP46 intron 2, alpha(1)-antichymotrypsine Ala17Thr, bleomycin hydrolase I443V, lectin-like oxidized low-density lipoprotein receptor (OLR1) 3'-UTR (+1071) and (+1073), and very-low-density lipoprotein receptor (VLDLR) 5'-UTR (CGG-repeat) polymorphisms., Results: In BACE1 exon 5, genotype CC+CT acts as a protective factor in Apolipoprotein E (ApoE) epsilon 4 carriers [odds ratio (OR) = 0.57; 95% confidence interval (CI): 0.38-0.88], and as a risk factor in ApoE epsilon 4 non-carriers (OR = 1.33; 95% CI: 1.00-1.78). OLR1 3'-UTR (+1073) allele C is associated with increased risk (OR = 1.23; 95% CI: 1.01-1.50). VLDLR 5'-UTR genotype 2 is associated with increased risk (OR = 1.70; 95% CI: 1.09-2.63) in the Asian population and is protective (OR = 0.48; 95% CI: 0.26-0.86) in the non-Asian population. Other studied polymorphisms are not associated with AD., Conclusions: The overall impact on AD risk of the genes for which meta-analyses are now available is rather limited. Additional meta-analyses of other different genes encoding for A beta production, aggregation and degradation mediators might help in determining the risk profile for AD.
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- 2008
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212. Serum levels and genetic variation of TGF-beta1 are not associated with Alzheimer's disease.
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Rodríguez-Rodríguez E, Sánchez-Juan P, Mateo I, Llorca J, Infante J, García-Gorostiaga I, Berciano J, and Combarros O
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- Aged, Aged, 80 and over, Alzheimer Disease diagnosis, DNA Mutational Analysis, Female, Gene Frequency genetics, Genetic Markers genetics, Genetic Predisposition to Disease genetics, Genetic Testing, Genotype, Humans, Male, Middle Aged, Predictive Value of Tests, Risk Factors, Sensitivity and Specificity, Alzheimer Disease blood, Alzheimer Disease genetics, Genetic Variation genetics, Polymorphism, Genetic genetics, Transforming Growth Factor beta1 blood, Transforming Growth Factor beta1 genetics
- Abstract
Objective: As transforming growth factor-beta1 (TGF-beta1) determines important neurotrophic and neuroprotective actions, we postulated serum TGF-beta1 levels could be low in Alzheimer's disease (AD), and TGF-beta1 genetic variation could be associated with AD risk through modulating serum TGF-beta1 levels., Methods: TGF-beta1 (-800) (rs 1800468), (-509) (rs 1800469) and (+869) (rs 1982073) polymorphisms were genotyped in 412 AD patients and 406 controls. We measured serum TGF-beta1 levels (by ELISA) in 63 AD patients and compared them with 77 age- and gender-matched non-demented controls., Results: Serum TGF-beta1 levels were not different in AD patients than in controls. Distribution of the allele and genotype frequencies of TGF-beta1 polymorphisms did not differ between AD patients and controls. There was no significant correlation between serum TGF-beta1 levels and TGF-beta1 polymorphisms., Conclusion: Serum TGF-beta1 concentration is not a potential biomarker for AD, and TGF-beta1 genetic variants (-800, -509, and +869) are not risk factors for AD.
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- 2007
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213. Association of genetic variants of ABCA1 with Alzheimer's disease risk.
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Rodríguez-Rodríguez E, Mateo I, Llorca J, Sánchez-Quintana C, Infante J, García-Gorostiaga I, Sánchez-Juan P, Berciano J, and Combarros O
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- ATP Binding Cassette Transporter 1, Aged, Aged, 80 and over, Alleles, Apolipoprotein E4 genetics, Female, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Risk Factors, ATP-Binding Cassette Transporters genetics, Alzheimer Disease genetics, Genetic Variation
- Abstract
ABCA1 plays key roles in cholesterol transport and apolipoprotein E (APOE) metabolism in the brain. To evaluate the relationship between ABCA1 genetic variants and Alzheimer's disease (AD), independently or in concert with the APOE epsilon4 allele, we examined three ABCA1 polymorphisms located in the coding region (R219K, I883M, and R1587K) and two ABCA1 polymorphisms in the promoter region (C-14T and C-477T) in a group of 372 Spanish AD patients and 440 controls. The ABCA1 219K, 883I, 1587R haplotype was significantly associated with AD, conferring a risk of 1.78 (P = 0.007). The ABCA1 C-14T polymorphism modified the risk of AD in an APOE epsilon4 allele-dependent fashion: in APOE epsilon4 carriers, homozygous for the ABCA1 -14T allele had 3.7 times higher risk of developing AD (OR = 13.99) than carriers of the ABCA1 -14CC and CT genotypes (OR = 3.79). These data suggest that the development of AD might be influenced by either a qualitative change of the ABCA1 protein caused by coding region variants (219K, 883I, and 1587R), or by a quantitative change in ABCA1 expression caused by promoter region variant (-14T) in concert with the APOE epsilon4 allele., ((c) 2007 Wiley-Liss, Inc.)
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- 2007
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214. Interaction between estrogen receptor-alpha and butyrylcholinesterase genes modulates Alzheimer's disease risk.
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Combarros O, Riancho JA, Arozamena J, Mateo I, Llorca J, Infante J, Sánchez-Juan P, Zarrabeitia MT, and Berciano J
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- Aged, Aged, 80 and over, Alleles, Alzheimer Disease diagnosis, Aromatase genetics, Female, Humans, Male, Middle Aged, Odds Ratio, Risk Factors, Spain, Alzheimer Disease genetics, Butyrylcholinesterase genetics, Estrogen Receptor alpha genetics, Genetic Predisposition to Disease
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- 2007
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215. VEGF serum levels are not associated with Parkinson's disease.
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Infante J, Mateo I, Rodríguez-Rodríguez E, Berciano J, and Combarros O
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- Adult, Age Distribution, Aged, Aged, 80 and over, Causality, Down-Regulation physiology, Female, Genetic Predisposition to Disease genetics, Humans, Male, Middle Aged, Nerve Degeneration metabolism, Nerve Degeneration physiopathology, Neurons metabolism, Polymorphism, Genetic genetics, Sex Distribution, Substantia Nigra metabolism, Substantia Nigra physiopathology, Vascular Endothelial Growth Factor A genetics, Cytoprotection physiology, Parkinson Disease blood, Parkinson Disease physiopathology, Vascular Endothelial Growth Factor A blood, Vascular Endothelial Growth Factor A deficiency
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- 2007
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216. Low serum VEGF levels are associated with Alzheimer's disease.
