Did you arrive here by via search engine?
Click here to view the original version of this article

Click to Print This Page
(This section will not print)

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 Objectives
Upon completion of this Cyberounds®, you should be able to:
  • Identify genetic risk factors for Early-onset Parkinson's disease (EOPD)
  • List the clinical characteristics of EOPD and apply them to the differential diagnosis of EOPD
  • Compare EOPD and late-onset PD
  • Discuss treatment options for EOPD.

 

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.

Name Locus Gene Original report At risk populations Mode of inheritance Clinical features
PARK1 4q21.3 α -synuclein
(a major
component of Lewy bodies,(94) the pathological hallmark of PD)
1997. A large family of Italian descent with multiple affected individuals (mean age- at- onset 46)(10) Extremely rare. Reported in families from Germany, Italy, United States, Greece, Spain, Korea Autosomal dominant
(point mutations in α-synuclein).
Similar to idiopathic PD, but carriers may also develop dementia.
(14)
PARK2 6q25.2 - q27 Parkin initially discovered in 1998.21 mutations were initially identified in familial cases of EOPD(20) The most common genetic risk factor for EOPD.(21)(22)

Frequency of mutation carriers increases with younger age- at- onset24

ubiquitous, 22 but may be higher in Hispanics24
Autosomal recessive.
Role of a single mutation controversial (12)(25) (29)(30) (31)(32) (33)(34) (35)(36) (37)(38) (39)(40) (41)
EOPD, usually slowly progressive and may require less levodopa treatment. (25)
Can respond well to deep brain stimulation. (95)
PARK4 4q α -synuclein
(similar to PARK1)
  American and European families Autosomal dominant
(duplications or triplications in the gene).

Incomplete penetrance
(33% in one report.(14))
Early onset; often accompanied by dementia. Carriers of tripli-cations may be more likely to develop dementia than carriers of
dupli-cations (96)
PARK5 4p14 UCHL1 Single report of a German family(97) Two siblings with age- at- onset 49 and 51   Indistin- guishable from idiopathic PD
PARK6 1p35 - p36 PTEN induced kinase-1 (PINK-1) Initially described in three con- sanguin- eous European families in 2001. (42)(98) Mutations are ubiquitous, however, very rare (48)(99) (100)(101) (102)(103) (104)(105) (106) Autosomal recessive. Role of a single mutation controversial Slowly progressive, with early onset of drug induced dyskinesias, similar to PRKN. (42)(43)
May be associated with psychiatric symptoms including affective and delusional disorders. (107)
may benefit from DBS95
PARK7 1P36 DJ-1 Discovered in 2003 in two European families. (108) Extremely rare. (109)(110)
Described in families in the Netherlands, Italy, Uruguay
Autosomal recessive Similar to idiopathic PD
PARK8 12p11.2 - q13.1 Leucine-Rich Repeat Kinase 2 (LRRK2) Discovered in 2004(111) Ubiquitous, most common in North African Arab and Ashkenazi Jews. Autosmal dominant (incomplete penetrance) May present as EOPD or late-onset PD. presentation may be hetero-geneous, (112)(113)(114) but good response to treatment with levodopa and dopamine agonists is often reported. Treatment may be complicated by dyskinesia. (53)
PARK9 1p36 ATP13A2 Identified in 2006 in con- sanguin- eous Jordanian families.(64) Jordan Autosomal recessive Childhood onset of parkinson- ism, dystonia, spasticity. Abnormal MRI
Gluco-cerebro-sidase 1q21 Gluco-cerebro-sidase (GBA)   Ubiquitous. Common in Ashkenazi Jews susceptibility gene Similar to idiopathic PD; higher frequency of self reported cognitive impairment

EOPD frequently appears with dystonia or stiffness (rigidity) and can be misdiagnosed.

