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Onofre Combarros

Publications and source records attributed to Onofre Combarros.

At least 37 records · Page 2Linked to original sources
PubMed2004

Polymorphism at codon 469 of the intercellular adhesion molecule-1 gene is not associated with sporadic Alzheimer's disease.

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.

Aged↗
PubMed2003

Initial semeiology in children with Charcot-Marie-Tooth disease 1A duplication.

The aim of this study was to describe the initial signs and symptoms in Charcot-Marie-Tooth disease type 1A (CMT-1A). Twelve secondary cases with CMT-1A were serially evaluated. Ages at initial clinical examination ranged between 1 month and 5 years (mean, 2 years) and final ages between 6 and 23 years (mean, 13 years). First signs of the disease were detected at initial or upon serial examinations in all 12 patients at ages ranging between 1 and 10 years (median, 4 years). The most frequent signs were lower limb areflexia in 12, difficulty in heel walking in 8, nerve enlargement in 6, atrophy of intrinsic foot muscles in 6, clawing of toes in 5, pes cavus or cavus varus in 4, shortening of Achilles tendon in 3, peroneal weakness in 1, and stocking hypoesthesia in 1. Only three patients were symptomatic at the initial evaluation. We conclude that initial CMT-1A signs usually appear in early childhood, although they may be quite subtle and require serial examinations for detection. Lower limb areflexia is the only constant early sign.

Adolescent↗
PubMed2003

Hereditary neuropathies.

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.

Animals↗
PubMed2003

Interaction of the H63D mutation in the hemochromatosis gene with the apolipoprotein E epsilon 4 allele modulates age at onset of Alzheimer's disease.

The H63D mutation in the hemochromatosis gene (HFE) has recently been considered as a risk factor in Alzheimer's disease (AD) with advancing age at onset of the disease, independently of the apolipoprotein E (ApoE) epsilon4 allele effect. We examined the distribution of the H63D mutation and ApoE genotypes as a function of age at AD onset in 328 patients with sporadic AD. Our data show that the mutant H63D allele potentially interacts with the ApoE epsilon4 allele to significantly reduce age at onset of AD compared to ApoE epsilon4 carriers alone, but has no effect on age at onset in ApoE epsilon4 non-carriers.

Age of Onset↗
PubMed2003

Age-dependent association between the Q7R polymorphism in the Saitohin gene and sporadic Alzheimer's disease.

A vigorous controversy exists over whether tau tangles or amyloid-beta plaques are the primary cause of neurodegeneration in Alzheimer's disease (AD), and it is not well established whether genetic variation in tau is associated with AD. A recently identified novel protein, named Saitohin (STH), shares tissue expression pattern with tau, and preliminary evidence in a North American population indicates that a polymorphism at codon 7 (Q7R) of the STH gene is a predisposing factor for sporadic AD. A case-control study utilizing a clinically well-defined group of 315 sporadic AD patients and 307 control subjects was performed to test this association. The current study reveals that increased risk of AD associated with the STH RR genotype (OR 2.17, p = 0.04) is limited to late-onset (after the age of 72 years) AD cases.

Age of Onset↗
PubMed2002

Polymorphism at codon 174 of the prion-like protein gene is not associated with sporadic Alzheimer's disease.

Alzheimer's disease (AD) and prion diseases are associated with the occurrence of protein aggregates called amyloid fibrils, containing the amyloid-beta peptide in AD, and a modified form (PrP(Sc)) of the normal cellular prion protein (PrP(c)) in prion diseases. PrP(c) is encoded by the prion protein gene, and a common polymorphism at codon 129 of this gene is a determinant of susceptibility to acquired and sporadic prion diseases but not for sporadic AD. A recently identified novel protein, named Doppel, shares biochemical and structural homology with PrP(c). Preliminary evidence in a German population indicates that a polymorphism at codon 174 of the prion-like protein (PRND) gene encoding for Doppel protein is a predisposing factor for both prion diseases and sporadic AD. A case-control study utilizing a clinically well-defined group of 283 sporadic AD patients and 288 control subjects was performed to test this association. The current study does not demonstrate any significant difference in T174M PRND genotype or allele frequencies between AD patients and controls. Our study in the Spanish population argues against the hypothesis that the PRND gene is causally related to AD.

Aged↗
PubMed2002

No synergistic effect between -850 tumor necrosis factor-alpha promoter polymorphism and apolipoprotein E epsilon 4 allele in Alzheimer's disease.

