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Original Contribution |

Predictors of Parkin Mutations in Early-Onset Parkinson Disease:  The Consortium on Risk for Early-Onset Parkinson Disease Study FREE

Karen S. Marder, MD, MPH; Ming X. Tang, PhD; Helen Mejia-Santana, MS; Llency Rosado, MD; Elan D. Louis, MD, MS; Cynthia L. Comella, MD; Amy Colcher, MD; Andrew D. Siderowf, MD, MSCE; Danna Jennings, MD; Martha A. Nance, MD; Susan Bressman, MD; William K. Scott, PhD; Caroline M. Tanner, MD, PhD; Susan F. Mickel, MD; Howard F. Andrews, PhD; Cheryl Waters, MD; Stanley Fahn, MD; Barbara M. Ross, BSc; Lucien J. Cote, MD; Steven Frucht, MD; Blair Ford, MD; Roy N. Alcalay, MD; Michael Rezak, MD, PhD; Kevin Novak, PhD; Joseph H. Friedman, MD; Ronald F. Pfeiffer, MD; Laura Marsh, MD; Brad Hiner, MD; Gregory D. Neils, BS; Miguel Verbitsky, PhD; Sergey Kisselev, MS; Elise Caccappolo, PhD; Ruth Ottman, PhD; Lorraine N. Clark, PhD
[+] Author Affiliations

Author Affiliations: Department of Neurology (Drs Marder, Tang, Rosado, Louis, Waters, Fahn, Cote, Frucht, Ford, Alcalay, Caccappolo, and Ottman and Ms Mejia-Santana), Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Drs Marder, Tang, Louis, Verbitsky, Caccappolo, and Clark; Ms Ross; and Mr Kisselev), Gertrude H. Sergievsky Center (Drs Marder, Tang, Louis, and Ottman), and Department of Pathology and Cell Biology and Center for Human Genetics (Dr Clark), College of Physicians and Surgeons, and Department of Epidemiology, Mailman School of Public Health (Drs Louis and Ottman and Ms Ross), Columbia University, The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, and Department of Neurology, Albert Einstein College of Medicine of Yeshiva University (Dr Bressman), and Data Coordinating Center (Dr Andrews and Mr Neils) and Division of Epidemiology (Dr Ottman), New York State Psychiatric Institute, New York; Section of Movement Disorders, Department of Neurology, Rush University, Chicago (Dr Comella), and Department of Neurology, NorthShore University Health System, Evanston, and Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago (Drs Rezak and Novak), Illinois; Parkinson's Disease and Movement Disorders Center, Pennsylvania Hospital (Drs Colcher and Siderowf), and Department of Neurology, University of Pennsylvania Health System (Drs Colcher and Siderowf), Philadelphia; The Institute for Neurodegenerative Disorders, New Haven, Connecticut (Dr Jennings); Struthers Parkinson's Center, Park Nicollet Clinic, Golden Valley, Minnesota (Dr Nance); Dr John T. Macdonald Foundation, Department of Human Genetics, Miami Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida (Dr Scott); Parkinson's Institute, Sunnyvale, California (Dr Tanner); Departments of Neurology, Marshfield Clinic, Marshfield (Dr Mickel), and Medical College of Wisconsin, Milwaukee (Dr Hiner); Parkinson's Disease and Movement Disorders Center of NeuroHealth, Warwick, and Department of Clinical Neurosciences, The Warren Alpert School of Medicine of Brown University, Providence, Rhode Island (Dr Friedman); Department of Neurology, College of Medicine, University of Tennessee Health Science Center, Memphis (Drs Friedman and Pfeiffer); and Morris K. Udall Parkinson's Disease Research Center of Excellence and Departments of Psychiatry and Behavioral Sciences and Neurology and Neurological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (Dr Marsh).


Arch Neurol. 2010;67(6):731-738. doi:10.1001/archneurol.2010.95.
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Published online

Background  Mutations in the parkin gene are the most common genetic cause of early-onset Parkinson disease (PD). Results from a multicenter study of patients with PD systematically sampled by age at onset have not been reported to date.

Objective  To determine risk factors associated with carrying parkin mutations.

Design  Cross-sectional observational study.

Setting  Thirteen movement disorders centers.

Participants  A total of 956 patients with early-onset PD, defined as age at onset younger than 51 years.

Main Outcome Measures  Presence of heterozygous, homozygous, or compound heterozygous parkin mutations.

Results  Using a previously validated interview, 14.7% of patients reported a family history of PD in a first-degree relative. Sixty-four patients (6.7%) had parkin mutations (3.9% heterozygous, 0.6% homozygous, and 2.2% compound heterozygous). Copy number variation was present in 52.3% of mutation carriers (31.6% of heterozygous, 83.3% of homozygous, and 81.0% of compound heterozygous). Deletions in exons 3 and 4 and 255delA were common among Hispanics (specifically Puerto Ricans). Younger age at onset (<40 years) (odds ratio [OR], 5.0; 95% confidence interval [CI], 2.8-8.8; P = .001), Hispanic race/ethnicity (OR compared with white non-Hispanic race/ethnicity, 2.7; 95% CI, 1.3-5.7; P = .009), and family history of PD in a first-degree relative (OR compared with noncarriers, 2.8; 95% CI, 1.5-5.3; P = .002) were associated with carrying any parkin mutation (heterozygous, homozygous, or compound heterozygous). Hispanic race/ethnicity was associated with carrying a heterozygous mutation (OR compared with white non-Hispanic race/ethnicity, 2.8; 95% CI, 1.1-7.2; P = .03) after adjustment for covariates.

Conclusions  Age at onset, Hispanic race/ethnicity, and family history of PD are associated with carrying any parkin mutation (heterozygous, homozygous, or compound heterozygous) and heterozygous mutations alone. The increased odds of carrying a parkin mutation among Hispanics warrants further study.

Mutations in the parkin gene (PARK2, OMIM #600116)1,2 are the most common genetic risk factors for early-onset Parkinson disease (EOPD).313 Early-onset Parkinson disease has been defined variably as age at onset (AAO) of 45 years or younger or 55 years or younger. Patients with parkin mutations having an AAO older than 70 years have also been described.7,1416 In patients with Parkinson disease (PD) who have an AAO of 45 years or younger from families with an autosomal recessive mode of inheritance, the frequency of parkin mutations may be as high as 49%,3 while the reported range is 15% to 18% in patients without a family history of PD.4,6,17 Age at onset is inversely correlated with the frequency of parkin mutations in familial3 and sporadic6 cases. The role of heterozygous parkin mutations as causative or susceptibility factors remains controversial.1820 Studies37,1416 of familial and sporadic cases have consistently found that patients with heterozygous mutations have older AAO and are more likely to be represented in sporadic samples than are patients with homozygous or compound heterozygous mutations.

