Early-onset Parkinson's Disease
Roy N. Alcalay, M.D., M.Sc., and Karen Marder, M.D., M.P.H.
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.
Within the past 12 months, Dr. Alcalay reports no commercial conflicts of interest and Dr. Marder has received grant/research support from Neurogen.
Albert Einstein College of Medicine, CCME staff and interMDnet staff have nothing to disclose.
Release Date: 06/28/2010
Termination Date: 06/28/2013
Estimated time to complete: 1 hour(s).
Albert Einstein College of Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Albert Einstein College of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
Learning ObjectivesUpon completion of this Cyberounds®, you should be able to:
Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease, affecting up to 1% of the U.S. population older than 65.(1) PD is also rapidly increasing in developing countries.(2) Early-onset PD (EOPD) is less common than late-onset PD. It is estimated that 3-10% of PD cases have an age-at-onset of 40 or younger.(3) The definition of EOPD versus late-onset PD varies in different studies but most define EOPD as first presentation of motor symptoms before the age of 40 or 50.(3)(4)(5) While there are many similarities between EOPD and late-onset PD, EOPD has its unique features. In this Cyberounds® we will review the clinical information known about EOPD. We will divide our review into three sections: etiology, evaluation, and clinical course and treatment.
Etiology of EOPD
Smoking and caffeine consumption confer a decreased risk of EOPD (protective).
The etiology of EOPD, like PD in general, is largely unknown. EOPD is considered a complex disorder and is most likely associated with the effects of multiple genes in combination with environmental factors. Many environmental factors have been linked with PD: the most studied include pesticide exposure, caffeine intake and smoking.(6) Smoking and caffeine consumption confer a decreased risk of EOPD (protective); however, the mechanism behind this association is unknown.(7) Whether reduced smoking and caffeine consumption are secondary to premorbid personality traits (less addictive behavior) or whether specific genetic factors mediate this behavior is unknown.(7)
The role of prenatal and early life exposures in the pathogenesis of PD has not been well defined.(8)(9) Ever since the first causative mutation in α-synuclein (SNCA) was identified in 1997,(10) a wealth of information with regard to the genetics of PD has been accumulated. Several genes and chromosomal loci have been linked with PD and have been designated PARK1 - PARK14. Mutation carriers often develop PD earlier than non-carriers [except for Leucine-Rich Repeat Kinase 2 (LRRK2) carriers].
Frequently, the genes associated with PD are classified as autosomal dominant and autosomal recessive; however, these traditional genetic definitions may not apply. For example, many of the recessive genetic mutations may increase the risk of EOPD even when only a single copy is inherited (e.g., PRKN, DJ-1(11) and PINK-1).(12) The distinction between an autosomal dominant genetic mutation with incomplete penetrance (e.g., LRRK2(13) and α-synuclein(14)) and a susceptibility gene [e.g., glucocerebrosidase (GBA)] is not well defined. Table 1 describes the genetic mutations associated with EOPD, the populations in which the genetic mutations have been described and the clinical course which was reported in the carriers.
GBA mutations may be the most frequent genetic risk factor for PD in selected populations.
Table 1. Selected Genetic Mutations Associated with EOPD.
EOPD frequently appears with dystonia or stiffness (rigidity) and can be misdiagnosed.
PARK-1, PARK-4: α-synuclein (SNCA)
PARK-2: Parkin (PRKN)
The role of a single PRKN mutation in the pathogenesis of EOPD is controversial.(12)(25)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41) In one large EOPD genetic study, there were more heterozygote PRKN mutation carriers than homozygotes/compound heterozygotes;(23) carriers of a single PRKN mutation often develop EOPD with a later age-at-onset than carriers of two mutations.(24)
PARK-6: PTEN induced kinase-1 (PINK-1)
PARK-8: Leucine-Rich Repeat Kinase 2 (LRRK2)
Mutation frequency varies by ethnicity. The I2020T is found in Japanese,(55) the R1441C, Y1699C in Caucasians(56) and the most frequently reported LRRK2 mutation, G2019S, is ubiquitous, and may be found in up to 1% of sporadic and 4% of familial PD cases worldwide.(53) Furthermore, up to 39% of Northern African Arab(57) and 18.3% of Ashkenazi Jewish(13)(58) PD cases carry the mutation. The Gly2385Arg variant, for which frequency in Chinese controls is roughly 4%, has also been associated with PD.(59)(60)(61)
Disease course may be indistinguishable from idiopathic PD. Many studies have tried to characterize mutation carriers. A single study of a North American EOPD sample reported that LRRK2 carriers were less likely to suffer from tremor and were more likely to manifest the postural instability gait difficulty motor phenotype (PIGD).(62) An Israeli study comparing presenting symptoms in G2019S mutation carriers to those in GBA carriers further reported that LRRK2 carriers were more likely to present initially with gait impairment.(63)
PARK 9: ATP13A2
EOPD patients are less likely to have cognitive impairment.
