Browsing by Author "Marques, I."
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- Arx-related disorders: several distinct phenotypes, one mutated genePublication . Sá, M.J.; Soares, G.; Silva, J.; Fortuna, A.; Santos, R.; Marques, I.; Jorge, P.
- Classical fragile-X phenotype in a female infant disclosed by comprehensive genomic studiesPublication . Jorge, P.; Garcia, E.; Gonçalves, A.; Marques, I.; Maia, N.; Rodrigues, B.; Santos, H.; Fonseca, J.; Soares, G.; Correia, C.; Reis-Lima, M.; Cirigliano, V.; Santos, R.BACKGROUND: We describe a female infant with Fragile-X syndrome, with a fully expanded FMR1 allele and preferential inactivation of the homologous X-chromosome carrying a de novo deletion. This unusual and rare case demonstrates the importance of a detailed genomic approach, the absence of which could be misguiding, and calls for reflection on the current clinical and diagnostic workup for developmental disabilities. CASE PRESENTATION: We present a female infant, referred for genetic testing due to psychomotor developmental delay without specific dysmorphic features or relevant family history. FMR1 mutation screening revealed a methylated full mutation and a normal but inactive FMR1 allele, which led to further investigation. Complete skewing of X-chromosome inactivation towards the paternally-inherited normal-sized FMR1 allele was found. No pathogenic variants were identified in the XIST promoter. Microarray analysis revealed a 439 kb deletion at Xq28, in a region known to be associated with extreme skewing of X-chromosome inactivation. CONCLUSIONS: Overall results enable us to conclude that the developmental delay is the cumulative result of a methylated FMR1 full mutation on the active X-chromosome and the inactivation of the other homologue carrying the de novo 439 kb deletion. Our findings should be taken into consideration in future guidelines for the diagnostic workup on the diagnosis of intellectual disabilities, particularly in female infant cases.
- Development and validation of a multiplex-PCR assay for X-linked intellectual disabilityPublication . Jorge, P.; Oliveira, B.; Marques, I.; Santos, R.BACKGROUND: X-linked intellectual disability is a common cause of inherited cognitive deficit affecting mostly males. There are several genetic causes implicated in this condition, which has hampered the establishment of an accurate diagnosis. We developed a multiplex-PCR assay for the mutational hotspot regions of the FMR1, AFF2 and ARX genes. METHODS: The multiplex-PCR was validated in a cohort of 100 males selected to include known alleles for the FMR1 repetitive region: five full mutations (250-650 CGGs), ten premutations (70-165 CGGs) and eighty-five in the normal range (19-42 CGGs). Sequencing or Southern blotting was used to confirm the results, depending on the allele class. In this cohort, with the exception of one sample showing an AFF2 intermediate-sized allele, all other samples were normal (8-34 CCGs). No ARX variant was found besides the c.429_452dup. The validated assay was applied to 5000 samples (64.4% males and 35.6% females). RESULTS: The normal-allelic range of both FMR1 and AFF2 genes as well as the nature of ARX variants identified was similar in both genders. The rate of homozygosity observed in female samples, 27.5% for FMR1 and 17.8% for AFF2 alleles, is comparable to that published by others. Two FMR1 premutations were identified, in a male (58 CGGs) and a female case [(CGG)(47)/(CGG)(61)], as well as several FMR1 or AFF2 intermediate-sized alleles. One AFF2 premutation (68 CCGs) and two putative full expansions were picked up in male subjects, which seems relevant considering the rarity of reported AFF2 mutations found in the absence of a family history. CONCLUSIONS: We developed a robust multiplex-PCR that can be used to screen the mutational hotspot regions of FMR1, AFF2 and ARX genes. Moreover, this strategy led to the identification of variants in all three genes, representing not only an improvement in allele-sizing but also in achieving a differential diagnosis. Although the distinction between females who are truly homozygous and those with a second pre- or full mutation sized allele, as well as a definitive diagnosis, requires a specific downstream technique, the use of this multiplex-PCR for initial screening is a cost-effective approach which widens the scope of detection.
- High Sensitivity Troponin T: A Biomarker of Ventricular Wall Stress in Acutely Decompensated Heart FailurePublication . Ferreira, J.; Santos, M.; Almeida, S.; Marques, I.; Bettencourt, P.; Cyrne-Carvalho, H.
- Influence of spironolactone on matrix metalloproteinase-2 in acute decompensated heart failurePublication . Ferreira, J.; Santos, M.; Oliveira, J.; Marques, I.; Bettencourt, P.; Cyrne-Carvalho, H.Matrix metalloproteinases (MMPs) are a family of enzymes important for the resorption of extracellular matrices, control of vascular remodeling and repair. Increased activity of MMP2 has been demonstrated in heart failure, and in acutely decompensated heart failure (ADHF) a decrease in circulating MMPs has been demonstrated along with successful treatment.
- Mineralocorticoid Receptor Antagonism in Acutely Decompensated Chronic Heart FailurePublication . Ferreira, J.; Santos, M.; Almeida, S.; Marques, I.; Bettencourt, P.; Cyrne-Carvalho, H.
- Mineralocorticoid receptor antagonism in acutely decompensated chronic heart failurePublication . Ferreira, J.P.; Santos, M.; Almeida, S.; Marques, I.; Bettencourt, P.; Cyrne-Carvalho, H.
- Mineralocorticoid receptor antagonism in acutely decompensated chronic heart failurePublication . Ferreira, J.; Santos, M.; Almeida, S.; Marques, I.; Bettencourt, P.; Cyrne-Carvalho, H.Spironolactone was likely to provide faster congestion relief. -------------------------------------------------------------------------------- Abstract Background/objectives Mineralocorticoid receptor antagonist (MRA) use in acutely decompensated chronic heart failure (ADCHF) may improve congestion through diuretic effect and prevent neurohormonal activation. We aimed to evaluate the clinical effect and safety of spironolactone in ADCHF. Methods Prospective, experimental, single-center, and single-blinded trial. Patients were treated with: standard ADCHF therapy or oral spironolactone 50–100 mg/d plus standard ADCHF therapy. Results During a 1 year period, 100 patients were enrolled, 50 included in the treatment group. Mean (SD) spironolactone dose (mg) at day 1 was 94.5 ± 23.3 and at day 3 was 62.7 ± 24.3. Worsening renal function (increase in pCr ≥ 0.3 mg/dL from day 1 to day 3) was more likely to occur in control group (20% vs. 4%; p = 0.038), serum potassium did not differ between groups, and plasma NTproBNP had a significant decrease in spironolactone group at day 3 (median [IQR], 2488 [4579] vs. 1555 [1832]; p = 0.05). Furthermore, a greater proportion of patients in the treatment group were free of congestion at day 3: less edema, rales, jugular venous pressure (JVP) and orthopnea (all, p < 0.05). In addition, a significantly higher proportion of patients were on oral furosemide at day 3 (44% vs. 82%; p < 0.001). Conclusions Our study supports the safety of high dose spironolactone in ADCHF and suggests a positive impact in the resolution of congestion. The important findings of our pilot study need to be confirmed in larger trials.
- Mineralocorticoid Receptor Antagonism in Acutely Decompensated Chronic Heart FailurePublication . Ferreira, J.; Santos, M.; Almeida, S.; Marques, I.; Bettencourt, P.; Cyrne-Carvalho, H.
- A multiplex assay for x‐linked intellectual disability assessmentPublication . Jorge, P.; Marques, I.; Oliveira, B.; Santos, R.