Parkinson disease was first described by James Parkinson in 1817. It is the second most common neurodegenerative disorder after Alzheimer disease (AD; 104300), affecting approximately 1% of the population over age 50 (Polymeropoulos et al., 1996).
... Parkinson disease was first described by James Parkinson in 1817. It is the second most common neurodegenerative disorder after Alzheimer disease (AD; 104300), affecting approximately 1% of the population over age 50 (Polymeropoulos et al., 1996). - Reviews Warner and Schapira (2003) reviewed the genetic and environmental causes of Parkinson disease. Feany (2004) reviewed the genetics of Parkinson disease and provided a speculative model of interactions among proteins implicated in PD. Lees et al. (2009) provided a review of Parkinson disease, with emphasis on diagnosis, neuropathology, and treatment. - Genetic Heterogeneity of Parkinson Disease Several gene loci implicated in autosomal dominant forms of Parkinson disease have been identified, including PARK1 (168601) and PARK4, due to mutation in or triplication of the alpha-synuclein gene (SNCA; 163890), respectively, on 4q22.1; PARK5 (191342), due to mutation in the UCHL1 gene on 4p14; PARK8 (607060), due to mutation in the LRRK2 gene (609007) on 12q12; PARK11 (607688), due to mutation in the GIGYF2 gene (612003) on 2q37; and PARK13 (610297), due to mutation in the HTRA2 gene (606441) on 2p12. PARK17 (614203) is caused by mutation in the VPS35 gene (601501) on chromosome 16q12, and PARK18 (614251) is caused by mutation in the EIF4G1 gene (600495) on chromosome 3q27. Several loci for autosomal recessive early-onset Parkinson disease have been identified: PARK2 (600116), caused by mutation in the gene encoding parkin (PARK2; 602544) on 6q25.2-q27; PARK6 (605909), caused by mutation in the PINK1 gene (608309) on 1p36; PARK7 (606324), caused by mutation in the DJ1 gene (PARK7; 602533) on 1p36; PARK14 (612953), caused by mutation in the PLA2G6 gene (603604) on 22q13; PARK15 (260300), caused by mutation in the FBXO7 gene (605648) on 22q12-q13; PARK19 (615528), caused by mutation in the DNAJC6 gene (608375) on 1p32; and PARK20 (615530), caused by mutation in the SYNJ1 gene (604297) on 21q22. PARK3 (602404) has been mapped to chromosome 2p13; PARK10 (606852) has been mapped to chromosome 1p34-p32; PARK16 (613164) has been mapped to chromosome 1q32. A locus on the X chromosome has been identified (PARK12; 300557). There is also evidence that mitochondrial mutations may cause or contribute to Parkinson disease (see 556500). Susceptibility to the development of the more common late-onset form of Parkinson disease has been associated with polymorphisms or mutations in several genes, including GBA (606463), MAPT (157140), MC1R (155555), ADH1C (103730), and genes at the HLA locus (see, e.g., HLA-DRA, 142860). Each of these risk factors independently may have a modest effect on disease development, but together may have a substantial cumulative effect (Hamza et al., 2010). Susceptibility to PD may also be conferred by expanded trinucleotide repeats in several genes causing other neurologic disorders usually characterized by spinocerebellar ataxia (SCA), including the ATXN2 (601517), ATXN3 (607047), TBP (600075), and ATXN8OS (603680) genes.
The diagnosis of classic idiopathic PD is primarily clinical, with manifestations including resting tremor, muscular rigidity, bradykinesia, and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The disease is progressive and usually has ... The diagnosis of classic idiopathic PD is primarily clinical, with manifestations including resting tremor, muscular rigidity, bradykinesia, and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The disease is progressive and usually has an insidious onset in mid to late adulthood. Pathologic features of classic PD include by a loss of dopaminergic neurons in the substantia nigra (SN) and the presence of Lewy bodies, intracellular inclusions, in surviving neurons in various areas of the brain, particularly the SN (Nussbaum and Polymeropoulos, 1997). Autosomal recessive juvenile Parkinson disease (PARK2; 600116), however, does not have Lewy body pathology (Nussbaum and Polymeropoulos, 1997). Many other diseases, both genetic and nongenetic, have parkinsonian motor features ('parkinsonism'), which most likely result from loss or dysfunction of the dopaminergic neurons in the SN, but may or may not have Lewy bodies on pathology. Thus, accurate diagnosis may be difficult without pathologic examination. Dementia with Lewy bodies (DLB; 127750) shows parkinsonism with Lewy bodies. However, parkinsonism without Lewy bodies characterizes progressive supranuclear palsy (PSP; 601104), frontotemporal dementia with parkinsonism (600274), autosomal dominant (128230) and recessive (605407) forms of Segawa syndrome, X-linked recessive Filipino type of dystonia (314250), multiple systems atrophy, and cerebrovascular disease.