Of note, the risk of PD in GBA mutation carriers is unknown. Furthermore, whether carrying two mutations (i.e., Gaucher disease patients) conveys a higher risk than a single mutation (i.e., heterozygotes) is also unknown.
Clinical Course of Patients with EOPD
Figure 1. Suggested Work-up For A Patient With Parkinsonism Below Age 30.
Click image for larger view.
If disease onset is 30 or older, the differential diagnosis should also include Parkinson’s Plus syndromes such as parkinsonism-dominant multiple system atrophy (MSA-P), which very rarely occurs before age 30.(76) In the evaluation of a patient with early onset parkinsonism, there are four conditions of significance that should be considered:
Thorough history, including family history (to rule out juvenile Huntington’s, spinocerebellar ataxia type II, spinocerebellar ataxia type III, and the above genetic forms of EOPD) and medication history, is required. If the patient is taking a dopamine blocker, either an antipsychotic medication (e.g., risperidone) or an antiemetic (e.g., metoclopramide), an attempt to replace these medications with medications with lower dopaminergic affinity (e.g., quetiapine or clozapine for delusional disorders) should be made.
The diagnosis of Wilson’s disease should also be considered, since the single most common neurological complication of Wilson’s disease is parkinsonism(77) and its treatment can significantly improve disease course.(77) Early dysarthria and personality changes may serve as clues for the diagnosis(77) but an ophthalmologic exam, including a slit lamp exam to look for a Kayser Fleischer ring as well as measurement of serum copper and ceruloplasmin levels, should be sought when the diagnosis is considered.
Diurnal variation, juvenile onset of symptoms and family history (autosomal dominant with incomplete penetrance) may suggest DRD. Often diagnosis is made through a therapeutic trial with levodopa (starting dose of 100 mg three times a day) and clinical follow-up for improvement. DRD patients will report significant improvement with treatment. DRD is not a neurodegenerative disorder and the disease may not progress over time.
Delaying levodopa treatment in EOPD seems reasonable.
The work-up for DRD can include genetic testing of the GTP cyclohydrolase gene; however, results may be inconclusive because DRD syndrome may be caused by mutations in other genes in the tetrahydrobiopterin synthesis pathway. A phenylalanine loading test is no longer performed because of lack of sensitivity. A fluorodopa PET scan may be helpful, as fluorodopa uptake is normal in DRD and reduced in EOPD. It is important to consider DRD in the differential diagnosis because its prognosis is better than EOPD’s and only a low dose of levodopa (indefinitely) may be required.
While functional imagining – including fluorodopa PET scan, dopamine active transporter (DAT) scan and single photon emission computed tomography (SPECT) – are abnormal in EOPD, anatomical imaging are usually normal in EOPD. Therefore, MRI imaging may help rule out alternative diagnoses including focal lesions, which may cause hemidystonia, and diseases of neurodegeneration associated with brain iron accumulation (NBIA).(78)
Figure 2. Suggested Work-up For A Patient With Parkinsonism Above Age 30.
Click image for larger view.
In summary, EOPD diagnosis is based on careful history and examination. Brain imaging to rule out focal lesions when symptoms are exclusively unilateral and a specific testing for Wilson’s disease are often helpful. Long-term follow-up and medication response will further help rule out alternative diagnoses including DRD and MSA-P.
