Certain Genetic Mutations Passed to Children Increase Risk of Dementia or ALS

Children who receive the C9orf72 genetic mutation from their parents are affected by frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS) at a younger age than the parent, according to a study published in JAMA Neurology.

The C9orf72 mutation is one of the most frequent mutations found in FTD and ALS. In FTD, the frontal and temporal lobes are affected first, causing changes in the individual’s personality and behavior. FTD is the most common form of dementia in young patients after Alzheimer’s disease.

Previous findings have shown a genetic link between FTD and ALS, particularly the mutation in the same C9orf72 gene.

“This research is based on our team’s previous result, which showed that the same C9orf72 mutation leads to both FTD and ALS,” said investigator Christine Van Broeckhoven. “As this mutation occurs in a substantial group of ALS and FTD patients, it is important to extract as much knowledge about this mutation and the disease process as possible.”

A fraction of patients with FTD show symptoms that are consistent with ALS, according to the investigators. The mutation in C9orf72 consists of a repetition of a short DNA sequence GGGGCC, which can expand in patients up to several thousands of repetitions. However, it remains unclear of why some patients get FTD, while others get ALS.

“The C9orf72 mutation is the most frequent mutation in FTD and ALS,” Van Broeckhoven said. “In the Belgian population, 37% of patients with ALS and 25% of patients with FTD can be explained by the presence of this C9orf72 mutation. The C9orf72 mutation is present in 88% of patients with FTD plus ALS.”

In 2016, the investigators found that the age of onset is determined by the number of GGGGCC repeats, and the more repetitions, the earlier the age of onset.

In the study, affected parents had a late age of onset while their affected children had an earlier age of onset. The investigators were able to demonstrate that the GGGGCC repeat in the C9orf72 gene expanded from a short sequence of repeats, of less than 200 repeats, to a long one, of more than 1000.

“In a new clinical study in 36 C9orf72 families, we analyzed the age of onset of the patients in 2 to 4 generations,” said investigator Dr Sara Van Mossevelde. “We found that there was a significant difference in the ages of onset between successive generations. In most families, the children were affected by the disease at a younger age, but there were no indications that the disease was progressing more quickly. We also found that in families with both FTD and ALS patients, if the parent had FTD the child was more likely to have FTD, and a similar principle applied to ALS.”

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