Percorrer por autor "Miranda, Beatriz"
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- Cascade Screening in Familial Hypercholesterolemia: Adult cascade screening versus CHILD reverse cascade screeningPublication . Miranda, Beatriz; Medeiros, Ana Margarida; Alves, Ana Catarina; Bourbon, MafaldaFamilial hypercholesterolemia (FH) is an inherited lipid disorder that increases the risk of developing cardiovascular disease (CVD). Despite most cascade screening programs are initiated by adult index cases, reverse cascade screening pediatric index cases is starting to be described. Therefore, in this work, we aimed to assess the outcome of both creening strategies (adult cascade screening and child reverse cascade screening) in families from the Portuguese FH Study (PFHS). The PFHS database was consulted, and 423 index cases genetically identified with FH (224 adults and 199 children) and their 997 relatives referred to the PFHS were analysed. From 224 adults with FH, 485 relatives were enrolled for cascade screening and 290 were identified with FH. From 199 paediatric cases with FH, 512 relatives were screened and 286 were identified with FH. Child reverse cascade screening presented a slightly higher diagnostic rate than adult cascade screening, 1.44 vs 1.29 new cases with FH per index case, and the age of the relatives identified was younger, 29 vs 37 years. For 94% of index children, relatives were referred (2.56 relatives per index), in contrast with the adult cohort whereas only 70% were referred with family-members (2.17 relatives per index). Overall, both screening approaches constitute valuable tools to identify new cases with FH, but the child reverse cascade screening notably creates the opportunity for more relatives to be tested at a younger age. However, it remains crucial to improve relatives' recruitment rate since early identification allows a correct FH diagnosis and treatment to prevent CVD.
- DLCN-PED – A New Proposal For Clinical Diagnosis Of Children And Young People With FHPublication . Miranda, Beatriz; Kafol, Jan; Humphries, Steve E.; Freiberger, Tomas; Medeiros, Ana Margarida; Sikonja, Jaka; Alves, Ana Catarina; Groselj, Urh; Bourbon, MafaldaFamilial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, and premature cardiovascular disease (CVD). The most used clinical diagnostic criteria to identify FH are the Dutch Lipid Clinic Network-(DLCN) and Simon Broome-(SB), being SB the only with specific criteria for children. This work aims to propose an adaptation of DLCN criteria, for children and young people (DLCN-PED) and assess the performance of this adaptation in the Portuguese and Slovenian FH registries. DLCN-PED includes data on clinical examinations, lipid profile, familial history of CVD and hypercholesterolemia. We propose that those with a DLCN-PED score3 should be referred for genetic testing. Index cases included were studied with an NGS panel including at least the three FH-causing genes prior to evaluation with DLCN-PED This work includes 1696 patients (Portugal=340, Slovenia=1356): 29% FH-positives (presenting likely pathogenic/pathogenic variants in FH genes), 71% FH-negatives (no detection of pathogenic variants). Individuals with variants of uncertain significance were not included. Scores had a range between 0-17, 58% presenting a score between 2-4. Across DLCN-PED scores, we observe a distribution overlap for both FH groups: FH-negatives from 0-8 and FH-positives from 0-17. Overall, DLCN-PED3 presents higher sensitivity compared to SB (93% vs 81%) and slightly lower specificity (55% vs 79%). DLCN-PED6 presents lower sensitivity compared to SB (67% vs 81%) but an enhanced specificity (91% vs 79%). The different analysis suggests that score cutoffs should be adapted according to the screening approach intended (sensitivity and specificity trade-off). Compared to DLCN, the DLCN-PED shows an improved performance (p-value=0.024). Given the crucial role of clinical diagnosis in FH identification, we have shown that the proposed DLCN-PED performs better than the general DLCN and is similar to SB with the advantage that is possible to personalize the cut offs and so it could improve FH assessment worldwide.