Mutations in the LRRK2 gene (609007) and the GBA gene commonly predispose to PD in individuals of Ashkenazi Jewish descent. Gan-Or et al. (2010) screened a cohort of 600 Ashkenazi PD patients for the common LRRK2 G2019S mutation ... Mutations in the LRRK2 gene (609007) and the GBA gene commonly predispose to PD in individuals of Ashkenazi Jewish descent. Gan-Or et al. (2010) screened a cohort of 600 Ashkenazi PD patients for the common LRRK2 G2019S mutation (609007.0006) and for 8 GBA mutations. Among all patients, 117 (19.5%) were heterozygous for GBA mutations, and 82 (13.7%) were heterozygous for the LRRK2 G2019S mutation, including 8 patients carrying both GBA and LRRK2 mutations. There were 6 (1.0%) homozygotes or compound heterozygotes GBA mutations carriers, and 1 (0.2%) patient homozygote for G2019S. Carriers of LRRK2 G2019S or GBA mutations had a significantly earlier average age at onset (57.5 and 57.7 years) than noncarriers (61.0 years); the 8 with mutations in both genes had a similar average age at onset (57.4 years). A phenotypic comparison of those with the G2019S mutation, GBA mutations, and noncarriers of these mutations showed that more of those with the G2019S mutation reported muscle stiffness/rigidity (p = 0.007) and balance disturbances (p = 0.008), while more GBA mutation carriers reported slowness/bradykinesia (p = 0.021). However, the most common presenting symptom in both groups was tremor (about 50%). These results suggested distinct effects of LRRK2 or GBA mutations on the initial symptoms of PD in some cases.
Investigating the postulate that PD may have an environmental cause, Barbeau et al. (1985) noted that many potential neurotoxic xenobiotics are detoxified by hepatic cytochrome P450. They studied one such system in 40 patients with Parkinson disease and ... Investigating the postulate that PD may have an environmental cause, Barbeau et al. (1985) noted that many potential neurotoxic xenobiotics are detoxified by hepatic cytochrome P450. They studied one such system in 40 patients with Parkinson disease and 40 controls, and found that significantly more patients than controls had partially or totally defective 4-hydroxylation of debrisoquine (608902). Poor metabolizers had earlier onset of disease. Bordet et al. (1994) investigated a genetic polymorphism of the cytochrome P450 CYP2D6 gene (124030) in 105 patients with idiopathic Parkinson disease and 15 patients with diffuse Lewy body disease. They found no relationship between the CYP2D6 gene associated with poor metabolism of debrisoquine with either idiopathic Parkinson disease or diffuse Lewy body disease. Sandy et al. (1996) found no significant differences in CYP2D6 allelic frequencies between early-onset Parkinson disease cases (51 years of age or less) and controls. Kurth et al. (1993) found a single-strand conformation polymorphism in intron 13 of the monoamine oxidase B gene (309860) and found a significantly higher frequency of 1 allele in their parkinsonian population compared with the control group. Ho et al. (1995), however, were unable to substantiate this claim. Parboosingh et al. (1995) failed to find pathogenic mutations in either copper/zinc (147450) or manganese (147460) superoxide dismutase or in catalase (115500) in a single-strand conformation analysis of 107 unrelated patients with Parkinson disease, which included both familial and sporadic cases. Polymeropoulos (1997) noted that Polymeropoulos et al. (1997) had reported a total of 4 families in which mutation in the alpha-synuclein gene (SNCA; 163890) could be shown to be responsible for early-onset Parkinson disease. However, mutation was not detected in 50 individuals with sporadic Parkinson disease or in 2 other families with late onset of the illness. Wu et al. (2001) analyzed 224 Taiwanese patients with PD for MAOB intron 13 G (309860) and COMT L (V158M; 116790.0001) polymorphisms and found that the MAOB G genotype (G in men, G/G in women) was associated with a 2.07-fold increased relative risk for PD, an association which was stronger for men than for women. Although COMT polymorphism alone was not associated with an increased risk for PD, when it was considered in conjunction with the MAOB G genotype, there was a 2.4-fold increased relative risk for PD. In men, the combined alleles, MAOB G and COMT L, increased the relative risk for PD to 7.24. Wu et al. (2001) suggested that, in Taiwanese, the development of PD may be related to the