PARK-1, PARK-4: α-synuclein (SNCA)
Mutations in SNCA were the first genetic risk of PD to be identified.(10) Genetic alterations which cause a gain of function, including point mutations (PARK-1), duplications and triplications (PARK-4), have all been found in association with EOPD.(14)(15) In addition to gain of function mutations, Genome Wide Association Studies (GWAS) have implicated common single nucleotide polymorphisms (SNP) in SNCA in the pathogenesis of PD;(16)(17)(18)(19) However, the association of these SNPs association with PD is much weaker than the association with pathogenic mutations.

PARK-2: Parkin (PRKN)
Mutations in the PRKN gene are the most common genetic risk factors for EOPD.(20)(21)(22) While over 100 mutations have been identified in the PRKN gene, their frequency in non-familial samples is lower than previously reported.(23) PRKN mutation carriers usually have a younger age-at-onset than non-cariers,(24) require lower doses of levodopa therapy and may present with dystonia; however, one study suggested that dystonia is associated with the early age-at-onset rather than mutation status.(25) Carriers of two PRKN mutations may further differ from idiopathic EOPD in their preserved sense of smell,(26) and the lack of Lewy bodies on autopsy.(27) The presence of Lewy bodies in the substantia nigra in the midbrain is the pathological hallmark of PD. Of the six autopsies of mutation carriers which have been described, only two had Lewy bodies.(28)

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)
The natural history of PINK-1 related EOPD may be very similar to that of PRKN related EOPD.(42)(43) As in PRKN, carriers of mutations on both alleles, either homozygotes or compound heterozygotes, develop EOPD. Similar to PRKN, the role of heterozygous PINK-1carriers is controversial.(44)(45)(46)(47)(48)(49)(50) However, in contrast to PRKN, PINK-1 related EOPD presents with impaired olfaction(51) and a recent report of a single autopsy reported Lewy body pathology.(52)

PARK-8: Leucine-Rich Repeat Kinase 2 (LRRK2)
LRRK2 mutations are the most frequently identified genetic mutations in late-onset PD.(53) In contrast to the other PARK mutations, mutation frequency may be similar in late-onset PD and EOPD.(53)(54) A single study of 953 EOPD individuals reported that LRRK2 is the third most common genetic risk factor for EOPD after PRKN and GBA.(23) Different mutations have been identified in LRRK2, and as with SNCA, pathogenic mutations are probably gain of function mutations.

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
Mutations in ATP13A2 are linked to a distinct syndrome, Kufor Rakeb syndrome.(64) Affected individuals develop a progressive neurodegenerative disease in their first decade including dementia, dystonia, spasticity and parkinsonism. Levodopa may improve symptoms only transiently.(65) MRI findings suggest iron accumulation in the basal ganglia; however, autopsy data are not available.(66)

Glucocerebrosidase (GBA)
While only recently identified, GBA mutations may be the most frequent genetic risk factor for PD in selected populations.(23) The association between GBA mutations and PD was initially reported in carriers of two GBA mutation, who by definition suffer from Gaucher disease.(67) More recent case-control studies indicate that even a single GBA mutation is a risk factor for PD.(68) Furthermore, GBA mutations have been linked with earlier age-at-onset.(68)(69)(70) GBA mutations are ubiquitous, but more common in Ashkenazi Jews, among whom one out of twelve carries a mutation in GBA. GBA-associated EOPD may be indistinguishable from EOPD but mutations may be associated with higher risk of cognitive impairment. In a sample of 699 North American EOPD cases, including 37 GBA carriers, mutation status was linked with self-report of cognitive impairment but not with worse performance on a cognitive screening test.(71) These findings concur with autopsy findings of cortical Lewy bodies – rather than brain-stem Lewy bodies – in GBA mutation carriers.(72)(73)

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.

