MIND
September 7, 2010

When Parkinson's Comes Early

Roy N. Alcalay, M.D., M.Sc. and Karen Marder, M.D., M.P.H.
Early-Onset Parkinson's disease (EOPD) can be difficult to diagnose. Genes play a role.
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.

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. 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. 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. (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. Smoking and caffeine consumption are actually associated with a decreased risk of EOPD, but the cause for this association is still not clear. (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.

The Genetics of EOPD

Ever since researchers identified the first gene mutation involved in PD ( α-synuclein, or SNCA) back in 1997, 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. 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.

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%, and a Dutch study of 187 EOPD participants reported mutation frequency of 4%. Even more recently, a study of 953 EOPD patients in the United States reported a mutation frequency of 16%. 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%). 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.

In summary, the cause of EOPD in most people who develop the disease remains somewhat of a mystery. It is thought that there is an interaction between different genes and the environment that contributes to the development of EOPD. But studies to spell out these interactions are lacking. While much has been discovered in the past decade, most risk factors for EOPD – genetic and environmental – remain unknown.

Diagnosing EOPD

The symptoms that EOPD patients show can vary widely, which sometimes makes diagnosing the disease difficult for doctors. Many people – about 40% of EOPD patients – have a "rest tremor", that is, a tremor is present when the affected limb is at rest. In these cases, diagnosis may be easier to make. However, EOPD often appears with dystonia (muscle contractions which cause twisting and repetitive movements or abnormal postures) and can be misdiagnosed. EOPD diagnosis is tricky because the patient’s symptoms can vary so widely, and it may therefore be confused with a number of other ailments. EOPD can be easily confused with other diagnoses. 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. The presence of additional neurological deficits (e.g., impaired eye movements) can serve as a clue that the underlying condition is not EOPD.

There are several other diseases that may be considered before EOPD is diagnosed. One is a disease called Wilson’s disease, as the single most common neurological symptom in it is parkinsonism.

To correctly diagnose EOPD, a doctor will need to take a thorough history, including one’s family history (to rule out other diseases, like juvenile Huntington’s, and various others) as well as his or her medication history. If the patient is taking a prescription drug known as a "dopamine blocker," this should be made clear to the doctor, and possibly replaced with a different kind of medication. Dopamine is a brain chemical, or neurotransmitter, whose declining levels in specific areas of brain are thought to be responsible for PD. Therefore, taking a dopamine blocker may lead to symptoms or otherwise interfere with an EOPD diagnosis.

There are several other diseases that may be considered before EOPD is diagnosed. One is a disease called Wilson’s disease, as the single most common neurological symptom in it is parkinsonism and its treatment can significantly improve a patient’s prognosis. Early dysarthria (slurred speech) and personality changes may also serve as clues for the diagnosis, but an eye exam for certain telltale signs of Wilson’s (the Kayser–Fleischer ring, the result of copper deposits), as well as blood tests for copper and ceruloplasmin levels should be performed when the PD diagnosis is being considered.

Changes in the symptoms of stiffness throughout the day – with worsening of symptoms every evening – can be a sign of another disease called dopa-responsive dystonia (DRD). Affected individuals are usually diagnosed in the first two decades of life, and may have a positive family history. The diagnosis for this disease is usually made through trying the patient on the common PD drug levodopa and then watching for signs of improvement, as DRD patients will report significant improvement with treatment. DRD is not a neurodegenerative disorder and the disease may not progress over time. It is important for a doctor to consider DRD as he is attempting to diagnose a patient, because its prognosis is better than EOPD’s and only a low dose of levodopa may be required.

While functional imagining – like PET scan and other more specific scans, like dopamine active transporter (DAT) – are abnormal in EOPD, anatomical imaging is usually normal in EOPD. For this reason, MRIs may help rule out alternative diagnoses and ultimately help the doctor home in on EOPD.

In summary, EOPD diagnosis is based on taking a careful history and examination of the patient. Brain imaging to rule out focal brain lesions when symptoms seem to be the result of trauma to just one side of the brain and specific testing for Wilson’s disease are often helpful. Long-term follow-up and medication response can also help rule out alternative diagnoses including DRD.

How Does EOPD Progress?

The symptoms of EOPD are similar to late-onset PD in many ways. The common motor symptoms include muscle rigidity, rest tremor, bradykinesia (slow body movements), and postural instability, and are the same in both forms of the disease. However, EOPD patients may show dystonia at the onset of the disease, which makes the diagnosis of EOPD difficult to distinguish from dystonia in general and from DRD. There are no long term studies that compare EOPD to late-onset PD, and most of the studies that do exist don’t break down their findings according to the genetic profiles of the patients involved in the study.

In addition to the slower progression of motor problems, EOPD patients are less likely to have cognitive impairment than late-onset PD patients.