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Mateo I, Llorca J, Infante J, Rodríguez-Rodríguez E, Fernández-Viadero C, Peña N, Berciano J, and Combarros O
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- Age Factors, Aged, Aged, 80 and over, Alzheimer Disease genetics, Apolipoprotein E4 genetics, Case-Control Studies, Female, Humans, Male, Middle Aged, Polymorphism, Genetic, Severity of Illness Index, Sex Factors, Vascular Endothelial Growth Factor A genetics, Alzheimer Disease blood, Vascular Endothelial Growth Factor A blood
- Abstract
Objective: As vascular endothelial growth factor (VEGF) determines important neurotrophic and neuroprotective actions, we postulated serum VEGF levels could be abnormally low in patients with Alzheimer's disease (AD)., Methods: We measured serum VEGF levels (VEGF(165) isoform by ELISA) in 51 patients with AD by National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorder Association criteria and compared with 66 age- and gender-matched non-demented controls. Patients with AD were stratified into levels of dementia severity by the Clinical Dementia Rating scale. Serum VEGF levels were stratified into upper (>309 pg/ml), middle (207-309 pg/ml), and lower (<207 pg/ml) tertiles. VEGF (-2,578) (rs 699,947) and VEGF (-634) (rs 2,010,963) polymorphisms were genotyped in patients with AD and controls., Results: The mean concentration of VEGF in the serum of patients with AD (215.9 pg/ml, SD 101.5) was significantly lower than that of the controls (308.6 pg/ml, SD 223.9, P = 0.004), and decreased serum VEGF levels were associated with AD in a dose-dependent manner, the lower tertile of serum VEGF levels being associated with a fivefold increased risk for AD when compared with the upper tertile. There was no significant correlation between serum VEGF levels and age, sex, APOE alleles, AD dementia severity nor VEGF gene polymorphisms., Conclusion: Decrease in serum VEGF levels could contribute to the neurodegenerative process in AD.
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- 2007
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217. Poly (ADP-ribose) polymerase-1 (PARP-1) genetic variants are protective against Parkinson's disease.
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Infante J, Sánchez-Juan P, Mateo I, Rodríguez-Rodríguez E, Sánchez-Quintana C, Llorca J, Fontalba A, Terrazas J, Oterino A, Berciano J, and Combarros O
- Subjects
- Adult, Age of Onset, Aged, Aged, 80 and over, Case-Control Studies, Female, Heterozygote, Humans, Male, Microsatellite Repeats genetics, Middle Aged, Odds Ratio, Poly (ADP-Ribose) Polymerase-1, Promoter Regions, Genetic, Genetic Variation, Parkinson Disease genetics, Poly(ADP-ribose) Polymerases genetics
- Abstract
Poly (ADP-ribose) polymerase-1 (PARP-1) is involved in crucial pathogenic events in Parkinson's disease (PD). We studied the effect of promoter variations of PARP-1 gene on the risk for PD in a case-control association study comprising 146 PD patients and 161 controls from Northern Spain. Three polymorphisms from the promoter region of PARP-1 gene were analyzed: -410C/T, -1672G/A, and a (CA)n microsatellite. A protective effect against PD was found for heterozygosity at (-410) (OR 0.44) and (CA)n microsatellite (OR 0.53) polymorphisms, and heterozygosity at (-1672) polymorphism delayed by 4 years on the onset age of PD. Variations in the regulatory region of PARP-1 gene might modify the risk for PD.
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- 2007
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218. Interaction between prion protein and interleukin-1A genes increases early-onset Alzheimer's disease risk.
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Combarros O, Llorca J, Sánchez-Juan P, Mateo I, Infante J, Rodríguez E, Sánchez-Quintana C, and Berciano J
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- Age of Onset, Aged, Aged, 80 and over, Female, Gene Frequency, Genotype, Humans, Interleukin-1alpha metabolism, Male, Mental Status Schedule, Middle Aged, Odds Ratio, Prions metabolism, Alzheimer Disease genetics, Genetic Predisposition to Disease genetics, Interleukin-1alpha genetics, Prions genetics, Risk
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- 2007
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219. Charcot-Marie-Tooth disease type 1A duplication with severe paresis of the proximal lower limb muscles: a long-term follow-up study.
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Berciano J, Gallardo E, García A, Infante J, Mateo I, and Combarros O
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- Adolescent, Adult, Aged, Aged, 80 and over, Charcot-Marie-Tooth Disease complications, Female, Follow-Up Studies, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Muscle Weakness etiology, Muscular Atrophy, Paresis physiopathology, Pedigree, Pelvis, Phenotype, Thigh pathology, Charcot-Marie-Tooth Disease genetics, Charcot-Marie-Tooth Disease pathology, Muscle, Skeletal pathology, Paresis etiology
- Abstract
Objective: To describe a large pedigree with Charcot-Marie-Tooth disease type 1A (CMT1A) duplication in which severe pelvic and thigh musculature weakness occurred in two patients, detected by analysing the leg muscle atrophy pattern on magnetic resonance imaging (MRI)., Methods: The pedigree comprised 18 patients, aged between 15 and 85 (median 46) years, who were serially evaluated for up to three decades. All 18 patients and 13 non-affected at-risk people underwent electrophysiological examination. An MRI study of lower limb musculature was carried out in four patients. Three patients underwent sural-nerve biopsy. Genetic testing was carried out in 17 patients and in all 13 at-risk normal people., Results: Fourteen patients were asymptomatic or slightly disabled. The two oldest patients, aged 84 and 80, showed a moderate phenotype. Two other patients, aged 70 and 53, showed late-onset and gradually progressive peroneal paresis extending up to the thigh and pelvic musculature, resulting in waddling gait. MRI scans of all three patients with a mild phenotype showed subtle and subclinical fatty infiltration of calf anterolateral muscle compartments, with thigh muscle involvement in one patient, and extensive atrophy of intrinsic foot muscles. In the youngest patient with proximal leg weakness, the MRI scan showed massive fatty atrophy of all the calf muscles, posteromedial thigh muscle compartments, and internal and external hip rotator muscles. Sural-nerve biopsy specimens showed hypertrophic neuropathy with no superimposed inflammation. Good correlation was seen between electrophysiological and genetic testing., Conclusions: Late in the clinical course, a small proportion of patients with CMT1A develop severe proximal leg weakness, and long-term follow-up is essential for its detection. MRI scans may show subclinical involvement of the thigh musculature.
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- 2006
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220. No association between low density lipoprotein receptor genetic variants and Alzheimer's disease risk.