Summary
The cause of EOPD in most individuals who develop the disease remains unknown. It is estimated that an interaction between different genes and environmental factors contributes to the development of EOPD; however, data are lacking. The overall genetic contribution to EOPD is also unknown. Very few studies have analyzed the contribution of known genetic mutations to EOPD in samples which were not ascertained by family history. An Australian study of 74 EOPD participants found a mutation frequency of 7%(74) and a Dutch study of 187 EOPD participants reported mutation frequency of 4%.(34) More recently, a study of 953 EOPD participants from 13 movement disorders centers in the United States reported a mutation frequency of 16%.(23) This research reported a higher mutation frequency 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 those with first degree family history of PD (24% versus 14%).(23) Genotyping common GBA mutations and including participants of diverse ethnicities including Ashkenazi Jews and Hispanics, in whom mutation frequency is higher (LRRK2 G2019S in Ashkenazi Jews and PRKN in Hispanics), explain the higher frequency of mutation carriers. While much has been discovered in the past decade, most risk factors for EOPD – genetic and environmental - remain unknown.

Clinical Course of Patients with EOPD

Evaluation
The presentation of EOPD can be very variable. When it presents with rest tremor – in roughly 40% of cases(75)– diagnosis may be easier to make. However, EOPD frequently appears with dystonia or stiffness (rigidity)(75) and can be misdiagnosed. The differential diagnosis of EOPD is broad.(3) Important factors in establishing a differential diagnosis include age-at-onset of symptoms and the presence of neurological manifestations in addition to parkinsonism. If onset of symptoms is before age 30, the differential diagnosis of EOPD includes primarily metabolic and genetic disorders.(3)

Figure 1. Suggested Work-up For A Patient With Parkinsonism Below Age 30.

Article 467 - Figure 1 - 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:

  1. Wilson’s disease
  2. Dopa-responsive dystonia (DRD)
  3. Drug-induced parkinsonism
  4. Focal basal ganglia lesion (which can imitate unilateral dystonia)

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.

Article 476 - Figure 2  - 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.

Clinical Course
The clinical features of EOPD are similar to late-onset PD. The cardinal motor features of rigidity, rest tremor, bradykinesia and postural instability are the same. However, patients may present with dystonia at onset,(25)(79) which makes the diagnosis of EOPD difficult to distinguish from dystonia in general and from dopa-responsive dystonia specifically. There are no longitudinal prospective studies comparing EOPD to late-onset PD, and most available retrospective studies do not stratify their findings by the genetic status of the participants.

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)

Treatment

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:

  1. EOPD patients are more likely to develop motor complications from levodopa treatment; specifically, fluctuations and dyskinesia. After five years of treatment, 91% of EOPD develop motor complications and after 10 years 100% are affected.(82)(83)
  2. There is conflicting evidence as to whether levodopa treatment itself has deleterious effects on dopaminergic cells in the substantia nigra;(88) however, a randomized controlled double-blind study failed to show deleterious effects of levodopa treatment on the progression of PD.(89)

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)

Summary

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.