In the brains of Alzheimer's disease (AD) patients, microglia cells are activated and produce inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha). A recent study conducted in Northern Ireland showed that a polymorphism in the promotor region (-850) of the TNF-alpha gene increased the risk of AD associated with carriage of the apolipoprotein E (APOE) epsilon 4 allele. In a case-control study restricted to a population from Northern Spain and utilizing 321 sporadic AD patients and 312 control subjects, we have found that the -850 TNF-alpha polymorphism does not interact with the APOE gene to increase the risk associated with the epsilon 4 allele.

Age of Onset↗
PubMed2002

The myeloperoxidase gene in Alzheimer's disease: a case-control study and meta-analysis.

Myeloperoxidase (MPO) presence has been demonstrated in microglia associated with senile plaques, and contributes to Alzheimer's disease (AD) pathology through oxidation-induced damage. Recently, a functional biallelic (G/A) polymorphism in the promotor region (-463) of the MPO gene has been associated with susceptibility to AD, but the reports of this association have been inconsistent. A case-control study utilizing a clinically well-defined group of 315 sporadic AD patients and 327 control subjects was performed to test this association. The current study does not demonstrate any significant difference in MPO genotype or allele frequencies between AD patients and controls. A meta-analysis of all studies available gave a non-significant (P=0.83) odds ratio of 1.02 for the MPO GG genotype. Our study in the Spanish population as well as the meta-analysis argue against the hypothesis that the MPO gene is causally related to AD.

Aged↗
PubMed2002

Lack of association between cathepsin D genetic polymorphism and Alzheimer disease in a Spanish sample.

Cathepsin D (catD) is an intracellular aspartyl protease that exhibits beta and gamma secretase-like activity to cleave amyloid precursor protein into beta amyloid peptide. The T-allele of a biallelic (alleles C and T) polymorphism in the exon 2 of the catD gene has been found to be associated with increased risk of Alzheimer disease (AD) in two independent German populations. Other groups have been unable to replicate this association in Caucasian American and Northern Ireland populations. Moreover, a small and no significant tendency for the T-allele to be protective for AD has been demonstrated in Caribbean Hispanics. A case control study utilizing a clinically well-defined group of 311 sporadic AD patients and 346 control subjects was performed to test this association in an ethnically homogeneous population from Spain. We did not observe any association between the T-allele of the catD gene and the disease. Furthermore, catD was not predictive of AD in an interactive fashion when considering apolipoprotein E, age, or gender.

Aged↗
PubMed2002

Gene dose-dependent association of interleukin-1A [-889] allele 2 polymorphism with Alzheimer's disease.

Interleukin (IL)-1 is a potent proinflammatory cytokine that is markedly overexpressed in the brains of patients with Alzheimer's disease (AD). The IL-1A [-889] allele 2 has been shown to increase AD risk, probably by upregulating the inflammatory cascade in the disease process. A case-control study utilizing a clinically well-defined group of 298 sporadic AD patients and 306 control subjects was performed to test this association. Our data show that the IL-1A allele 2 is a risk factor in a dose-dependent manner, the risk of developing AD with two copies of the IL-1A allele 2 (odds ratio 3.1, 95 % CI 1.30-7.45) being approximately double that of one copy of the IL-1A allele 2 (odds ratio 1.4, 95 % CI 0.99-1.94, P for trend = 0.0004). Furthermore, the risk associated with the IL-1A allele 2 was not restricted to AD patients of a particular age, and we could confirm this association in our early-onset and late-onset AD patients.

Aged↗
PubMed2002

Candidate gene association studies in sporadic Alzheimer's disease.

The genetics of Alzheimer's disease (AD) is complex. Three genes (amyloid precursor protein, presenilin 1 and presenilin 2) have been described in the relatively rare, early-onset, autosomal dominant familial form of AD. In the common, non-familial (sporadic) late-onset AD, the major known genetic risk factor is the epsilon4 allele of the apolipoprotein E (APOE) gene. However, at least half of the people who develop AD do not carry this allele, and not all people who do carry this allele develop AD even if they live to an old age. Therefore, approximately 30 other candidate genes involving a protein in a critical pathway in the pathogenesis of disease (principally interaction with amyloid-beta, oxidative stress and inflammation/apoptosis) have been considered as risk factors for sporadic AD. Then these genes have been sequenced in search of genetic variability or polymorphisms, and each putative polymorphism has been reported to alter the risk of AD either directly or by an interaction with the APOE epsilon4 allele. However, positive-association studies with these candidate genes have not been consistently confirmed.

Age of Onset↗
PubMedDate not supplied

CD14 receptor polymorphism and Alzheimer's disease risk.

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.

Aged↗