In 2004, we initiated the Consortium on Risk for Early-Onset PD study (CORE-PD), a multisite study to systematically determine the range of phenotypic manifestations among patients with EOPD who carry parkin mutations and among their family members. Herein, we present the baseline characteristics of 956 patients recruited at 13 sites in the CORE-PD and the features associated with carrying heterozygous, homozygous, and compound heterozygous parkin mutations.

The CORE-PD was built on the infrastructure created for the Genetic Epidemiology of PD study, using many of the same instruments.2123 Patients with PD recruited in the Genetic Epidemiology of PD study between July 1998 and June 2003 were ascertained based on AAO of motor signs younger than 51 years (early-onset PD [EOPD]) or 51 years or older (late-onset PD), regardless of the presence or absence of a family history of PD. Patients with EOPD were oversampled and included 247 cases of PD.21 All patients were recruited from the Center for Parkinson Disease and Other Movement Disorders at Columbia University and underwent an identical evaluation that included taking a medical history, administering the Unified Parkinson's Disease Rating Scale,24 and videotaping the patients to document PD and essential tremor. Only patients having PD with AAO younger than 51 years in whom DNA samples were available (n = 247) were included in the CORE-PD study.

Recruitment of additional patients (n = 709) for CORE-PD began in July 2004. Institutional review boards at all participating sites approved the protocols and consent procedures. Patients with PD were recruited from each of 13 sites based on requirements of AAO younger than 51 years and Mini-Mental State Examination25 score exceeding 23 to ensure that a reliable history could be obtained from each patient. In addition to the Mini-Mental State Examination, part I of the CORE-PD assessment included collection of demographic information, administration of the Unified Parkinson's Disease Rating Scale, a family history interview,22 and provision of a blood sample for DNA analysis sent to the Human Genetics Resource Center DNA and Coriell Cell Repositories (http://ccr.coriell.org) of the National Institute of Neurological Disorders and Stroke. An aliquot of DNA was subsequently sent to Columbia University for analysis. All examiners were unaware of the genetic status of the patients at the time of recruitment and thereafter. Although the identity of each patient with PD was known at each site, information sent to the coordinating site at Columbia University and the Human Genetics Resource Center DNA and Coriell Cell Repositories was deidentified. In part II of the CORE-PD, patients who carried parkin mutations and a sample of those who did not carry parkin mutations were administered a detailed neuropsychological, psychiatric, and risk factor assessment. We performed identical examinations on first-degree relatives of all patients in part II. Families were expanded sequentially by collection of the same information on first-degree relatives of each newly discovered family member who had PD or carried a parkin mutation. Data derived from the part 2 evaluation will be presented in a separate publication.

MOLECULAR GENETIC ANALYSIS

In this study, we report data on all 956 patients with PD, including 247 patients previously reported from the Genetic Epidemiology of PD study26,27 and 709 newly recruited patients from the CORE-PD. In the Genetic Epidemiology of PD study, parkin was completely sequenced in the first 101 patients with PD.26 The next 246 patients with PD were screened for point mutations using denaturing high-performance liquid chromatography. Amplicons were directly sequenced (n = 126) or analyzed using a parkin genotyping array (n = 20)28 in DNA samples with abnormal elution profiles.

Primers and denaturing high-performance liquid chromatography conditions used for analysis of parkin have been described previously.29 To identify copy number variation (exon deletions and duplications) within parkin, semiquantitative multiplex polymerase chain reaction (PCR) was performed on all samples.26

In the CORE-PD, we screened 709 samples for point mutations using denaturing high-performance liquid chromatography and the parkin genotyping array28 and for copy number variation (exon deletions and duplications) using semiquantitative multiplex PCR.26 The genotyping array was used to analyze amplicons in DNA samples with abnormal elution profiles and has excellent sensitivity and specificity for detection of sequence variants compared with the criterion standard of sequencing.28 The primers used for PCR amplification of parkin exons 1 through 12 and intron-exon boundaries and sequencing have been described previously.30 Cycle sequencing was performed on the purified PCR product per the manufacturer's instructions (BigDye; Applied Biosystems, Foster City, California). Products were analyzed on a genetic analyzer (ABI3700, Applied Biosystems). Chromatograms were viewed using commercially available software (Sequencher; Gene Codes Corporation, Ann Arbor, Michigan), and sequence variants were determined. All sequence variants identified were confirmed by analysis in a separate PCR, followed by bidirectional sequencing.

Parkin was previously sequenced in 105 white non-Hispanic control subjects.26 To determine whether novel variants identified in black non-Hispanics or Hispanics in the present study were mutations, we sequenced parkin in 139 Hispanic and 119 black non-Hispanic controls without dementia from the Washington Heights–Inwood Columbia Aging Project (New York, New York) who had normal findings on neurologic examinations.31,32 Based on the published literature and the sequence data from controls, variants with a frequency of 1% or less were classified as mutations. Additional criteria used to classify new variants as mutations included predicted effect on the encoded protein (null, truncation, missense, splice, or synonymous), evolutionary conservation of the affected amino acid residue or region, and location in conserved functional domains. We classified sequence variants with no known functional significance as polymorphisms if their frequency was at least 1% in racially/ethnically matched controls in published studies2,4,28,33 or in the present study. We considered a variant as “variant of uncertain significance” if it had been previously reported as a mutation in at least 1 racial/ethnic group but had a similar frequency among cases and controls in another racial/ethnic group and the variant was predicted to affect protein function using analysis software (SIFT, http://sift.jcvi.org/).34 Nine patients carrying 7 variants of uncertain significance were identified. In this study, we consider these variants of uncertain significance as parkin noncarriers. We also performed all analyses with these variants excluded.

