PARKINSON'S DISEASE GENE
DISCOVERED By Sean Henahan, Access Excellence
ST.LOUIS- The discovery of a gene associated with a rare form of Parkinson's
disease provides researchers with a long sought piece to the puzzling pathogenesis
of this disease.
A team of researchers at Washington University School of Medicine in
St. Louis have characterized a rare disease, aceruloplasminemia, that causes
a rare form of Parkinson's. Aceruloplasminemia is caused by a mutation in
the ceruloplasmin gene, which is involved in iron transport.
Patients with this gene mutation do not make ceruloplasmin, a protein
that removes iron from cells. The iron then accumulates in cells in the
brain's basal ganglia region and causes neurological problems. These include
the tremors and gait abnormalities associated with Parkinson's disease,
according to Jonathan D. Gitlin, M.D., associate professor of pediatrics,
Washington University School of Medicine.
Neurologists have long hypothesized that Parkinson's disease results
from a combination of genetic and environmental factors. The current discovery
is important because it is the first time a genetic cause of Parkinson's
disease has been identified.
"This is a clearly defined piece of the puzzle and there haven't
been many of those in this particular disease. I think that's what's most
exciting," Gitlin said.
Gitlin and colleagues discovered the genetic form of Parkinson's during
a study of a Japanese family that had Parkinson symptoms and low levels
of ceruloplasmin. Autopsy and biopsy analyses of brain and liver tissue
of a different Japanese patient led to the conclusion that this abnormality
was caused by increased iron deposition. Gitlin's lab then obtained DNA
from another Japanese family and identified a mutation on the ceruloplasmin
gene located on chromosome 3. All of the patients with the mutation had
basal ganglion damage characteristic of Parkinson's disease
This finding gives researchers important new information which could
lead to innovations in the diagnosis and treatment of Parkinson's disease.
Genetic screening based on these findings may also help doctors diagnose
patients with neurologic disorders for which no cause is known. Ultimately,
the identification of this mutation could help prevent the onset of Parkinson's
"Hopefully, if you find out early, it might be the kind of disease
that if there was some kind of therapy, you could prevent it," he said.
Dr. Gitlin believes this form of Parkinson's disease has been underdiagnosed
in the past. He recommends that patients with undiagnosed movement disorders
ask their doctors to look for aceruloplasminemia.
Scientists have known for some time what neurotransmitter is depleted
in Parkinson's disease patients (dopamine) and where it is depleted (the
basal ganglia). What is not known is what initiates and maintains this neurodegenerative
process. Some studies have hinted at familial linkages while others have
implicated environmental factors ranging from drinking water and cycad nuts
to toxic drugs and poor education.
Earlier this year Swedish researchers reported data from animal studies
supporting the hypothesis that Parkinson's is caused by a lack of sufficient
dopaminotrophic support. Researchers at the Karolinska institute in Stockholm
conducted a series of experiments in mice using a cloned version of a natural
protein associated with nerve cell growth called glial cell line-derived
neurotrophic factor (GDNF).
The researchers concluded that intracerebral GDNF administration exerts
both protective and reparative effects on the nigrostriatal dopamine system,
which may have implications for the development of new treatment strategies
for Parkinson's disease.
Dr. Gitlin's research appears in the March 28 issue of the Proceedings
of the National Academy of Sciences. The Swedish data appeared in Nature,
Olson et al., v.373, 1/26/95.
Nearly one million people in the U.S. have Parkinson's disease. This
is a mysterious disease with no known cause or cure. The cause of Parkinson's
disease is currently thought to be a combination of environmental and genetic
The symptoms of Parkinson's disease were first described by British physician
Dr. James Parkinson in 1812. The first symptom is often an involuntary tremor.
As the disease progresses, the muscles become stiff and the face loses all
expression. Patients also develop difficulty walking and standing.
The first treatment breakthrough came with levadopa. The drug essentially
replaces the lost dopamine in the brain. However, large doses are required,
resulting in undesirable side effects, such as nausea, heart problems & dementia.
The subsequent development of carbidopa, which is given in conjunction with
levadopa, allows a smaller dose of levadopa to be used, resulting in fewer
Many patients respond well at first to this combination therapy, but
after a couple years of treatment the effects may begin to wear off. At
the same time, prolonged use of levadopa can have serious side effects including
involuntary movements of the limbs and psychological disturbances.
A new treatment called seligiline has recently become available which
has a completely different mechanism of action from levadopa. The drug is
potent inhibitor of an enzyme called 'monoamine oxidase B' which breaks
down dopamine. This means more dopamine can be preserved in the brain. The
drug appears to have a neuroprotective effect and may delay the onset of
Transmitted: 95-03-29 19:26:06 EST