Footnotes

1Hirtz D, Thurman DJ, Gwinn-Hardy K, Mohamed M, Chaudhuri AR, Zalutsky R. How common are the "common" neurologic disorders? Neurology 2007;68(5):326-337.
2Dorsey ER, Constantinescu R, Thompson JP, et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology 2007;68(5):384-386.
3Schrag A, Schott JM. Epidemiological, clinical, and genetic characteristics of early-onset parkinsonism. Lancet Neurol 2006;5(4):355-363.
4Kostic VS, Filipovic SR, Lecic D, Momcilovic D, Sokic D, Sternic N. Effect of age-at-onset on frequency of depression in Parkinson's disease. J Neurol Neurosurg Psychiatry 1994;57(10):1265-1267.
5Butterfield PG, Valanis BG, Spencer PS, Lindeman CA, Nutt JG. Environmental antecedents of young-onset Parkinson's disease. Neurology 1993;43(6):1150-1158.
6Tanner CM. Advances in environmental epidemiology. Mov Disord;25 Suppl 1:S58-62.
7Marder K, Logroscino G. The ever-stimulating association of smoking and coffee and Parkinson's disease. Ann Neurol 2002;52(3):261-262.
8Logroscino G. The role of early life environmental risk factors in Parkinson disease: what is the evidence? Environ Health Perspect 2005;113(9):1234-1238.
9Bronstein J, Carvey P, Chen H, et al. Meeting report: consensus statement-Parkinson's disease and the environment: collaborative on health and the environment and Parkinson's Action Network (CHE PAN) conference 26-28 June 2007. Environ Health Perspect 2009;117(1):117-121.
10Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 1997;276(5321):2045-2047.
11Clark LN, Afridi S, Mejia-Santana H, et al. Analysis of an early-onset Parkinson's disease cohort for DJ-1 mutations. Mov Disord 2004;19(7):796-800.
12Klein C, Lohmann-Hedrich K, Rogaeva E, Schlossmacher MG, Lang AE. Deciphering the role of heterozygous mutations in genes associated with parkinsonism. Lancet Neurol 2007;6(7):652-662.
13Ozelius LJ, Senthil G, Saunders-Pullman R, et al. LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. N Engl J Med 2006;354(4):424-425.
14Nishioka K, Hayashi S, Farrer MJ, et al. Clinical heterogeneity of alpha-synuclein gene duplication in Parkinson's disease. Ann Neurol 2006;59(2):298-309.
15Waters CH, Miller CA. Autosomal dominant Lewy body parkinsonism in a four-generation family. Ann Neurol 1994;35(1):59-64.
16Edwards TL, Scott WK, Almonte C, et al. Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann Hum Genet;74(2):97-109.
17Satake W, Nakabayashi Y, Mizuta I, et al. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat Genet 2009;41(12):1303-1307.
18Simon-Sanchez J, Schulte C, Bras JM, et al. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet 2009;41(12):1308-1312.
19Maraganore DM, de Andrade M, Elbaz A, et al. Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA 2006;296(6):661-670.
20Lucking CB, Durr A, Bonifati V, et al. Association between early-onset Parkinson's disease and mutations in the parkin gene. N Engl J Med 2000;342(21):1560-1567.
21Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998;392(6676):605-608.
22Hedrich K, Eskelson C, Wilmot B, et al. Distribution, type, and origin of Parkin mutations: Review and case studies. Mov Disord 2004;19(10):1146-1157.
23Alcalay R, Caccappolo E, Mejia-Santana H, et al. Frequency and phenotypic characteristics of PRKN LRRK2, GBA, PINK1 and DJ1 Mutation carriers in Early Onset PD: the CORE-PD study. . Neurology 2010;74((Suppl 2) ):A2.
