 |
|
Clinical Features and Gene Analysis in Korean Patients With Early-Onset Parkinson Disease
Eun Joo Chung, MD;
Chang-Seok Ki, MD, PhD;
Won Yong Lee, MD, PhD;
In-Suk Kim, MD, PhD;
Ji-Youn Kim, MD
Arch Neurol. 2006;63:1170-1174.
ABSTRACT
| |
Background Systematic analysis of clinical features and gene mutations has not been performed in Korean patients with early-onset Parkinson disease (PD).
Objective To investigate the clinical characteristics and genetic background of Korean patients with early-onset PD.
Design Clinical and genetic study.
Setting University hospital.
Patients Ninety-four patients with early-onset PD (mean ± SD age at onset, 39.8 ± 7.3 years) of 1100 patients with PD.
Interventions Analysis of clinical characteristics and mutation analysis of the parkin and PTEN-induced kinase (PINK1) genes by direct sequencing and gene-dosage analysis using the multiplex ligation–dependent probe amplification technique.
Main Outcome Measures The correlation between age at onset and clinical characteristics and the clinical features of patients with onset before age 30 years vs patients with onset after age 30 years.
Results Because age at onset was younger, levodopa-induced dyskinesia and off-dystonia were more frequently observed (P=.008). Patients affected before age 30 years showed more frequent levodopa-induced dyskinesia and off-dystonia (P=.002). We identified 3 patients (5%) with parkin gene mutations but none with the PINK1 mutation.
Conclusions Earlier onset of levodopa-induced dyskinesia and off-dystonia were characteristic features of early-onset PD, especially before an onset age of 30 years. However, parkin gene mutations were less frequent in these patients than in Japanese groups reported elsewhere.
INTRODUCTION
Although Parkinson disease (PD) is a common age-related neurodegenerative disorder, it also can manifest earlier in life. When parkinsonism presents before age 40 to 50 years, it is referred to as early-onset PD (EOPD).1-3 Patients with EOPD have been known to have a more benign course, to rarely have dementia, to respond better to levodopa therapy, but to develop more severe levodopa-induced dyskinesia (LID) and motor fluctuations.4-6
Despite the uncertain etiology of most PD, a previous study7 suggested that genetic factors play a more important role in the pathogenesis of EOPD than in older-onset PD. To date, more than 10 genetic loci and 6 genes ( -synuclein, parkin, ubiquitin carboxy-terminal hydrolase L1, PTEN-induced kinase [PINK1], Parkinson disease [autosomal recessive, early onset] 7, and leucine-rich repeat kinase 2) have been linked to PD.8-13 Among these, the mutations in the parkin genes have been frequently documented in patients with EOPD worldwide.3, 14-16
Because there are, to our knowledge, no systematic studies of the clinical features and gene mutations in Korean patients with EOPD, we investigated the clinical characteristics and gene mutations in the parkin and PINK1 genes of patients with EOPD in Korea. For mutation analysis of the parkin gene, we introduced gene-dosage analysis using the recently developed multiplex ligation–dependent probe amplification technique,17 which has proved to be a reliable tool for the diagnosis of genetic diseases characterized by large gene deletions or duplications.18
METHODS
PATIENTS
Early-onset PD was defined as PD beginning before age 50 years. We enrolled 94 patients with EOPD (8.5%; 55 men and 39 women; mean ± SD age at onset, 39.8 ± 7.3 years) of 1100 patients with PD. The diagnosis of PD was based on the National Institute of Neurological Disorders and Stroke diagnostic criteria.19 Patients were excluded if they had a history of encephalitis, repeated strokes, head trauma, or treatment with neuroleptics or if they had atypical features other than the known phenotypes associated with the parkin mutation, such as dystonia and hyperreflexia.
CLINICAL ANALYSIS
We performed a detailed clinical study that included age at onset, disease duration, presence of family history, first presenting symptoms, presence of dystonia before treatment, and dysautonomic symptoms. For cognitive assessment, we used the Korean version of the Mini-Mental State Examination with informed consent.20 The cutoff score for cognitive impairment was less than 25. We examined patient drug response: the presence of LID or off-dystonia. We analyzed the relationship between age at onset and the clinical characteristics. To compare differences in the clinical characteristics according to age at onset, we divided patients with EOPD into 2 groups: those younger than 30 years (younger group) and those older than 30 years (older group).