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Rodríguez E, Mateo I, Llorca J, Sánchez-Quintana C, Infante J, Berciano J, and Combarros O
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- Aged, Aged, 80 and over, Alleles, Exons genetics, Female, Gene Frequency, Genetic Predisposition to Disease genetics, Genotype, Haplotypes, Humans, Male, Middle Aged, Risk Factors, Alzheimer Disease genetics, Polymorphism, Genetic, Receptors, LDL genetics
- Abstract
A number of studies suggest that brain cholesterol metabolism may play a role in Alzheimer's disease (AD) development, probably through modulation of amyloid beta production. The discovery that apolipoprotein E (APOE) epsilon4 allele is a risk factor for sporadic AD raises the possibility that the receptors to which APOE binds on the surface of neurons are also involved in the neurodegenerative process. To evaluate the relationship between low density lipoprotein receptor (LDLR) genetic variant and AD, independently or in concert with the APOE epsilon4 allele, we examined three LDLR polymorphisms located in exons 8 (rs 11669576), 10 (rs 5930), and 13 (rs 5925), in a large group of 322 Spanish AD patients and 314 controls. The current study does not demonstrate an association between LDLR genotypes or haplotypes and AD, neither in the total sample nor when the populations were stratified for the presence or absence of the APOE epsilon4 allele., ((c) 2006 Wiley-Liss, Inc.)
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- 2006
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221. Stiff man-like syndrome and generalized myokymia in spinocerebellar ataxia type 3.
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Berciano J, Infante J, García A, de Pablos C, Amer G, Polo JM, Volpini V, and Combarros O
- Subjects
- Adult, Aged, Alleles, Ataxin-3, Atrophy, Brain Stem pathology, Cerebellum pathology, Diagnosis, Differential, Disease Progression, Female, Humans, Machado-Joseph Disease diagnosis, Magnetic Resonance Imaging, Male, Middle Aged, Myokymia diagnosis, Nerve Tissue Proteins genetics, Neurologic Examination, Nuclear Proteins genetics, Ophthalmoplegia diagnosis, Ophthalmoplegia genetics, Pedigree, Phenotype, Repressor Proteins genetics, Stiff-Person Syndrome diagnosis, Tomography, X-Ray Computed, Machado-Joseph Disease genetics, Myokymia genetics, Stiff-Person Syndrome genetics
- Abstract
We describe the novel association of spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) phenotype combining classical clinical presentation and semeiology mimicking stiff man syndrome (SMS). The studied pedigree comprises seven affected members in three generations. Their clinical picture consisted of cerebellar ataxia, pyramidal signs, facial myokymia, and ophthalmoplegia. The proband was a 39-year-old man in whom such a clinical picture, 5 years after onset at age 29, evolved to severe SMS and widespread myokymia. Electrophysiological study revealed continuous muscle activity in proximal limb muscles. Molecular study demonstrated the MJD gene mutation in all four examined patients with 73 to 76 CAG repeats in the expanded allele. We conclude that an excess of motor unit activity including stiff man-like syndrome and widespread myokymia may be an integral part of the SCA3 clinical spectrum., ((c) 2006 Movement Disorder Society.)
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- 2006
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222. Case-control study of vascular endothelial growth factor (VEGF) genetic variability in Alzheimer's disease.
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Mateo I, Llorca J, Infante J, Rodríguez-Rodríguez E, Sánchez-Quintana C, Sánchez-Juan P, Berciano J, and Combarros O
- Subjects
- Aged, Aged, 80 and over, Alzheimer Disease metabolism, Alzheimer Disease physiopathology, Brain metabolism, Brain pathology, Brain physiopathology, Case-Control Studies, DNA Mutational Analysis, Female, Gene Frequency, Genetic Testing, Genotype, Haplotypes, Humans, Male, Middle Aged, Spain, Alzheimer Disease genetics, Genetic Predisposition to Disease genetics, Genetic Variation genetics, Polymorphism, Genetic genetics, Vascular Endothelial Growth Factor A genetics
- Abstract
Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis and blood vessel function. Recent evidence indicates that VEGF facilitates memory and learning through stimulating angiogenesis and neurogenesis in the rat hippocampal dendate gyrus. Abnormal regulation of VEGF expression has been reported in the pathogenesis of both atherosclerosis and motoneuron degeneration in amyotrophic lateral sclerosis, with low VEGF-producing polymorphisms (-2578 allele A and -634 allele G) conferring increased susceptibility for the development of the disorders. We tested whether these polymorphisms downregulating expression of VEGF might increase the risk of developing Alzheimer's disease (AD). So, we performed a case-control study in 362 Spanish AD patients and 428 healthy controls. The current study does not demonstrate an association between VEGF (-2578) and VEGF (-634) genotypes or haplotypes and AD.
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- 2006
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223. Genetic interaction between two apolipoprotein E receptors increases Alzheimer's disease risk.
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Rodríguez E, Mateo I, Llorca J, Sánchez-Quintana C, Infante J, Berciano J, and Combarros O
- Subjects
- Aged, Aged, 80 and over, Confidence Intervals, Exons, Female, Genotype, Humans, Male, Middle Aged, Odds Ratio, Polymorphism, Genetic, Alzheimer Disease genetics, Low Density Lipoprotein Receptor-Related Protein-1 classification, Low Density Lipoprotein Receptor-Related Protein-1 genetics
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- 2006
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224. LRRK2 G2019S is a common mutation in Spanish patients with late-onset Parkinson's disease.
- Author
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Infante J, Rodríguez E, Combarros O, Mateo I, Fontalba A, Pascual J, Oterino A, Polo JM, Leno C, and Berciano J
- Subjects
- Age of Onset, Aged, Antiparkinson Agents adverse effects, Antiparkinson Agents therapeutic use, Female, Gene Frequency, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Levodopa adverse effects, Levodopa therapeutic use, Male, Middle Aged, Spain epidemiology, Mutation physiology, Parkinson Disease epidemiology, Parkinson Disease genetics, Protein Serine-Threonine Kinases genetics
- Abstract
Mutations in the leucine-rich repat kinase 2 (LRRK2) gene have been shown to cause both autosomal dominant and sporadic Parkinson's disease (PD). The common G2019S mutation shows wide geographical distribution while R1441G has been only reported in Northern Spain. The overall frequency of these mutations remains to be established. To determine the prevalence of G2019S and R1441G mutations in our population of Cantabria (Northern Spain), we recruited 105 consecutive PD patients and 310 controls and conducted genetic analysis of these mutations. G2019S was detected in eight late-onset patients (7.6%). Five of them had no relevant family history. R1441G was not detected in any of our study subjects. The prevalence of G2019S mutation in unselected late-onset PD patients might be higher than previously reported: 3/16 (18.7%) of familial PD and 5/82 (6.1%) of sporadic PD.
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- 2006
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225. Cholesteryl ester transfer protein (CETP) polymorphism modifies the Alzheimer's disease risk associated with APOE epsilon4 allele.