DIAGNOSIS OF PD IN RELATIVES

Information on the family history of PD in first-degree relatives was obtained by administering a reliable validated interview to each patient.22 An algorithm was created to generate a final diagnosis for PD in each first-degree relative based on the family history interview. For relatives diagnosed as having PD, a level of certainty was assigned as definite, probable, possible, uncertain, or unlikely. A best-estimate diagnosis of PD was assigned for each relative.21 It was previously demonstrated that a conservative diagnosis of PD (definite, probable, or possible PD) had the best combination of sensitivity and specificity of PD.21 In the present study, if any first-degree relative met the conservative definition of PD, the family history of PD was considered positive.

STATISTICAL ANALYSIS

Demographic and clinical characteristics of patients with PD who carried a parkin mutation (heterozygous, homozygous, or compound heterozygous carriers) and patients who did not (noncarriers) were compared using χ2 test for categorical variables and 2-tailed t test for continuous variables. Logistic regression models were constructed to examine whether demographic features (including AAO, racial/ethnic group, family history of PD, education, and sex) were associated with carrying a parkin mutation. Age at onset was categorized as younger than 40 years (n = 311) or 40 to 50 years (n = 644) (AAO was missing for 1 subject). Racial/ethnic group was categorized as white non-Hispanic, black non-Hispanic, Hispanic, or other. Multiple racial/ethnic groups were included in the “other” category; 70.4% described themselves as Asian. Family history of PD was categorized using a conservative definition of PD in any first-degree relative.22 Additional models were constructed to examine the association of these characteristics with parkin heterozygosity compared with parkin noncarrier (reference) and with parkin homozygosity or compound heterozygosity (combined) compared with parkin noncarrier (reference).

Demographic and clinical characteristics of the patients are summarized in Table 1. Sixty-four patients with PD (6.7%) had parkin mutations (37 [3.9%] heterozygous, 6 [0.6%] homozygous, and 21 [2.2%] compound heterozygous). The prevalence of mutations declined with AAO from 57.1% (8 of 14) among patients with AAO younger than 20 years to 30.2% (13 of 43) for 20 to 29 years, 9.1% (23 of 254) for 30 to 39 years, and 3.1% (20 of 644) for 40 to 50 years (P < .001, test for linear trend) (AAO was missing for 1 patient). None of 12 black non-Hispanics carried a parkin mutation, whereas 5.7% (48 of 838) of white non-Hispanic patients, 15.6% (12 of 77) of Hispanic patients, and 14.8% (4 of 27) of patients in “other” racial/ethnic groups combined did (P = .002) (race/ethnicity was missing for 2 patients).

Table Graphic Jump LocationTable 1. Demographic and Clinical Characteristics of the Cohort

No black patients but 9 white patients endorsed Hispanic race/ethnicity (Mexican) and were classified in the Hispanic category. One patient carried a heterozygous exon 6 deletion. Among patients who reported a family history of PD in a first-degree relative, 11.8% carried parkin mutations compared with 5.7% of patients who did not have a family history of PD (P = .007). Copy number variation was present in 52.3% of mutation carriers (31.6% of heterozygous, 83.3% of homozygous, and 81.0% of compound heterozygous carriers). There was no reported consanguinity.

All parkin carriers were similar in age, but compound heterozygous and heterozygous carriers were significantly younger than noncarriers. Each mutation carrier group had significantly younger AAO than the noncarrier group. Compound heterozygous and homozygous carriers each had significantly younger AAO than heterozygous carriers. The mean (SD) age was 41.7 (6.7) years among white non-Hispanics, 36.6 (6.9) years among black non-Hispanics, 39.7 (8.1) years among Hispanics, and 40.4 (8.3) years among other racial/ethnic groups. White non-Hispanics were significantly older than black non-Hispanics (P = .05).

The presence of dystonia as an initial symptom did not differ between carriers (0.0%) and noncarriers (1.7%) of parkin mutations (P = .40). Similarly, there was no difference in reported response to levodopa; 93.4% of carriers compared with 90.5% of noncarriers reported a response to antiparkinson medications when tried in an adequate dose (P = .60).

Logistic models examining the association of demographic risk factors with the presence of any parkin mutation or the presence of heterozygous mutations compared with noncarriers are summarized in Table 2 and Table 3. Age at onset was inversely related to the presence of any parkin mutation after adjustment for race/ethnicity and for family history of PD in a first-degree relative. Education and sex were not associated with mutation status in this model. Compared with white non-Hispanic race/ethnicity, Hispanic race/ethnicity was associated with carrying a parkin mutation in the model examining the presence of any parkin mutation (odds ratio [OR], 2.7; 95% confidence interval [CI], 1.3-5.7; P = .009) (Table 2) and in the model examining heterozygous carriers compared with noncarriers (2.8; 1.1-7.2; P = .03) (Table 3). When patients with mutations in both alleles (compound heterozygous and homozygous) were compared with noncarriers, AAO (OR, 18.6; 95% CI, 5.5-63.8; P < .001) and family history of PD (3.5; 1.4-9.2; P = .01) were significant, but Hispanic race/ethnicity was no longer significant (data not shown). When patients having 2 mutations were compared with patients having a single mutation (heterozygous), AAO was inversely associated with carrying 2 mutations (OR, 6.6; 95% CI, 1.6-27.1; P = .008), but neither race/ethnicity nor family history was associated with carrying 2 mutations.

Table Graphic Jump LocationTable 2. Odds of Carrying Any Parkin Mutation (Heterozygous, Homozygous, or Compound Heterozygous) Compared With Probands Who Are Noncarriers of Parkin Mutationsa
Table Graphic Jump LocationTable 3. Odds of Carrying a Single Heterozygous Parkin Mutation Compared With Probands Who Are Noncarriers of Parkin Mutationsa

All analyses were repeated after exclusion of 35 LRRK2 G2019S mutation carriers, 45 glucocerebrosidase N370S carriers, and 23 glucocerebrosidase L444P carriers. One heterozygous parkin carrier (deletion) also carried a G2019S mutation, and 3 heterozygous parkin carriers had GBA mutations (2 L444P and 1 N370S). The inverse relationship between AAO and carrying any parkin mutation (n = 57) or a single mutation and the relationship between family history of PD and carrying either 1 or 2 mutations remained. Adjusting for AAO and family history of PD, the association between Hispanic race/ethnicity and carrying any parkin mutation (OR, 2.6; 95% CI, 1.1-5.9; P = .03) or a heterozygous mutation (3.7; 1.3-10.1; P = .01) persisted.

