Factors influencing the clinical expression of intermediate CAG repeat length mutations of the Huntington's disease gene

J Neurol. 2015 Feb;262(2):277-84. doi: 10.1007/s00415-014-7559-5. Epub 2014 Nov 8.


Our aim is to elucidate the clinical variables associated with the development of manifest HD in patients with intermediate CAG repeat lengths. 2,167 participants were seen throughout 44 research sites in the United States, Canada or Australia over a five-year natural history observational study (2006-2011) (Trial # NCT00313495). The Chi-square test and a generalised linear model were used to examine the differences in demographics and cognitive tests among three groups of CAG repeat length. The mixed model was then used to examine the time effect on cognitive assessments by CAG groups. No patient with CAG repeat length 27-35 developed manifest HD, whereas three patients with 36-39 did. Total motor score, maximal chorea score and maximal dystonia score were significantly different at baseline (p < 0.001) for each measure between those patients with a repeat length 27-35 versus those 36-39; as were total functional assessment, independence scale and total functional capacity (p < 0.001). Being aged 65 years or more (OR 5.81, 95 % CI 0.37-90.58, p = 0.02) and smoking (OR 13.99, 95 % CI 2.03-96.44, p = 0.007) were related to manifest HD in patients with CAG 36-39; those with an associated university degree or higher education were less frequently diagnosed as manifest HD (OR 0.10, 95 % CI 0.02-0.54, p = 0.007). Age, smoking and lower education achievement were found to be significantly associated with higher odds of manifest HD in patients with intermediate CAG repeat length mutations.

Publication types

  • Multicenter Study
  • Observational Study

MeSH terms

  • Adult
  • Aged
  • Disease Progression
  • Female
  • Humans
  • Huntingtin Protein
  • Huntington Disease / complications
  • Huntington Disease / genetics*
  • Huntington Disease / physiopathology*
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / genetics*
  • Trinucleotide Repeat Expansion / genetics*


  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins