Posted - February 2020 in Research Highlights
Missense mutations also related to earlier onset
Missense mutations are related to an earlier age of onset in people with the main dominantly inherited forms of HSP.
This large study of 239 people from 89 families in Portugal with a dominant form of HSP or hereditary ataxia also established a progressively younger age of onset from 38 years old in the first generation to have the disease, to 32 years old in the second, and 18 years old in the third generation.
BACKGROUND: Hereditary spastic paraplegias present a high variability of age at onset, ranging from childhood to older age. Our objective was to identify the determinants of age at onset in autosomal dominant HSP (AD-HSP) in a large cohort of patients and families.
METHODS: We included 239 patients from 89 families identified in the Portuguese multisource population-based survey of hereditary ataxias and spastic paraplegias. Patients were systematically examined by a team of neurologists, admitted for complete clinical workup and tested for SPG3, SPG4 and SPG31.
RESULTS: Average age at onset was 38.2 years in the first generation, 32.3 years in the second and 17.5 years in the third, with a significant decrease of average age at onset between generations (p < .001). A decrease in the average age at onset was seen in all genotypes (SPG4: p < .001; SPG3: p = .15; SPG31: p < .001). In families with more than one generation (n = 38), this decrease was observed in 78.9%. In multivariate linear regression model, the independent effect of generation in anticipation of age at onset was confirmed (p < .001), adjusting for family, genotype and mutation. We also observed a significant lower age at onset in patients with missense versus truncating mutations (p = .015) in patients with SPG4.
CONCLUSION: These results confirm the impact of missense mutations in an earlier age at onset in SPG4 patients. Even though the age at onset could be affected by subjectivity, our results are consistent with the presence of an anticipation phenomenon in AD-HSP.
SOURCE: J Neurol Sci. 2019 Dec 24;410:116646. doi: 10.1016/j.jns.2019.116646. [Epub ahead of print] PMID: 31887672 Copyright © 2019 Elsevier B.V. All rights reserved.
Determinants of age at onset in Portuguese cohort of autosomal dominant spastic paraplegia.
1 Neurology Department, Centro Hospitalar Entre Douro e Vouga, Santa Maria da Feira, Portugal. Electronic address: [email protected]
2 Neurology Department, Centro Hospitalar Entre Douro e Vouga, Santa Maria da Feira, Portugal.
3 Institute for Molecular and Cell Biology, I3S, Porto, Portugal.
4 Neurology Department, Centro Hospitalar Entre Douro e Vouga, Santa Maria da Feira, Portugal; Departamento de Ciências da Saúde Pública e Forenses e Educação Médica, Faculdade de Medicina, Universidade do Porto, Porto, Portugal; EPIUnit – Instituto de Saúde Pública, Universidade do Porto, Porto, Portugal.
5 Neurology Department, Centro Hospitalar Entre Douro e Vouga, Santa Maria da Feira, Portugal; Institute for Molecular and Cell Biology, I3S, Porto, Portugal.