- Author
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Rodríguez E, Mateo I, Infante J, Llorca J, Berciano J, and Combarros O
- Subjects
- Aged, Aged, 80 and over, Alleles, Apolipoprotein E4, Cholesterol Ester Transfer Proteins, Confidence Intervals, DNA Mutational Analysis methods, Exons, Female, Gene Frequency, Genotype, Humans, Isoleucine genetics, Male, Middle Aged, Odds Ratio, Promoter Regions, Genetic, Retrospective Studies, Risk Factors, Spain, Valine genetics, Alzheimer Disease genetics, Apolipoproteins E genetics, Carrier Proteins genetics, Genetic Predisposition to Disease, Glycoproteins genetics, Polymorphism, Genetic
- Abstract
Cholesterol regulates the production of amyloid beta (Abeta), which is central to the pathogenesis of Alzheimer's disease (AD), with high cellular cholesterol promoting and low cellular cholesterol reducing Abeta in vitro and in vivo. High density lipoprotein (HDL) plays a central role in the removal of excess cholesterol from cells, and cholesteryl ester transfer protein (CETP) is a crucial protein involved in the regulation of HDL levels. Two common polymorphisms in the promoter region (C-629A) and exon 14 I405V of the CETP gene are associated with CETP activity and HDL levels. To investigate if these sequence variants in CETP might be of importance in mediating susceptibility to AD, independently or in concert with apolipoprotein E (APOE) epsilon4 allele, we studied a sample of 286 Spanish AD patients and 315 healthy controls. In APOE epsilon4 carriers, homozygous for the CETP (-629) A allele had approximately a three times lower risk of developing AD (odds ratio 2.33, 95% CI 1.01-5.37), than homozygous and heterozygous carriers of the CETP (-629) C allele (odds ratio 7.12, 95% CI 4.51-11.24, P for APOE epsilon4/CETP (-629) AA genotype interaction < 0.001). Our data suggest that CETP behaves as a modifier gene of the AD risk associated with the APOE epsilon4 allele, possibly through modulation of brain cholesterol metabolism.
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- 2006
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226. Charcot-Marie-Tooth disease type 1A duplication: spectrum of clinical and magnetic resonance imaging features in leg and foot muscles.
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Gallardo E, García A, Combarros O, and Berciano J
- Subjects
- Action Potentials, Adolescent, Adult, Charcot-Marie-Tooth Disease physiopathology, Child, Female, Foot, Humans, Male, Middle Aged, Motor Neurons, Muscle, Skeletal physiopathology, Neural Conduction, Charcot-Marie-Tooth Disease pathology, Leg, Magnetic Resonance Imaging, Muscle, Skeletal pathology
- Abstract
MRI is an ideal method for identifying areas of muscle atrophy and fatty infiltration. Studies comparing clinical and MRI features of foot and leg muscle atrophy in Charcot-Marie-Tooth disease type 1A (CMT-1A) duplication are lacking. The aim of this study is to describe clinical and MRI patterns of lower limb amyotrophy in CMT-1A. A total of 10 secondary CMT-1A patients and 1 proband patient with de novo mutation were prospectively evaluated. Ages of patients ranged from 8 to 61 years (median, 24). Disease severity in terms of ability to walk and run was established using a nine-point functional disability scale (FDS). We administered the CMT neuropathy score (CMTNS), based on patient's symptoms, neurological examination and neurophysiological testing. Muscle strength of flexo-extensor ankle and toe muscles was assessed manually with the standard Medical Research Council scale. In all 11 patients, leg MRI study included T1- and T2-weighted spin-echo sequences in coronal and axial planes, and a T1-weighted spin-echo sequence with chemical sift fat suppression before and after paramagnetic contrast agent injection. In seven patients both feet were simultaneously studied in coronal and axial planes. Six patients had pes cavus, an FDS score of 0 (normal), mild CMTNS and normal muscle power of foot flexo-extensors. In these six patients, MRI showed muscle fatty infiltration of intrinsic foot muscles mainly involving the lumbricals, all four leg muscle compartments being preserved. The remaining five patients had FDS scores from 1 (cramps or fatigability) to 3 (walking difficulty), mild to moderate CMTNS and variable weakness of peroneal musculature. In these five patients MRI showed, besides intrinsic foot muscle involvement, variable and distally accentuated fatty infiltration of the lateral, anterior and superficial posterior leg muscle compartments and, to a lesser degree, of the deep posterior compartment. In four patients muscle oedema and post-contrast enhancement was noted. MRI demonstrated fatty infiltration of clinically normal muscles. We conclude that clinical-MRI patterns of lower limb muscle atrophy vary with evolution of semiology. Selective involvement of intrinsic foot muscles is the characteristic pattern of CMT-1A cases with minimal disease signs. Afterwards this pattern usually combines variable involvement of leg muscles. Our findings help to clarity the pathogenesis of pes cavus in the disease.
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- 2006
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227. Interaction between dopamine beta-hydroxylase and interleukin genes increases Alzheimer's disease risk.
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Mateo I, Infante J, Rodríguez E, Berciano J, Combarros O, and Llorca J
- Subjects
- Aged, Aged, 80 and over, Amyloid beta-Peptides metabolism, Cerebral Cortex enzymology, Dopamine metabolism, Female, Genotype, Humans, Male, Middle Aged, Norepinephrine metabolism, Polymorphism, Genetic genetics, Risk, Alzheimer Disease genetics, Dopamine beta-Hydroxylase genetics, Epistasis, Genetic, Interleukin-1 genetics, Interleukin-6 genetics
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- 2006
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228. Very late-onset Friedreich's ataxia with minimal GAA1 expansion mimicking multiple system atrophy of cerebellar type.
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Berciano J, Infante J, García A, Polo JM, Volpini V, and Combarros O
- Subjects
- Age of Onset, Aged, Evoked Potentials, Somatosensory physiology, Friedreich Ataxia pathology, Friedreich Ataxia physiopathology, Humans, Magnetic Resonance Imaging methods, Male, Multiple System Atrophy diagnosis, Neural Conduction physiology, Spinal Cord pathology, Cerebellum pathology, Friedreich Ataxia genetics, Membrane Glycoproteins genetics, Multiple System Atrophy etiology, Trinucleotide Repeat Expansion genetics
- Abstract
Very late-onset Friedreich's ataxia (VLOFA) is characterized by symptomatic onset after 40 years of age and, usually, a benign phenotype. We describe a sporadic case with onset at 53 years of age and a novel VLOFA phenotype mimicking multiple system atrophy (MSA) of cerebellar type associated with minimal GAA1 expansion. We detected several atypical features for a diagnosis of MSA, which should alert to the possibility of an inherited ataxia.
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- 2005
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229. Central nervous system involvement in hereditary neuropathy with liability to pressure palsies: description of a large family with this association.
