Disease Strikes Children of ALS Parents with C9orf72 Mutations at Younger Ages, Study Finds

If parents pass on mutations in the C9orf72 gene, their children not only develop amyotrophic lateral sclerosis (ALS) or frontotemporal dementia but do so at an earlier age due to an expansion of the mutation.

This finding makes it easier for physicians to determine when to start monitoring an individual carrying a C9orf72 mutation.

But researchers leading the study, “Clinical evidence for disease anticipation in families segregating a C9orf72 repeat expansion,” did not find evidence of a more rapid disease course in younger generations. The work was published in the journal JAMA Neurology.

“This research is based on our team’s previous results, which showed that the same C9orf72 mutation leads to both frontotemporal dementia and ALS,” Christine Van Broeckhoven, a professor at VIB–University of Antwerp in Belgium, and the study’s senior author, said in a press release.

“As this mutation occurs in a substantial group of ALS and frontotemporal dementia patients, it is important to extract as much knowledge about this mutation and the disease process as possible.”

The C9orf72 mutation is the most common genetic cause of both ALS and frontotemporal dementia. The genetic flaw consists of repetitions of a short DNA sequence. Oddly enough, these repetitions tend to multiply, and can reach many thousand copies in some patients.

In an earlier study, the research team showed that the number of repeats was linked to the age at which patients started displaying symptoms. When a child became sick at an younger age than the parent, researchers found that the mutation had “expanded” from 200 repeats in the older generation to more than a 1,000 in the child. The finding explained why people within the same family could fall ill at very different ages.

In their new study, researchers looked at data from up to four generations — across 36 families — of people with the mutation, and showed that their earlier observations followed a pattern. Successive generations fell ill at earlier ages.

“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,” said Dr. Sara Van Mossevelde, the study’s lead author.

Researchers do not know why the same type of mutation causes ALS in some people, and frontotemporal dementia in others. The study offers a clue, however, since results showed that one disease or the other predominated.

“We also found that in families with both FTD [frontotemporal dementia] and ALS patients, if the parent had FTD the child was more likely to have FTD, and a similar principle applied to ALS,” said Van Mossevelde.

“These data provide supportive evidence for the occurrence of disease anticipation in families carrying a C9orf72 repeat expansion, and may help clinicians decide from which age onward it may be relevant to clinically follow presymptomatic individuals who carry a C9orf72 repeat expansion,” the researchers wrote.