Factor VIII haplotypes frequencies in Tunisian hemophiliacs A

<p>Abstract</p> <p>Background</p> <p>The development of inhibitors against factor 8 (F8) is the most serious complication of replacement therapy with F8 in children with severe hemophilia. It was suggested that mismatched F8 replacement therapy may be a risk factor for the development of anti-factor F8 alloantibodies. Recently four single nucleotide polymorphisms (SNPs) encoding six distinct haplotypes, designated H1 through H6, were studied in different populations. Two SNPs are components of the A2 and C2 immunodominant-inhibitor epitopes.</p> <p>The aim of this study is to determine the different types of haplotypes in relation with inhibitors developments and their frequencies in our Tunisian hemophiliac population.</p> <p>Materials and methods</p> <p>95/116 Tunisian patients with hemophilia A undergoing treatment at Hemophilia Treatment Center, Aziza Othmana hospital, participate in this study. Among them only six patients develop inhibitors. The four SNPs were amplified and sequenced.</p> <p>Results and Discussion</p> <p>In a total of 77 patients, we identified the H1, H2, H3 and the infrequent H5 haplotypes. The H1 and H2 haplotypes, which have the same amino acid sequence in the recombinant F8 molecules used clinically, are the most represented with the frequency of 0.763 and 0.157 respectively. This distribution is almost similar to that of Caucasians in which the frequencies are respectively 0.926 and 0.074, whereas it is 0.354 and 0.374 among Subsaharians. Four patients with inhibitors studied here have the H1 haplotype. For one patient who has a large deletion including the exon 10 we can't identify his haplotype. Theses frequencies may explain partially the low level of inhibitors in our patients.</p

Les médicaments qui interfèrent avec les bilans biologiques : revue de la littérature

Contexte : Le bilan biologique fait partie intégrante du processus de diagnostic qui oriente les décisions de prise en charge thérapeutique. Cependant, ces analyses restent sujettes à des interférences endogènes ou exogènes qui altèrent le résultat. Objectif : L’objectif de notre travail était de fournir un aperçu actualisé et complet des interférences les plus documentées dues aux médicaments, afin que l’interprétation des résultats soit fiable et la prise en charge du patient, meilleure. Sources des données : Il s’agit d’une revue systématique exhaustive de la littérature réalisée en 2018. La recherche bibliographique a été réalisée dans différentes bases de données en ligne, à savoir Pubmed, ScienceDirect et Google Scholar. Sélections des études : Seules les publications en français ou en anglais concernant les médicaments à usage humain ont été retenues. Les interférences avec les examens biologiques, dues aux médicaments, que les investigateurs ont étudiées, concernaient uniquement le dosage sanguin (sérum / plasma). Extraction des données : Un tableur Excel a servi à exploiter les résultats. Au total, 82 articles ont été retenus. Les interférences étudiées touchaient 47 paramètres biologiques correspondant à différents bilans : bilan hormonal, bilan hépatique, bilan rénal. Synthèse des données : Les mécanismes rapportés dans notre littérature étaient à 56,9 % d’ordre analytique, à 17,82 % d’ordre physiologique et à 20,11 % d’ordre pharmacologique. Le reste des mécanismes (5,17 %) n’étaient pas définis. Conclusions : Les cliniciens devraient être vigilants lors de la validation et de l’interprétation des résultats d’un examen biologique pour les patients recevant ces types de médicaments. Enfin le dialogue clinico-biologiste est la meilleure garantie pour éviter des explorations complémentaires inutiles, souvent lourdes et coûteuses.  ABSTRACT Background: Biological assessment is an integral part of the diagnostic process that guides therapeutic management decisions. However, these analyses remain subject to interference from endogenous or exogenous factors, which may alter the results. Objective: To provide an up-to-date and comprehensive overview of the most commonly documented types of interference attributable to medications, to ensure reliable interpretation of test results and better management of patients. Data Sources: This comprehensive systematic review of the literature was carried out in 2018. The bibliographic search was carried out in various online databases, specifically PubMed, ScienceDirect and Google Scholar. Study Selection: Only publications in French or English concerning medicinal products for human use were retained. The investigators’ examination of drug-related interference with laboratory tests was limited to blood assays (serum or plasma). Data Extraction: An Excel spreadsheet was used to analyze the results. A total of 82 articles were selected. The interferences studied affected 47 biological parameters corresponding to various types of assessment: hormonal, hepatic, and renal. Data Synthesis: The mechanisms reported in the literature identified were analytical (56.9%), physiological (17.82%), and pharmacological (20.11%). The remainder of the mechanisms (5.17%) were not defined. Conclusions: Clinicians should be vigilant in validating and interpreting laboratory test results for patients receiving these types of drugs. Dialogue between clinicians and biological scientists is the best way to avoid unnecessary additional testing, which is often cumbersome and costly

