Percorrer por autor "Ferreira, Ana Cristina"
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- Doenças mitocondriais na era da sequenciação de nova geração: estudo de 450 doentesPublication . Nogueira, Célia; Pereira, Cristina; Silva, Lisbeth; Laranjeira, Mateus; Lopes, Altina; Neiva, Raquel; Rodrigues, Esmeralda; Campos, Teresa; Martins, Esmeralda; Bandeira, Anabela; Coelho, Margarida; Magalhães, Marina; Damásio, Joana; Gaspar, Ana; Janeiro, Patrícia; Gomes, Levy; Ferreira, Ana Cristina; Jacinto, Sandra; Vieira, José Pedro; Diogo, Luísa; Santos, Helena; Mendonça, Carla; Vilarinho, LauraAs doenças mitocondriais (DM) são doenças raras, clínica e geneticamente heterogéneas, de difícil diagnóstico, para as quais não existe uma terapia eficaz. O desenvolvimento da tecnologia de sequenciação de nova geração (NGS) revolucionou o diagnóstico molecular deste grupo de doenças, permitindo a identificação de novos genes associados a estas patologias. Nesta nova era genética, através da utilização da tecnologia de NGS, estudamos um grupo de 450 doentes suspeitos de DM, sem etiologia molecular. A nossa estratégia combinada de NGS, englobou a sequenciação de um painel de 213 genes nucleares associados a DM e do DNA mitocondrial completo. Neste estudo, identificamos variantes causais em 134 (30%) doentes analisados, 88 dos quais apresentaram variantes no DNA nuclear e 46 no DNA mitocondrial, tratando-se na maioria de doentes pediátricos (66%). Neste grupo de doentes, identificamos 72 variantes patogénicas descritas na literatura e 20 novas variantes provavelmente patogénicas, assim como 62 variantes de significado indeterminado. Como laboratório nacional de referência para o estudo e investigação das DM, demonstramos o contributo da tecnologia de NGS para esclarecer a etiologia molecular destes doentes, para expandir o espectro mutacional associado a estas patologias e oferecer um diagnóstico pré-natal e aconselhamento genético aos casais em risco.
- Familial and Multifactorial Chylomicronemia Syndrome: Insights from Clinically Diagnosed Cases in PortugalPublication . Alves, Ana Catarina; Ferreira, Maria; Ferreira, Ana Cristina; Padeira, Gonçalo; Gaspar, Ana; Duarte, João Sequeira; Rato, Quitéria; Gonçalves, Filipa Sousa; Aguiar, Patrício; Cruz, Diogo; Bourbon, MafaldaFamilial Chylomicronemia Syndrome (FCS) is a rare autosomal recessive disorder caused by biallelic pathogenic variants in one of five canonical genes, LPL, APOC2, GPIHBP1, APOA5, and LMF1. These variants result in impaired hydrolysis of triglyceride-rich lipoproteins, leading to clinical features such as xanthomas, abdominal pain, hepatomegaly, hepatosplenomegaly, lipemia retinalis, and recurrent pancreatitis. In contrast, Multifactorial Chylomicronemia Syndrome (MCS) often involves monoallelic variants in these genes and/or a high polygenic risk score, contributing to the severe hypertriglyceridemia phenotype. Clinically, FCS and MCS have a similar presentation, requiring genetic analysis for differentiation. This study aimed to clinically and molecularly characterize 42 individuals with severe hypertriglyceridemia in Portugal. Biochemical lipid profile and molecular analysis of the five canonical genes were performed. Moulin's score was applied to 14 cases; for the remaining cases, all data could not be obtained. The average pre-treatment triglyceride level was 2570 mg/dL. Fourteen individuals had pancreatitis, four had hepatomegaly, and three presented with both conditions. Eight cases have biallelic variants: five in LPL (three with identical variants, two with different variants), one in APOC2, one frameshift variant in LMF1 and one total exon 4 deletion in GPIHBP1 (all with identical variants). For these cases, the Moulin score obtained was FCS very likely. Twenty cases have heterozygous variants in LPL, APOA5, LMF1, and GPIHBP1 and were classified as MCS. For one of these cases, the Moulin score was FCS very likely. Ten patients have a negative genetic study, 5 of which had a score of unlikely FCS. Four are still under study. Early identification of FCS is critical to prevent or mitigate its severe complications. A confirmed molecular diagnosis enables accurate differentiation between FCS and MCS, leading to improved clinical management and prognosis. This study underscores the importance of integrating genetic analysis into the diagnostic workup of severe hypertriglyceridemia.
