JACKSONVILLE, Fla., Dec 25, 2011 (BUSINESS WIRE) --
A global team of neuroscientists, led by researchers at Mayo
Clinic in Florida, have found the gene responsible for a brain
disorder that may be much more common than once believed. In the Dec. 25
online issue of Nature
Genetics, the researchers say they identified 14 different
mutations in the gene CSF1R that lead to development of
hereditary diffuse leukoencephalopathy
with spheroids (HDLS). This is a devastating disorder of the brain's
white matter that leads to death between ages 40 and 50. People who
inherit the abnormal gene always develop HDLS.
The finding is important because the researchers suspect that HDLS is
more common than once thought. According to the study's senior
investigator, neurologist Zbigniew
Wszolek, M.D., a significant number of people who tested positive
for the abnormal gene in this study had been diagnosed with a wide range
of other conditions. These individuals were related to a patient known
to have HDLS, and so their genes were also examined.
"Because the symptoms of HDLS vary so widely -- everything from behavior
and personality changes to seizures and movement
problems -- these patients were misdiagnosed as having either schizophrenia,
epilepsy,
frontotemporal
dementia, Parkinson's
disease, multiple
sclerosis, stroke,
or other disorders," says Dr. Wszolek. "Many of these patients were
therefore treated with drugs that offered only toxic side effects.
"Given this finding, we may soon have a blood test that can help doctors
diagnose HDLS, and I predict we will find it is much more common than
anyone could have imagined," he says.
Dr. Wszolek is internationally known for his long-term effort to bring
together researchers from around the world to help find cases of rare
brain disorders and discover their genetic roots.
Dr. Wszolek's interest in HDLS began when a severely disabled patient
came to see him in 1995 and mentioned that other members of his family
were affected. He was able to definitively diagnose the disease upon
autopsy of the patient because of changes in the white matter. Until
then, only one family in Sweden had been diagnosed with HDLS.
Dr. Wszolek began to search for other cases, and his Mayo Clinic
colleague, Dennis
Dickson, M.D., a pathologist, recalled seeing such changes in a
brain while he was in training. Dr. Dickson located two more cases in
Florida and Michigan, and Dr. Wszolek began to talk about HDLS at every
research presentation he made throughout the world. He soon had brain
samples from Norway, the United Kingdom, and Canada, and from different
areas in the U.S. He and his team of investigators and collaborators
have since published numerous studies describing the disorder and have
held five international meetings on HDLS.
In this study, which included 38 researchers from 12 institutions in
five countries, the study's first author, Rosa Rademakers, Ph.D., led
the effort to find the gene responsible for HDLS. Her laboratory studied
DNA samples from 14 families in which at least one member was diagnosed
with HDLS and compared these with samples from more than 2,000
disease-free participants. The gene was ultimately found using a
combination of traditional genetic linkage studies and recently
developed state-of-the art sequencing methods. Most family members
studied -- who were found to have HDLS gene mutations -- were not
diagnosed with the disease, but with something else, thus emphasizing
the notion that HDLS is an underdiagnosed disorder.
The CSF1R protein is an important receptor in the brain that is
primarily present in microglia, a type of immune cells. "We identified a
different CSF1R mutation in every HDLS family that we studied,"
says Dr. Rademakers. "All mutations are located in the kinase
domain of CSF1R which is critical for its activity, suggesting
that these mutations may lead to deficient microglia activity. How this
leads to the loss of brain cells in HDLS patients is not yet understood,
but we now have an important lead to study."
"With no other disease have we found so many affected families so
quickly," says Dr. Wszolek. "That tells me this disease is not rare, but
quite common."
He adds, "It is fantastic that you can start an investigation with a
single case and end up, with the help of many hands, in what we believe
to be a world-class gene discovery."
The study was funded by a Mayo benefactor and the Mayo Foundation.
Additionally, Mayo Clinic in Florida is a Morris
K. Udall Parkinson's Disease Research Center of Excellence supported
by the National Institute of Neurological Disorders and Stroke.
About Mayo Clinic
Mayo
Clinic is a nonprofit worldwide leader in medical care,
research, and education for people from all walks of life. For more
information, visit
www.mayoclinic.org/about/
and
www.mayoclinic.org/news .
SOURCE: Mayo Clinic
Mayo Clinic
Emily Hiatt
507-284-5005 (days)
507-284-2511 (evenings)
newsbureau@mayo.edu
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