Researchers have identified a new mutation linked to the genetic form of frontotemporal dementia, according to an article in the July 10 issue of Neurology.

Frontotemporal dementia, one form of which is known as Pick’s disease, involves progressive shrinking of the frontal and temporal lobes. Consequently, early changes often involve language problems and personality changes, often with inappropriate social behavior. Unlike Alzheimer’s disease dementia, the disease does not affect memory in the early stages. The lack of early presentation of memory deficits can lead to incorrect psychiatric diagnoses.

“We are hopeful that this finding will help us better understand how this disease works and eventually help us develop new therapies for the disease,” said study author Amalia Bruni, MD, of the Regional Neurogenetic Centre in Lamezia Terme, Italy.

The researchers discovered a new mutation in the gene named progranulin in an extended family in southern Italy. The genealogy of this family has been reconstructed for 15 generations, going back to the 16th century; 36 family members have had frontotemporal dementia.

For this study, DNA tests were conducted on 70 family members, including 13 people with the disease. “This is an important result that we pursued for more than 10 years,” said study co-author Ekaterina Rogaeva, PhD, with the Centre for Research in Neurodegenerative Diseases at the University of Toronto.

The mutation identified is in a gene on chromosome 17. The mutation leads to a loss of progranulin, a protein growth factor for brain cells. The mutation causes only half of the protein to be produced because only one copy of the gene is active. Production of too much progranulin has been associated with cancer.

The new gene mutation was found in nine family members with the disease and 10 people who are currently too young to have symptoms. However, four people with the disease did not have the gene mutation. Bruni noted that these four people belong to a branch of the family with the disease in at least three generations. “These results are intriguing, since the family has two genetically distinct diseases that appear almost identical,” said Bruni.

The Italian family had no cases with two copies of the mutated gene. “We would have expected to see cases with two copies of the mutated gene, especially since this family shares much of the same genetic material, as there have been at least five marriages between first cousins over the years,” Bruni said. “It’s possible that loss of both copies of the progranulin gene leads to the death of embryos, and that’s why there were no cases with two copies of the mutated gene.”

“Another intriguing aspect in this Italian family is the variable age at onset, which ranged from 35 to 87 years in the family members who inherited the same mutation. Our future research will try to identify the modifying factors responsible for the severity of the disorder,” said Rogaeva.