- Familial chylomicronemia syndrome in PortugalPublication . Alves, Ana Catarina; Miranda, Beatriz; Sequeira, Sílvia; Moldovan, Oana; Nunes, Catarina; Antunes, Henedina; Martins, Esmeralda; Gonçalves, Rute; Duarte, Sequeira; Guerra, António; Gaspar, Ana; Salgado, Miguel; Azevedo, Aida; Araújo, Francisco; Ferreira, Ana Cristina; Rato, Quitéria; Palma, Isabel; Bourbon, MafaldaFamilial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder of lipoprotein metabolism. It is characterized by marked elevation of triglyceride and chylomicron levels, lipaemic plasma, recurrent pancreatitis, eruptive xanthoma, hepatosplenomegaly, andliapemiaretinalis. All genes associated with FCS (LPL, APOC2, APOA5, LMF1 and GPHBP1) have an effect on the activity of lipoprotein lipase (LPL). The aim of this study is to present all cases with FCS clinical diagnosis, studied in our laboratory.
- Familial Chylomicronemia Syndrome: Clinical and Molecular Data From a Portuguese CohortPublication . Alves, Ana Catarina; Ferreira, Maria; Ferreira, Ana Cristina; Padeira, Gonçalo; Gaspar, Ana; Duarte, João Sequeira; Rato, Quitéria; Gonçalves, Filipa Sousa; Aguiar, Patrício; Cruz, Diogo; Raimundo, Anabela; Bourbon, MafaldaFamilial Chylomicronemia Syndrome (FCS) is a rare autosomal recessive disorder caused by biallelic variants in LPL, APOC2, GPIHBP1, APOA5, or LMF1. These defects impair triglyceride-rich lipoprotein hydrolysis, leading to xanthomas, abdominal pain, hepatomegaly, lipemia retinalis, and recurrent pancreatitis. Multifactorial Chylomicronemia Syndrome (MCS) often results from monoallelic variants in these genes and/or a high polygenic risk score, presenting a similar phenotype; thus, genetic testing is required for accurate differentiation. This study aimed to clinically and genetically characterize 45 individuals with severe hypertriglyceridemia in Portugal. Lipid profile and molecular analysis of the five canonical genes were performed. Moulin’s score was applied in 17 cases. The mean pretreatment triglyceride level was 2570 mg/dL. Sixteen individuals had pancreatitis, four had hepatomegaly, and three both conditions. Ten cases carried biallelic variants: five in LPL (three identical, two compound heterozygous), one in APOC2, one frameshift in LMF1, one frameshift and one stop in APOA5, and one total exon 4 deletion in GPIHBP1 (all identical variants). All were classified as “very likely FCS” by Moulin’s score. Twenty-one individuals had heterozygous variants in LPL, APOA5, LMF1, and GPIHBP1 and were considered MCS; three of them also scored as “very likely FCS.” Ten patients had negative genetic studies (five scored as “unlikely FCS”), and four remain under investigation. Early recognition of FCS is crucial to prevent life-threatening complications. A confirmed molecular diagnosis enables precise distinction between FCS and MCS, improving management and prognosis. These findings underscore the importance of incorporating genetic testing into the diagnostic workup of severe hypertriglyceridemia in Portugal.