GENETIC ANALYSIS
With informed consent, screening for mutations in the parkin and PINK1 genes were performed in 55 of 94 patients with EOPD. Genomic DNA was extracted from peripheral blood leukocytes, and all coding exons and flanking introns of the parkin and PINK1 genes were amplified and sequenced. Multiplex ligation–dependent probe amplification was conducted according to the supplied protocol using a parkin probe kit (MRC-Holland, Amsterdam, the Netherlands). Using Genscan and Genotyper and a spreadsheet program (Microsoft Excel; Microsoft Corp, Redmond, Wash), peak areas of each fragment were compared with those of a control sample to obtain a dosage quotient representing the gene dosage of each amplicon. Detailed methods for data analysis can be found on the manufacturer's Web site (http://www.mrc-holland.com). Because a positive control was not included in the multiplex ligation–dependent probe amplification analysis, a real-time polymerase chain reaction method was used to confirm the deletion or duplication mutations identified in the present study.
STATISTICAL ANALYSIS
Correlation between age at onset and clinical variables was assessed using a Wilcoxon rank sum test, a Wilcoxon rank sum test with the Bonferroni correction, and Spearman correlation coefficients. To compare groups (younger vs older), Fisher exact and Wilcoxon rank sum tests were used. P<.05 was used as the criterion for statistical significance.
RESULTS
CLINICAL DATA
Mean ± SD age at onset was 39.8 ± 7.3 years, and mean ± SD disease duration of parkinsonism was 50.1 ± 43.8 months. Patients with an earlier age at onset had a longer disease duration (P<.001). Although tremor at rest (43%) was the most frequent initial symptom, followed by akinetic-rigid syndrome (33%), the frequency of initial symptoms did not correlate with age at onset (P>.99). Dystonia in the course of the disease before levodopa therapy negatively correlated with age at onset (P = .04). Dysautonomic symptoms did not correlate with age at onset. Of 56 patients who completed the Korean version of the Mini-Mental State Examination, the score was less than 25 in 7 patients (13%) in the younger group. Hoehn and Yahr stage at entry and Mini-Mental State Examination score did not correlate with age at onset. Clinical features and their correlation with age at onset in patients with EOPD are summarized in Table 1.
|
|
|
|
Table 1. Clinical Features and Their Correlation With Age at Onset in 94 Patients With EOPD
|
|
|
Sixty-five of 94 patients were treated with levodopa. Levodopa-induced dyskinesia and off-dystonia were observed in 21 (32%) and 30 (46%) of the levodopa-treated patients. The frequencies of LID (P=.008) and off-dystonia (P=.002) were negatively correlated with age at onset (Table 2).
|
|
|
|
Table 2. Clinical Features Related to Levodopa Treatment and Their Correlation With Age at Onset in 65 Patients With EOPD
|
|
|
Comparing the clinical characteristics between the younger group and the older group, disease duration was longer in the younger group. Both LID (P=.01) and off-dystonia (P=.02) were more frequently observed in the younger group. Treatment duration before developing off-dystonia was longer in the younger group than in the older group (P=.02). Other clinical characteristics evaluated were not significantly different in comparisons between the 2 groups (Table 3).
|
|
|
|
Table 3. Comparison of Clinical Variables Between the Younger Group and the Older Group*
|
|
|
CLINICAL FEATURES OF PATIENTS WITH PARKIN GENE MUTATIONS
Mutations in the parkin gene were detected in 3 (5%) of 55 patients, but none had the PINK1 gene mutation. The 3 patients with parkin gene mutations (patients 3, 18, and 65) were compound heterozygous for Ex2del/Ex7del, Ex2del/Ex11dup, and Ex3del/Ex7del, respectively (Figure and Table 4). Parkin gene mutations were confirmed by means of a real-time polymerase chain reaction method. No patients with parkin gene mutations had a family history of parkinsonism, and mean ± SD age at onset was younger than that in patients without parkin gene mutations (22.7 ± 14.2 vs 39.9 ± 6.5 years). The clinical features of patients with the PARK2 gene mutation are summarized in Table 4. Patient 18 received agonist monotherapy (ropinirole hydrochloride, 6 mg/d) with good response. DNA samples from the parents of patient 65 were available for segregation analysis and revealed that the proband's parents carried 1 of the 2 deletion mutations.
