Dec 18, 2009 - News

LRRK2 Implications for Parkinson’s Disease


More than a million Americans have Parkinson’s disease, and another 50,000 are diagnosed each year. There is active research to try to understand this devastating condition, but scientists still don’t really know what causes it.   There are no clear environmental triggers for the disease, and genetics doesn’t seem to play a large role either — it is estimated to be involved in fewer than 10% of cases.

Of the few known genetic causes of Parkinson’s, one of the most common is the LRRK2 G2019S mutation. While the average person has a 1-2% chance of developing Parkinson’s, the risk for someone with the G2019S mutation is much higher and increases with age. One recent study found that a person who inherits this mutation from either parent has a 28% chance of developing Parkinson’s by the age of 59, 51% by the age of 69 and 74% by the age of 79.

Previous research had suggested that the LRRK2 G2019S mutation is associated with a form of Parkinson’s where the predominant symptom is tremor.   But a new study, published this week in the Archives of Neurology, suggests that carriers of this mutation are in fact more likely to manifest a different form of Parkinson’s called the postural instability and gait difficulty (PIGD) phenotype.    Though this result must be borne out by further studies, it could have important implications for what mutation carriers can expect from their disease: the PIGD phenotype of Parkinson’s is associated with a less favorable prognosis.

Dr. Roy Alcalay and colleagues analyzed the DNA of 691 people with early-onset Parkinson’s disease (symptoms starting before age 51) from13 movement disorder centers throughout the United States, 26 of whom carried the LRRK2 G2019S mutation.   Patients were scored for various measures of tremor and the PIGD phenotype using the Unified Parkinson’s Disease Rating Scale (UPDRS).   A ratio of the two scores was then used to assign a designation as tremor dominant, PIGD, or intermediate.   Earlier studies of LRRK2 G2019S carriers did not employ this careful scoring system.

After adjusting for Ashkenazi Jewish ancestry (the G2019S mutation is especially common in this group) and disease duration, Alcalay et al. found that mutation carriers were more likely than non-carriers to have the PIGD phenotype.   Due to the small sample size it’s hard to say precisely how large the effect was, but the researchers estimate an increase in odds of 17.7 times, although the true increase may fall anywhere between 3.8 and 83.1 times.

In general, studies have indicated that the people with Parkinson’s who have the PIGD phenotype have more severe disease and faster cognitive decline than patients with tremor dominant disease.   Whether this prognosis applies to LRRK2 G2019S carriers with the PIGD phenotype remains to be tested.

More work with larger and more ethnically diverse study samples that are followed for a longer period of time will be needed to confirm these findings.

Even though it is the most common known genetic cause of Parkinson’s disease, the G2019S mutation is responsible for only a small fraction of all cases worldwide – about one or two in a hundred. But in some ethnic groups it is a much more frequent cause of the condition. According to published research, up to 40% of people of North African Arab ancestry and 20% of Ashkenazi Jewish people with Parkinson’s have this mutation.

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