- Fenilcetonúria em Portugal: 40 anos de rastreio neonatal (1979-2019)Publication . Ferreira, Filipa; Sousa, Luísa Azevedo Carmen; Neiva, Raquel; Fonseca, Helena; Marcão, Ana; Rocha, Hugo; Carmona, Célia; Ramos, Sónia; Bandeira, Anabela; Martins, Esmeralda; Campos, Teresa; Rodrigues, Esmeralda; Garcia, Paula; Diogo, Luísa; Ferreira, Ana Cristina; Sequeira, Silvia; Silva, Francisco; Rodrigues, Luísa; Gaspar, Ana; Janeiro, Patrícia; Amorim, António; Vilarinho, LauraA fenilcetonúria (PKU) é uma doença genética autossómica recessiva, devido a um erro hereditário do metabolismo dos aminoácidos. A PKU caracteriza-se por um aumento de fenilalanina, em resultado de uma deficiência da enzima hepática, fenilalanina hidroxilase (PAH), uma enzima codificada pelo gene PAH. É uma das 26 patologias integradas no painel das doenças rastreadas em Portugal, a partir de sangue colhido em papel de filtro para o “teste do pezinho”. A deteção precoce da doença tem como objetivo iniciar o tratamento nutricional atempadamente, de modo a prevenir os danos neurológicos nos doentes afetados. Em Portugal, desde 1979 e até ao final de 2019, foram rastreados através do Programa Nacional de Rastreio Neonatal 3 890 677 recém-nascidos. Sendo que, 356 são doentes com PKU e 37 são hiperfenilalaninemias moderadas. A prevalência ao nascimento da PKU e da hiperfenilalaninemia moderada no nosso país é de 1:10.929 e 1:36.123 recém-nascidos, respetivamente. Na Unidade de Rastreio Neonatal, Metabolismo e Genética do Departamento de Genética Humana do INSA foram caracterizados geneticamente 223 doentes. Neste estudo, foram identificadas 56 mutações já descritas na literatura, a maioria compostos heterozigóticos (74% dos doentes). As duas mutações mais prevalentes na população portuguesa são: c.782G>A (p.Arg261Gln), c.1066-10G>A (IVS10-11G>A), seguidas pelas mutações c.1162G>A (p.Val388Met) e c.194T>C (p.Ile65Thr). Este estudo revelou uma elevada heterogeneidade quer do ponto vista do fenótipo bioquímico quer ao nível molecular, o que poderá ser importante na resposta ao tratamento destes doentes uma vez que esta estará dependente do respetivo genótipo. Os dados deste estudo, contribuem para uma melhor compreensão e conhecimento epidemiológico da PKU em Portugal.
- Genetic Characterization of Brucella spp.: Whole Genome Sequencing-Based Approach for the Determination of Multiple Locus Variable Number Tandem Repeat ProfilesPublication . Pelerito, Ana; Nunes, Alexandra; Grilo, Teresa; Isidro, Joana; Silva, Catarina; Ferreira, Ana Cristina; Valdezate, Sylvia; Núncio, Maria Sofia; Georgi, Enrico; Gomes, João PauloBrucellosis is an important zoonosis that is emerging in some regions of the world, gaining increased relevance with the inclusion of the causing agent Brucella spp. in the class B bioterrorism group. Until now, multi-locus VNTR Analysis (MLVA) based on 16 loci has been considered as the gold standard for Brucella typing. However, this methodology is laborious, and, with the rampant release of Brucella genomes, the transition from the traditional MLVA to whole genome sequencing (WGS)-based typing is on course. Nevertheless, in order to avoid a disruptive transition with the loss of massive genetic data obtained throughout the last decade and considering that the transition timings will vary considerably among different countries, it is important to determine WGS-based MLVA alleles of the nowadays sequenced genomes. On this regard, we aimed to evaluate the performance of a Python script that had been previously developed for the rapid in silico extraction of the MLVA alleles, by comparing it to the PCR-based MLVA procedure over 83 strains from different Brucella species. The WGS-based MLVA approach detected 95.3% of all possible 1,328 hits (83 strains×16 loci) and showed an agreement rate with the PCR-based MLVA procedure of 96.4% for MLVA-16. According to our dataset, we suggest the use of a minimal depth of coverage of ~50x and a maximum number of ~200 contigs as guiding "boundaries" for the future application of the script. In conclusion, the evaluated script seems to be a very useful and robust tool for the in silico determination of MLVA profiles of Brucella strains, allowing retrospective and prospective molecular epidemiological studies, which are important for maintaining an active epidemiological surveillance of brucellosis.
