CMIN_DIA_SP_Artigos publicados em revistas indexadas na Pubmed/Medline
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- Cerebral vasculitis in Henoch‐Schönlein purpuraPublication . GONÇALVES, C.; FERREIRA, G.; MOTA, C.; VILARINHO, A.An Pediatr (Barc). 2004 Feb;60(2):188-9. [Cerebral vasculitis in Henoch-Schönlein purpura]. [Article in Spanish] Gonçalves C, Ferreira G, Mota C, Vilarinho A. PMID: 14757029 [PubMed - indexed for MEDLINE]
- Perioral pigmentation: What is your diagnosis?Publication . Santos, P.; Neto, C.; Machado, S.; Lobo, I.; Soares, J.; Selores, M.Pigmented spots in the skin and mucosa (lentigines) can be found in various diseases called familial lentiginosis syndromes; Peutz-Jeghers syndrome (PJS) is one of them. It is characterized by the association of mucocutaneous melanin pigmentation and hamartomatous gastrointestinal polyps. Patients with PJS are at increased risk of intussusception and cancer development (gastrointestinal and non-gastrointestinal tumors). We present a 5-year-old girl with pigmented macules of perioral and perinasal skin, lips, and buccal mucosa and review lentiginoses and the surveillance of PJS.
- MAN1B1 Deficiency: An Unexpected CDG-IIPublication . Rymen, D.; Peanne, R.; Millón, M.; Race, V.; Sturiale, L.; Garozzo, D.; Mills, P.; Clayton, P.; Asteggiano, C.; Quelhas, D.; Cansu, A.; Martins, E.; Nassogne, M.; Gonc¸alves-Rocha, M.; Topaloglu, H.; Jaeken, J.; Foulquier, F.; Matthijs, G.Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases, due to impaired protein and lipid glycosylation. In the present study, exome sequencing was used to identify MAN1B1 as the culprit gene in an unsolved CDG-II patient. Subsequently, 6 additional cases with MAN1B1-CDG were found. All individuals presented slight facial dysmorphism, psychomotor retardation and truncal obesity. Generally, MAN1B1 is believed to be an ER resident alpha-1,2-mannosidase acting as a key factor in glycoprotein quality control by targeting misfolded proteins for ER-associated degradation (ERAD). However, recent studies indicated a Golgi localization of the endogenous MAN1B1, suggesting a more complex role for MAN1B1 in quality control. We were able to confirm that MAN1B1 is indeed localized to the Golgi complex instead of the ER. Furthermore, we observed an altered Golgi morphology in all patients' cells, with marked dilatation and fragmentation. We hypothesize that part of the phenotype is associated to this Golgi disruption. In conclusion, we linked mutations in MAN1B1 to a Golgi glycosylation disorder. Additionally, our results support the recent findings on MAN1B1 localization. However, more work is needed to pinpoint the exact function of MAN1B1 in glycoprotein quality control, and to understand the pathophysiology of its deficiency.
- Increased red cell distribution width in Fanconi anemia: a novel marker of stress erythropoiesisPublication . Sousa, R.; Gonçalves, C.; Guerra, I.; Costa, E.; Fernandes, A.; Bom-Sucesso, M.; Azevedo, J.; Rodriguez, A.; Rius, R.; Seabra, C.; Ferreira, F.; Ribeiro, L.; Ferrão, A.; Castedo, S.; Cleto, E.; Coutinho, J.; Carvalho, F.; Barbot, J.; Porto, B.BACKGROUND: Red cell distribution width (RDW), a classical parameter used in the differential diagnosis of anemia, has recently been recognized as a marker of chronic inflammation and high levels of oxidative stress (OS). Fanconi anemia (FA) is a genetic disorder associated to redox imbalance and dysfunctional response to OS. Clinically, it is characterized by progressive bone marrow failure, which remains the primary cause of morbidity and mortality. Macrocytosis and increased fetal hemoglobin, two indicators of bone marrow stress erythropoiesis, are generally the first hematological manifestations to appear in FA. However, the significance of RDW and its possible relation to stress erythropoiesis have never been explored in FA. In the present study we analyzed routine complete blood counts from 34 FA patients and evaluated RDW, correlating with the hematological parameters most consistently associated with the FA phenotype. RESULTS: We showed, for the first time, that RDW is significantly increased in FA. We also showed that increased RDW is correlated with thrombocytopenia, neutropenia and, most importantly, highly correlated with anemia. Analyzing sequential hemograms from 3 FA patients with different clinical outcomes, during 10 years follow-up, we confirmed a consistent association between increased RDW and decreased hemoglobin, which supports the postulated importance of RDW in the evaluation of hematological disease progression. CONCLUSIONS: This study shows, for the first time, that RDW is significantly increased in FA, and this increment is correlated with neutropenia, thrombocytopenia, and highly correlated with anemia. According to the present results, it is suggested that increased RDW can be a novel marker of stress erythropoiesis in FA.