- Estudo Português de Hipercolesterolemia Familiar (1999-2021): relação fenótipo-genótipoPublication . Medeiros, Ana Margarida; Alves, Ana Catarina; Chora, Joana Rita; Miranda, Beatriz; Bourbon, Mafalda; em nome dos investigadores do Estudo Português de Hipercolesterolemia FamiliarA Hipercolesterolemia Familiar (FH) é uma condição genética comum do metabolismo dos lípidos, que se encontra subdiagnosticada. Existem três genes primários associados à FH (LDLR, APOB e PCSK9) e 5 genes fenocópias (LDLRAP1, LIPA, ABCG5, ABCG8 e APOE), que conferem um fenótipo semelhante à FH. Neste trabalho pretende-se apresentar a relação fenótipo-genótipo dos indivíduos com critérios clínicos de FH referenciados ao Estudo Português de Hipercolesterolemia Familiar. Até ao fim de 2021 foram estudados molecularmente 1005 indivíduos com critérios clínicos de FH. Destes, foram confirmados geneticamente com FH (FH positivos), 417 casos-índex (408 heterozigotos e 9 homozigotos). Com os estudos familiares identificaram- se adicionalmente 581 heterozigotos e 2 homozigotos. De entre os FH positivos, os casos-índex com variantes de alelo nulo apresentam um fenótipo mais severo do que os casos-índex com variantes de alelo defeituoso. Cerca de 1% dos casos-índex foram diagnosticados com outras causas monogénicas. Dos FH negativos, 34% apresenta hiper-Lp(a), 18% tem uma hipercolesterolemia de causa poligénica e 1% possui uma variante patogénica em heterozigotia nos genes fenocópias da FH. As diferentes causas genéticas contribuem para uma variedade de fenótipos que requerem diferentes formas de gestão da doença, terapias específicas e têm implicações na estratificação do risco cardiovascular e no rastreio dos familiares, sendo por esta razão essencial que seja identificada a etiologia da hipercolesterolemia o mais precocemente possível para melhorar o prognóstico dos indivíduos com FH.
- 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 Hypercholesterolemia (FH): 25 Years Of Findings In The Portuguese FH StudyPublication . Miranda, Beatriz; Medeiros, Ana Margarida; Alves, Ana Catarina; Bourbon, MafaldaFamilial Hypercholesterolemia (FH) is a hereditary condition characterized by elevated LDL-C levels, which leads to increased risk of atherosclerosis and cardiovascular events. FH presents an estimated frequency of 1/300 and is expected to affect almost 33,000 Portuguese individuals. Therefore, this work summarizes the advances achieved in 25 years of diagnosis and investigation within the Portuguese FH Study (EPHF). A lipid profile and genetic diagnosis were performed for 1291 referred index cases fulfilling FH clinical criteria (523 children, 768 adults) and 2288 relatives. In 2017, a Next Generation Sequencing panel including FH genes (LDLR, APOB, PCSK9) and FH phenocopy genes (LDLRAP1, APOE, LIPA, ABCG5, ABCG8) was implemented. In approximately 40% (n=464) of the EPHF cohort, a genetic cause of FH was identified: 451 index cases with heterozygous FH (HeFH) and 13 with homozygous FH (HoFH). The majority of pathogenic variants were found in the LDLR gene (93%), compared with APOB (5%) and PCSK9 (2%) genes. Cascade screening allowed the identification of FH in 624 relatives (622 HeFH and 2 HoFH). Among adults with FH, 20% present cardiovascular disease (CVD) and 17% have premature CVD. Variants of uncertain significance in FH genes were identified in 63 index cases. Within 60% of the EPHF cohort (group of index cases where the genetic cause of hypercholesterolemia was not identified), 35% present hyper-Lp(a). Other monogenic causes of dyslipidemia were discovered during genetic analysis: 4 cases with lysosomal lipase deficiency (LIPA gene) and 4 cases with sitosterolemia (ABCG5 and/or ABCG8 genes). The genetic identification of FH corresponds to 3% of the expected number of individuals affected in Portugal. Nevertheless, other rare lipid metabolism disorders were identified. To overcome FH underdiagnosis in Portugal and to promote early diagnosis and treatment to prevent CDV complications, a cost-effective screening chip array is under development.
