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Sitosterolemia In iberoamerican countries: 16 new cases and phenotype genotype analysis

2025-09-01Journal article Restricted access
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datacite.subject.fosCiências Médicas
dc.contributor.authorAlves, Ana Catarina
dc.contributor.authorChora, Joana Rita
dc.contributor.authorMiranda, Beatriz
dc.contributor.authorMedeiros, Ana Margarida
dc.contributor.authorGraça, Rafael
dc.contributor.authorBañares, Virginia G.
dc.contributor.authorAraujo, Maria Beatriz
dc.contributor.authorVilagut, Ferrán Trías
dc.contributor.authorSoler, Cristina
dc.contributor.authorMeavilla, Silvia
dc.contributor.authorToledo, Maria J. Benitez
dc.contributor.authorVolpe, Camila Garcia
dc.contributor.authorReyes, Ximena
dc.contributor.authorDell'Oca, Nicolás
dc.contributor.authorMartins, Paula
dc.contributor.authorMarado, Diana
dc.contributor.authorVilarinho, Laura
dc.contributor.authorDias, Aureliano Jorge
dc.contributor.authorFerreira, Ana Cristina
dc.contributor.authorPadeira, Gonçalo
dc.contributor.authorCasañas, Marta
dc.contributor.authorAlegre-González, Diana
dc.contributor.authorLozano, José Mosquera
dc.contributor.authorAguiar, Patrício
dc.contributor.authorGonçalves, Filipa Sousa
dc.contributor.authorErnaga, Ander
dc.contributor.authorApellaniz-Ruiz, Maria
dc.contributor.authorRubi, Rodrigo
dc.contributor.authorFigueroa, Nahún Muñoz
dc.contributor.authorVasquez, Norma Alejandra
dc.contributor.authorValdivielso, Pedro
dc.contributor.authorBourbon, Mafalda
dc.contributor.editorElsevier
dc.date.accessioned2025-12-03T12:20:11Z
dc.date.available2025-12-03T12:20:11Z
dc.date.issued2025-09-01
dc.description.abstractBackground: 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.eng
dc.description.abstractHighlights: -Sitosterolemia is a rare autosomal recessive lipid disorder caused by biallelic variants in the ABCG5/8 genes; - We report 16 cases from 5 Iberoamerican countries (12 index cases and 4 relatives); 15 had biallelic ABCG8 variants and 1 had a biallelic identical ABCG5 variant; - Sitosterolemia remains underdiagnosed due to the lack of systematic screening for inherited dyslipidemias in at-risk individuals; - We propose for the first time ACMG-adapted variant classification criteria for ABCG5/8 genes; - Timely genetic diagnosis allows appropriate treatment, preventing complications such as premature cardiovascular disease.eng
dc.description.sponsorshipMA-R received a Postdoctoral Junior Leader - IN- COMING Fellowship from “la Caixa”Foundation (ID: 100010434) and from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska Curie grant agreement No. 847648 (fellow- ship code: LCF/BQ/PI21/11830009). One of the Spanish cases was studied in NAGENCOL project (0011-1411-2019- 000049 - Estrategia navarra en medicina genómica aplicada a hipercolesterolemia) funded by the Government of Navarra (GEMA call 2019-2021).
dc.identifier.citationJ Clin Lipidol. 2025 Sep 1:S1933-2874(25)00381-2. doi: 10.1016/j.jacl.2025.08.020. Online ahead of print
dc.identifier.doi10.1016/j.jacl.2025.08.020
dc.identifier.eissn1876-4789
dc.identifier.issn1933-2874
dc.identifier.pmid41130816
dc.identifier.urihttp://hdl.handle.net/10400.18/10633
dc.language.isoeng
dc.peerreviewedyes
dc.publisherElsevier
dc.relationJunior Leader la Caixa Postdoctoral Fellowship Programme: Shaping the new generation of leaders in research
dc.relation.hasversionhttps://www.sciencedirect.com/science/article/pii/S1933287425003812?via%3Dihub
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectABCG5/8 Genes
dc.subjectIberoamerica
dc.subjectRare Lipid Disorders
dc.subjectSitosterolemia
dc.subjectGenotype-Phenotype Correlation
dc.subjectDoenças Cardio e Cérebro-vasculares
dc.subjectDoenças Genéticas
dc.titleSitosterolemia In iberoamerican countries: 16 new cases and phenotype genotype analysiseng
dc.typejournal article
dcterms.referenceshttps://ars.els-cdn.com/content/image/1-s2.0-S1933287425003812-mmc1.docx
dspace.entity.typePublication
oaire.awardTitleJunior Leader la Caixa Postdoctoral Fellowship Programme: Shaping the new generation of leaders in research
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/847648/EU
oaire.citation.startPageS1933-2874(25)00381-2
oaire.citation.titleJournal of Clinical Lipidology
oaire.fundingStreamH2020
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameEuropean Commission
relation.isProjectOfPublicatione715980d-fee2-4057-9784-83c530c44905
relation.isProjectOfPublication.latestForDiscoverye715980d-fee2-4057-9784-83c530c44905

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