|
|
|
|
Figure. Compound heterozygous mutations in the parkin gene compared with control subjects. Patient 65 had deletions of exons 2 and 7, patient 3 had a duplication of exon 11 and a deletion of exon 2, and patient 18 had deletions of exons 3 and 7. Solid arrows indicate deletions; open arrow, duplication.
|
|
|
|
|
|
|
Table 4. Demographic and Clinical Features of the 3 Patients With Parkin Gene Mutations
|
|
|
COMMENT
In this study, the frequency of EOPD is consistent with that in previous studies5, 21 of EOPD with onset before age 40 years. The observed initial symptoms in patients with EOPD, including the preponderance of akinetic-rigidity or resting tremor, is still controversial.4, 22 In our patients with EOPD, resting tremor was the most frequent presenting symptom, although there was no correlation with age at onset.
In this study, despite the low frequency of dystonia as an initial symptom, the frequency of dystonia before levodopa treatment was 6.4%. Furthermore, off-dystonia occurred in up to 46.2% of patients. We found that the younger the age at onset, the more likely the presence of total dystonia, including off-dystonia. This finding is in agreement with previous studies.23
Corresponding with a previous study,4 these clinical data show that axial symptoms, such as gait disturbance, were of low frequency. Cognitive impairment was rarely observed in these patients with EOPD with longer disease duration. This finding is consistent with that of previous studies.5 These clinical data show a high frequency of autonomic dysfunction in EOPD, similar to those of Giovannini and colleagues.5 However, in contrast to a previous study,22 there was no correlation between autonomic dysfunction and age at onset.
Consistent with previous studies,1, 4-5 this study confirmed that most patients with EOPD have a good response to levodopa therapy. We also found that LID and off-dystonia were more frequently identified in the younger-onset group. Because of the longer disease duration in the younger group, we assume that an increased incidence of LID and off-dystonia may result from not only early age at onset but also long disease duration.
As a result of the gene-dosage analysis, we found 3 patients who were compound heterozygous for parkin gene mutations. In the present study, parkin gene mutations were less frequent than reported in previous studies, and no mutation was found in the PINK1 gene.3, 16, 24 A possible explanation is that most of the patients with EOPD were sporadic cases. It is also possible that there might be an ethnic difference in the genetic background of EOPD.
The clinical phenotype of patients with parkin gene mutations was similar to that of patients without parkin gene mutations. Therefore, patients with parkin gene mutations could not be distinguished on the basis of clinical features and were distinguished from the whole patient population only by genetic testing.
AUTHOR INFORMATION
Correspondence: Won Yong Lee, MD, PhD, Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Ilwon-Dong, Kangnam-Gu, Seoul, 135-710, Korea (wylee{at}smc.samsung.co.kr).
Accepted for Publication: March 10, 2006.
Author Contributions: Drs Chung and Ki contributed equally to this work. Study concept and design: Lee. Acquisition of data: Chung, Ki, Lee, I.-S. Kim, and J.-Y. Kim. Analysis and interpretation of data: Chung, Ki, and Lee. Drafting of the manuscript: Chung, Ki, Lee, I.-S. Kim, and J.-Y. Kim. Critical revision of the manuscript for important intellectual content: Ki and Lee. Statistical analysis: Chung. Obtained funding: Chung, Ki, and Lee. Administrative, technical, and material support: Ki, I.-S. Kim, and J.-Y. Kim. Study supervision: Lee.
Funding/Support: This work was supported by a grant from the IN-SUNG Foundation for Medical Research (Dr Lee) and by grant SBRI C-A5-102-1 from the Samsung Biomedical Research Institute (Dr Ki).
