Gene Mutation May Be Major Cause of Dementia Variant

In 2011, a gene responsible for some cases of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) was identified. It is an abnormal variant of a gene on chromosome 9 called C90RF72.

“The discovery of the C90RF72 gene mutation as a cause of FTD and ALS represents a clear victory in the war against neurodegenerative disorders,” John Hodges, M.D., a professor of cognitive neurology and an FTD expert at the University of New South Wales in Australia, wrote in the March 2012 Brain. His hope was that “unraveling the molecular pathology would lead to a cure for these devastating diseases.”

Now Hodges and his colleagues have conducted a study that sheds more light on the relationship between FTD and the C90RF72 mutation. Their results were published online January 20 in JAMA Neurology.

During a five-year period at an FTD referral center, Hodges and his coworkers evaluated 114 consecutive patients with FTD, FTD-ALS, or corticobasal syndrome. They found that 14 (12 percent) of the patients had the C90RF72 mutation. This is precisely the same rate that Dutch researchers found in an FTD cohort (Psychiatric News, May 18, 2012).

The researchers were particularly interested in the relationship between the mutation and behavioral-variant FTD (bvFTD). This is a form of FTD characterized by early and progressive changes in personality, emotional blunting, and/or loss of empathy. They found that out of 29 patients with bvFTD, 10 had the mutation (a frequency rate of 34 percent). Thus the mutation appears to be a common cause of bvFTD.

Moreover, the 10 bvFTD patients harboring the mutation were more likely to have a family member with ALS than were 19 bvFTD patients not carrying the gene mutation. Psychotic symptoms—especially persecutory, negative, and paranoid delusions—were more common in patients with the mutation than without. Psychiatric illness in family members was significantly more common in mutation carriers than in those without the mutation.

The findings also have some broader implications, the researchers pointed out. Since most of the bvFTD mutation carriers had a family member with ALS, often in conjunction with psychiatric illness in family members, it’s possible that the mutation might contribute to psychiatric disorders as well as to FTD and ALS. Indeed, a recent study conducted by other researchers and published July 9, 2013, in the Annals of Neurology found a high prevalence of psychiatric disorders in the first-degree relatives of ALS patients who had the mutation.

“Patients with frontotemporal degenerative changes often develop behavioral symptoms in their 50s and may be referred to psychiatrists for diagnosis and treatment,” Robert Roca, M.D., said in an interview. In addition to being vice president and medical director of Sheppard Pratt Health System in Towson, Md., he is chair of the APA Council on Geriatric Psychiatry.

“We need to be aware that the emergence of behavioral disinhibition, loss of empathy, compulsive behaviors, and psychosis in late middle age can be early signs of FTD even in the absence of conspicuous signs of cognitive impairment. This study shows that a specific mutation on chromosome 9 is associated with some of these clinical manifestations, particularly the presence of delusions. This allows us to make a more precise diagnosis and helps us explain to patients and families why these disturbing changes are occurring.

“At this point there are no specific treatment implications, but every step we make toward understanding the causes of disease brings us closer to treatments that may alter the course of disease.”

The research was funded by the Motor Neuron Disease Association and the National Health and Medical Research Council of Australia. ■