Clinical trajectories of genetic variants in ALS: a European observational study within PRECISION-ALS.

OBJECTIVE

To investigate the association between , , and variants on the clinical trajectory of ALS patients in Europe.

METHODS

Nine ALS centers with population-based registries provided data on demographic and disease characteristics - at diagnosis and longitudinally - as part of PRECISION ALS. These data were harmonized and collated for analysis.

RESULTS

21,820 ALS patients were identified, 9,887 underwent genetic testing for at least one of the 4 genes of interest. 9.8% of patients carried a hexanucleotide expansion in 2.9% carried a pathogenic variant in ; 1.4% carried a pathogenic variant in and 0.8% carried a pathogenic variant in Only one p.A5V variant was identified in this dataset. The most frequently identified variant was p.D91A, with evidence of other variant clusters in Belgium, Italy and the United Kingdom. variants were clustered in the Netherlands and Italy. Earlier ages of onset were demonstrated compared to wild-type populations; 59.58 (IQR 62.5, p < 2.2e-16), 54.19 (IQR 19.4, p = 6.304e-14), 58.30 (IQR 16.23, p = 0.00024) and 51.16 (IQR 25.08, p = 1.58e-06). was more bulbar (p < 0.0001) in onset and more spinal (p < 0.0001). Those carrying variants spent distinctly different periods in each of the King's stages.

CONCLUSIONS

Genetic forms of ALS have an earlier age of onset, have distinct patterns in their sites of disease onset, and progress differently as compared to populations without such major-effect genes. There is also evidence of disease clusters across Europe suggestive of founder effects.