- Familial Partial Lipodystrophy, Dunnigan- type: 2 families identified in a genetic laboratoryPublication . Alves, Ana Catarina; Medeiros, Ana Margarida; Ferreira, Maria; Miranda, Beatriz; Moldavan, Oana; Travessa, André; Rodrigues, Márcia; Bourbon, MafaldaLipodystrophies are a clinically heterogeneous group of acquired or inherited disorders affecting adipose tissue distribution. familial partial lipodystrophy, Dunnigan-type (FPLD2, OMIM 151660) is the most prevalent subtype and is an autosomal dominant disease characterized by the selective absence of adipose tissue in the extremities and trunk, with fat accumulation in the face, neck, and supraclavicular region. Individuals exhibit a muscular, hypertrophic appearance, particularly in the lower limbs. Affected individuals are born with a normal fat distribution but may present hyperlipidemia in childhood and begin to progressively lose subcutaneous fat after puberty. Later in life, they frequently develop metabolic complications, including hypertriglyceridemia, insulin resistance, diabetes mellitus, hepatic steatosis, and hypertension. In women, acanthosis nigricans, hirsutism, menstrual irregularities, and polycystic ovarian disease are commonly observed. Notably, the phenotype appears more pronounced in females, potentially leading to underdiagnosis in males due to lighter physical changes. Approximately 75% of patients with a clinical diagnosis of FPLD2 reported in the literature carry the same LMNA variant, p.(Arg482Trp) in exon 6 of the Lamina gene (LMNA) The aim of this study was to clinically and molecularly characterize two Portuguese families with a clinical diagnosis of lipodystrophy. We present the clinical and genetic characterization of two kindreds with multiple affected family members of different ages. Sequencing of the LMNA gene was performed by PCR and direct sequencing of all exons. Both index cases were found to carry the most common LMNA variant in heterozygosity p.(Arg482Trp), a missense variant in exon 6. Family screening identified six additional heterozygous carriers in Family I (including two children) and four in Family II (including one children). Both index cases were women and exhibited the characteristic of FPLD2 phenotype. Given the high prevalence of premature and severe cardiovascular events in these patients, early diagnosis is crucial for implementing appropriate treatment strategies and preventing disease progression. The genetic diagnosis allows for an earlier diagnosis, granting a better clinical counselling regarding lifestyle modifications since adolescence and a personalized treatment plan to reduce their risk of coronary heart disease (CHD).
- Functional Studies in LDLR to Improve Genetic Diagnosis in Familial HypercholesterolemiaPublication . Alves, Ana Catarina; Graça, Rafael; Ferreira, Maria Simões; Correia, Bernardo Amaro; Medeiros, Ana Margarida; Miranda, Beatriz; Chora, Joana Rita; Bourbon, MafaldaFamilial hypercholesterolemia (FH) is the most common inherited disorder of lipid metabolism, affecting approximately 1 in 300 individuals. FH is an autosomal semidominant disorder and was the first genetic lipid metabolism disorder to be molecularly characterized. Individuals with FH present elevated blood cholesterol levels from birth, leading to a high cumulative risk of developing cardiovascular disease. Pathogenic variants in the low-density lipoprotein receptor (LDLR) gene are the primary cause of FH, with more than 4,000 variants identified to date. However, only 15% of these have been functionally characterized in vitro, demonstrating their impact (or lack of) on LDL receptor function. This study highlights the role of functional studies in genetic diagnosis and personalized medicine, using the Portuguese Familial hypercholesterolemia Study (EPHF) as an example of how these studies have clinical impact. Functional studies of LDLR are crucial for understanding how this receptor activity regulates cholesterol clearance. In a cohort of 1088 individuals (1073 heterozygotes and 15 homozygotes) with a clinical diagnosis of FH, 164 different LDLR variants were identified. To date, 70 of these variants have been functionally studied within the EPHF and 38 have been characterized by other labs. This functional characterization contributed to obtain a definitive genetic diagnosis for 847 individuals, marking a significant step towards personalized medicine and the effective management of FH. These studies not only improve the classification of LDLR variants but also directly influence treatment decisions and patient outcomes. By advancing the functional characterization of these variants, we contribute to more specialized and precise diagnostics, leading to more tailored therapeutic approaches for cholesterol-related disorders.