The specific parkin mutations detected in heterozygous, homozygous, and compound heterozygous carriers are listed in Table 4. The 7 variants of uncertain significance detected among 9 patients included Asp18Asn, Ala82Glu (n = 2), Pro437Leu (n = 2), Pro153Arg, ATG-23C>T, ATG-43T>C, and Met192Leu. Findings were not significantly different when these variants were excluded from all analyses.

Table Graphic Jump LocationTable 4. Parkin Mutations by Racial/Ethnic Group and Zygosity

The nationalities of 77 Hispanic patients included 21 from the Dominican Republic, 20 from Puerto Rico, 15 from Mexico, 8 from Ecuador, and fewer than 5 patients each from Cuba, Peru, Columbia, Chile, and Ecuador. The 12 Hispanic parkin carriers included 7 Puerto Ricans, 2 Mexicans, 1 Cuban, 1 Dominican, and 1 Peruvian. Six patients (5 Puerto Rican and 1 Mexican) carried deletions in exons 3 and 4. Both homozygous carriers with deletions in exons 3 and 4 were of Puerto Rican descent; family history of PD was reported by one but was unavailable for the other (Table 4). None of the other carriers with deletions in exons 3 and 4 reported a family history of PD. The second most common mutation among Hispanics was 255delA, present among 3 Puerto Ricans in association with deletions in exons 3 and 4 and in 1 Mexican heterozygous carrier.

To date, this is the largest systematically collected sample of patients with EOPD recruited solely on the basis of AAO. We demonstrated among patients with EOPD that carrying any parkin mutation or a heterozygous mutation is inversely related to AAO and that having a parkin mutation is more common among those with a family history of PD in a first-degree relative. Parkin mutations, in particular deletions in exons 3 and 4 and 255delA, are common among Hispanics (specifically Puerto Ricans).

The low frequency of parkin mutations in this sample (6.7%) may reflect the reduced penetrance of parkin mutations (particularly among heterozygous carriers, who represent 58% of mutation carriers) and the fact that 93.9% of the sample had AAO older than 30 years. Using the kin-cohort method in a sample of 72% heterozygous cases, a penetrance of 7% at age 65 years was reported among first-degree relatives estimated to be heterozygous parkin carriers.27 This was not significantly different from among those estimated to be noncarrier relatives or control relatives. The frequency of parkin mutation carriers in the present study—36.8% (21 of 57) among those with AAO younger than 30 years and 6.1% (35 of 572) among those with AAO of 30 to 45 years—is similar to a large sporadic series6 that reported 33.8% (23 of 68) among those with AAO younger than 30 years and 8.0% (14 of 175) among those with AAO of 30 to 45 years. In addition, variants previously considered mutations have been identified with similar frequency among racially/ethnically matched control groups.26,33 We now consider these normal variants, further reducing the frequency of reported mutations.

The role of heterozygosity has remained controversial; some authors believe that heterozygous point mutations are not pathogenic,20 and others believe that deletions rather than point mutations are more likely to have functional consequences.35 Our finding that patients with a parkin mutation in the heterozygous state have younger AAO of PD than those who do not have mutations after adjustment for race/ethnicity and family history of PD supports the concept that parkin heterozygosity is a susceptibility factor for PD. Heterozygosity may lead to disease by means of haploinsufficiency, dominant negative effects, or gain of function.19,36 Positron emission tomography studies3739 showed reduced fluorodopa F 18 uptake among nigrostriatal terminals in the caudate and posterior putamen of symptomatic and asymptomatic heterozygotes compared with controls, a reduction similar to that found in sporadic PD. Transcranial sonography demonstrated greater substantia nigra hyperechogenicity in symptomatic homozygotes and heterozygotes compared with controls.40 These functional and structural imaging findings suggest that heterozygous parkin carriers can compensate to maintain motor function in the face of mild dopaminergic deficits.41

Eight studies20,26,33,4246 have reported genetic variants that could lead to functionally relevant alterations of protein structure among controls with parkin mutation frequencies ranging from 0.0% to 3.9%. Most of these studies were limited by small sample size and by controls that were not racially/ethnically matched to cases. In the largest study to date,44 in addition to missense and frameshift mutations, 4 different dosage mutations were seen among 356 controls from South Tyrol, Italy, and from Germany. One control with a missense mutation was examined 3 years after the first examination and had evidence of increased echogenicity on transcranial sonography of the substantia nigra, consistent with mild parkinsonism. These findings suggest that parkin heterozygosity may increase PD susceptibility rather than directly cause PD. A similar pathogenic role has been proposed for PINK119 and GBA.47,48 In addition to the possibility of interaction with functional variants in other genes, there is new evidence that environmental factors such as exposure to maneb or paraquat during critical periods early in life may be associated with EOPD.49

Although the numbers were few, it seems that deletions in exons 3 and 4 and the frameshift mutation 255delA are common among Hispanic patients with PD, in particular Puerto Ricans, after adjustment for AAO and family history of PD. In a 2004 study,2 these 2 mutations and 3 others (deletions in exons 3 and 4 and in Arg275Trp) accounted for 35.1% (133 of 379) of unrelated mutation carriers reported from 1998 through 2003 and suggest hot spots for “small” mutations in exons 2 and 7 and rearrangements most commonly in exons 2 through 4. A potential founder mutation was reported in 3 families of Puerto Rican descent who carried deletions of exons 3 and 4, including 1 homozygous carrier.2,4 Using 10 microsatellite markers, a haplotype was identified. All 3 Puerto Rican carriers of deletions of exons 3 and 4 shared at least 1 common allele at all markers except D6S1277 and D6S2436 that flanked the gene.2 A patient with PD from northern Germany who carried this deletion50 did not share the common haplotype.2 One member of these 3 families reported previously, a compound heterozygous carrier,2 is included in the present study.

The 255delA was the second most common mutation recognized among Hispanics in this study. In a series of 37 patients from Spain with AAO of 40 years or younger or with a recessive pattern of inheritance, 7 patients with PD (18.9%) carried a parkin mutation, including 4 patients with homozygous 255delA mutations. Three of these 4 patients reported a family history of PD.51 The 255delA was seen in 1 of 200 control chromosomes in that series.51 We did not detect this mutation in 139 controls of Caribbean Hispanic descent. It is suggested that the 255delA frameshift mutation may be an ancestral European mutation.52 Further exploration of Hispanic patients having PD with respect to genetic modifiers of AAO of PD and phenotypic variability is warranted.

