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The p.Ala1035Val variant in Niemann–Pick type C1: Clinical and molecular characterization in Brazilian and Portuguese patients suggests a shared founder effect

2026-04-01Artigo científico Acesso restrito
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datacite.subject.fosCiências Médicas
datacite.subject.sdg03:Saúde de Qualidade
dc.contributor.authorAlegretti, Ana Paula
dc.contributor.authorHammerschmidt, Tatiane
dc.contributor.authorRibeiro, Isaura
dc.contributor.authorQuelhas, Dulce
dc.contributor.authorPolese-Bonato, Márcia
dc.contributor.authorSaraiva-Pereira, Maria Luiza
dc.contributor.authorMartins, Esmeralda
dc.contributor.authorGuigliani, Roberto
dc.contributor.authorEncarnação, Marisa
dc.contributor.authorAlves Sandra
dc.contributor.authorRegla Vargas, Carmen
dc.date.accessioned2026-05-20T08:49:51Z
dc.date.available2026-05-20T08:49:51Z
dc.date.issued2026-04-01
dc.description.abstractIntroduction: Niemann–Pick disease type C1 (NPC1, OMIM 257220) is a rare, progressive, and fatal autosomal recessive lysosomal storage disorder caused by pathogenic variants in the NPC1 gene. These variants disrupt intracellular lipid trafficking, leading to the accumulation of cholesterol and glycosphingolipids and resulting in severe, multisystem dysfunction for which no cure currently exists. Materials and methods: To investigate the potential founder effect and shared ancestry of the p.Ala1035Val variant, we analyzed 30 genetically confirmed NPC1 cases, comprising 18 Brazilian (12 of whom were homozygous) and 12 Portuguese participants (3 of whom were homozygous), each carrying at least one p.Ala1035Val allele. Diagnosis was established by clinical evaluation, biochemical assays, and filipin staining, with molecular confirmation by NPC1 genotyping. Results: All analyzed individuals exhibited a conserved haplotype across the SNVs in exons 6 (c.644 A > G, p.His215Arg), 12 (c.1926G > C, p.Ile642Met), 17 (c.2572 A > G, p.Ile858Val), and 18 (c.2793C > T, p.Asn931=), strongly supporting a shared founder effect consistent with an Iberian-associated ancestral background. Among Brazilian (n = 14), visceral involvement occurred in 10/14 (71.4%), predominantly hepatosplenomegaly (6/14, 42.9%), and developmental/cognitive alterations in 10/14 (71.4%), followed by ataxia or gait disturbance in 4/14 (28.6%). Among the Portuguese (n = 3), all presented with visceral involvement, characterized by hepatosplenomegaly (3/3, 100%); one had developmental delay (1/3, 33.3%), and none exhibited ataxia/gait disturbance. Despite the small sample size, clinical patterns appeared similar between the two groups, with differences likely reflecting sampling variability. Discussion: These findings expand the known variant spectrum of NPC1 in Brazilian and Portuguese populations, supporting a possible founder effect resulting from Portuguese colonisation. They also highlight the clinical value of haplotype analysis as a tool for tracing disease origin and improving stratification in medical settings. Furthermore, they emphasise the importance of refining early diagnostic strategies to optimise patient management and improve outcomes in NPC, while highlighting the need for larger, multicenter studies to corroborate this hypothesis and refine its clinical and genetic implications.eng
dc.description.sponsorshipThis work was supported by: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/MEC-Brasil); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq/MCTI – number: 200234/2025-0); Fundo de Incentivo à Pesquisa e Eventos (FIPE/HCPA – number 2018-0648) and Instituto Nacional de Saúde Doutor Ricardo Jorge, Porto, Portugal (INSA), Porto, Portugal.
dc.identifier.citationMol Genet Metab. 2026 Jun;148(2):110111. doi: 10.1016/j.ymgme.2026.110111. Epub 2026 Apr 1
dc.identifier.doi10.1016/j.ymgme.2026.110111
dc.identifier.issn1096-7192
dc.identifier.pmid41936136
dc.identifier.urihttp://hdl.handle.net/10400.18/11308
dc.language.isoeng
dc.peerreviewedyes
dc.publisherElsevier
dc.relation.hasversionhttps://www.sciencedirect.com/science/article/pii/S109671922600394X?via%3Dihub
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectFounder Effect
dc.subjectHaplotype
dc.subjectMolecular Analysis
dc.subjectNiemann-Pick type C
dc.subjectDoenças Lisossomais de Sobrecarga
dc.subjectEstudos Haplotípicos
dc.subjectDoenças Genéticas
dc.subjectGenética Humana
dc.subjectBrazil
dc.subjectPortugal
dc.titleThe p.Ala1035Val variant in Niemann–Pick type C1: Clinical and molecular characterization in Brazilian and Portuguese patients suggests a shared founder effecteng
dc.typejournal article
dcterms.referenceshttps://ars.els-cdn.com/content/image/1-s2.0-S109671922600394X-mmc1.docx
dspace.entity.typePublication
oaire.citation.issue2
oaire.citation.startPage110111
oaire.citation.titleMolecular Genetics and Metabolism
oaire.citation.volume148
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85
person.familyNameEncarnação
person.familyNameAlves
person.givenNameMarisa
person.givenNameSandra
person.identifier.ciencia-id4819-A750-4620
person.identifier.ciencia-idB618-7244-EEE2
person.identifier.orcid0000-0002-3726-2851
person.identifier.orcid0000-0002-8881-9197
person.identifier.ridP-4261-2016
person.identifier.scopus-author-id35423679100
person.identifier.scopus-author-id7102194200
relation.isAuthorOfPublication8a2ba4f3-145b-4ad1-bf13-15ca98bc23a2
relation.isAuthorOfPublication86f5db62-774d-4f8a-83ea-55d8ca5e0b46
relation.isAuthorOfPublication.latestForDiscovery8a2ba4f3-145b-4ad1-bf13-15ca98bc23a2

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