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Determinants of age at onset in a Portuguese cohort of autosomal dominant spastic paraplegia. | LitMetric

AI Article Synopsis

  • - The study aimed to understand age at onset of autosomal dominant hereditary spastic paraplegias (AD-HSP) by examining 239 patients from 89 families in Portugal, finding that the average age at onset decreases across generations, from about 38 years in the first generation to 17.5 years in the third generation
  • - A significant drop in age at onset was observed across various genotypes, particularly in families with multiple generations, supporting the idea of "anticipation," where younger generations experience earlier onset of symptoms
  • - Patients with missense mutations, particularly in the SPG4 genotype, had a notably earlier age at onset compared to those with truncating mutations, highlighting the potential impact of specific genetic variations on disease

Article Abstract

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.

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Source
http://dx.doi.org/10.1016/j.jns.2019.116646DOI Listing

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