- Author
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Sanahuja J, Franco E, Rojas-García R, Gallardo E, Combarros O, Begué R, Granés P, and Illa I
- Subjects
- Adult, Central Nervous System metabolism, Central Nervous System physiopathology, DNA Mutational Analysis, Family Health, Female, Gene Deletion, Genetic Predisposition to Disease genetics, Genetic Testing, Hereditary Central Nervous System Demyelinating Diseases genetics, Hereditary Central Nervous System Demyelinating Diseases physiopathology, Hereditary Sensory and Motor Neuropathy complications, Hereditary Sensory and Motor Neuropathy genetics, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Mutation genetics, Nerve Fibers, Myelinated metabolism, Neural Conduction genetics, Pedigree, Peripheral Nerves metabolism, Peripheral Nerves pathology, Peripheral Nerves physiopathology, Central Nervous System pathology, Chromosomes, Human, Pair 17 genetics, Hereditary Central Nervous System Demyelinating Diseases pathology, Hereditary Sensory and Motor Neuropathy pathology, Myelin Proteins genetics, Nerve Fibers, Myelinated pathology
- Abstract
Objective: To describe a large family with hereditary neuropathy with liability to pressure palsies associated with central nervous system demyelination., Design: We examined the 18 members of a pedigree. Genetic analysis was performed on 15 subjects, standard nerve conduction studies on 10 subjects, and brain magnetic resonance imaging studies on 8 subjects., Results: Hereditary neuropathy with liability to pressure palsies was confirmed in 9 patients of the pedigree. Brain magnetic resonance imaging findings showed multiple areas of demyelination in 6 of 6 affected members and were normal in 2 of 2 healthy relatives. Magnetic resonance imaging abnormalities were predominantly located in the subcortical frontal white matter. All patients had acute and recurrent nerve palsies, while clinical features of central nervous system involvement were not a characteristic of this pedigree., Conclusions: We demonstrate that this association, previously reported in sporadic cases, is not coincidental. Therefore, patients with hereditary neuropathy with liability to pressure palsies can present central nervous system white matter lesions, and the role of the PMP22 (peripheral myelin protein 22) gene deletion in the central nervous system should be further studied.
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- 2005
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230. Novel mutation of SACS gene in a Spanish family with autosomal recessive spastic ataxia.
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Criscuolo C, Saccà F, De Michele G, Mancini P, Combarros O, Infante J, Garcia A, Banfi S, Filla A, and Berciano J
- Subjects
- Adult, Chromosome Disorders genetics, Electromyography, Genes, Recessive genetics, Humans, Male, Spain, Ataxia complications, Ataxia genetics, Heat-Shock Proteins genetics, Muscle Spasticity complications, Mutation, Missense genetics, Point Mutation genetics
- Abstract
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an inherited neurodegenerative disorder characterized by early-onset, spastic ataxia and peripheral neuropathy. It was originally described in an inbred population of Quebec and later in some other countries. We report a new missense SACS mutation (7848C>T) in a Spanish family whose phenotype is similar to that of the previously described ARSACS patients. 7848C>T is the first SACS mutation reported in Spain confirming worldwide distribution of the disease., (Copyright (c) 2005 Movement Disorder Society.)
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- 2005
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231. [Competing risks of death and Hardy-Weinberg equilibrium in case-control studies of gene-disease association].
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Llorca J, Prieto-Salceda D, Combarros O, Dierssen-Sotos T, and Berciano J
- Subjects
- Aged, Alzheimer Disease genetics, Genotype, Humans, Models, Genetic, Mutation, Odds Ratio, Selection Bias, Case-Control Studies, Genetic Diseases, Inborn genetics, Genetic Diseases, Inborn mortality, Genetic Predisposition to Disease genetics, Linkage Disequilibrium genetics
- Abstract
Objective: To study the impact of competing risks on Hardy-Weinberg equilibrium and their consequences in case-control studies of gene-late onset disease association., Methods: Based on a population born in Hardy-Weinberg equilibrium for a particular gene, the genetic composition when the gene is associated with a lethal early-onset disease and its consequences on a late-onset disease can be deduced. Odds ratios estimates are unbiased in case-control studies when controls are sampled by density, even if the controls are in Hardy-Weinberg disequilibrium., Results: An example in which a mutant gene is associated with early mortality is presented, producing a departure from Hardy-Weinberg equilibrium; as a result, controls in later ages are in disequilibrium, producing an odds ratio equal to 1.61., Conclusion: Although the main causes of Hardy-Weinberg disequilibrium in controls are selection bias or genotyping error, a competing risk of death associated with the mutant gene would also result in Hardy-Weinberg disequilibrium among controls.
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- 2005
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232. Autosomal dominant cerebellar ataxias in Spain: molecular and clinical correlations, prevalence estimation and survival analysis.
- Author
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Infante J, Combarros O, Volpini V, Corral J, Llorca J, and Berciano J
- Subjects
- Adolescent, Adult, Central Nervous System pathology, Central Nervous System physiopathology, Cerebellar Ataxia diagnosis, Child, Child, Preschool, Chromosome Disorders diagnosis, DNA Mutational Analysis, Female, Genetic Testing, Genetic Variation genetics, Genotype, Humans, Male, Middle Aged, Mutation genetics, Ocular Motility Disorders genetics, Phenotype, Prevalence, Pyramidal Tracts physiopathology, Reflex, Abnormal genetics, Retinal Degeneration genetics, Spain epidemiology, Survival Analysis, Trinucleotide Repeat Expansion, Cerebellar Ataxia epidemiology, Cerebellar Ataxia genetics, Chromosome Disorders epidemiology, Chromosome Disorders genetics, Genes, Dominant
- Abstract
Introduction: The genetic and clinical profile of autosomal dominant cerebellar ataxias (ADCA) displays marked geographical and ethnical variability., Materials and Methods: We have analysed the molecular and clinical correlations in an ethnically homogeneous sample of 30 Spanish ADCA kindreds. Minimal point prevalence for the region of Cantabria was estimated., Results: Seventy per cent of the families harboured known mutations. Areflexia, slow saccades and hypopallesthesia predominated in SCA2; nystagmus, pyramidal signs or areflexia restricted to the legs in SCA 3; and retinal degeneration, pyramidal signs and slow saccades in SCA 7. Anticipation and intergenerational instability were greater in SCA 7. Length of expansions and age at onset were inversely correlated in all SCA subtypes. Larger expansions correlated with areflexia in SCA 2, with pyramidal signs in SCA 3 and with early visual impairment in SCA 7. Survival was similar among the different SCA subtypes. Prevalence of ADCA in Cantabria was 1.6 cases per 100,000 population., Conclusions: This report shows the epidemiological, clinical and genetic profile of ADCA in Spain, providing additional data regarding the broad clinical heterogeneity of these disorders and the variability of the genotype-phenotype correlations.
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- 2005
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233. CD14 receptor polymorphism and Alzheimer's disease risk.