interaction of 2 or more genes involved in dopamine metabolism. The demonstration of linkage of idiopathic Parkinson disease to 17q21 (Scott et al., 2001) made the tau gene (MAPT; 157140) a good candidate as a susceptibility gene for idiopathic PD. Martin et al. (2001) tested 5 single-nucleotide polymorphisms (SNPs) within the MAPT gene for association with PD in a sample of 1,056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center. They used family-based tests of association. The sample consisted of 426 affected and 579 unaffected family members; 51 individuals had unclear PD status. Both individual SNPs and SNP haplotypes in the MAPT gene were analyzed. Significant evidence of association was found for 3 of the 5 SNPs tested. Strong evidence of association was found with haplotype analysis, with a positive association with 1 haplotype (p = 0.009) and a negative association with another haplotype (p = 0.007). Substantial linkage disequilibrium (p less than 0.001) was detected between 4 of the 5 SNPs. The study was interpreted as implicating MAPT as a susceptibility gene for idiopathic Parkinson disease. Kwok et al. (2005) identified 2 functional SNPs in the GSK3B (605004) gene that influenced GSK3B transcriptional activity and correlated with enhanced phosphorylation of MAPT in vitro, respectively. Conditional logistic regression analysis of the genotypes of 302 Caucasian PD patients and 184 Chinese PD patients found an association between the GSK3B polymorphisms, MAPT haplotype, and risk of PD. Kwok et al. (2005) concluded that GSK3B polymorphisms interact with MAPT haplotypes to modify disease risk in PD. Among 52 Finnish patients with PD, Mattila et al. (2002) found an increased frequency of the interleukin 1-beta gene (IL1B; 147720) -511 polymorphism compared to controls (allele frequency of 0.96 in PD and 0.73 in controls; p = 0.001). The calculated relative risk of PD for patients carrying at least one IL1B allele was 8.8. West et al. (2002) reported that a single-nucleotide polymorphism within the parkin core promoter, -258T/G, is located in a region of DNA that binds nuclear protein from human substantia nigra in vitro, and functionally affects gene transcription. In a population-based series of 296 PD cases and 184 controls, the -258G allele was associated with idiopathic PD (odds ratio 1.52, P less than 0.05). Excess of nitric oxide (NO) has been shown to exert neurotoxic effects in the brain. Moreover, inhibition of 2 enzyme isoforms of nitric oxide synthase (NOS; see 163731), neuronal NOS (nNOS) and inducible NOS (iNOS), results in neuroprotective effects in the MPTP model of PD. Levecque et al. (2003) performed a community-based case-control study of 209 PD patients enrolled in a French health insurance organization for agricultural workers and 488 European controls. Associations were observed with a G-to-A polymorphism in exon 22 of iNOS, designated iNOS 22 (OR for AA carriers, 0.50; 95% CI, 0.29-0.86; p = 0.01), and a T-to-C polymorphism in exon 29 of nNOS, designated nNOS 29 (OR for carriers of the T allele, 1.53; 95% CI, 1.08-2.16; p = 0.02). No association was observed with a T-to-C polymorphism in exon 18 of nNOS, designated nNOS 18. Moreover, a significant interaction of the nNOS polymorphisms with current and/or past cigarette smoking was found (nNOS 18, p = 0.05; nNOS 29, p = 0.04). Levecque et al. (2003) suggested that NOS1 may be a modifier gene in PD. Chan et al. (2003) found that the slow acetylator (243400) genotype for N-acetyltransferase-2 (NAT2; 612182) was associated with PD in Hong Kong Chinese. The frequency of slow acetylator genotype was significantly higher in 99 patients with PD than in 126 control subjects (68.7% vs 28.6%) with an odds ratio of 5.53 after adjusting for age, sex, and smoking history. In a subgroup analysis, smoking had no modifying effect on the association between genotype and PD. In 2 apparently sporadic patients with Parkinson disease, Marx et al. (2003) found an arg621-to-cys (R621C) mutation in synphilin-1 (603779.0001). Li et al. (2002) reported genetic linkage of a locus controlling age at onset in Alzheimer disease (AD; 104300) and PD to a 15-cM region on chromosome 10q. Li et al. (2003) combined gene expression studies on hippocampus obtained from AD patients and controls with their previously reported linkage data to identify 4 candidate genes. Allelic association studies for age-at-onset effects in 1,773 AD patients and 1,041 