Frontotemporal dementia and amyotrophic lateral sclerosis, also known
as Lou Gehrig's disease -- two fatal neurodegenerative disease with
distinct symptoms -- are triggered by a common mutation in many cases,
according to researchers who say they have identified the mutated gene.
In the study, reported in the September 21 online issue of Neuron,
the scientists described the discovery of a genetic mutation that is
accountable for almost 12 percent of familial FTD and more than 22
percent of familial ALS samples studied.
They also report that the defect is the strongest genetic risk
factor found to date for the more common, non-inherited, sporadic forms
of these diseases. It was found in 3 percent of sporadic FTD and 4
percent of sporadic ALS samples in the largest clinical patient series.
The study was led by scientists at the Mayo Clinic in Florida, in
collaboration with researchers at UCSF, the University of British
Columbia and UCLA. The finding emerged from the identification and study
of a family stricken by both ALS and FTD, reported last year. In that
study, led by the UCSF scientists and published in the Journal of
Neurology, Neurosurgery and Psychiatry, the researchers honed in on the
region in which the gene was located.
"Both clinically and at the molecular level this discovery is going
to significantly improve our understanding of these diseases," said
co-author Adam Boxer, MD, PhD, of the UCSF Memory and Aging Center, the
lead author on the 2010 paper. The discovery makes it possible to
develop a diagnostic test for the mutation, as well as to create animal
models that may be used to help unravel the molecular mysteries
connecting the mutation to the diseases, he said.
In the current study, a detailed molecular genetic characterization
of the family that Boxer described was done in the laboratory of senior
author Rosa Rademakers, PhD, from the Mayo Clinic. She and colleagues
identified the gene and the specific mutation within it.
The mutation consists of from hundreds to thousands of extra copies
of a six-letter DNA sequence GGGGCC strung end to end within a region of
human chromosome nine. The mutation occurs within a gene of unknown
function called C9ORF72.
After identifying the mutation, the Mayo researchers searched for it
in DNA from other patients with both familial and sporadic forms of the
diseases, where they found the strong associations.
FTD is characterized by disturbances in decision making, language
skills, behavior and emotional expression, and is as common as
Alzheimer's disease in people younger than 65, according to Boxer. ALS
is a neuromuscular disease, leading to muscle paralysis and respiratory
failure, often within three to five years. However, it is not unusual
for patients diagnosed with one of the two diseases to exhibit symptoms
of the other.
Since 2006, six separate groups have reported evidence for a genetic
link between the disorders and the same chromosomal region. In the
study led by Boxer last year, the researchers described clinical aspects
of the disease within the family, and homed in more closely to the gene
than others had.
The pattern of protein deposition in the brains of family members in
the study may eventually shed light on common aspects of the
neurodegenerative process that occurs in both diseases, Boxer said.
There is only one standard medical treatment for ALS, riluzole, which extend life for about six months, he said.
There is no known effective treatment to slow FTD. However,
neurologists have generally become much better at recognizing the
degenerative disorder, according to Boxer.
Boxer and Bruce Miller, MD, the director of the UCSF Memory and
Aging Center and a co-author of both studies, are leaders in FTD
research, diagnosis and patient care.
"Ten years ago some neurologists did not acknowledge the existence
of FTD," Boxer says. "Today we are much better at diagnosing the
disease, although sometimes it still takes an expert to distinguish it
from Alzheimer's or from psychiatric disorders.
"We're actively trying to develop treatments for FTD, and we believe
this discovery will pave the way for major advances in these efforts."
The researchers used a technique called linkage analysis to narrow
the search for the gene by comparing affected and unaffected family
members. Another group of scientists -- reporting in the same online
edition of Neuron on the same gene -- found that C9ORF72 emerged
as being significantly associated with FTD and ALS in a genome-wide scan
of patients in Finland.