- LEIGH SYNDROME: A CASE REPORT WITH A MITOCHONDRIAL DNA MUTATIONPublication . Lopes, T.; Coelho, M.; Bordalo, D.; Bandeira, A.; Bandeira, A.; Vilarinho, L.; Fonseca, P.; Carvalho, S.; Martins, C.; Oliveira, J.Objective: Leigh syndrome is a neurodegenerative disorder with an incidence of 1:40,000 live births. It presents wide clinical, biochemical, and genetic heterogeneity, but with homogenous neuropatoradiological alterations. There is no specific treatment, and the prognosis is reserved. This case report aimed familiarize health professionals with the disease. Case Description: A 16-month-hold girl who was followed in outpatient clinic due to axial hypotonia and delayed psychomotor development. Karyotype, auditory evoked potentials and ophthalmologic evaluation were normal. Evidence of hyperlactacidemia and hypocitrullinemia was detected in the patient. After performing brain magnetic resonance under anesthesia, hypotonia got worse, and the patient was hospitalized after an episode of cyanosis and apnea. The electroencephalogram showed no epileptiform activity. Neuroimaging revealed bilateral lenticular hyperintensity, especially in the putamen and in the left globus pallidus regions. Molecular analysis revealed an 8993T>G (MT-ATP6) mutation in the mitochondrial DNA. Comments: Between 10 and 30% of individuals with Leigh syndrome have mitochondrial DNA mutations. The decompensation after anesthetic intercurrences is typically associated with neurological deterioration and, in this case, increased the diagnosis suspicion. It is important to alert for similar cases and to reduce invasive diagnostic tests if the diagnosis is suspected.
- Long-term trends in mortality and AIDS-defining events after combination ART initiation among children and adolescents with perinatal HIV infection in 17 middle- and high-income countries in Europe and Thailand: A cohort studyPublication . Judd, A.; Chappell, E.; Turkova, A.; Le Coeur, S.; Noguera-Julian, A.; Goetghebuer, T.; Doerholt, K.; Galli, L.; Pajkrt, D.; Marques, L.; Collins, I.; Gibb, D.; González-Tome, M.; Navarro, M.; Warszawski, J.; Königs, C.; Spoulou, V.; Prata, F.; Chiappini, E.; Naver, L.; Giaquinto, C.; Thorne, C.; Marczynska, M.; Okhonskaia, L.; Posfay-Barbe, K.; Ounchanum, P.; Techakunakorn, P.; Kiseleva, G.; Malyuta, R.; Volokha, A.; Ene, L.; Goodall, R.Background: Published estimates of mortality and progression to AIDS as children with HIV approach adulthood are limited. We describe rates and risk factors for death and AIDS-defining events in children and adolescents after initiation of combination antiretroviral therapy (cART) in 17 middle- and high-income countries, including some in Western and Central Europe (W&CE), Eastern Europe (Russia and Ukraine), and Thailand. Methods and findings: Children with perinatal HIV aged <18 years initiating cART were followed until their 21st birthday, transfer to adult care, death, loss to follow-up, or last visit up until 31 December 2013. Rates of death and first AIDS-defining events were calculated. Baseline and time-updated risk factors for early/late (≤/>6 months of cART) death and progression to AIDS were assessed. Of 3,526 children included, 32% were from the United Kingdom or Ireland, 30% from elsewhere in W&CE, 18% from Russia or Ukraine, and 20% from Thailand. At cART initiation, median age was 5.2 (IQR 1.4-9.3) years; 35% of children aged <5 years had a CD4 lymphocyte percentage <15% in 1997-2003, which fell to 15% of children in 2011 onwards (p < 0.001). Similarly, 53% and 18% of children ≥5 years had a CD4 count <200 cells/mm3 in 1997-2003 and in 2011 onwards, respectively (p < 0.001). Median follow-up was 5.6 (2.9-8.7) years. Of 94 deaths and 237 first AIDS-defining events, 43 (46%) and 100 (42%) were within 6 months of initiating cART, respectively. Multivariable predictors of early death were: being in the first year of life; residence in Russia, Ukraine, or Thailand; AIDS at cART start; initiating cART on a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen; severe immune suppression; and low BMI-for-age z-score. Current severe immune suppression, low current BMI-for-age z-score, and current viral load >400 c/mL predicted late death. Predictors of early and late progression to AIDS were similar. Study limitations include incomplete recording of US Centers for Disease Control (CDC) disease stage B events and serious adverse events in some countries; events that were distributed over a long time period, and that we lacked power to analyse trends in patterns and causes of death over time. Conclusions: In our study, 3,526 children and adolescents with perinatal HIV infection initiated antiretroviral therapy (ART) in countries in Europe and Thailand. We observed that over 40% of deaths occurred ≤6 months after cART initiation. Greater early mortality risk in infants, as compared to older children, and in Russia, Ukraine, or Thailand as compared to W&CE, raises concern. Current severe immune suppression, being underweight, and unsuppressed viral load were associated with a higher risk of death at >6 months after initiation of cART.