Author Affiliations: Departments of Neurology (Drs Chung, Lee, and J.-Y. Kim) and Laboratory Medicine (Drs Ki and I.-S. Kim), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
REFERENCES
| |
1. Quinn N, Critchley P, Marsden CD. Young onset Parkinson's disease. Mov Disord. 1987;2:73-91.
FULL TEXT
| PUBMED
2. Marder K, Levy G, Louis ED, et al. Familial aggregation of early- and late-onset Parkinson's disease. Ann Neurol. 2003;54:507-513.
FULL TEXT
|
ISI
| PUBMED
3. Hedrich K, Marder K, Harris J, et al. Evaluation of 50 probands with early-onset Parkinson's disease for Parkin mutations. Neurology. 2002;58:1239-1246.
FREE FULL TEXT
4. Gibb WR, Lees AJ. A comparison of clinical and pathological features of young- and old-onset Parkinson's disease. Neurology. 1988;38:1402-1406.
FREE FULL TEXT
5. Giovannini P, Piccolo I, Genitrini S, et al. Early-onset Parkinson's disease. Mov Disord. 1991;6:36-42.
FULL TEXT
|
ISI
| PUBMED
6. Pederzoli M, Girotti F, Scigliano G, Aiello G, Carella F, Caraceni T. L-dopa long-term treatment in Parkinson's disease: age-related side effects. Neurology. 1983;33:1518-1522.
FREE FULL TEXT
7. Tanner CM, Ottman R, Goldman SM, et al. Parkinson disease in twins: an etiologic study. JAMA. 1999;281:341-346.
FREE FULL TEXT
8. Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the -synuclein gene identified in families with Parkinson's disease. Science. 1997;276:2045-2047.
FREE FULL TEXT
9. Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;392:605-608.
FULL TEXT
| PUBMED
10. Wintermeyer P, Kruger R, Kuhn W, et al. Mutation analysis and association studies of the UCHL1 gene in German Parkinson's disease patients. Neuroreport. 2000;11:2079-2082.
ISI
| PUBMED
11. Valente 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;68:895-900.
FULL TEXT
|
ISI
| PUBMED
12. Bonifati V, Rizzu P, van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science. 2003;299:256-259.
FREE FULL TEXT
13. Funayama 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;51:296-301.
FULL TEXT
|
ISI
| PUBMED
14. Abbas N, Lucking CB, Ricard S, et al, French Parkinson's Disease Genetics Study Group and the 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;8:567-574.
FREE FULL TEXT
15. Kann M, Jacobs H, Mohrmann K, et al. Role of parkin mutations in 111 community-based patients with early-onset parkinsonism. Ann Neurol. 2002;51:621-625.
FULL TEXT
|
ISI
| PUBMED
16. Lucking CB, Durr A, Bonifati V, et al, 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;342:1560-1567.
FREE FULL TEXT
17. Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res. 2002;30:e57.
FREE FULL TEXT
18. Sellner LN, Taylor GR. MLPA and MAPH: new techniques for detection of gene deletions. Hum Mutat. 2004;23:413-419.
FULL TEXT
|
ISI
| PUBMED
19. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol. 1999;56:33-39.
FREE FULL TEXT
20. Kang YW, Na DL, Hahn S. The validity study on the Korean Mini-Mental State Examination (K-MMSE) in dementia patients. J Korean Neurol Assoc. 1997;15:300-307.
21. Zetusky WJ, Jankovic J, Pirozzolo FJ. The heterogeneity of Parkinson's disease: clinical and prognostic implications. Neurology. 1985;35:522-526.
FREE FULL TEXT
22. Muthane UB, Swamy HS, Satishchandra P, Subhash MN, Rao S, Subbakrishna D. Early onset Parkinson's disease: are juvenile- and young-onset different? Mov Disord. 1994;9:539-544.
FULL TEXT
|
ISI
| PUBMED
23. Kidron D, Melamed E. Forms of dystonia in patients with Parkinson's disease. Neurology. 1987;37:1009-1011.
FREE FULL TEXT
24. Paviour DC, Surtees RA, Lees AJ. Diagnostic considerations in juvenile parkinsonism. Mov Disord. 2004;19:123-135.
FULL TEXT
|
ISI
| PUBMED
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
|
