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Gene related to inherited dementia discovered

A team of Canadian and U.S. researchers say they have identified the mutated gene that causes an inherited form of the most common type of dementia other than Alzheimer's disease.

Known as frontotemporal dementia, or FTD, the condition represents about 15 per cent of all dementia cases worldwide, including up to an estimated 100,000 in Canada. About half of these cases are inherited.

"We've discovered the genetic cause of an important inherited type of dementia," said Dr. Ian Mackenzie, a neuropathologist at the University of British Columbia, whose work led to the discovery of the mutated progranulin gene on chromosome 17.

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"The immediate implications are that we can now begin to offer genetic counselling and genetic testing for affected families," Dr. Mackenzie said from Vancouver. "And perhaps even the more important slightly long-term goal is that the knowledge we've gained has very strong implications for possible treatment strategies."

Several scientists not involved in the project hailed the finding as exciting, but cautioned that progranulin may be only one gene behind the disease and that finding an effective treatment could take many years.

Dr. Mario Masellis, a neurologist at Sunnybrook Health Sciences Centre in Toronto, said progranulin is the second mutated gene found to relate to inherited cases of FTD. The other, known as tau, was isolated in DNA from a group of families in Europe.

"The two genes together account for a proportion of the familial cases, but don't account for all familial cases," said Dr. Masellis. "It's an important discovery . . . It's like they're getting pieces of a puzzle and they've now found a second piece of the genetic puzzle. But there are likely other pieces that need to be discovered as well."

Like Alzheimer's, FTD is incurable, but its onset is typically much earlier, with symptoms beginning in the 50s or 60s. Unlike Alzheimer's disease, FTD does not usually destroy memory.

But FTD can be equally devastating for patients and their families: those afflicted undergo profound changes in personality and behaviour, and their ability to speak can be so severely compromised that many eventually become virtually mute.

"They either become very withdrawn and emotionally blunt or they may become very emotionally disinhibited," said Dr. Mackenzie. "They may laugh inappropriately, they may cry inappropriately, they may burst out in anger at something very, very minor.

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"The reason it's disturbing to the family and friends is that it's often very socially inappropriate behaviour," he said, explaining that people with FTD may begin swearing frequently, shoplifting, making impulsive purchases they can't afford and grabbing food off other people's plates.

Some lose all sense of personal hygiene, going for days without bathing, and may become hypersexual, even masturbating in public - often with a complete lack of self-awareness that they are doing anything wrong, he said.

The hunt for the genetic mutation began when Dr. Mackenzie was analyzing brain tissue from people who had died with dementia. The tissue looked different from that of patients with Alzheimer's, whose entire brains show a buildup of plaque and thread-like tangles.

"These patients were clearly different," said Dr. Mackenzie, noting that only the frontal portion of the brain - the area responsible for language and emotion - had been affected. There was no buildup of matter, but the front parts of the brain had shrunk severely.

Normally, Dr. Mackenzie would see one of two such cases a year - but he was seeing dozens.

He took his findings to Dr. Howard Feldman, head of UBC's Alzheimer's clinic, and they began collecting generational case histories on family members and DNA samples from those still living.

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The UBC team formed a collaboration with Dr. Mike Hutton of the Mayo Clinic in Jacksonville, Fla., who had helped discover the mutated tau gene along with European scientists in 1998. For 18 months, the genetic detectives at Mayo hit one dead-end after another. They decided to switch gears and began painstakingly sequencing a strip of 160 genes on chromosome 17, where the mutation was believed to occur.

About halfway through - and within days - they nailed it.

"When I got the e-mail that they'd found it . . . I sat there sort of stunned for a few minutes," recalled Dr. Mackenzie. "When you start this the ultimate dream is yes, we're going to find the gene. When you find it, it's this tremendous eureka moment."

DNA testing of families affected by inherited FTD - including about two dozen members who had developed symptoms - allowed researchers to pinpoint the defective gene.

"Everybody who had the disease had the mutation; nobody who was normal had the mutation," he said. "So it was an absolute match."

The gene is responsible for expressing progranulin protein, a growth factor essential for healthy neurons. The mutation causes too little progranulin to be produced, causing frontotemporal brain cells to die.

The research was presented Sunday in Madrid at the International Conference on Alzheimer's Disease and Related Disorders and published in the online edition of Nature.

Dr. Jack Diamond, scientific director of the Alzheimer Society of Canada, said the next challenge is to find ways of increasing progranulin or substitute growth factors in the brain.

"These approaches are difficult but not out of reach," Dr. Diamond said in a statement. "Moreover, with the abnormal gene identified it now becomes possible using genetic engineering to create a mouse model of FTD which can be used to test new therapeutic drugs for this disorder."

Dr. Masellis said the concept is feasible, but he cautioned that the complexity of FTD may mean that several underlying biological processes are involved in the disease.

"The idea is a good one and we have technologies that can allow us to do this, but I still think you're talking about a ways down the road," he said. "That's why it's difficult to say that just targeting one particular process is going to make the disease all better."

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