- Mucopolissacaridoses em população pediátrica: resultados de uma abordagem de precoce no âmbito do projeto FINDPublication . Gaspar, Paulo; Neiva, Raquel; Silva, Lisbeth; Diogo, Luísa; Ferreira, Ana Cristina; Miranda, Ana M.; Antunes, Diana; Louro, Pedro; Ribeiro, Sara; Oliveira, Sara; Garcia, Paula; Rodrigues, Esmeralda; Campos, Teresa; Silva, Carmen; Janeiro, Patricia; Sousa, Sérgio; Lopes, Altina; Nogueira, Célia; Pereira, Cristina; Alves, Sandra; Teles, Elisa Leão; Vilarinho, LauraAs Mucopolissacaridoses (MPSs), constituem um subgrupo das Doenças Lisossomais de Sobrecarga, causadas por deficiências em enzimas lisos somais, que catalisam a degradação dos glicosaminoglicanos. As MPSs têm apresentação multissistémica, heterogénea e consequentemente de diagnóstico difícil. O projeto FIND tem como objetivo alertar os clínicos para sinais e sintomas de risco ao mesmo tempo que disponibiliza uma ferramenta de diagnóstico. Este estudo pretende descrever uma abordagem desenvolvida no âmbito do projeto FIND para identificar doentes com mucopolissacaridoses (MPSs) em idade pediátrica, antes do aparecimento dos sintomas mais graves. A identificação atempada permitirá uma intervenção terapêutica precoce, assim como oferecer aconselhamento genético às famílias afetadas. O projeto FIND permitiu a identificação de 12 doentes de MPSs e a sua refe renciação para os respetivos centros de tratamento. Este estudo, para além da sua vertente educativa, coloca à disposição dos clínicos um ótimo meio para a identificação e caraterização de casos sinto máticos de MPS em idade pediátrica.
- Reverse phenotyping after ngs panel of x-linked intellectual disability unravels creatine transporter (SLC6A8) deficiencyPublication . Padeira, Gonçalo; Jacinto, Sandra; Venâncio, Margarida; Marcão, Ana; Conceição, Carla; Ferreira, Ana CristinaX-linked intellectual disability (XLID) is characterized by extensive genetic heterogeneity. Next-generation sequencing (NGS) have been used in these cases as a cost-effective diagnosis approach. Genetic findings often reveal variants unforeseen during clinical investigation, prompting the need for reevaluation of specific features designated as reverse phenotyping (RP). X-linked creatine transporter deficiency (CTD) is a potentially treatable intellectual disability caused by pathogenic variants in the SLC6A8 gene leading to impaired creatine transport into the brain. A 7-year-old boy with intellectual disability, speech delay, hyperactivity and epilepsy was referred to Metabolic and Neuropediatric Clinic. Family history identified a mother with learning difficulties and a maternal uncle with intellectual disability, indicating a possible X-linked inheritance. NGS intellectual disability panel identified a variant classified as probably pathogenic (c.880_881del (p(Lys294Alafs*2)) in the SLC6A8 gene, in hemizygosity which prompted referral to Metabolic and Neuropediatric Clinic. Reverse phenotyping was carried out with biochemical and imaging assessment that showed: high urinary Creatine-Creatinine ratio (2.17; RV 0.04-1.07) with normal guanidinoacetate acid and absence of creatine peak in brain MRI spectroscopy, confirming the diagnosis. Genetic studies on female family members are ongoing. He started treatment with creatine, arginine and glycine in the last appointment. CTD is a rare disease that has been reported in more than 150 individuals worldwide. We present a case in which the diagnostic approach was reverse phenotyping, through biochemical and imaging studies, after the identification of pathogenic variants in SLC6A8 by NGS panel. The efficacy of its treatment remains controversial with variable results, and a close evaluation will be needed.
