Clinical Evidence for Disease Anticipation in Families Segregating a C9orf72 Repeat Expansion (S21.006)

Objective: We aim to provide clinical evidence for the occurrence of disease anticipation in families with FTD and/or ALS caused by a C9orf72 repeat expansion. Background: We have recently provided evidence for an association of the G4C2 repeat expansion size with onset age and methylation state of the 59 flanking CpG island. We also identified in several informative C9orf72 parent-child transmissions earlier onset ages, increasing expansion sizes and/or increasing methylation states of the 59 CpG island in accordance with anticipation. (Gijselinck I. et al., Mol Psychiatry 2015) Methods: We investigated differences in onset age and disease duration between successive generations of 29 C9orf72 families and within 30 individual parent-offspring pairs, and investigated differences in phenotype between successive generations of 43 families and within 86 parent-child pairs. Results: Patients from the youngest generation had a significantly younger onset age than patients from the second generation. We also observed a significantly younger onset age in the offspring of parent-offspring pairs with a mean difference of 7.2 +/- 7.8 years. Disease duration was not significantly different between generations or between parents and their offspring, but (FTD-)ALS patients had a significantly shorter disease duration than patients with pure dementia. A significantly higher proportion of patients from the second generation was diagnosed with ALS in comparison with patients from the third generation. Furthermore, we observed a significant association between the phenotype in a parent and the phenotype in the child. No clear differences were observed between maternal and paternal transmission. Conclusions: We provided clinical arguments for disease anticipation in C9orf72 families with an earlier onset age, but no shorter disease duration, in younger generations. The gender of the transmitting parent apparently had no effect. The clinical phenotype of the parent however, was significantly associated with the phenotype of the affected child. Disclosure: Dr. Van Mossevelde has nothing to disclose. Dr. Van Der Zee has nothing to disclose. Dr. Gijselinck has nothing to disclose. Dr. Sleegers has nothing to disclose. Dr. Van Langenhove has nothing to disclose. Dr. Sieben has nothing to disclose. Dr. De Bleecker has nothing to disclose. Dr. Ivanoiu has received research support from GEHC as an investigator. Dr. Deryck has nothing to disclose. Dr. Santens has nothing to disclose. Dr. Baumer has nothing to disclose. Dr. Van Den Broeck has nothing to disclose. Dr. Mattheijssens has nothing to disclose. Dr. Peeters has nothing to disclose. Dr. De Jonghe has nothing to disclose. Dr. De Deyn has nothing to disclose. Dr. Cras has nothing to disclose. Dr. Vandenberghe has received research support from GE Healthcare, Wyeth, Eli Lilly u0026 Company, Medivation, and Pfizer, Inc. Dr. Martin has nothing to disclose. Dr. Cruts has nothing to disclose. Dr. Engelborghs has nothing to disclose. Dr. Van Broeckhoven has nothing to disclose.