24Marder KT, M –X. Mejia-Santana, H. Rosado, L. Louis, ED. Comella, C. Colcher, A. Siderowf, A. Jennings, D. Nance, M. Bressman, S. Scott, WK. Tanner, C. Mickel, S. Andrews, H. Waters, C. Fahn, S. Ross, B. Cote, L. Frucht, S. Ford, B. Alcalay, RN. Rezak, M. Novak, K. Friedman, J. Pfeiffer, R. Marsh, L. Hiner, B. Caccoppolo, E. Ottman, R. Clark, LN. . Predictors of Parkin Mutations in Early Onset Parkinson disease: the CORE-PD Study. Arch Neurol 2010;In press.
25Lohmann E, Periquet M, Bonifati V, et al. How much phenotypic variation can be attributed to parkin genotype? Ann Neurol 2003;54(2):176-185.
26Khan NL, Katzenschlager R, Watt H, et al. Olfaction differentiates parkin disease from early-onset parkinsonism and Parkinson disease. Neurology 2004;62(7):1224-1226.
27Klein C, Lohmann K. Parkinson disease(s): is "Parkin disease" a distinct clinical entity? Neurology 2009;72(2):106-107.
28Pramstaller PP, Schlossmacher MG, Jacques TS, et al. Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers. Ann Neurol 2005;58(3):411-422.
29Lucking CB, Durr A, Bonifati V, et al. Association between early-onset Parkinson's disease and mutations in the parkin gene. French Parkinson's Disease Genetics Study Group. N Engl J Med 2000;342(21):1560-1567.
30Hedrich K, Marder K, Harris J, et al. Evaluation of 50 probands with early-onset Parkinson's disease for Parkin mutations. Neurology 2002;58(8):1239-1246.
31Abbas N, Lucking CB, Ricard S, et al. A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson's Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease. Hum Mol Genet 1999;8(4):567-574.
32Periquet M, Latouche M, Lohmann E, et al. Parkin mutations are frequent in patients with isolated early-onset parkinsonism. Brain 2003;126(Pt 6):1271-1278.
33Camargos ST, Dornas LO, Momeni P, et al. Familial Parkinsonism and early onset Parkinson's disease in a Brazilian movement disorders clinic: phenotypic characterization and frequency of SNCA, PRKN, PINK1, and LRRK2 mutations. Mov Disord 2009;24(5):662-666.
34Macedo MG, Verbaan D, Fang Y, et al. Genotypic and phenotypic characteristics of Dutch patients with early onset Parkinson's disease. Mov Disord 2009;24(2):196-203.
35Hertz JM, Ostergaard K, Juncker I, et al. Low frequency of Parkin, Tyrosine Hydroxylase, and GTP Cyclohydrolase I gene mutations in a Danish population of early-onset Parkinson's Disease. Eur J Neurol 2006;13(4):385-390.
36Chung EJ, Ki CS, Lee WY, Kim IS, Kim JY. Clinical features and gene analysis in Korean patients with early-onset Parkinson disease. Arch Neurol 2006;63(8):1170-1174.
37Bras J, Guerreiro R, Ribeiro M, et al. Analysis of Parkinson disease patients from Portugal for mutations in SNCA, PRKN, PINK1 and LRRK2. BMC Neurol 2008;8:1.
38Vinish M, Prabhakar S, Khullar M, Verma I, Anand A. Genetic screening reveals high frequency of PARK2 mutations and reduced Parkin expression conferring risk for Parkinsonism in North West India. J Neurol Neurosurg Psychiatry 2009.
39Klein C, Lohmann-Hedrich K. Impact of recent genetic findings in Parkinson's disease. Curr Opin Neurol 2007;20(4):453-464.
40Kay DM, Moran D, Moses L, et al. Heterozygous parkin point mutations are as common in control subjects as in Parkinson's patients. Ann Neurol 2007;61(1):47-54.
41Pankratz N, Kissell DK, Pauciulo MW, et al. Parkin dosage mutations have greater pathogenicity in familial PD than simple sequence mutations. Neurology 2009;73(4):279-286.
42Bentivoglio AR, Cortelli P, Valente EM, et al. Phenotypic characterisation of autosomal recessive PARK6-linked parkinsonism in three unrelated Italian families. Mov Disord 2001;16(6):999-1006.
43Valente EM, Brancati F, Ferraris A, et al. PARK6-linked parkinsonism occurs in several European families. Ann Neurol 2002;51(1):14-18.