Correspondence: Karen S. Marder, MD, MPH, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, 630 W 168th St, Unit 16, New York, NY 10032 (ksm1@columbia.edu).

Accepted for Publication: October 19, 2009.

Author Contributions:Study concept and design: Marder, Neils, Caccappolo, Ottman, and Clark. Acquisition of data: Marder, Mejia-Santana, Rosado, Louis, Comella, Colcher, Siderowf, Jennings, Nance, Bressman, Scott, Tanner, Mickel, Andrews, Waters, Fahn, Ross, Cote, Frucht, Ford, Rezak, Novak, Friedman, Pfeiffer, Marsh, Hiner, Neils, Verbitsky, Kisselev, Ottman, and Clark. Analysis and interpretation of data: Marder, Tang, Nance, Scott, Ross, Frucht, Alcalay, Marsh, Verbitsky, Kisselev, Caccappolo, Ottman, and Clark. Drafting of the manuscript: Marder and Andrews. Critical revision of the manuscript for important intellectual content: Marder, Tang, Mejia-Santana, Rosado, Louis, Comella, Colcher, Siderowf, Jennings, Nance, Bressman, Scott, Tanner, Mickel, Waters, Fahn, Ross, Cote, Frucht, Ford, Alcalay, Rezak, Novak, Friedman, Pfeiffer, Marsh, Hiner, Neils, Verbitsky, Kisselev, Caccappolo, Ottman, and Clark. Statistical analysis: Tang, Louis, Scott, Cote, and Ottman. Obtained funding: Marder, Ottman, and Clark. Administrative, technical, and material support: Rosado, Colcher, Bressman, Fahn, Ross, Novak, Friedman, Neils, Verbitsky, and Kisselev. Study supervision: Mejia-Santana, Bressman, Andrews, Alcalay, Hiner, Caccappolo, and Clark.

Financial Disclosure: Dr Friedman is a coinvestigator with Acadia Pharmaceuticals, Astra-Zeneca, Boehringer-Ingelheim, Cephalon, EMD Serono, EpiVax, GlaxoSmithKline, Novartis, Pfizer, Teva Pharmaceuticals, and Valeant Pharmaceuticals. Dr Pfeiffer has received royalties from Butterworth Heinemann (Elsevier), CRC Press (Taylor & Francis), and Human Press; has received honoraria for lectures from Boehringer-Ingelheim, GlaxoSmithKline, Novartis, Teva, and UCB/Schwarz and for consulting from Boehringer-Ingelheim, Kyowa, Prestwick, UCB/Schwarz, Solvay, and Vernalis; has received research grants and contracts from Boehringer-Ingelheim, Cephalon, Eisai, Kyowa, Merck (Germany), Novartis, Santhera, and UCB/Schwarz; has received legal consulting fees from Davis Graham & Stubbs and Spriggs & Hollingsworth; and has served as coeditor in chief of Parkinsonism and Related Disorders. Dr Marsh has served as a consultant to Acadia Pharmaceuticals, Boehringer-Ingelheim, Merck Serono, and Ovation Pharmaceutical and has received research support from Boehringer-Ingelheim, Eli Lilly and Company, Forest Research Institute, and the National Institutes of Health.

Funding/Support: This study was funded by grants NS36630, UL1 RR024156, and AG007232 from the National Institutes of Health and by the Parkinson's Disease Foundation. This study contributed samples and clinical data to the Human Genetics Resource Center DNA and Coriell Cell Repositories (http://ccr.coriell.org) of the National Institute of Neurological Disorders and Stroke and received DNA back in kind that was used for analyses reported herein.

Additional Contributions: Paul Greene, MD, Diana Ruiz, BS, Miran Salgado, MD, and Mark Gudesblatt, MD, assisted with the study.

