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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 disease.

"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.


BACKGROUND

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 factors.

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 side effects.

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 Parkinson's symptoms.

Transmitted: 95-03-29 19:26:06 EST


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