The diagnosis of inherited metabolic diseases by microarray gene expression profiling

<p>Abstract</p> <p>Background</p> <p>Inherited metabolic diseases (IMDs) comprise a diverse group of generally progressive genetic metabolic disorders of variable clinical presentations and severity. We have undertaken a study using microarray gene expression profiling of cultured fibroblasts to investigate 68 patients with a broad range of suspected metabolic disorders, including defects of lysosomal, mitochondrial, peroxisomal, fatty acid, carbohydrate, amino acid, molybdenum cofactor, and purine and pyrimidine metabolism. We aimed to define gene expression signatures characteristic of defective metabolic pathways.</p> <p>Methods</p> <p>Total mRNA extracted from cultured fibroblast cell lines was hybridized to Affymetrix U133 Plus 2.0 arrays. Expression data was analyzed for the presence of a gene expression signature characteristic of an inherited metabolic disorder and for genes expressing significantly decreased levels of mRNA.</p> <p>Results</p> <p>No characteristic signatures were found. However, in 16% of cases, disease-associated nonsense and frameshift mutations generating premature termination codons resulted in significantly decreased mRNA expression of the defective gene. The microarray assay detected these changes with high sensitivity and specificity.</p> <p>Conclusion</p> <p>In patients with a suspected familial metabolic disorder where initial screening tests have proven uninformative, microarray gene expression profiling may contribute significantly to the identification of the genetic defect, shortcutting the diagnostic cascade.</p

Colombia's cyberinfrastructure for biodiversity: Building data infrastructure in emerging countries to foster socioeconomic growth

Science and innovation are not a luxury but a prerequisite for social and economic development (Annan, 2003)

RICORS2040 : The need for collaborative research in chronic kidney disease

Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still confuse CKD with chronic kidney insufficiency or failure. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is 'solved' by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated ageing and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19) and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality that is 10- to 100-fold higher than similar-age peers, and life expectancy is shortened by ~40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth greatest global cause of death by 2040 and the second greatest cause of death in Spain before the end of the century, a time when one in four Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded Centres for Biomedical Research (CIBER) network structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients and the European Kidney Health Alliance. Leading Spanish kidney researchers grouped in the kidney collaborative research network Red de Investigación Renal have now applied for the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) call for collaborative research in Spain with the support of the Spanish Society of Nephrology, Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Riñón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true

The pharmacogenetic basis of clinical response to azathioprine therapy

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Let's get personal:predicting thiopurine and fluoropyrimidine toxicity

The US FDA now recognizes the need to individualize treatment paradigms using biomarkers that predict response to therapy. In clinical practice the best example of this is TPMT testing, which is used to rationalize the starting dose of azathioprine and mercaptopurine. The more recent addition of drug metabolite monitoring means that thiopurine therapy can now be personalized to unprecedented levels. Of interest, parallels exist between TPMT deficiency as an explanation for thiopurine toxicity and DPD deficiency in fluoropyrimidine toxicity. For these drugs, variations in a single locus predict severe toxicity. However, while TPMT testing has translated into routine clinical practice, DPD testing has not. This article summarizes the recent research investigating interindividual differences in the metabolism of thiopurine and fluoropyrimidine drugs, and explores the attitudes which influence the uptake of pharmacogenetic testing. </jats:p

The pharmacogenetic basis of individual variation in thiopurine metabolism

Thiopurines are an important class of immunosuppressive therapy, which have been used in clinical practice for over 50 years. Despite this extensive experience many of the pharmacodynamic and pharmacokinetic properties of these drugs remain unknown. As a consequence there is often no clear explanation for the individual variation in response to treatment, both in terms of efficacy or adverse drug reactions. This review, which emphasizes practice in gastroenterology, summarizes the current understanding of thiopurine drug metabolism and highlights the role of nongenetic and genetic factors other than TPMT, which should be a focus for future research. Correlation of polymorphic variations in these genes with clinical outcomes is expected to clarify the basis for interindividual differences in thiopurine metabolism and enable a more personalized approach to therapy. </jats:p