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Combarros O, Infante J, Rodríguez E, Llorca J, Peña N, Fernández-Viadero C, and Berciano J
- Subjects
- Aged, Aged, 80 and over, Alzheimer Disease epidemiology, Apolipoproteins E, Case-Control Studies, Female, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Male, Middle Aged, Odds Ratio, Promoter Regions, Genetic, RNA, Messenger biosynthesis, Reverse Transcriptase Polymerase Chain Reaction methods, Tumor Necrosis Factors, Alzheimer Disease genetics, Lipopolysaccharide Receptors genetics, Polymorphism, Genetic, Risk
- Abstract
Activation of microglial cells is involved in the inflammatory component of Alzheimer's disease (AD), and it may be triggered by infectious pathogens. CD14, a receptor upregulated in activated microglia, plays a central role in innate immunity through recognition of bacterial lipopolysaccharide and initiation of inflammatory response. A polymorphism in the promoter region (-260) of the CD14 receptor has been found to be related to increased risk of bacterial infections and inflammatory diseases such as atherosclerosis. In a case-control study utilizing a clinically well-defined group of 310 sporadic AD patients and 310 control subjects, we investigated whether the CD14 (-260) polymorphism might be responsible for susceptibility to AD, and we also examined the combined gene effects between CD14 and APOE and several other proinflammatory cytokine genes. The current study does not demonstrate an association between CD14 (-260) polymorphism and AD, neither through an independent effect nor through interaction with APOE epsilon4 allele or interleukin (IL)-1A, IL-6, IL-8, tumor necrosis factor (TNF)-alpha, and intercellular adhesion molecule-1 polymorphisms.
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- 2005
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234. Interaction between interleukin-6 and intercellular adhesion molecule-1 genes and Alzheimer's disease risk.
- Author
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Combarros O, Infante J, Llorca J, Peña N, Fernández-Viadero C, and Berciano J
- Subjects
- Aged, Aged, 80 and over, Chi-Square Distribution, Confidence Intervals, Female, Genotype, Glutamic Acid genetics, Humans, Intercellular Adhesion Molecule-1 genetics, Lysine genetics, Male, Meta-Analysis as Topic, Middle Aged, Odds Ratio, Polymorphism, Genetic, Alzheimer Disease genetics, Alzheimer Disease metabolism, Intercellular Adhesion Molecule-1 metabolism, Interleukin-6 metabolism, Risk
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- 2005
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235. Interleukin-8, intercellular adhesion molecule-1 and tumour necrosis factor-alpha gene polymorphisms and the risk for multiple system atrophy.
- Author
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Infante J, Llorca J, Berciano J, and Combarros O
- Subjects
- Adult, Aged, Case-Control Studies, Chi-Square Distribution, Female, Genotype, Humans, Male, Middle Aged, Odds Ratio, Intercellular Adhesion Molecule-1 genetics, Interleukin-8 genetics, Multiple System Atrophy genetics, Polymorphism, Genetic, Risk, Tumor Necrosis Factor-alpha genetics
- Abstract
In a case-control study using a clinically well-defined group of 41 multiple system atrophy (MSA) patients and 93 control subjects, the interleukin (IL)-8 (-251) TT genotype was associated with an approximately fourfold increased risk for MSA and, furthermore, this risk increased elevenfold with the simultaneous presence of the intercellular adhesion molecule-1 (ICAM-1: E469K) KK genotype, suggesting a gene-gene interaction. These data support a role for inflammation-related genes in risk for MSA.
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- 2005
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236. Consistency in gene-Alzheimer's disease association studies.
- Author
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Llorca J, Dierssen-Sotos T, Combarros O, and Berciano J
- Subjects
- Cathepsin D genetics, Genotype, Humans, Low Density Lipoprotein Receptor-Related Protein-1 genetics, Odds Ratio, Peroxidase genetics, Polymorphism, Genetic genetics, Alzheimer Disease genetics
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- 2005
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237. The chemokine receptor CCR5-Delta32 gene mutation is not protective against Alzheimer's disease.
- Author
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Combarros O, Infante J, Llorca J, Peña N, Fernández-Viadero C, and Berciano J
- Subjects
- Aged, Aged, 80 and over, Apolipoprotein E4, Apolipoproteins E genetics, Female, Gene Frequency, Genotype, Humans, Male, Middle Aged, Sequence Analysis, DNA methods, Alleles, Alzheimer Disease genetics, Gene Deletion, Receptors, CCR5 genetics
- Abstract
Chronic local inflammatory reaction involving reactive microglia is one of the major pathological events in Alzheimer's disease (AD). There is growing evidence that the chemokine receptor CCR5 is up-regulated in AD brain and plays a role in the recruitment and accumulation of microglia in senile plaques. A 32-base pair deletion in the CCR5 gene (CCR5-Delta32 mutant allele) confers resistance to HIV-1 infection by preventing expression of the receptor on the cell surface. Several other reports have shown a similar protective effect of CCR5-Delta32 mutation towards certain chronic inflammatory diseases. Given the potential importance of CCR5 in brain inflammation, we hypothesized that individuals carrying the CCR5-Delta32 allele would show a reduced risk of AD. So, we performed a case-control study in 376 Spanish AD patients and 369 healthy controls. The frequency of the CCR5-Delta32 allele in our AD sample was 7.8%, not significantly different from our control sample group (5.8%). The present study indicates that the CCR5-Delta32 allele is not a preventive factor for AD.
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- 2004
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238. Spinocerebellar ataxia type 2 with Levodopa-responsive parkinsonism culminating in motor neuron disease.
- Author
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Infante J, Berciano J, Volpini V, Corral J, Polo JM, Pascual J, and Combarros O
- Subjects
- Alleles, Atrophy pathology, Brain Stem pathology, Female, Humans, Magnetic Resonance Imaging, Middle Aged, Motor Neuron Disease complications, Motor Neuron Disease diagnosis, Parkinsonian Disorders complications, Pedigree, Phenotype, Spinocerebellar Ataxias complications, Spinocerebellar Ataxias diagnosis, Antiparkinson Agents therapeutic use, Levodopa therapeutic use, Motor Neuron Disease genetics, Parkinsonian Disorders drug therapy, Parkinsonian Disorders genetics, Spinocerebellar Ataxias genetics
- Abstract
We describe an exceptional spinocerebellar ataxia type 2 (SCA2) phenotype combining cerebellar ataxia, levodopa-responsive parkinsonism, and motor neuron symptoms. We conclude that motor neuron symptoms and signs may be a striking manifestation in SCA2, masking pre-existing cerebellar and extrapyramidal semeiology., (Copyright 2004 Movement Disorder Society)
- Published
- 2004
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239. No evidence for association of the monocyte chemoattractant protein-1 (-2518) gene polymorphism and Alzheimer's disease.