- Genetic Diagnosis of Familial Hypercholesterolaemia (FH) In Portugal: Insights from the Portuguese FH StudyPublication . Miranda, Beatriz; Medeiros, Ana Margarida; Alves, Ana Catarina; Bourbon, MafaldaThis work summarises the outcomes of FH genetic testing in the PFHS.
- Hipercolesterolemia familiar homozigótica em Portugal: caracterização de casos diagnosticados geneticamente no âmbito do Estudo Português de Hipercolesterolemia Familiar, 1999-2023Publication . Medeiros, Ana Margarida; Alves, Ana Catarina; Miranda, Beatriz; Chora, Joana Rita; Aguiar, Patrício; Amaro, Mário; Bruges, Margarida; Ferreira, Sofia; Furtado, António; Gaspar, Ana; Gonçalves, Filipa Sousa; Lobarinhas, Goreti; Lourenço, Guilherme; Martins, Paula; Antunes, Sofia Moura; Palma, Isabel; Rato, Quitéria; Torres, Diogo; Rico, Miguel Toscano; Travessa, André; Bourbon, MafaldaHipercolesterolemia Familiar (FH) é uma condição autossómica semidominante causada por variantes patogénicas ou provavelmente patogénicas nos genes LDLR, APOB e PCSK9. A FH pode apresentar-se na forma monoalélica (FH heterozigótica) ou bialélica (FH homozigótica). A forma homozigótica é mais rara e com fenótipo mais grave. Indivíduos com FH homozigótica geralmente apresentam hipercolesterolemia severa (LDL>400mg/dL), xantomas e doença cardiovascular aterosclerótica (DCVA) prematura em idade jovem. Até 2023, foram referenciados ao Estudo Português de Hipercolesterolemia Familiar 1291 casos-índex. Neste estudo foram analisados os casos com FH homozigótica. Foram identificados 15 casos com FH homozigótica: 5 com a mesma variante bialélica no LDLR, 7 com variantes bialélicas diferentes no LDLR, 1 com variantes bialélicas diferentes no PCSK9, e 2 com variantes nos genes LDLR e APOB. A maioria dos indivíduos eram adultos (73%) e do sexo feminino (87%), 13% apresentando xantomas tendinosos e 36% com DCVA. Variantes de alelo nulo estão associadas a um fenótipo mais grave e a uma menor resposta ao tratamento, sendo necessária terapêutica independente da atividade do recetor de LDL. O diagnóstico genético permite identificar com precisão as variantes e os tipos de alelos, e implementar uma abordagem terapêutica mais personalizada nestes indivíduos.
- Homozygous Familial Hypercholesterolaemia: Insights From Portuguese Cases and Follow-up DataPublication . Medeiros, Ana Margarida; Alves, Ana Catarina; Miranda, Beatriz; Chora, Joana Rita; Aguiar, Patrício; Amaro, Mário; Bruges, Margarida; Ferreira, Sofia; Furtado, António; Gaspar, Ana; Gonçalves, Filipa Sousa; Lobarinhas, Goreti; Lourenço, Guilherme; Martins, Paula; Antunes, Sofia Moura; Palma, Isabel; Rato, Quitéria; Torres, Diogo; Rico, Miguel Toscano; Travessa, André; Bourbon, MafaldaAims: Present the clinical/genetic and follow-up data on individuals genetically identified with HoFH.