Genetically Predisposed Patients May Develop ALS At Earlier Age Interview with:
Prof. Dr. Christine Van Broeckhoven PhD DSc
Professor in Molecular Biology and GeneticsUniversity of Antwerp
Science Director, VIB Center for Molecular Neurology
Research Director, Laboratory for Neurogenetics, Institute Born-Bunge
Senior Group Leader, Neurodegenerative Brain Diseases
University of Antwerp and
Dr. Sara Van Mossevelde, MD
Center for Molecular Neurology, VIB
Institute Born-Bunge, University of Antwerp
Department of Neurology and Memory Clinic
Hospital Network Antwerp Middelheim and Hoge Beuken
Antwerp, Belgium What is the background for this study? What are the main findings?

Response: Patients with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) and a C9orf72 repeat expansion present with highly variable onset ages of disease. In the Belgian patient cohort the onset ages ranged from 29 to 82 years of age. This high variability suggested the influence of modifying factors on disease expression. As in other repeat expansion diseases, repeat length is the prime candidate as genetic modifier. In a molecular study (Gijselinck et al., Molecular psychiatry 2016), we were able to provide evidence for an inverse correlation of repeat length with onset age in affected parent – affected children in a C0orf72 families. Also, the degree of methylation of the C9orf72 repeat correlated with repeat size.

In this clinical study of affected parent – affected children pairs we provided additional evidence for the occurrence of disease anticipation in C9orf72 pedigrees by analyzing age at onset, disease duration and age at death in successive generations. Within 36 C9orf72 pedigrees with available age data of patients in two to four generations, we observed a significant decrease in age at onset across successive generation while no generational effect was seen on disease burden, disease duration or age at death. What should readers take away from your report?

Response: Our clinical data supported the occurrence of disease anticipation in C9orf72 expansion families by means of an earlier age at onset age in successive generations. But in contrast with other diseases associated with repeat expansions, our results suggested that disease anticipation in C9orf72 families results in earlier ages at onset but not in a more aggressive disease course with shorter disease duration. Also interesting was the association between the clinical phenotype of an affected child and that of the affected parent. If the affected parent had ALS the child was more likely to develop ALS and similarly in case of cognitive dysfunction (FTD).

In the majority of the families the children developed the disease at an earlier age. It is advisable to clinically follow-up presymptomatic carriers of a C9orf72 repeat expansion. It is not yet possible to predict the age at onset. There is no strict correlation between repeat length and onset age, and in some families there was seemingly no disease anticipation, or a repeat retraction occurred leading to a shorter repeat than that of the affected parent, or an affected child had a later onset age than the affected parent. So more long-term observations of parent – children in C9orf72 families will be needed. What recommendations do you have for future research as a result of this study?

Response: Replication of our observations in other populations is needed to confirm our findings as well provide additional new data regarding the C9orf72 disease anticipation. Both clinical and molecular studies in larger C9orf72 patient groups and families will be essential to better understand the molecular mechanisms underlying repeat expansions and their causal relationship with brain neurodegeneration and clinical disease. For example we observed that the average difference in onset age between affected offspring and an affected mother was 4.6 years less than with an affected father, though not significant. If follow-up studies are capable of providing significant evidence for this finding this would imply that paternal transmission is more prone to repeat expansion and disease anticipation. Also, in this study, we could not reliable investigate if disease anticipation due to C9orf72 repeat expansion leads to a higher risk of ALS than FTD in the affected offspring. New methods to accurately measure the size of the C9orf72 repeat expansion can help to answer these questions. Thank you for your contribution to the community.

Citation: JAMA

Van Mossevelde S, van der Zee J, Gijselinck I, Sleegers K, De Bleecker J, Sieben A, Vandenberghe R, Van Langenhove T, Baets J, Deryck O, Santens P, Ivanoiu A, Willems C, Bäumer V, Van den Broeck M, Peeters K, Mattheijssens M, De Jonghe P, Cras P, Martin J, Cruts M, De Deyn PP, Engelborghs S, Van Broeckhoven C, for the Belgian Neurology (BELNEU) Consortium. Clinical Evidence of Disease Anticipation in Families Segregating a C9orf72 Repeat Expansion. JAMA Neurol. Published online February 13, 2017. doi:10.1001/jamaneurol.2016.4847

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Last Updated on February 15, 2017 by Marie Benz MD FAAD