In general, disease progression is slower(80)(81) and patients with EOPD may be more likely to suffer from dyskinesias as a complication of dopaminergic therapy than patients with late-onset PD;(82) however, the association between EOPD and the development of dyskinesia was inconsistently reported(75) and may be related to the longer disease duration expected in patients with EOPD.
In addition to milder motor progression, EOPD patients are less likely to have cognitive impairment.(83) Dementia is rare in EOPD, at least in its early stages when studied in a community-based sample.(84) It is unknown whether EOPD patients are less likely to dement than individuals with late-onset PD or if the frequency of dementia among EOPD cohorts was low because of their younger age at the examination. In spite of the milder motor and cognitive profile of EOPD, psychiatric co-morbidities are common in EOPD and most often include depression and anxiety.(83)
The impact of Parkinson on EOPD individuals differs from its impact on late-onset PD individuals.(85) Many EOPD individuals are first diagnosed when their young children are still living at home and require their care. Not infrequently, they are forced to retire early.(3)(85) Motor impairment from the disease, therefore, impairs their lifestyle in a way which is more disruptive than in late-onset PD.(85) Mortality in EOPD is estimated to be at least two times that of the unaffected population,(83) and disease duration is therefore highly variable. It has been described to range between 10-40 years;(83)
Symptomatic treatment of EOPD is similar to that of PD, though in some cases (e.g., PRKN) the dose of levodopa required for symptomatic treatment is low, and because they are young, higher doses of levodopa can be given as needed.(86) Currently, there is no FDA-approved disease modifying therapy. Therefore, treatment should be tailored per signs and symptoms with a primary goal of keeping patients independent as long as possible. The initial decision in the management of EOPD is whether pharmacological treatment is warranted.(86) Levodopa in combination with an inhibitor of L-aromatic amino acid decarboxylase (DDI) is the most effective treatment for PD.(87) However, many clinicians would not introduce it as the first line of treatment in EOPD for several reasons:
Patients with EOPD are expected to live up to four decades with the disease.
Given that EOPD individuals are expected to live for 10-40 years with the disease, delaying levodopa treatment in EOPD seems reasonable. Alternative treatments include anticholinergics, monoamine oxidase B inhibitors (MAO-B inhibitors), amantadine and dopamine agonists. MAO-B inhibitors, including selegiline and rasagiline, are of special interest. Some studies suggest that selegiline and rasagiline may have a disease modifying effect.(90)(91)
Describing the treatment options for PD is beyond the scope of this Cyberounds®; however, a proposed treatment plan would include postponing pharmacotherapy as long as symptoms are mild. When needed, treatment with MAO-B can be initiated. In addition, either amantadine, or a dopamine agonist (both ropinorole and pramipexole are approved in the United States) can be added. Side effects of dopamine agonists, including impulse control disorders, daytime somnolence and edema should be monitored.(92) When symptoms can no longer be controlled by dopamine agonists or if side effects develop, levodopa in combination with DDI should be introduced. Lastly, many patients with EOPD will develop motor side effects,(82) including severe fluctuations in motor function and dyskinesia, and may benefit from deep brain stimulation (DBS).(86)
Non-motor complications of EOPD should be assessed and treated, including constipation, orthostatic hypotension and cognitive impairment. Of all non-motor complications, depression can be very debilitating and can potentially be treated. Given the high frequency of depression in EOPD,(3) careful screening and prompt treatment are recommended. Phase II data support treatment with nortriptyline(93) and serotonin specific reuptake inhibitors (SSRI) are also often used.
In sum, patients with EOPD are expected to live up to four decades with the disease. Careful treatment with dopaminergic and non-dopaminergic treatment may improve their quality of life and prolong their life expectancy.(86)
Parkinson’s disease is a degenerative disorder. Its presentation at early age of onset presents a challenge both in differential diagnosis and in management. Affected individuals are expected to live with motor impairment for 10-40 years. In addition, the risk of cognitive impairment and depression may further impact quality of living. As in early-onset Alzheimer’s disease, clues to genetic causes of the disease may be forthcoming from these individuals.