During the past decade or so, it has become increasingly evident that frontotemporal dementia (FTD)—the second most common type of presenile dementia—and amyotrophic lateral sclerosis (ALS) are part of a disease continuum.
A few months ago, a major cause of both FTD and ALS was identified. It is an abnormal variant of a gene on chromosome 9 called C90RF72.
Additional evidence suggesting that this gene variant plays a major role in FTD and ALS was reported in the March Brain by a group of Dutch scientists led by John van Swieten, M.D., Ph.D., a professor of neurology at Erasmus Medical Center in Rotterdam.
The researchers looked for the abnormal gene variant in a cohort of 353 subjects with sporadic or familial FTD with or without ALS and in 522 neurologically normal controls. They found it in 42 (12 percent) of the subjects with FTD, but in only three (0.6 percent) of the controls. Moreover, 37 of the 42 FTD subjects who had the variant had a positive family history of FTD, with an autosomal dominant mode of inheritance in 25 of them.
They also examined the clinical features of the 42 FTD subjects with the variant. Subjects’ ages at onset of disease ranged from 39 to 76; the average age was 57. The first symptoms were often apathy, disinhibition, obsessive-compulsive behavior, memory complaints, or language deficits; seven out of the 42 subjects also had ALS.
Thus, this abnormal variant of C90RF72 is “an important cause of FTD with and without ALS,” van Swieten and his colleagues concluded.
A British study reported in the same issue of Brain produced another intriguing and unanticipated finding—a strong association between the abnormal gene variant and psychotic symptoms.
“We were extremely excited to identify such a powerful association between the mutation and psychosis, especially as psychotic symptoms are so rare in FTD in general,” Julie Snowden, Ph.D., told Psychiatric News. Snowden, a consultant neuropsychologist and honorary professor of neuropsychology at the University of Manchester, was the lead scientist in this study.
Snowden and her colleagues evaluated 398 subjects with FTD or related syndromes for the abnormal gene variant. They found the variant in 32 (8 percent) of them. Moreover, more than one-third of these subjects displayed florid and bizarre psychotic symptoms. One, for example, had gone to the emergency room of his local hospital complaining about pieces of plastic emanating from his head. Another told the police that a man dressed in a gorilla outfit was hiding in her garden. Yet a third wore trousers on his head and underpants on his arms. “The presence of psychosis dramatically increased the odds that patients carried the mutation,” Snowden and her team said.
“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 an accompanying editorial. His hope is that “unraveling the molecular pathology will lead to a cure for these devastating diseases.”
Currently the role of the protein made by the normal version of the C90RF72 gene is unknown, David Mann, Ph.D., a professor of neuropathology at the University of Manchester and a member of Snowden’s study team, told Psychiatric News. However, the abnormal C90RF72 variant that causes FTD seems to make RNA messages aggregate and form toxic bodies. Yet how these toxic bodies impact cell function is unclear.
When should psychiatrists suspect that patients might have FTD caused by an abnormal variant of the C90RF72 gene? The following features should raise suspicion, Snowden told Psychiatric News:
Psychosis occurs for the first time in later life.
The patient shows a poor response to antipsychotic medications.
The patient’s psychosis shows strong delusional features.
The psychosis occurs in the context of “frontal” behavioral features, which have a progressive course (socially inappropriate behavior, apathy, loss of sympathy and empathy, loss of insight, repetitive behaviors, and stereotypies).
There are physical signs of ALS.
There is a family history of dementia and/or ALS.
If psychiatrists suspect that a patient might have FTD caused by an abnormal C90RF72 gene, how should they test for it?
“Clinical genetic services are now beginning to offer genetic testing for the C90RF72 mutation,” Snowden noted.
Regarding what interventions might benefit a patient who has the mutation, Snowden said, “Treatments are currently very limited and symptomatic only. For example, SSRIs are sometimes used to reduce the severity of repetitive behaviors in FTD,” she said.
The Dutch study was funded by Stichting Dioraphte Foundation, Nuts Ohra Foundation, Hersenstichting Nederland, Alzheimer Nederland, and Neuroscience Campus Amsterdam. The British study was funded by the U.K. Medical Research Council, the Wellcome Trust, and Alzheimer’s Research U.K.
An abstract of “The Clinical and Pathological Phenotype of C90RF72 Hexanucleotide Repeat Expansions” is posted at http://brain.oxfordjournals.org/content/135/3/723.abstract. An abstract of “Distinct Clinical and Pathological Characteristics of Frontotemporal Dementia Associated With C90RF72 Mutations” is posted at http://brain.oxfordjournals.org/content/135/3/693.abstract.