44Brooks J, Ding J, Simon-Sanchez J, Paisan-Ruiz C, Singleton AB, Scholz SW. Parkin and PINK1 mutations in early-onset Parkinson's disease: comprehensive screening in publicly available cases and control. J Med Genet 2009;46(6):375-381.
45Marongiu R, Ferraris A, Ialongo T, et al. PINK1 heterozygous rare variants: prevalence, significance and phenotypic spectrum. Hum Mutat 2008;29(4):565.
46Abou-Sleiman PM, Muqit MM, McDonald NQ, et al. A heterozygous effect for PINK1 mutations in Parkinson's disease? Ann Neurol 2006;60(4):414-419.
47Ibanez P, Lesage S, Lohmann E, et al. Mutational analysis of the PINK1 gene in early-onset parkinsonism in Europe and North Africa. Brain 2006;129(Pt 3):686-694.
48Kumazawa R, Tomiyama H, Li Y, et al. Mutation analysis of the PINK1 gene in 391 patients with Parkinson disease. Arch Neurol 2008;65(6):802-808.
49Hedrich K, Hagenah J, Djarmati A, et al. Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit? Arch Neurol 2006;63(6):833-838.
50Chishti MA, Bohlega S, Ahmed M, et al. T313M PINK1 mutation in an extended highly consanguineous Saudi family with early-onset Parkinson disease. Arch Neurol 2006;63(10):1483-1485.
51Ferraris A, Ialongo T, Passali GC, et al. Olfactory dysfunction in Parkinsonism caused by PINK1 mutations. Mov Disord 2009;24(16):2350-2357.
52Samaranch L, Lorenzo-Betancor O, Arbelo JM, et al. PINK1-linked parkinsonism is associated with Lewy body pathology. Brain;133(Pt 4):1128-1142.
53Healy DG, Falchi M, O'Sullivan SS, et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol 2008;7(7):583-590.
54Goldwurm S, Di Fonzo A, Simons EJ, et al. The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late-onset Parkinson's disease and originates from a common ancestor. J Med Genet 2005;42(11):e65.
55Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F. A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol 2002;51(3):296-301.
56Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004;44(4):601-607.
57Lesage S, Durr A, Tazir M, et al. LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs. N Engl J Med 2006;354(4):422-423.
58Clark LN, Wang Y, Karlins E, et al. Frequency of LRRK2 mutations in early- and late-onset Parkinson disease. Neurology 2006;67(10):1786-1791.
59Di Fonzo A, Wu-Chou YH, Lu CS, et al. A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson's disease risk in Taiwan. Neurogenetics 2006;7(3):133-138.
60Tan EK. Identification of a common genetic risk variant (LRRK2 Gly2385Arg) in Parkinson's disease. Ann Acad Med Singapore 2006;35(11):840-842.
61Tan EK, Zhao Y, Skipper L, et al. The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: genetic and functional evidence. Hum Genet 2007;120(6):857-863.
62Alcalay RN, Mejia-Santana H, Tang MX, et al. Motor phenotype of LRRK2 G2019S carriers in early-onset Parkinson disease. Arch Neurol 2009;66(12):1517-1522.
63Gan-Or Z, Bar-Shira A, Mirelman A, et al. LRRK2 and GBA mutations differentially affect the initial presentation of Parkinson disease. Neurogenetics 2009.
64Ramirez A, Heimbach A, Grundemann J, et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 2006;38(10):1184-1191.
65Williams DR, Hadeed A, al-Din AS, Wreikat AL, Lees AJ. Kufor Rakeb disease: autosomal recessive, levodopa-responsive parkinsonism with pyramidal degeneration, supranuclear gaze palsy, and dementia. Mov Disord 2005;20(10):1264-1271.
66Schneider SA, Paisan-Ruiz C, Quinn NP, et al. ATP13A2 mutations (PARK9) cause neurodegeneration with brain iron accumulation. Mov Disord.
67Neudorfer O, Giladi N, Elstein D, et al. Occurrence of Parkinson's syndrome in type I Gaucher disease. QJM 1996;89(9):691-694.
