Background In Huntington’s disease (HD) 50–70% of the variation in age of onset has been attributed to the disease causing CAG repeat with the rest being due to other genetic and environmental factors. Age of motor onset (AMO) of symptoms is widely used in clinical practice and in analyses of potential genetic modifiers of disease but is difficult to determine accurately. Previous reports have indicated that there are some differences in the AMO-CAG length relationship within Europe. Therefore we investigated whether such systematic differences occurred within the European HD population and where they occurred.
Methods We analysed data from 1281 subjects from Registry with AMO and CAG repeat in the range 40–50. Linear modelling and post-hoc tests examined the effect of country of residence and geographical subregion of Europe.
Results A significant influence of country on AMO-CAG relationship was found. Norway and Poland showed significantly younger ages of onset and Denmark older ages of onset with the differences increasing as CAG length increased such that at 50 CAG the difference in onset was almost 6 months. Some less significant differences between European subregions were also detected.
Conclusions All studies using AMO and potentially other clinical variables need to consider country of collection in analysis strategies. The differences observed could be due to genetic population stratification: this is likely to account for the regional differences, though the differences between countries are most likely due to systematic differences in health systems or clinical practice.
- age at motor onset
- motor phenotype
- CAG repeat length
- genetic modifiers