- The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysisPublication . Slogrove, A.; Schomaker, M.; Davies, M.; Williams, P.; Balkan, S.; Ben-Farhat, J.; Calles, N.; Chokephaibulkit, K.; Duff, C.; Eboua, T.; Kekitiinwa-Rukyalekere, A.; Maxwell, N.; Pinto, J.; Seage, G.; Teasdale, C.; Wanless, S.; Warszawski, J.; Wools-Kaloustian, K.; Yotebieng, M.; Timmerman, V.; Collins, I.; Goodall, R.; Smith, C.; Patel, K.; Paul, M.; Gibb, D.; Vreeman, R.; Abrams, E.; Hazra, R.; Van Dyke, R.; Bekker, L.; Mofenson, L.; Vicari, M.; Essajee, S.; Penazzato, M.; Anabwani, G.; Q Mohapi, E.; N Kazembe, P.; Hlatshwayo, M.; Lumumba, M.; Goetghebuer, T.; Thorne, C.; Galli, L.; van Rossum, A.; Giaquinto, C.; Marczynska, M.; Marques, L.; Prata, F.; Ene, L.; Okhonskaia, L.; Rojo, P.; Fortuny, C.; Naver, L.; Rudin, C.; Le Coeur, S.; Volokha, A.; Rouzier, V.; Succi, R.; Sohn, A.; Kariminia, A.; Edmonds, A.; Lelo, P.; Ayaya, S.; Ongwen, P.; Jefferys, L.; Phiri, S.; Mubiana-Mbewe, Mw.; Sawry, S.; Renner, L.; Sylla, M.; Abzug, M.; Levin, M.; Oleske, J.; Chernoff, M.; Traite, S.; Purswani, M.; Chadwick, E.; Judd, A.; Leroy, V.Background: Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in "real-life" settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia. Methods and findings: Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5-5.2) years for the total cohort and 6.4 (3.6-8.0) years in Europe, 3.7 (2.0-5.4) years in North America, 2.5 (1.2-4.4) years in South and Southeast Asia, 5.0 (2.7-7.5) years in South America and the Caribbean, and 2.1 (0.9-3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3-2.1) years in North America to 7.1 (5.3-8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4-2.6) years in North America to 7.9 (6.0-9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%-2.8%), 15.6% (15.1%-16.0%), and 11.3% (10.9%-11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%-1.1%]) and highest in South America and the Caribbean (4.4% [3.1%-6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%-6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%-13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria. Conclusion: To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses.
- Inherited p40phox deficiency differs from classic chronic granulomatous diseasePublication . van de Geer, A.; Nieto-Patlán, A.; Kuhns, D.; Tool, A.; Arias, A.; Bouaziz, M.; de Boer, M.; Franco, J.; Gazendam, R.; van Hamme, J.; van Houdt, M.; van Leeuwen, K.; Verkuijlen, P.; van den Berg, T.; Alzate, J.; Arango-Franco, C.; Batura, V.; Bernasconi, A.; Boardman, B.; Booth, C.; Burns, S.; Cabarcas, .; Bensussan, N.; Charbit-Henrion, F.; Corveleyn, A.; Deswarte, C.; Azcoiti, M.; Foell, D.; Gallin, J.; Garcés, C.; Guedes, M.; Hinze, C.; Holland, S.; Hughes, S.; Ibañez, P.; Malech, H.; Meyts, I.; Moncada-Velez, M.; Moriya, K.; Neves, E.; Oleastro, M.; Perez, L.; Rattina, V.; Oleaga-Quintas, C.; Warner, N.; Muise, A.; López, J.; Trindade, E.; Vasconcelos, J.; Vermeire, S.; Wittkowski, H.; Worth, A.; Abel, L.; Dinauer, M.; Arkwright, P.; Roos, D.; Casanova, J.t; Kuijpers, T.; Bustamante, J.Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMA-induced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD.
