Mutations, Clinical Findings and Survival Estimates in South American Patients with X-Linked Adrenoleukodystrophy
Open accessAbstract
UNLABELLED: In this study, we analyzed the ABCD1 gene in X-linked adrenoleukodystrophy (X-ALD) patients and relatives from 38 unrelated families from South America, as well as phenotypic proportions, survival estimates, and the potential effect of geographical origin in clinical characteristics. METHODS: X- ALD patients from Brazil, Argentina and Uruguay were invited to participate in molecular studies to determine their genetic status, characterize the mutations and improve the genetic counseling of their families. All samples were screened by SSCP analysis of PCR fragments, followed by automated DNA sequencing to establish the specific mutation in each family. Age at onset and at death, male phenotypes, genetic status of women, and the effect of family and of latitude of origin were also studied. RESULTS: We identified thirty-six different mutations (twelve novel). This population had an important allelic heterogeneity, as only p.Arg518Gln was repeatedly found (three families). Four cases carried de novo mutations. Intra-familiar phenotype variability was observed in all families. Out of 87 affected males identified, 65% had the cerebral phenotype (CALD). The mean (95% CI) ages at onset and at death of the CALD were 10.9 (9.1-12.7) and 24.7 (19.8-29.6) years. No association was found between phenotypic manifestations and latitude of origin. One index-case was a girl with CALD who carried an ABCD1 mutation, and had completely skewed X inactivation. CONCLUSIONS: This study extends the spectrum of mutations in X-ALD, confirms the high rates of de novo mutations and the absence of common mutations, and suggests a possible high frequency of cerebral forms in our population.
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The mutation c.1816 T > C, p.S606P is shown to be pathogenic in at least seven patients according to the ALD mutation database.
“Two of the three cases which were not recognized by a cutoff ≥ 0.02 for the ratio of C26:0/C22:0 presented with the mutation c.1816 T > C, p.S606P (both females), shown to be pathogenic in at least seven patients according to the ALD mutation database (http://adrenoleukodystrophy.info18–21.”
From Defining diagnostic cutoffs in neurological patients for serum very long chain fatty acids (VLCFA) in genetically confirmed X-Adrenoleukodystrophy (2020) · cites this paper as [21]
Table 1 in Results > Molecular results lists c.1816T>C (p.Ser606Pro) in a male patient with cerebral X-linked adrenoleukodystrophy, supporting its association with disease. Our copy does not say the ALD mutation database classifies this variant as pathogenic in at least seven patients; the table documents one patient in this series. (LLM, conf=0.84)
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- Authors
- Pereira, F. D. S., Matte, U., Habekost, C. T., Castilhos, R. M. D., El Husny, A. S., Lourenço, C. M., Vianna-Morgante, A. M., Giuliani, L., Galera, M. F., Honjo, R., Kim, C. A., Politei, J., Vargas, C. R., & Jardim, L. B.
- Affiliations
- Universidade Federal do Rio Grande do Sul (BR)
- Universidade de São Paulo (BR)
- Universidade Federal de Mato Grosso do Sul (BR)
- Universidade de Cuiabá (BR)
- Hospital Fernández (AR)
- Corresponding author
- Pereira, Fernanda dos Santos
- Habekost, Clarissa Troller
- Castilhos, Raphael Machado de
- Lourenço, Charles Marques
- Giuliani, Liane
- Galera, Marcial Francis
- Honjo, Rachel
- Kim, Chong Ae
- Politei, Juan
- Vargas, Carmen Regla
- Jardim, Laura Bannach
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-03-29
- Volume
- 7
- Issue
- 3
- Pages
- e34195
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3315551
- OpenAlex
- W2032122670
- Cited by
- 30
- References
- 5
- Citations by year
- 2026: 3 · 2024: 1 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 4 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 3 · 2013: 1 · 2012: 2
- FWCI
- 2.05
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (publishedVersion)
- Americanae (AECID Library) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
- Funders
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Hospital de Clínicas de Porto Alegre
- Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul
- Fundação Instituto de Pesquisas Econômicas
- Instituto Nacional de Genética Médica Populacional
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and rare skin diseases.
- Keywords
- X-linked adrenoleukodystrophy, ABCD1 gene, ABCD1 mutations, novel mutations, de novo mutations, allelic heterogeneity, cerebral adrenoleukodystrophy, survival estimates, age of onset, age at death, X chromosome inactivation, phenotypic variability, genetic counseling, South American patients, Brazil, Argentina, Uruguay
- MeSH terms
- Adolescent, Adrenoleukodystrophy, Adult, Alleles, Argentina, Brain, Brazil, Child, Child, Preschool, Female, Genotype, Humans, Infant, Male, Middle Aged, Mutation, Phenotype, Uruguay, Polymerase Chain Reaction, Sequence Analysis, DNA, Age of Onset, Polymorphism, Single-Stranded Conformational
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