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Macedo  MGVerbaan  DFang  Y  et al.  Genotypic and phenotypic characteristics of Dutch patients with early onset Parkinson's disease. Mov Disord 2009;24 (2) 196- 203
PubMed Link to Article
Hertz  JMOstergaard  KJuncker  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
PubMed Link to Article
Chung  EJKi  CSLee  WYKim  ISKim  JY Clinical features and gene analysis in Korean patients with early-onset Parkinson disease. Arch Neurol 2006;63 (8) 1170- 1174
PubMed Link to Article
Bras  JGuerreiro  RRibeiro  M  et al.  Analysis of Parkinson disease patients from Portugal for mutations in SNCA, PRKN, PINK1 and LRRK2BMC Neurol 2008;8e1http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2248204/?tool=pubmed. Accessed March 7, 2010
Link to Article
Vinish  MPrabhakar  SKhullar  MVerma  IAnand  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 2010;81 (2) 166- 170
PubMed Link to Article
Foroud  TUniacke  SKLiu  L  et al. Parkinson Study Group, Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease. Neurology 2003;60 (5) 796- 801
PubMed Link to Article
Oliveira  SAScott  WKMartin  ER  et al.  Parkin mutations and susceptibility alleles in late-onset Parkinson's disease. Ann Neurol 2003;53 (5) 624- 629
PubMed Link to Article
Sun  MLatourelle  JCWooten  GF  et al.  Influence of heterozygosity for parkin mutation on onset age in familial Parkinson disease: the Gene PD study. Arch Neurol 2006;63 (6) 826- 832
PubMed Link to Article
Broussolle  ELücking  CBGinovart  NPollak  PRemy  PDürr  A [18F]-dopa PET study in patients with juvenile-onset PD and parkin gene mutations. Neurology 2000;55 (6) 877- 879
PubMed Link to Article
Klein  CLohmann-Hedrich  K Impact of recent genetic findings in Parkinson's disease. Curr Opin Neurol 2007;20 (4) 453- 464
PubMed Link to Article
Klein  CLohmann-Hedrich  KRogaeva  ESchlossmacher  MGLang  AE Deciphering the role of heterozygous mutations in genes associated with parkinsonism. Lancet Neurol 2007;6 (7) 652- 662
PubMed Link to Article
Kay  DMMoran  DMoses  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
PubMed Link to Article
Marder  KLevy  GLouis  ED  et al.  Familial aggregation of early- and late-onset Parkinson's disease [published correction appears in Ann Neurol. 2003;54(5):693]. Ann Neurol 2003;54 (4) 507- 513
PubMed Link to Article
Marder  KLevy  GLouis  ED  et al.  Accuracy of family history data on Parkinson's disease. Neurology 2003;61 (1) 18- 23
PubMed Link to Article
Levy  GLouis  EDMejia-Santana  H  et al.  Lack of familial aggregation of Parkinson disease and Alzheimer disease. Arch Neurol 2004;61 (7) 1033- 1039
PubMed
Fahn  SElton  RMembers of the UPDRS Development Committee, Unified Parkinson's Disease Rating Scale. Fahn  SMarsden  CCalne  DGoldstein  MRecent Developments in Parkinson's Disease 2 New York, NY Macmillan Healthcare Information1987;153- 163293- 304
Folstein  MFFolstein  SE McHugh  PRP “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12 (3) 189- 198
PubMed Link to Article
Clark  LNAfridi  SKarlins  E  et al.  Case-control study of the parkin gene in early-onset Parkinson disease. Arch Neurol 2006;63 (4) 548- 552
PubMed Link to Article
Wang  YClark  LNLouis  ED  et al.  Risk of Parkinson disease in carriers of parkin mutations: estimation using the kin-cohort method. Arch Neurol 2008;65 (4) 467- 474
PubMed Link to Article
Clark  LNHaamer  EMejia-Santana  H  et al.  Construction and validation of a Parkinson's disease mutation genotyping array for the Parkin gene. Mov Disord 2007;22 (7) 932- 937
PubMed Link to Article
Pigullo  SDe Luca  ABarone  P  et al.  Mutational analysis of parkin gene by denaturing high-performance liquid chromatography (DHPLC) in essential tremor. Parkinsonism Relat Disord 2004;10 (6) 357- 362
PubMed Link to Article
West  APeriquet  MLincoln  S  et al. French Parkinson's Disease Genetics Study Group; European Consortium on Genetic Susceptibility on Parkinson's Disease, Complex relationship between parkin mutations and Parkinson disease. Am J Med Genet 2002;114 (5) 584- 591
PubMed Link to Article
Stern  YGurland  BTatemichi  TKTang  MXWilder  DMayeux  R Influence of education and occupation on the incidence of Alzheimer's disease. JAMA 1994;271 (13) 1004- 1010
PubMed Link to Article
Tang  MXStern  YMarder  K  et al.  The APOE-ε4 allele and the risk of Alzheimer disease among African Americans, whites, and Hispanics. JAMA 1998;279 (10) 751- 755
PubMed Link to Article
Okubadejo  NBritton  ACrews  C  et al.  Analysis of Nigerians with apparently sporadic Parkinson disease for mutations in LRRK2, PRKN and ATXN3. PLoS One 2008;3 (10) e3421Accessed March 7, 2010
PubMed Link to Article
Ng  PCHenikoff  S SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 2003;31 (13) 3812- 3814
PubMed Link to Article
Pankratz  NKissell  DKPauciulo  MW  et al. Parkinson Study Group–PROGENI Investigators, Parkin dosage mutations have greater pathogenicity in familial PD than simple sequence mutations. Neurology 2009;73 (4) 279- 286
PubMed Link to Article
Klein  CLohmann  K Parkinson disease(s): is “parkin disease” a distinct clinical entity? Neurology 2009;72 (2) 106- 107
PubMed Link to Article
Hilker  RKlein  CGhaemi  M  et al.  Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial parkinsonism associated with mutations in the parkin gene. Ann Neurol 2001;49 (3) 367- 376
PubMed Link to Article
Portman  ATGiladi  NLeenders  KL  et al.  The nigrostriatal dopaminergic system in familial early onset parkinsonism with parkin mutations. Neurology 2001;56 (12) 1759- 1762
PubMed Link to Article
Scherfler  CKhan  NLPavese  N  et al.  Striatal and cortical pre- and postsynaptic dopaminergic dysfunction in sporadic parkin-linked parkinsonism. Brain 2004;127 (pt 6) 1332- 1342
PubMed Link to Article
Hagenah  JMKonig  IRBecker  B  et al.  Substantia nigra hyperechogenicity correlates with clinical status and number of parkin mutated alleles. J Neurol 2007;254 (10) 1407- 1413
PubMed Link to Article
van Nuenen  BFWeiss  MMBloem  BR  et al.  Heterozygous carriers of a parkin or PINK1 mutation share a common functional endophenotype. Neurology 2009;72 (12) 1041- 1047
PubMed Link to Article
Lincoln  SJMaraganore  DMLesnick  TG  et al.  Parkin variants in North American Parkinson's disease: cases and controls. Mov Disord 2003;18 (11) 1306- 1311
PubMed Link to Article
Lesage  SLohmann  ETison  FDurif  FDürr  ABrice  AFrench Parkinson's Disease Genetics Study Group, Rare heterozygous parkin variants in French early-onset Parkinson disease patients and controls. J Med Genet 2008;45 (1) 43- 46
PubMed Link to Article
Brüggemann  NMitterer  MLanthaler  AJ  et al.  Frequency of heterozygous parkin mutations in healthy subjects: need for careful prospective follow-up examination of mutation carriers. Parkinsonism Relat Disord 2009;15 (6) 425- 429
PubMed Link to Article
Brooks  JDing  JSimon-Sanchez  JPaisan-Ruiz  CSingleton  ABScholz  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
PubMed Link to Article
Nuytemans  KMeeus  BCrosiers  D  et al.  Relative contribution of simple mutations vs. copy number variations in five Parkinson disease genes in the Belgian population. Hum Mutat 2009;30 (7) 1054- 1061
PubMed Link to Article
Clark  LNRoss  BMWang  Y  et al.  Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease. Neurology 2007;69 (12) 1270- 1277
PubMed Link to Article
Gan-Or  ZGiladi  NRozovski  U  et al.  Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology 2008;70 (24) 2277- 2283
PubMed Link to Article
Costello  SCockburn  MBronstein  JZhang  XRitz  B Parkinson's disease and residential exposure to maneb and paraquat from agricultural applications in the central valley of California. Am J Epidemiol 2009;169 (8) 919- 926
PubMed Link to Article
Kann  MJacobs  HMohrmann  K  et al.  Role of parkin mutations in 111 community-based patients with early-onset parkinsonism. Ann Neurol 2002;51 (5) 621- 625
PubMed Link to Article
Muñoz  ETolosa  EPastor  P  et al.  Relative high frequency of the c.255delA parkin gene mutation in Spanish patients with autosomal recessive parkinsonism. J Neurol Neurosurg Psychiatry 2002;73 (5) 582- 584
PubMed Link to Article
Periquet  MLücking  CVaughan  J  et al. French Parkinson's Disease Genetics Study Group; European Consortium on Genetic Susceptibility in Parkinson's Disease, Origin of the mutations in the parkin gene in Europe: exon rearrangements are independent recurrent events, whereas point mutations may result from founder effects. Am J Hum Genet 2001;68 (3) 617- 626
PubMed Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Demographic and Clinical Characteristics of the Cohort
Table Graphic Jump LocationTable 2. Odds of Carrying Any Parkin Mutation (Heterozygous, Homozygous, or Compound Heterozygous) Compared With Probands Who Are Noncarriers of Parkin Mutationsa
Table Graphic Jump LocationTable 3. Odds of Carrying a Single Heterozygous Parkin Mutation Compared With Probands Who Are Noncarriers of Parkin Mutationsa
Table Graphic Jump LocationTable 4. Parkin Mutations by Racial/Ethnic Group and Zygosity