68Sidransky E, Nalls MA, Aasly JO, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med 2009;361(17):1651-1661.
69Clark LN, Ross BM, Wang Y, et al. Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease. Neurology 2007;69(12):1270-1277.
70Nichols WC, Pankratz N, Marek DK, et al. Mutations in GBA are associated with familial Parkinson disease susceptibility and age-at-onset. Neurology 2009;72(4):310-316.
71Alcalay RN, Mejia-Santana H, Tang MX, et al. Self-report of cognitive impairment and mini-mental state examination performance in PRKN, LRRK2, and GBA carriers with early onset Parkinson's disease. J Clin Exp Neuropsychol:1-5.
72Clark LN, Kartsaklis LA, Wolf Gilbert R, et al. Association of glucocerebrosidase mutations with dementia with lewy bodies. Arch Neurol 2009;66(5):578-583.
73Neumann J, Bras J, Deas E, et al. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain 2009;132(Pt 7):1783-1794.
74Mellick GD, Siebert GA, Funayama M, et al. Screening PARK genes for mutations in early-onset Parkinson's disease patients from Queensland, Australia. Parkinsonism Relat Disord 2009;15(2):105-109.
75Gibb WR, Lees AJ. A comparison of clinical and pathological features of young- and old-onset Parkinson's disease. Neurology 1988;38(9):1402-1406.
76Gilman S, Wenning GK, Low PA, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008;71(9):670-676.
77Walshe JM, Yealland M. Wilson's disease: the problem of delayed diagnosis. J Neurol Neurosurg Psychiatry 1992;55(8):692-696.
78McNeill A, Birchall D, Hayflick SJ, et al. T2* and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation. Neurology 2008;70(18):1614-1619.
79Inzelberg R, Schecthman E, Paleacu D, et al. Onset and progression of disease in familial and sporadic Parkinson's disease. Am J Med Genet A 2004;124A(3):255-258.
80Lewis SJ, Foltynie T, Blackwell AD, Robbins TW, Owen AM, Barker RA. Heterogeneity of Parkinson's disease in the early clinical stages using a data driven approach. J Neurol Neurosurg Psychiatry 2005;76(3):343-348.
81Alves G, Wentzel-Larsen T, Aarsland D, Larsen JP. Progression of motor impairment and disability in Parkinson disease: a population-based study. Neurology 2005;65(9):1436-1441.
82Kostic V, Przedborski S, Flaster E, Sternic N. Early development of levodopa-induced dyskinesias and response fluctuations in young-onset Parkinson's disease. Neurology 1991;41(2 ( Pt 1)):202-205.
83Schrag A, Ben-Shlomo Y, Brown R, Marsden CD, Quinn N. Young-onset Parkinson's disease revisited--clinical features, natural history, and mortality. Mov Disord 1998;13(6):885-894.
84Mayeux R, Denaro J, Hemenegildo N, et al. A population-based investigation of Parkinson's disease with and without dementia. Relationship to age and gender. Arch Neurol 1992;49(5):492-497.
85Schrag A, Hovris A, Morley D, Quinn N, Jahanshahi M. Young- versus older-onset Parkinson's disease: impact of disease and psychosocial consequences. Mov Disord 2003;18(11):1250-1256.
86Diaz NL, Waters CH. Current strategies in the treatment of Parkinson's disease and a personalized approach to management. Expert Rev Neurother 2009;9(12):1781-1789.
87Tintner R, Jankovic J. Treatment options for Parkinson's disease. Curr Opin Neurol 2002;15(4):467-476.
88Fahn S. Is levodopa toxic? Neurology 1996;47(6 Suppl 3):S184-195.
89Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson's disease. N Engl J Med 2004;351(24):2498-2508.
90Olanow CW, Rascol O, Hauser R, et al. A double-blind, delayed-start trial of rasagiline in Parkinson's disease. N Engl J Med 2009;361(13):1268-1278.
91Olanow CW. Attempts to obtain neuroprotection in Parkinson's disease. Neurology 1997;49(1 Suppl 1):S26-33.