- Author
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Combarros O, Infante J, Llorca J, and Berciano J
- Subjects
- Aged, Aged, 80 and over, Confidence Intervals, Female, Gene Frequency genetics, Genotype, Humans, Logistic Models, Male, Middle Aged, Odds Ratio, Alzheimer Disease genetics, Chemokine CCL2 genetics, Polymorphism, Genetic genetics
- Abstract
Activation of microglia is a central part of the chronic inflammatory process in Alzheimer disease (AD). The monocyte chemoattractant protein-1 (MCP-1) is a chemokine that plays a role in microglial migration and accumulation at sites of beta-amyloid deposition in senile plaques in the AD brain. A polymorphism in the regulatory region (-2518) of the MCP-1 gene affects the level of MCP-1 expression, and has been associated with a stronger inflammatory response and higher peripheral tissue damage in chronic inflammatory diseases. We investigated whether the MCP-1 (-2518) polymorphism might be responsible for susceptibility to AD in a large Spanish population, utilizing a clinically well-defined group of 328 sporadic AD patients and 315 control subjects. We also examined the combined gene effects between MCP-1 and other proinflammatory cytokine genes such as interleukin-1A (IL-1A) and tumor necrosis factor-alpha (TNF-alpha), and the apolipoprotein E (APOE) gene. In the present study, neither the MCP-1 (-2518) G allele itself nor its interaction with the IL-1A (-889) allele 2, TNF-alpha (-850) allele T or APOE epsilon4 allele conferred increased risk for AD.
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- 2004
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240. Polymorphism at codon 469 of the intercellular adhesion molecule-1 gene is not associated with sporadic Alzheimer's disease.
- Author
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Rodero L, Infante J, Palacio E, Llorca J, Berciano J, and Combarros O
- Subjects
- Aged, Aged, 80 and over, Alzheimer Disease epidemiology, Case-Control Studies, Female, Gene Frequency, Genotype, Humans, Male, Middle Aged, Spain epidemiology, Alzheimer Disease genetics, Codon genetics, Intercellular Adhesion Molecule-1 genetics, Polymorphism, Genetic genetics
- Abstract
Activation of microglia is a central part of the chronic inflammatory response in Alzheimer's disease (AD). Intercellular adhesion molecule-1 (ICAM-1) is a cell surface receptor that may act in AD to adhere microglia to beta amyloid fibrils within senile plaques. Preliminary evidence in an Italian population indicates that a polymorphism at codon 469 of the ICAM-1 gene is a predisposing factor for sporadic AD. Another group has been unable to replicate this association in a Finnish population. A case-control study utilizing a clinically well-defined group of 283 sporadic AD patients and 283 control subjects was performed to test this association in an ethnically homogeneous population from Spain. The current study does not demonstrate any significant difference in E469K genotype or allele frequencies between AD patients and controls. Our study in the Spanish population argues against the hypothesis that polymorphism at codon 469 of the ICAM-1 gene is causally related to AD., (Copyright 2003 Wiley-Liss, Inc.)
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- 2004
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241. Gene-gene interaction between interleukin-1A and interleukin-8 increases Alzheimer's disease risk.
- Author
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Infante J, Sanz C, Fernández-Luna JL, Llorca J, Berciano J, and Combarros O
- Subjects
- Aged, Aged, 80 and over, Alzheimer Disease epidemiology, Female, Humans, Interleukin-1 metabolism, Interleukin-8 metabolism, Male, Middle Aged, Risk Factors, Alzheimer Disease genetics, Genetic Predisposition to Disease epidemiology, Interleukin-1 genetics, Interleukin-8 genetics
- Published
- 2004
- Full Text
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242. Autosomal dominant axonal Charcot-Marie-Tooth disease type 2 (CMT2G) maps to chromosome 12q12-q13.3.
- Author
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Nelis E, Berciano J, Verpoorten N, Coen K, Dierick I, Van Gerwen V, Combarros O, De Jonghe P, and Timmerman V
- Subjects
- Adolescent, Adult, Age of Onset, Aged, Charcot-Marie-Tooth Disease physiopathology, Child, Female, Haplotypes genetics, Humans, Lod Score, Male, Middle Aged, Pedigree, Spain, Charcot-Marie-Tooth Disease classification, Charcot-Marie-Tooth Disease genetics, Chromosome Mapping, Chromosomes, Human, Pair 12 genetics, Genes, Dominant genetics
- Published
- 2004
- Full Text
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243. Polymorphism at codon 66 of the brain-derived neurotrophic factor gene is not associated with sporadic Alzheimer's disease.
- Author
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Combarros O, Infante J, Llorca J, and Berciano J
- Subjects
- Aged, Aged, 80 and over, Alleles, Alzheimer Disease epidemiology, Apolipoprotein E4, Apolipoproteins E genetics, Female, Gene Frequency, Genotype, Humans, Male, Middle Aged, Neuropsychological Tests, Reverse Transcriptase Polymerase Chain Reaction, Risk, Spain epidemiology, Alzheimer Disease genetics, Brain-Derived Neurotrophic Factor genetics, Codon genetics, Polymorphism, Genetic genetics
- Abstract
Memory acquisition and consolidation are associated with an increase in brain-derived neurotrophic factor (BDNF) in synapses, particularly those innervating the hippocampus and cerebral cortex. A polymorphism producing an amino acid substitution (valine to methionine) at codon 66 of the BDNF gene could affect intracellular processing and secretion of BDNF and lead to impairments in hippocampal function. Preliminary evidence in an Italian population indicates that this polymorphism is a predisposing factor for sporadic Alzheimer's disease (AD). A case-control study utilizing a clinically well-defined group of 237 sporadic AD patients and 218 control subjects was performed to test this association. The current study does not demonstrate any significant difference in Val66Met BDNF genotype or allele frequencies between AD patients and controls. Our study in the Spanish population argues against the hypothesis that this polymorphism is causally related to AD., (Copyright 2004 S. Karger AG, Basel)
- Published
- 2004
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244. Expanded GAA repeats and clinical variation in Friedreich's ataxia.
- Author
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Mateo I, Llorca J, Volpini V, Corral J, Berciano J, and Combarros O
- Subjects
- Adolescent, Adult, Age of Onset, Disease Progression, Female, Friedreich Ataxia complications, Genotype, Humans, Male, Phenotype, Friedreich Ataxia genetics, Friedreich Ataxia pathology, Gene Expression Regulation, Trinucleotide Repeat Expansion
- Abstract
Introduction: One of the main features of Friedreich's ataxia (FA) is phenotypic variability that can now be explained by the molecular mechanism (GAA expansion) underlying the disease., Materials and Methods: We have analyzed genotype-phenotype correlations in a group of 40 patients homozygous for the GAA expansion., Results: The smaller GAA expansion (GAA1 allele) size correlated with age at onset and progression disease rate, but we found no correlation between the larger GAA expansion (GAA2 allele) size and these clinical parameters. The frequency of pes cavus, scoliosis, axonal sensory neuropathy and areflexia increased with the size of GAA1, whereas some signs such as sphincter disturbances, cerebellar atrophy on MRI, amyotrophy, dysarthria and decreased vibration sense were associated with increased duration of the disease., Conclusion: GAA1 size is the main determinant of FA phenotype and GAA2 size is a poor predictor of clinical variation. Some clinical features are independent of GAA1 and GAA2 sizes and are determined by the duration of the disease.