Contribution of BRCA1 5382insC mutation in triple negative breast cancer in Tunisia

Abstract Background Triple negative breast cancer (TNBC) has been classified as a disease subgroup defined by the lack of expression of estrogen and progesterone receptors as well as the absence of the human epidermal growth factor receptor-2 (HER2) overexpression. Germline mutations in the BRCA1 gene have been associated with TNBC. Approximately 70% of breast cancers arising in BRCA1 mutation carriers and up to 23% of breast cancers in BRCA2 carriers display a triple negative phenotype. However, the contribution and the frequency of BRCA1 mutations in individuals with TNBC, not specifically selected for age at diagnosis or enriched family history of breast/ovarian cancer, have not been investigated in the Tunisian population and are to be established. The aim of the present study was to assess the contribution and the prevalence of recurrent BRCA1 germline mutation (5382inC) in Tunisian women with TNBC unselected for family history or age at onset. Methods For BRCA1 5382inC mutation detection, the exon 20 coding region and exon–intron boundaries of BRCA1 was analyzed using direct DNA sequencing. A total of 33 DNA samples from Tunisian women diagnosed with TNBC and unselected for family history or age at onset were analyzed. Results The 5382inC mutation was identified in 2 out of 33 women with TNBC with an overall prevalence of 6% (2/33). The detection rate of the 5382inC mutation among TNBC women with family history of breast cancer was 25% (2/8). The two 5382inC mutation carriers were postmenopausal and diagnosed at the age of 50 and 57. When stratified by age, the frequency of BRCA1 mutation in patients diagnosed at age ≥ 50 years was 8.7% (2/23). Conclusions Our results confirm a noticeable contribution of BRCA1 5382inC mutation in TNBC development in Tunisia and further indicate that screening for 5382insC mutation in the BRCA1 gene is of interest in genetic testing in our population. Additionally, our data highlight that receptor triple negativity could be an effective selection criterion for BRCA1 genetic test in our population and should therefore be considered in genetic testing guidelines in Tunisia

First report of molecular diagnosis of Tunisian hemophiliacs A: Identification of 8 novel causative mutations

Abstract Introduction Hemophilia A is an X linked recessive hemorrhagic disorder caused by mutations in the F8 gene that lead to qualitative and/or quantitative deficiencies of coagulation factor VIII (FVIII). Molecular diagnosis of hemophilia A is challenging because of the high number of different causative mutations that are distributed throughout the large F8 gene. Molecular studies of these mutations are essential in order to reinforce our understanding of their pathogenic effect responsible for the disorder. Aim In this study we have performed molecular analysis of 28 Tunisian hemophilia A patients and analyzed the F8 mutation spectrum. Methods We screened the presence of intron 22 and intron 1 inversion in severe hemophilia A patients by southern blotting and polymerase chain reaction (PCR). Detection of point mutations was performed by dHPLC/sequencing of the coding F8 gene region. We predict the potential functional consequences of novel missense mutations with bioinformatics approaches and mapping of their spatial positions on the available FVIII 3D structure. Results We identified 23 different mutations in 28 Tunisian hemophilia A patients belonging to 22 unrelated families. The identified mutations included 5 intron 22 inversions, 7 insertions, 4 deletions and 7 substitutions. In total 18 point mutations were identified, of which 9 are located in exon 14, the most mutated exonic sequence in the F8 gene. Among the 23 mutations, 8 are novel and not deposited in the HAMSTeRS database nor described in recently published articles. Conclusion The mutation spectrum of Tunisian hemophilia A patients is heterogeneous with the presence of some characteristic features. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1693269827490715</p

Identification of genetic defects underlying FVII deficiency in 10 patients belonging to eight unrelated families of the North provinces from Tunisia

Abstract Inherited factor VII (FVII) deficiency is a rare disorder characterized by a bleeding phenotype varying from mild to severe. To date, more than 200 mutations have been described along the F7 gene encoding for FVII. The aim of this study was the identification of genetic defects underlying FVII deficiency in 10 patients belonging to eight unrelated families of the North provinces from Tunisia. Mutation detection was performed by sequencing the whole F7 gene coding region, exon-intron boundaries and about 400 bp of the promoter region. We identified 5 mutations in five unrelated families; the novel p.F328Y mutation and the reported mutations: p.R304Q, p.M298I, IVS1aG > A and p.G-39G. For the remaining 5 patients we didn’t identified any mutations using PCR/Sequencing protocol. In conclusion, this study represents the first comprehensive molecular series of FVII deficiency affected patients in Tunisia from the North. We will try in the future to continue the molecular study for Tunisian patients from Center and South provinces in order to have a complete idea about the FVII deficiency mutational profile in our country. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1288044089753085</p