Most common genetic
cause
of Parkinson's Disease identified
Newswise — Researchers have found that a
single mutation in a recently discovered Parkinson's disease gene is
responsible for 5 percent of inherited Parkinson's disease cases.
The finding opens the door to the possibility of genetic screening
for the LRRK2 gene mutation, which is believed to be the most common
genetic cause of inherited Parkinson's disease identified to date.
The study, conducted by William C.
Nichols, PhD, a geneticist at Cincinnati Children's Hospital Medical
Center, is one of three Parkinson's studies published in the
Tuesday, January 18 online edition of The Lancet. The study
will appear in the January 29 edition of the journal. The second
study is by Nicholas W. Wood, MD, of the Institute of Neurologyin
London. The third study is by Vincenzo Bonifati, MD, PhD, of Erasmus
MCin Rotterdam, Netherlands.
Parkinson's disease, a disorder of the
nervous system that causes tremors and muscular rigidity, affects
more than one million people in the United States and is the second
most common neurodegenerative disorder - second only to Alzheimer's
disease in frequency.
The Cincinnati Children's study focused
on a group of 767 Parkinson's disease patients from 358 different
families. The patients were recruited by specialists from 59 medical
centers associated with the Parkinson Study Group, a non-profit,
cooperative group of Parkinson's disease experts from the United
States, Canada and Puerto Rico. The study found that 5 percent of
the patients carried the same LRRK2 mutation. The Wood report
focused on Parkinson's disease patients without a known family
history of the disease. Dr. Wood found the same LRRK2 gene mutation
in eight of 482 individuals in the study. The Bonifati study
identified the same LRRK2 gene mutation as the Cincinnati Children's
study. Bonifati found the mutation in four of 61 families with a
history of Parkinson's disease.
"When we began, we really didn't know
how frequent the mutation in the LRRK2 gene would be, but to find
the same single mutation in the genome in Parkinson's patients is
pretty dramatic. No other mutation in any other known Parkinson's
gene has been found in such high frequency," said Dr. Nichols, who
is the lead author of the Cincinnati Children's study.
LRRK2 is one of five Parkinson's disease
genes in which mutations have been identified. The gene was
identified in October 2004 by Andrew Singleton, PhD, of the National
Institute on Agingat the National Institutes of Health, who is a
co-author of the Nichols and Wood studies in The Lancet. The LRRK2
gene was isolated on a region of chromosome 12 called PARK8 by Dr.
Singleton and colleagues who studied five families with a history of
Parkinson's disease.
Individual genes can have many
mutations, which is also true of the LRRK2 gene. Dr. Singleton has
identified other mutations in the LRRK2 gene, but those mutations
were not manifested to the same degree as the mutation described in
the Nichols' study, which was found to occur in about one of every
22 patients with inherited Parkinson's disease.
"It looks like mutations in this gene
are going to account for far more than mutations in other
Parkinson's disease genes identified to date. Finding the same
mutation in a single gene accounting for such a large percentage of
patients is quite remarkable, and this mutation should be included
in any future genetic testing for the disease," Dr. Nichols said.
The patients in the Cincinnati
Children's study who had the mutation did have longer disease
duration at the time of their clinical evaluation for the study, but
their symptoms were less severe, suggesting that the mutation in
LRRK2 is associated with slower disease progression, Dr. Nichols
said.
Parkinson's disease is a progressive
disorder that is caused by the degeneration of nerve cells in the
portion of the brain that controls movement. The disease occurs when
certain nerve cells die or become impaired and can no longer produce
dopamine. Without dopamine, individuals can develop tremor or
trembling in hands, arms, legs, jaw, and face along with rigidity or
stiffness of the limbs, slowness of movement; and impaired balance
or coordination. Patients may also have difficulty walking, talking,
or completing other simple tasks. The incidence of Parkinson's
disease increases with age.
Until recently, it was thought that
environmental factors were the primary cause of Parkinson's disease.
A genetic link was thought to exist in the rare early onset form of
the disease in people diagnosed before age 40 (children as young as
14 have been diagnosed with the juvenile form of Parkinson's
disease), but not in the more common form of the disease in which
people, on average, are diagnosed at about 60 years. The first
Parkinson's disease gene was identified in 1997.
Dr. Nichols is a geneticist who
specializes in the identification of novel disease genes. In
addition to Parkinson's disease, he conducts research on primary
pulmonary hypertension and juvenile rheumatoid arthritis.
The Cincinnati Children's study was
funded by the National Institute of Neurological Disorders and
Strokeof the National Institutes of Health.
Cincinnati Children's conducted this
research in conjunction with Dr. Singleton of the National Institute
on Aging, and Tatiana Foroud, PhD, of Indiana University Medical
Center, who is also a co-author and principal investigator of an $8
million grant from the National Institute of Neurological Disorders
and Stroke (NINDS).