- Sitosterolaemia: a case of rare hypercholesterolaemia in FH patient’s cohortPublication . Alves, Ana Catarina; Medeiros, Ana; Padeira, Gonçalo; Ferreira, Ana Cristina; Bourbon, MafaldaAims: Familial Hyperpercholesterolaemia (FH) is the most common of all genetic hypercholesterolaemias. However there are other rare disorders presenting the same phenotype (phenocopies). Sitosterolaemia is one of those rare recessive disorders in which patients can present high levels of LDL-C but, most importantly, they present vegetal fat accumulation in tendons and arteries, leading also to increased cardiovascular risk. The defect in this case is in transporter genes responsible for the intestinal and biliary transport of plant sterols (ABCG5/ABCG8). AIMS: to identify the genetic cause of hypercholesterolaemia in a clinical FH patient presenting a severe phenotype.
- Sitosterolemia In iberoamerican countries: 16 new cases and phenotype genotype analysisPublication . Alves, Ana Catarina; Chora, Joana Rita; Miranda, Beatriz; Medeiros, Ana Margarida; Graça, Rafael; Bañares, Virginia G.; Araujo, Maria Beatriz; Vilagut, Ferrán Trías; Soler, Cristina; Meavilla, Silvia; Toledo, Maria J. Benitez; Volpe, Camila Garcia; Reyes, Ximena; Dell'Oca, Nicolás; Martins, Paula; Marado, Diana; Vilarinho, Laura; Dias, Aureliano Jorge; Ferreira, Ana Cristina; Padeira, Gonçalo; Casañas, Marta; Alegre-González, Diana; Lozano, José Mosquera; Aguiar, Patrício; Gonçalves, Filipa Sousa; Ernaga, Ander; Apellaniz-Ruiz, Maria; Rubi, Rodrigo; Figueroa, Nahún Muñoz; Vasquez, Norma Alejandra; Valdivielso, Pedro; Bourbon, Mafalda; ElsevierBackground: Sitosterolemia is a rare autosomal recessive lipid disorder caused by biallelic pathogenic variants in ABCG5 or ABCG8 genes. It is characterized by elevated plasma plant sterol concentrations, xanthomas, and an increased risk of premature cardiovascular disease. As happens with familial hypercholesterolemia (FH), sitosterolemia is subdiagnosed and is frequently confounded with FH, resulting in inappropriate management. This study aims to describe newly identified cases across Iberoamerican countries and to highlight the need for improved diagnostic strategies. Methods: We report 16 cases of molecularly confirmed sitosterolemia from 5 Iberoamerican countries (Argentina, Mexico, Portugal, Spain, and Uruguay), including 12 index cases and 4 relatives identified by cascade screening. Clinical, biochemical, and molecular data were collected and analyzed. β-sitosterol levels were measured when possible, and variant classification followed American College of Medical Genetics and Genomics (ACMG) guidelines with disease-specific adaptations. Results: Fifteen individuals had biallelic variants in ABCG8 and 1 had a homozygous frameshift variant in ABCG5. Ten distinct ABCG8 variants were identified, including 7 nonsense and 3 missense variants. Xanthomas were observed in 56% of cases. Most cases were initially diagnosed as FH, with a diagnostic delay of up to 30 years. Treatment with ezetimibe, alone or combined with statins, led to biochemical and clinical improvement, including xanthoma regression in some cases. Conclusion: Sitosterolemia remains underdiagnosed due to lack of systematic screening and clinical overlap with FH. Our findings highlight the importance of including ABCG5/8 in genetic testing panels and of recognizing clinical clues for early diagnosis, enabling targeted treatment and prevention of adverse outcomes. Adapted ACMG variant classification improves interpretability for ABCG5/8-related sitosterolemia.