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Is Genetic Parkinsonís a Different Form of the Disease?

People who develop Parkinson’s disease (PD) because of mutations in a gene called parkin have signs and symptoms that may differ from those of people with non-inherited PD, according to new research published online on March 4 in JAMA Neurology. This finding suggests that form of inherited PD might be distinct from more common “sporadic” PD. The research may help explain why the diseases respond differently to levodopa therapy.

The majority of people with PD do not inherit the disease. The disease is sporadic, meaning it has no known cause. However, in a small number of people, the disease is caused by a genetic mutation. For example, in people with young onset PD (those in their 20s, 30s and 40s), sometimes the disease is caused by mutations in the parkin gene. People with this genetic mutation experience some of the same symptoms as people with PD, such as tremor, and studies show that their brains lose neurons in the same region of the brain.

However, doctors and researchers also noticed differences between this form of genetic parkinsonism and sporadic PD. For example, although people with parkin mutations are diagnosed earlier (in their early 30s) typically their severe symptoms are not as severe and they are better able to control their symptoms over the long-term with levodopa than are people with sporadic PD. Also, Lewy bodies, the clumps of protein that are a hallmark of sporadic PD, are rare in the brains of people with parkin mutations. These differences led researchers to wonder whether the inherited PD was a distinct disorder.

To help answer this question, researchers led by Janice Holton, Ph.D., Fellow of the Royal College of Pathology at University College London, compared clinical, genetic and autopsy findings of 14 people, now deceased, who had lived with PD. The group included five unrelated people with parkin mutations, five people with sporadic PD, and four people without PD or parkin mutations (controls). 


  • The people with parkin mutations started experiencing symptoms between ages 25 and 46 and responded well to levodopa therapy. Their initial symptoms included hand and leg tremor and gait difficulties. As these people progressed into late stage PD, they experienced falls, freezing of gait and painful muscle contractions called dystonia.
  • People with the parkin mutation had a similar loss of dopamine neurons in the substantia nigra region of the brain just like those with sporadic PD.  However, unlike sporadic PD, these people did not have nearly the same loss of neurons in other brain regions, including parts that affect cognitive function.
  • People with parkin mutations either had very few Lewy bodies or none at all.
  • The controls showed no symptoms of PD or other neurodegenerative diseases. They had 50 percent more neurons in the substantia nigra than people with parkin mutations. One person, who died at the age of 81 without any neurological symptoms, had a small amount of Lewy bodies in the brain (common in about 15 percent of healthy individuals at time of death).

What Does It Mean?

An important question for scientists is whether all forms of PD are the same. If there are different forms of PD, then people may one day benefit from individualized treatment. This current study supports the hypothesis that PD caused by a mutation in the parkin gene is not identical to sporadic PD.

Previous research has also shown that people with PD caused by the parkin gene may be different from those with sporadic PD. First, they develop the disease at a much younger age, sometimes in their mid-teens. Second, parkin-PD progression is probably slower than sporadic PD and may involve different parts of the brain. For example, people with parkin-PD do not develop smell impairment as often as people with sporadic PD do. The current study highlights the previously reported pathological differences between parkin-PD and idiopathic PD – in the former there is tissue loss in the substantia nigra and in the latter, tissue loss is associated with Lewy bodies. 

These results will help people whose PD is caused by a mutation in the parkin gene, along with their families, to better understand how their disease may likely progress and how to prepare accordingly. For example, they know that the disease may progress more slowly. 

For researchers, understanding that parkin gene mutations lead to a different form of PD may help them to more easily test potential medications.  For instance, a clinical trial testing whether a new compound might slow the progression of PD could fail if too many people with parkin PD are in the comparison or control group since their PD already progresses quite slowly and may be different from sporadic PD.

Ultimately, understanding and properly identifying what may be many different forms of PD will be important to advancing clinical research and the development of new therapies.

Reference: Doherty KM, Silveira-Moriyama L, Parkkinen L, Healy DG, Farrell M, Mencacci NE, Ahmed Z, Brett FM, Hardy J, Quinn N, Counihan TJ, Lynch T, Fox ZV, Revesz T, Lees AJ, Holton JL (2013) Parkin Disease: A Clinicopathologic Entity? JAMA Neurol:1–9.  

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Source Date: Mar 29 2013