Browsing by Issue Date, starting with "2018-05"
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- SIGMAR1 gene mutation causing Distal Hereditary Motor Neuropathy in a Portuguese familyPublication . Almendra, L.; Laranjeira, F.; Fernández-Marmiesse, A.; Negrão, L.SIGMAR1 gene encodes a non-opioid endoplasmic reticulum (ER) protein which is involved in a large diversity of cell functions and is expressed ubiquitously in both central and peripheral nervous systems. Alterations of its normal function may contribute to two different phenotypes: juvenile amyotrophic lateral sclerosis (ALS 16) and distal hereditary motor neuropathies (dHMN). We present the case of a female patient, of 37-years-old, with distal muscle weakness and atrophy beginning in childhood and slowly progressive in the first two decades of life. Neurological examination revealed a symmetrical severe muscle wasting and weakness in distal lower and upper limbs, with claw hands, footdrop with equinovarus deformity and hammer toes, generalized areflexia and normal sensory examination. The electrodiagnostic study revealed a pure chronic motor peripheral nerve involvement without signs of demyelination. The molecular study found the deletion c.561_576del on exon 4 and a deletion of all exon 4, in the SIGMAR1 gene.
- Measles outbreak in a tertiary level hospital, Porto, Portugal, 2018: challenges in the post-elimination eraPublication . Sá Machado, R.; Perez Duque, M.; Almeida, S.; Cruz, I.; Sottomayor, A.; Almeida, I.; R Oliveira, J.; Antunes, D.A measles outbreak has been occurring in a healthcare setting in Porto, Portugal, since early March 2018, posing public health challenges for a central hospital and the community. Up to 22 April, 96 cases were confirmed, 67 in vaccinated healthcare workers, mostly between 18-39 years old. Following identification of the first cases, control measures were rapidly implemented. Concomitantly, other measles cases were notified in the Northern Region of the country. No common epidemiological link was identified.
- 3D echoendoscopy and miniprobes for rectal cancer stagingPublication . Castro-Poças, F.; Dinis-Ribeiro, M.; Rocha, A.; Araújo, T.; Pedroto, I.Background: rectal cancer staging using rigid probes or echoendoscopes has some limitations. The aim of the study was to compare rectal cancer preoperative staging using conventional endoluminal ultrasonography with three-dimensional endoscopic ultrasonography and miniprobes. Materials and methods: sixty patients were included and evaluated with: a) a conventional echoendoscope (7.5 and 12 MHz); b) miniprobes (12 MHz); and c) the Easy 3D Freescan software for three-dimensional endoscopic ultrasonography. The reference or gold standard was conventional endoluminal ultrasonography in all cases and pathological assessment for those without preoperative therapy. The differences in T and N staging accuracy in both longitudinal and circumferential extension were evaluated. Results: with regard to T staging, conventional endoluminal ultrasonography had an accuracy of 85% (compared to pathological analysis), and the agreement between miniprobes vs conventional endoluminal ultrasonography (kappa = 0.81) and three-dimensional endoscopic ultrasonography vs conventional endoluminal ultrasonography (k = 0.87) was significant. In addition, miniprobes had an accuracy of 82% and three-dimensional endoscopic ultrasonography had a higher accuracy (96%). With regard to N staging, conventional endoluminal ultrasonography had an accuracy of 91% with a sensitivity of 78%. However, the agreement between miniprobes and conventional endoluminal ultrasonography and three-dimensional endoscopic ultrasonography and conventional endoluminal ultrasonography (k = 0.70) was lower. Interestingly, miniprobes had a lower accuracy of 81% whereas three-dimensional endoscopic ultrasonography had an accuracy of 100% without any false negative. No false positives were observed in any of the techniques. Accuracy for T and N staging was not influenced by longitudinal or circumferential extensions of the tumor in all types of endoscopic ultrasonography analyzed. Conclusions: miniprobes and especially three-dimensional endoscopic ultrasonography may be relevant during rectal cancer staging.
- 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.
- Metabolic control of T cell immune response through glycans in inflammatory bowel diseasePublication . Dias, A.; Correia, A.; Pereira, M.; Almeida, C.; Alves, I.; Pinto, V.; Catarino, T.; Mendes, N.; Leander, M.; Oliva-Teles, M.; Maia, L.; Delerue-Matos, C.; Taniguchi, N.i; Lima, Margarida; Pedroto, I.; Marcos-Pinto, Ricardo; Lago, P.; Reis, C.; Vilanova, M.; Pinho, S.Mucosal T lymphocytes from patients with ulcerative colitis (UC) were previously shown to display a deficiency in branched N-glycosylation associated with disease severity. However, whether this glycosylation pathway shapes the course of the T cell response constituting a targeted-specific mechanism in UC remains largely unknown. In this study, we demonstrated that metabolic supplementation of ex vivo mucosal T cells from patients with active UC with N-acetylglucosamine (GlcNAc) resulted in enhancement of branched N-glycosylation in the T cell receptor (TCR), leading to suppression of T cell growth, inhibition of the T helper 1 (Th1)/Th17 immune response, and controlled T cell activity. We further demonstrated that mouse models displaying a deficiency in the branched N-glycosylation pathway (MGAT5-/-, MGAT5+/-) exhibited increased susceptibility to severe forms of colitis and early-onset disease. Importantly, the treatment of these mice with GlcNAc reduced disease severity and suppressed disease progression due to a controlled T cell-mediated immune response at the intestinal mucosa. In conclusion, our human ex vivo and preclinical results demonstrate the targeted-specific immunomodulatory properties of this simple glycan, proposing a therapeutic approach for patients with UC.
- Identification of rare de novo epigenetic variations in congenital disordersPublication . Barbosa, M.; Joshi, R.; Garg, P.; Martin-Trujillo, A.; Patel, N.; Jadhav, B.; Watson, C.; Gibson, W.; Chetnik, K.; Tessereau, C.; Mei, H.; De Rubeis, S.; Reichert, J.; Lopes, F.; Vissers, L.; Kleefstra, T.; Grice, D.; Edelmann, L.; Soares, G.; Maciel, P.; Brunner, H.; Buxbaum, J.; Gelb, B.; Sharp, A.Certain human traits such as neurodevelopmental disorders (NDs) and congenital anomalies (CAs) are believed to be primarily genetic in origin. However, even after whole-genome sequencing (WGS), a substantial fraction of such disorders remain unexplained. We hypothesize that some cases of ND-CA are caused by aberrant DNA methylation leading to dysregulated genome function. Comparing DNA methylation profiles from 489 individuals with ND-CAs against 1534 controls, we identify epivariations as a frequent occurrence in the human genome. De novo epivariations are significantly enriched in cases, while RNAseq analysis shows that epivariations often have an impact on gene expression comparable to loss-of-function mutations. Additionally, we detect and replicate an enrichment of rare sequence mutations overlapping CTCF binding sites close to epivariations, providing a rationale for interpreting non-coding variation. We propose that epivariations contribute to the pathogenesis of some patients with unexplained ND-CAs, and as such likely have diagnostic relevance.