October 22, 2014
   
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Early-Onset Parkinson's Disease

 
Dr. Alcalay is Assistant Professor of Neurology, and Dr. Marder is Professor of Neurology (in the Sergievsky Center, Taub Institute and Psychiatry), Columbia University College of Physicians and Surgeons, New York.

Michael J. Fox’s personal battle with Parkinson’s disease (PD), which he revealed to the public twelve years ago, has likely opened many people’s eyes to the disease in a whole new way. Previously, it may have been thought of as a mysterious disease of the elderly in which their bodies inexplicably shook (in fact, PD was known as "Shaking Palsy" in the days before Dr. Parkinson described it in 1817.) But PD is actually the second most common neurodegenerative disease after Alzheimer’s, and affects upwards of 1 in 100 Americans older than 65.(1)

The definition of EOPD versus late-onset PD varies according to which expert you talk to but most define EOPD as first presentation of motor symptoms before the age of 40 or 50.

PD diagnosis is also rising rapidly in developing countries.(2) What is now known as early-onset PD (EOPD) – Fox’s form of the disease – is less common than late-onset PD. It is estimated that between 3% and 10% of all PD cases are diagnosed with the person is younger than 40.(3) The definition of EOPD versus late-onset PD varies according to which expert you talk to but most define EOPD as first presentation of motor symptoms before the age of 40 or 50.(3)(4)(4)(5) (Fox was only 30 years old when he was diagnosed; see Fox’s organization, michaeljfox.org, for information on his personal story and research initiatives). While there are many similarities between EOPD and late-onset PD, EOPD has some unique features. In this article, we’ll talk about how PD "operates," including the genes thought to be involved, as well as how it is diagnosed in the clinical setting and what treatment options exist for EOPD nowadays.

The Basics of EOPD: What We Know So Far

How and why early onset Parkinson's disease originates in certain people is still largely unknown, as is also the case with PD. EOPD is considered a complex disorder and is most likely the result of the effects of many genes working in combination with a handful of environmental factors. Some of the environmental factors that have been linked to PD include exposure to pesticides, caffeine intake, and smoking.(6) Smoking and caffeine consumption are actually associated with a decreased risk of EOPD, but the cause for this association is still not clear.(7) (This unexplained link should not, however, be taken as license to smoke, since smoking can lead a whole host of other serious diseases.) It is not clear yet what role prenatal and early life exposures may play in the development PD.(8)(9)

The Genetics of EOPD

Ever since researchers identified the first gene mutation involved in PD ( α-synuclein, or SNCA) back in 1997,(10) a wealth of information about the genetics of PD has accumulated. Several genes have now been linked to PD, which are dubbed PARK1 - PARK16. People who carry one of these mutations often develop PD earlier than non-carriers.

The genes associated with PD are usually classified as autosomal dominant (meaning that you just need one copy of the gene from either parent for the disease to develop) and autosomal recessive (where two copies of the gene need to be present). But it is not clear that these traditional definitions actually apply to EOPD. For example, with certain genes that are thought to be autosomal recessive, one’s risk for EOPD seems to be increased even if there only one copy present.(11)(12) Additionally, the lines are still blurry between genes in which mutations cause PD (autosomal dominant) and genes that make an individual more susceptible to the disease, which makes the race to find genetic connections all the more difficult.(13)(14)

Early in the disease, when only one limb is affected, it is often mistaken with an orthopedic diagnosis (such as frozen shoulder). The different medical conditions which can imitate EOPD are different in those younger than 30 and those older than 30.

Most of the genes linked to PD are very rare, and were found in selected patients with a strong family history of PD. You can read about these genes in Table 1. Of the genetic risks of EOPD, three genes are more common: parkin, LRRK2 and GBA. Parkinson's is more common in people who develop the disease very early – before age 30 – in Hispanics and with those with family history. LRRK2 and GBA are more common in Ashkenazi Jews, a population in which roughly one third of all EOPD patients carry a mutation in one of these two genes.

Very few studies have looked at the roles of genetic mutations to EOPD in people who were not brought into the study because of their family history of PD. An Australian study of 74 EOPD participants found a mutation frequency of 7%,(15) and a Dutch study of 187 EOPD participants reported mutation frequency of 4%.(16) Even more recently, a study of 953 EOPD patients in the United States reported a mutation frequency of 16%.(17) This study reported a higher mutation rate in Ashkenazi Jews compared to non-Jews (32% versus 14%), in those with age-at-onset 30 or lower when compared to age-at-onset above 30 (41% versus 15%), and in people with first degree (i.e., parent, child, or sibling) family histories of PD (24% versus 14%).(17) Genotyping the common GBA mutations and including patients of many ethnicities, including those who have a higher mutation rate (like Ashkenazi Jews and Hispanics), explain the higher frequency of mutation carriers.

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