References

Kitada  TAsakawa  SHattori  N  et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998;392 (6676) 605- 608
PubMed Link to Article
Hedrich  KEskelson  CWilmot  B  et al.  Distribution, type, and origin of parkin mutations: review and case studies. Mov Disord 2004;19 (10) 1146- 1157
PubMed Link to Article
Lücking  CBDürr  ABonifati  V  et al. European Consortium on Genetic Susceptibility in Parkinson's Disease; French Parkinson's Disease Genetics Study Group, Association between early-onset Parkinson's disease and mutations in the parkin gene. N Engl J Med 2000;342 (21) 1560- 1567
PubMed Link to Article
Hedrich  KMarder  KHarris  J  et al.  Evaluation of 50 probands with early-onset Parkinson's disease for Parkin mutations. Neurology 2002;58 (8) 1239- 1246
PubMed Link to Article
Abbas  NLücking  CBRicard  S  et al. French Parkinson's Disease Genetics Study Group; European Consortium on Genetic Susceptibility in Parkinson's Disease, A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. Hum Mol Genet 1999;8 (4) 567- 574
PubMed Link to Article
Periquet  MLatouche  MLohmann  E  et al. French Parkinson's Disease Genetics Study Group; European Consortium on Genetic Susceptibility in Parkinson's Disease, Parkin mutations are frequent in patients with isolated early-onset parkinsonism. Brain 2003;126 (pt 6) 1271- 1278
PubMed Link to Article
Lohmann  EPeriquet  MBonifati  V  et al. French Parkinson's Disease Genetics Study Group; European Consortium on Genetic Susceptibility in Parkinson's Disease, How much phenotypic variation can be attributed to parkin genotype? Ann Neurol 2003;54 (2) 176- 185
PubMed Link to Article
Camargos  STDornas  LOMomeni  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
PubMed Link to Article
Macedo  MGVerbaan  DFang  Y  et al.  Genotypic and phenotypic characteristics of Dutch patients with early onset Parkinson's disease. Mov Disord 2009;24 (2) 196- 203
PubMed Link to Article
Hertz  JMOstergaard  KJuncker  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
PubMed Link to Article
Chung  EJKi  CSLee  WYKim  ISKim  JY Clinical features and gene analysis in Korean patients with early-onset Parkinson disease. Arch Neurol 2006;63 (8) 1170- 1174
PubMed Link to Article
Bras  JGuerreiro  RRibeiro  M  et al.  Analysis of Parkinson disease patients from Portugal for mutations in SNCA, PRKN, PINK1 and LRRK2BMC Neurol 2008;8e1http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2248204/?tool=pubmed. Accessed March 7, 2010
Link to Article
Vinish  MPrabhakar  SKhullar  MVerma  IAnand  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 2010;81 (2) 166- 170
PubMed Link to Article
Foroud  TUniacke  SKLiu  L  et al. Parkinson Study Group, Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease. Neurology 2003;60 (5) 796- 801
PubMed Link to Article
Oliveira  SAScott  WKMartin  ER  et al.  Parkin mutations and susceptibility alleles in late-onset Parkinson's disease. Ann Neurol 2003;53 (5) 624- 629
PubMed Link to Article
Sun  MLatourelle  JCWooten  GF  et al.  Influence of heterozygosity for parkin mutation on onset age in familial Parkinson disease: the Gene PD study. Arch Neurol 2006;63 (6) 826- 832
PubMed Link to Article
Broussolle  ELücking  CBGinovart  NPollak  PRemy  PDürr  A [18F]-dopa PET study in patients with juvenile-onset PD and parkin gene mutations. Neurology 2000;55 (6) 877- 879
PubMed Link to Article
Klein  CLohmann-Hedrich  K Impact of recent genetic findings in Parkinson's disease. Curr Opin Neurol 2007;20 (4) 453- 464
PubMed Link to Article
Klein  CLohmann-Hedrich  KRogaeva  ESchlossmacher  MGLang  AE Deciphering the role of heterozygous mutations in genes associated with parkinsonism. Lancet Neurol 2007;6 (7) 652- 662
PubMed Link to Article
Kay  DMMoran  DMoses  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
PubMed Link to Article
Marder  KLevy  GLouis  ED  et al.  Familial aggregation of early- and late-onset Parkinson's disease [published correction appears in Ann Neurol. 2003;54(5):693]. Ann Neurol 2003;54 (4) 507- 513
PubMed Link to Article
Marder  KLevy  GLouis  ED  et al.  Accuracy of family history data on Parkinson's disease. Neurology 2003;61 (1) 18- 23
PubMed Link to Article
Levy  GLouis  EDMejia-Santana  H  et al.  Lack of familial aggregation of Parkinson disease and Alzheimer disease. Arch Neurol 2004;61 (7) 1033- 1039
PubMed
Fahn  SElton  RMembers of the UPDRS Development Committee, Unified Parkinson's Disease Rating Scale. Fahn  SMarsden  CCalne  DGoldstein  MRecent Developments in Parkinson's Disease 2 New York, NY Macmillan Healthcare Information1987;153- 163293- 304
Folstein  MFFolstein  SE McHugh  PRP “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12 (3) 189- 198
PubMed Link to Article
Clark  LNAfridi  SKarlins  E  et al.  Case-control study of the parkin gene in early-onset Parkinson disease. Arch Neurol 2006;63 (4) 548- 552
PubMed Link to Article
Wang  YClark  LNLouis  ED  et al.  Risk of Parkinson disease in carriers of parkin mutations: estimation using the kin-cohort method. Arch Neurol 2008;65 (4) 467- 474
PubMed Link to Article