In general, the disease progresses more slowly than late-onset PD. But patients with EOPD may be more likely to suffer from dyskinesias (motor/movement problems) as a side-effect of treatment with drugs like levodopa than patients with late-onset PD. However, the link between EOPD and the development of dyskinesia is still blurry, and it could simply be due to the fact that patients with EOPD suffer from the disease for more years than people with late-onset PD.

In addition to the slower progression of motor problems, EOPD patients are less likely to have cognitive impairment than late-onset PD patients. Dementia is rare in EOPD, at least in its early stages. It is unknown whether EOPD patients are less likely to experience dementia than those with late-onset PD or if the frequency of dementia among EOPD patients is lower simply because of their younger age at the examination. In spite of these milder symptoms of EOPD, other type of psychiatric problems can be common in EOPD and most often include depression and anxiety.

The impact of the disease on patients suffering from EOPD is different from its impact on late-onset PD patients. For example, many EOPD individuals are first diagnosed when they still have young children living at home who require their care. In many cases, EOPD patients are forced to retire early because of the toll that the disease takes on them physically and/or mentally. Also, for obvious reasons, problems with motor functions tend to impair their lifestyle in a way that is more disruptive to EOPD patients than it would be for late-onset PD. Mortality in EOPD is estimated to be at least two times that of the general population, so the duration of the disease varies quite a bit. It has been estimated to range between 10-40 years.

Treatment Options

Treatment for the symptoms of EOPD is similar to that of PD, though in some cases (such as when the gene mutation PRKN is present) the dose of levodopa needed may be low – but because EOPD patients are young, higher doses of levodopa can be given as needed.

Levodopa is a precursor of dopamine, that important brain chemical whose supplies have been shown to dwindle in PD patients. Levodopa actually gets converted to dopamine after it arrives in the brain from the bloodstream. Currently, there is no FDA-approved therapy that tackles the disease itself; treatments are simply aimed at reducing symptoms. Therefore, treatment is generally tailored to the patients’ signs and symptoms with a major goal being to keep patients independent as long as possible.

The first decision that needs to be made in the management of EOPD is whether pharmacological treatment is needed. Levodopa in combination with another drug, a dopa decarboxylase inhibitor or DDI, is the most effective treatment for PD so far. However, many doctors do not introduce it as the first line of treatment in EOPD for a couple of reasons. One is that EOPD patients are more likely to develop motor problems from levodopa treatment. After five years of treatment, 91% of EOPD patients develop motor complications and after 10 years 100% are affected. The second reason is that there is conflicting evidence about whether levodopa treatment itself has some negative effects on brain cells that use dopamine; however, one well-executed study failed to show negative effects of levodopa treatment on the progression of PD.

Given that EOPD patients are expected to live for 10-40 years with the disease, delaying levodopa treatment in this group of people is usually a reasonable option. There are some alternative treatments, which include anticholinergic drugs, monoamine oxidase B inhibitors (MAO-B inhibitors), amantadine, and dopamine agonists. MAO-B inhibitors, including the drugs selegiline and rasagiline, are of special interest because some studies have suggested that these drugs may actually have an effect on the disease itself, rather than simply treating the symptoms.

Describing all the treatment options for PD is beyond the scope of this article, but a practical treatment plan would include the following. As mentioned earlier, postponing prescription medications as long as symptoms are mild and the patient is able to function well is often a good idea. When the symptoms progress, treatment with an MAO-B inhibitor may be started. In addition, either amantadine or a dopamine agonist (both ropinorole and pramipexole are available in the United States) can be added. There are some side effects of dopamine agonists, like problems with impulse control, increased drowsiness during the day, and edema (fluid build-up), which are important for one’s doctor to monitor. When symptoms are no longer kept in check by dopamine agonists or if side effects develop, then levodopa along with DDI may be introduced. Lastly, many patients with EOPD develop side effects that affect their motor skills, which include large fluctuations in motor function and dyskinesia: these patients may benefit from a technique called deep brain stimulation (DBS), which has been shown to be effective in certain diseases like PD.

Your doctor should also monitor and treat other, non-motor symptoms of EOPD, including constipation, dizzy spells known as orthostatic hypotension, and cognitive impairment. Of all the non-motor symptoms, depression can be very debilitating but can be treated. Given the high frequency of depression in EOPD patients, careful screening and early treatment are recommended.

Final Thoughts

It’s important to remember that patients with EOPD are expected to live up to four decades with the disease, which is a long time to live with a disease by any measure. Going to a doctor who is well-acquainted with the disease and can monitor and treat one’s symptoms effectively will improve the EOPD patient’s quality of life prolong his or her life expectancy. Though EOPD and late-onset PD are diseases that the medical community is still learning about, there are effective, long-term treatment options out there, and more will surely follow in coming years as researchers learn more about the disease and how best to treat it.

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