- Genomic imbalances defining novel intellectual disability associated lociPublication . Lopes, Fátima; Torres, Fátima; Soares, Gabriela; Barbosa, Mafalda; Silva, João; Duque, Frederico; Rocha, Miguel; Sá, Joaquim; Oliveira, Guiomar; Sá, Maria João; Temudo, Teresa; Sousa, Susana; Marques, Carla; Lopes, Sofia; Gomes, Catarina; Barros, Gisela; Jorge, Arminda; Rocha, Felisbela; Martins, Cecília; Mesquita, Sandra; Loureiro, Susana; Cardoso, Elisa Maria; Cálix, Maria José; Dias, Andreia; Martins, Cristina; Mota, Céu R; Antunes, Diana; Dupont, Juliette; Figueiredo, Sara; Figueiroa, Sónia; Gama-de-Sousa, Susana; Cruz, Sara; Sampaio, Adriana; Eijk, Paul; Weiss, Marjan M; Ylstra, Bauke; Rendeiro, Paula; Tavares, Purificação; Reis-Lima, Margarida; Pinto-Basto, Jorge; Fortuna, Ana Maria; Maciel, PatríciaBackground: High resolution genome-wide copy number analysis, routinely used in clinical diagnosis for several years, retrieves new and extremely rare copy number variations (CNVs) that provide novel candidate genes contributing to disease etiology. The aim of this work was to identify novel genetic causes of neurodevelopmental disease, inferred from CNVs detected by array comparative hybridization (aCGH), in a cohort of 325 Portuguese patients with intellectual disability (ID). Results: We have detected CNVs in 30.1% of the patients, of which 5.2% corresponded to novel likely pathogenic CNVs. For these 11 rare CNVs (which encompass novel ID candidate genes), we identified those most likely to be relevant, and established genotype-phenotype correlations based on detailed clinical assessment. In the case of duplications, we performed expression analysis to assess the impact of the rearrangement. Interestingly, these novel candidate genes belong to known ID-related pathways. Within the 8% of patients with CNVs in known pathogenic loci, the majority had a clinical presentation fitting the phenotype(s) described in the literature, with a few interesting exceptions that are discussed. Conclusions: Identification of such rare CNVs (some of which reported for the first time in ID patients/families) contributes to our understanding of the etiology of ID and for the ever-improving diagnosis of this group of patients.
- Lipid Antigen Presentation by CD1b and CD1d in Lysosomal Storage Disease PatientsPublication . Pereira, C.; Pérez-Cabezas, B.; Ribeiro, H.; Maia, M.; Cardoso, M.; Dias, A.; Azevedo, O.; Ferreira, M.; Garcia, P.; Rodrigues, E.; Castro-Chaves, P.; Martins, Esmeralda; Aguiar, P.; Pineda, M.; Amraoui, Y.; Fecarotta, S.; Leão-Teles, E.; Deng, S.; Savage, P.; Macedo, M.The lysosome has a key role in the presentation of lipid antigens by CD1 molecules. While defects in lipid antigen presentation and in invariant Natural Killer T (iNKT) cell response were detected in several mouse models of lysosomal storage diseases (LSD), the impact of lysosomal engorgement in human lipid antigen presentation is poorly characterized. Here, we analyzed the capacity of monocyte-derived dendritic cells (Mo-DCs) from Fabry, Gaucher, Niemann Pick type C and Mucopolysaccharidosis type VI disease patients to present exogenous antigens to lipid-specific T cells. The CD1b- and CD1d-restricted presentation of lipid antigens by Mo-DCs revealed an ability of LSD patients to induce CD1-restricted T cell responses within the control range. Similarly, freshly isolated monocytes from Fabry and Gaucher disease patients had a normal ability to present α-Galactosylceramide (α-GalCer) antigen by CD1d. Gaucher disease patients' monocytes had an increased capacity to present α-Gal-(1-2)-αGalCer, an antigen that needs internalization and processing to become antigenic. In summary, our results show that Fabry, Gaucher, Niemann Pick type C, and Mucopolysaccharidosis type VI disease patients do not present a decreased capacity to present CD1d-restricted lipid antigens. These observations are in contrast to what was observed in mouse models of LSD. The percentage of total iNKT cells in the peripheral blood of these patients is also similar to control individuals. In addition, we show that the presentation of exogenous lipids that directly bind CD1b, the human CD1 isoform with an intracellular trafficking to the lysosome, is normal in these patients.