- Published
- 2004
- Full Text
- View/download PDF
245. Genetic association of CYP46 and risk for Alzheimer's disease.
- Author
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Combarros O, Infante J, Llorca J, and Berciano J
- Subjects
- Aged, Aged, 80 and over, Alzheimer Disease ethnology, Apolipoproteins E genetics, Case-Control Studies, Cholesterol 24-Hydroxylase, Female, Gene Frequency, Genotype, Humans, Introns genetics, Male, Middle Aged, Risk Factors, Alzheimer Disease genetics, Steroid Hydroxylases genetics
- Abstract
An increasing number of studies suggest that cholesterol plays an important role in regulating beta-amyloid (Abeta) metabolism in Alzheimer's disease (AD). One of the most important mechanisms for the elimination of excess brain cholesterol is its conversion into the 24S-hydroxycholesterol catalyzed by cholesterol 24S-hydroxylase (CYP46). Preliminary evidence indicates that an intron 2 CYP46 T/C gene polymorphismis associated with increased brain Abeta load and higher risk of AD. A case-control study utilizing a clinically well-defined group of 321 sporadic AD patients and 315 control subjects was performed to test this association. Our results indicate that the intron 2 CYP46 C/C genotype may predispose to AD, and this association is independent of the apolipoprotein E genotype., (2004 S. Karger AG, Basel)
- Published
- 2004
- Full Text
- View/download PDF
246. [Buttock mass and malignant sciatic nerve tumor].
- Author
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Rodero L, Canga A, Figols J, Berciano J, and Combarros O
- Subjects
- Aged, Buttocks, Combined Modality Therapy, Diagnosis, Differential, Electromyography, Humans, Magnetic Resonance Imaging, Male, Neoplasm Invasiveness, Nerve Sheath Neoplasms pathology, Nerve Sheath Neoplasms radiotherapy, Nerve Sheath Neoplasms surgery, Pain etiology, Peripheral Nervous System Neoplasms pathology, Peripheral Nervous System Neoplasms radiotherapy, Peripheral Nervous System Neoplasms surgery, Radiotherapy, Adjuvant, Sciatic Nerve surgery, Tarsal Tunnel Syndrome diagnosis, Nerve Sheath Neoplasms diagnosis, Peripheral Nervous System Neoplasms diagnosis, Sciatic Nerve pathology
- Abstract
Malignant peripheral nerve sheath tumors (MPNST) are rare. We report a case of a MPNST of the proximal sciatic nerve in the thigh, unassociated with pre-existing type 1 neurofibromatosis or history of radiation therapy. A 71-year-old man had a 6 month history of constant, severe, burning pain affecting the sole of the left foot. One month after the onset, the pain radiated to the left calf, posterior aspect of the thigh and buttock, and distal leg weakness followed. Three months prior to admission, the patient developed a large and painful mass in the buttock, that occupied the entire left gluteal region on examination. There was severe weakness of ankle and toe dorsiflexion and plantarflexion, decreased sensation on the lateral and posterior aspect of the left leg as well as on the dorsal and plantar surfaces of the foot, and absent ankle jerk. EMG showed denervation and motor unit loss in the short head of biceps femoris and muscles supplied by tibial and peroneal nerves on the left side. Magnetic resonance imaging revealed a 10-cm enhancing mass of the left sciatic nerve from the upper thigh to the greater sciatic notch. In surgery, a large MPNST with a high Ki67 labeling index (> 60 %) was subtotally removed from the sciatic nerve, and adjuvant radiation therapy was administered. In the ensuing months the tumor invaded the entire pelvic region. A high sciatic malignant tumor can present with a rapidly growing buttock mass and unilateral, neuropathic foot pain imitating the tarsal tunnel syndrome.
- Published
- 2004
247. Interleukin-1A (-889) genetic polymorphism increases the risk of multiple system atrophy.
- Author
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Combarros O, Infante J, Llorca J, and Berciano J
- Subjects
- Adult, Aged, Female, Genotype, Humans, Male, Middle Aged, Promoter Regions, Genetic genetics, Risk Factors, Interleukin-1 genetics, Multiple System Atrophy genetics, Multiple System Atrophy immunology, Polymorphism, Genetic genetics
- Abstract
In a case-control study using a clinically well-defined group of 30 multiple system atrophy (MSA) patients and 110 control subjects, homozygosity for interleukin-1A (IL-1A) allele 2 (high secretor of proinflammatory cytokine) in the regulatory region (-889) of the IL-1A gene was associated with a fivefold increased risk for MSA.
- Published
- 2003
- Full Text
- View/download PDF
248. Hereditary neuropathies.
- Author
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Berciano J and Combarros O
- Subjects
- Animals, Humans, Charcot-Marie-Tooth Disease classification, Charcot-Marie-Tooth Disease epidemiology, Charcot-Marie-Tooth Disease genetics, Charcot-Marie-Tooth Disease pathology, Charcot-Marie-Tooth Disease physiopathology
- Abstract
Purpose of Review: This review will update recent advances in the genetics, clinico-electrophysiological, pathological data and pathophysiology of Charcot-Marie-Tooth disease and related disorders., Recent Findings: Hereditary neuropathies continue to be in a state of constant flux, reflecting the rapid advances in the description of causative genes, three additional Charcot-Marie-Tooth genes having been identified in recent months. Such an ever-increasing body of genetic data provides valuable clues to the pathogenetic mechanisms of both nerve demyelination and nerve axonal degeneration. The classification of Charcot-Marie-Tooth disease is increasingly more complex as there are approximately 26 loci; for clinicians to reach a simplified classification is a pressing need. Genotypic-phenotypic correlations are still incomplete and will require further research, starting from both refined molecular investigations and detailed clinical, electrophysiological, and pathological studies. Recent epidemiological surveys have corroborated the fact that Charcot-Marie-Tooth disease is the most common type of hereditary neuropathy., Summary: Advances in molecular genetics in hereditary neuropathies, and mainly in Charcot-Marie-Tooth disease, have enriched our knowledge of this heterogeneous group of disorders. In spite of this there remain important and basic issues, such as an updated and revised classification of Charcot-Marie-Tooth disorders, the better delineation of phenotypic-genotypic correlations, and further research to map as yet non-localized loci or to identify unknown gene mutations.
- Published
- 2003
- Full Text
- View/download PDF
249. Original descriptions of peroneal muscular atrophy.
- Author
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Berciano J, Berciano MT, and Combarros O
- Subjects
- Charcot-Marie-Tooth Disease classification, History, 19th Century, Humans, Charcot-Marie-Tooth Disease history
- Published
- 2003
- Full Text
- View/download PDF
250. Age-dependent association between interleukin-1A (-889) genetic polymorphism and sporadic Alzheimer's disease. A meta-analysis.
- Author
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Combarros O, Llorca J, Sánchez-Guerra M, Infante J, and Berciano J
- Subjects
- Age of Onset, Association, Humans, Promoter Regions, Genetic, Aging, Alzheimer Disease genetics, Interleukin-1 genetics, Polymorphism, Genetic
- Published
- 2003
- Full Text
- View/download PDF
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