Clark  LNHaamer  EMejia-Santana  H  et al.  Construction and validation of a Parkinson's disease mutation genotyping array for the Parkin gene. Mov Disord 2007;22 (7) 932- 937
PubMed Link to Article
Pigullo  SDe Luca  ABarone  P  et al.  Mutational analysis of parkin gene by denaturing high-performance liquid chromatography (DHPLC) in essential tremor. Parkinsonism Relat Disord 2004;10 (6) 357- 362
PubMed Link to Article
West  APeriquet  MLincoln  S  et al. French Parkinson's Disease Genetics Study Group; European Consortium on Genetic Susceptibility on Parkinson's Disease, Complex relationship between parkin mutations and Parkinson disease. Am J Med Genet 2002;114 (5) 584- 591
PubMed Link to Article
Stern  YGurland  BTatemichi  TKTang  MXWilder  DMayeux  R Influence of education and occupation on the incidence of Alzheimer's disease. JAMA 1994;271 (13) 1004- 1010
PubMed Link to Article
Tang  MXStern  YMarder  K  et al.  The APOE-ε4 allele and the risk of Alzheimer disease among African Americans, whites, and Hispanics. JAMA 1998;279 (10) 751- 755
PubMed Link to Article
Okubadejo  NBritton  ACrews  C  et al.  Analysis of Nigerians with apparently sporadic Parkinson disease for mutations in LRRK2, PRKN and ATXN3. PLoS One 2008;3 (10) e3421Accessed March 7, 2010
PubMed Link to Article
Ng  PCHenikoff  S SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 2003;31 (13) 3812- 3814
PubMed Link to Article
Pankratz  NKissell  DKPauciulo  MW  et al. Parkinson Study Group–PROGENI Investigators, Parkin dosage mutations have greater pathogenicity in familial PD than simple sequence mutations. Neurology 2009;73 (4) 279- 286
PubMed Link to Article
Klein  CLohmann  K Parkinson disease(s): is “parkin disease” a distinct clinical entity? Neurology 2009;72 (2) 106- 107
PubMed Link to Article
Hilker  RKlein  CGhaemi  M  et al.  Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial parkinsonism associated with mutations in the parkin gene. Ann Neurol 2001;49 (3) 367- 376
PubMed Link to Article
Portman  ATGiladi  NLeenders  KL  et al.  The nigrostriatal dopaminergic system in familial early onset parkinsonism with parkin mutations. Neurology 2001;56 (12) 1759- 1762
PubMed Link to Article
Scherfler  CKhan  NLPavese  N  et al.  Striatal and cortical pre- and postsynaptic dopaminergic dysfunction in sporadic parkin-linked parkinsonism. Brain 2004;127 (pt 6) 1332- 1342
PubMed Link to Article
Hagenah  JMKonig  IRBecker  B  et al.  Substantia nigra hyperechogenicity correlates with clinical status and number of parkin mutated alleles. J Neurol 2007;254 (10) 1407- 1413
PubMed Link to Article
van Nuenen  BFWeiss  MMBloem  BR  et al.  Heterozygous carriers of a parkin or PINK1 mutation share a common functional endophenotype. Neurology 2009;72 (12) 1041- 1047
PubMed Link to Article
Lincoln  SJMaraganore  DMLesnick  TG  et al.  Parkin variants in North American Parkinson's disease: cases and controls. Mov Disord 2003;18 (11) 1306- 1311
PubMed Link to Article
Lesage  SLohmann  ETison  FDurif  FDürr  ABrice  AFrench Parkinson's Disease Genetics Study Group, Rare heterozygous parkin variants in French early-onset Parkinson disease patients and controls. J Med Genet 2008;45 (1) 43- 46
PubMed Link to Article
Brüggemann  NMitterer  MLanthaler  AJ  et al.  Frequency of heterozygous parkin mutations in healthy subjects: need for careful prospective follow-up examination of mutation carriers. Parkinsonism Relat Disord 2009;15 (6) 425- 429
PubMed Link to Article
Brooks  JDing  JSimon-Sanchez  JPaisan-Ruiz  CSingleton  ABScholz  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
PubMed Link to Article
Nuytemans  KMeeus  BCrosiers  D  et al.  Relative contribution of simple mutations vs. copy number variations in five Parkinson disease genes in the Belgian population. Hum Mutat 2009;30 (7) 1054- 1061
PubMed Link to Article
Clark  LNRoss  BMWang  Y  et al.  Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease. Neurology 2007;69 (12) 1270- 1277
PubMed Link to Article
Gan-Or  ZGiladi  NRozovski  U  et al.  Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology 2008;70 (24) 2277- 2283
PubMed Link to Article
Costello  SCockburn  MBronstein  JZhang  XRitz  B Parkinson's disease and residential exposure to maneb and paraquat from agricultural applications in the central valley of California. Am J Epidemiol 2009;169 (8) 919- 926
PubMed Link to Article
Kann  MJacobs  HMohrmann  K  et al.  Role of parkin mutations in 111 community-based patients with early-onset parkinsonism. Ann Neurol 2002;51 (5) 621- 625
PubMed Link to Article
Muñoz  ETolosa  EPastor  P  et al.  Relative high frequency of the c.255delA parkin gene mutation in Spanish patients with autosomal recessive parkinsonism. J Neurol Neurosurg Psychiatry 2002;73 (5) 582- 584
PubMed Link to Article
Periquet  MLücking  CVaughan  J  et al. French Parkinson's Disease Genetics Study Group; European Consortium on Genetic Susceptibility in Parkinson's Disease, Origin of the mutations in the parkin gene in Europe: exon rearrangements are independent recurrent events, whereas point mutations may result from founder effects. Am J Hum Genet 2001;68 (3) 617- 626
PubMed Link to Article

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