92Antonini A, Tolosa E, Mizuno Y, Yamamoto M, Poewe WH. A reassessment of risks and benefits of dopamine agonists in Parkinson's disease. Lancet Neurol 2009;8(10):929-937.
93Menza M, Dobkin RD, Marin H, et al. A controlled trial of antidepressants in patients with Parkinson disease and depression. Neurology 2009;72(10):886-892.
94Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature 1997;388(6645):839-840.
95Moro E, Volkmann J, Konig IR, et al. Bilateral subthalamic stimulation in Parkin and PINK1 parkinsonism. Neurology 2008;70(14):1186-1191.
96Fuchs J, Nilsson C, Kachergus J, et al. Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication. Neurology 2007;68(12):916-922.
97Leroy E, Boyer R, Auburger G, et al. The ubiquitin pathway in Parkinson's disease. Nature 1998;395(6701):451-452.
98Valente EM, Bentivoglio AR, Dixon PH, et al. Localization of a novel locus for autosomal recessive early-onset parkinsonism, PARK6, on human chromosome 1p35-p36. Am J Hum Genet 2001;68(4):895-900.
99Deng H, Le W, Shahed J, Xie W, Jankovic J. Mutation analysis of the parkin and PINK1 genes in American Caucasian early-onset Parkinson disease families. Neurosci Lett 2008;430(1):18-22.
100Toft M, Myhre R, Pielsticker L, White LR, Aasly JO, Farrer MJ. PINK1 mutation heterozygosity and the risk of Parkinson's disease. J Neurol Neurosurg Psychiatry 2007;78(1):82-84.
101Djarmati A, Hedrich K, Svetel M, et al. Heterozygous PINK1 mutations: a susceptibility factor for Parkinson disease? Mov Disord 2006;21(9):1526-1530.
102Biswas A, Sadhukhan T, Majumder S, et al. Evaluation of PINK1 variants in Indian Parkinson's disease patients. Parkinsonism Relat Disord;16(3):167-171.
103Lee MJ, Mata IF, Lin CH, et al. Genotype-phenotype correlates in Taiwanese patients with early-onset recessive Parkinsonism. Mov Disord 2009;24(1):104-108.
104Fung HC, Chen CM, Hardy J, Singleton AB, Lee-Chen GJ, Wu YR. Analysis of the PINK1 gene in a cohort of patients with sporadic early-onset parkinsonism in Taiwan. Neurosci Lett 2006;394(1):33-36.
105Weng YH, Chou YH, Wu WS, et al. PINK1 mutation in Taiwanese early-onset parkinsonism : clinical, genetic, and dopamine transporter studies. J Neurol 2007;254(10):1347-1355.
106Choi JM, Woo MS, Ma HI, et al. Analysis of PARK genes in a Korean cohort of early-onset Parkinson disease. Neurogenetics 2008;9(4):263-269.
107Steinlechner S, Stahlberg J, Volkel B, et al. Co-occurrence of affective and schizophrenia spectrum disorders with PINK1 mutations. J Neurol Neurosurg Psychiatry 2007;78(5):532-535.
108Bonifati V, Rizzu P, van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 2003;299(5604):256-259.
109Hedrich K, Djarmati A, Schafer N, et al. DJ-1 (PARK7) mutations are less frequent than Parkin (PARK2) mutations in early-onset Parkinson disease. Neurology 2004;62(3):389-394.
110Tomiyama H, Li Y, Yoshino H, et al. Mutation analysis for DJ-1 in sporadic and familial parkinsonism: screening strategy in parkinsonism. Neurosci Lett 2009;455(3):159-161.
111Paisan-Ruiz C, Jain S, Evans EW, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 2004;44(4):595-600.
112Papapetropoulos S, Singer C, Ross OA, et al. Clinical heterogeneity of the LRRK2 G2019S mutation. Arch Neurol 2006;63(9):1242-1246.
113Tomiyama H, Li Y, Funayama M, et al. Clinicogenetic study of mutations in LRRK2 exon 41 in Parkinson's disease patients from 18 countries. Mov Disord 2006;21(8):1102-1108.
114Gaig C, Marti MJ, Ezquerra M, Rey MJ, Cardozo A, Tolosa E. G2019S LRRK2 mutation causing Parkinson's disease without Lewy bodies. J Neurol Neurosurg Psychiatry 2007;78(6):626-628.