relatives and 635 PD patients and 727 relatives further limited association to GSTO1 (605482) (p = 0.007) and a second transcribed member of the GST omega class, GSTO2 (612314) (p = 0.005), located next to GSTO1. The authors suggested that GSTO1 may be involved in the posttranslational modification of IL1B. Theuns et al. (2006) pointed out that it is widely accepted that genetic causes of susceptibility to complex diseases reflect a different spectrum of sequence variants than mutations that dominate monogenic disorders. This spectrum includes mutations that alter gene expression; in particular, promoter mutations have been shown to result in inherited diseases, including neurodegenerative brain diseases. They pointed to the fact that in Parkinson disease, 2 variants in the 5-prime regulatory region of NR4A2 (601828.0001 and 601828.0002) were found to be associated with familial PD and markedly reduced NR4A2 mRNA levels. Also, multiple association studies showed that variations in the 5-prime regulatory regions of SNCA (163890) and PARK2 (602544) increase PD susceptibility, with some variations increasing disease risk by modulating gene transcription. In Alzheimer disease (104300), promoter mutations in PSEN1 (104311) can explain the increased risk for early-onset AD by decreasing expression levels of PSEN1 in neurons. Considering 4 putative PD risk regions, SNCA, MAPT, GAK, and HLA-DRA in 2,000 late-onset PD patients and 1,986 unaffected controls from the NGRC population, Hamza et al. (2010) found that the risk of Parkinson disease was doubled for individuals who had 4 risk alleles (OR of 2.49, p = 6.5 x 10(-8)), and was increased 5-fold for individuals who had 6 or more risk alleles (OR of 4.95, p = 5.5 x 10(-13)). These findings supported the notion that Parkinson disease risk is due to cumulative effects of risk factors that each have a modest individual effect. - Association with the Glucocerebrosidase (GBA) Gene An association has been reported between parkinsonism and type I Gaucher disease (230800) (Neudorfer et al., 1996; Tayebi et al., 2001; Bembi et al., 2003), the most prevalent, recessively inherited disorder of glycolipid storage. Simultaneous occurrence of Parkinson disease and Gaucher disease is marked by atypical parkinsonism generally presenting by the fourth through sixth decades of life. The combination progresses inexorably and is refractory to conventional anti-Parkinson therapy (Varkonyi et al., 2003). Aharon-Peretz et al. (2004) studied the association of Parkinson disease with Gaucher disease, which is caused by mutation in the GBA gene (606463), which encodes the lysosomal enzyme glucocerebrosidase. They screened 99 Ashkenazi patients with idiopathic Parkinson disease, 74 Ashkenazi patients with Alzheimer disease, and 1,543 healthy Ashkenazi Jews for the 6 GBA mutations that are most common among Ashkenazi Jews. One or 2 mutant GBA alleles were found in 31 patients with Parkinson disease (31.3%): 28 were heterozygous and 3 were homozygous for one of these mutations. Among the 74 patients with Alzheimer disease, 3 (4.1%) were carriers of Gaucher disease. Among the 1,543 controls, 95 (6.2%) were carriers of Gaucher disease. Patients with Parkinson disease had significantly greater odds of being carriers of Gaucher disease than did patients with Alzheimer disease (OR = 10.8) or controls (OR = 7.0). Among the patients with Parkinson disease, those who were carriers of Gaucher disease were younger than those who were not carriers (mean age at onset, 60.0 years vs 64.2 years, respectively). Aharon-Peretz et al. (2004) suggested that some GBA mutations are susceptibility factors for Parkinson disease. Toft et al. (2006) did not find an association between PD and 2 common GBA mutations (L444P; 606463.0001 and N370S; 606463.0003) among 311 Norwegian patients with Parkinson disease. Mutant GBA alleles were identified in 7 (2.3%) patients and 8 (1.7%) controls. Tan et al. (2007) identified a heterozygous GBA L444P mutation in 8 (2.4%) of 331 Chinese patients with typical Parkinson disease and none of 347 controls. The age at onset was lower and the percentage of women higher in patients with the L444P mutation compared to those without the mutation. Tan et al. (2007) noted that the findings were significant because Gaucher disease is extremely rare among the Chinese. Gan-Or et al. (2008) found that 75 (17.9%) of 420 Ashkenazi Jewish patients with PD carried a GBA mutation, compared to 4.2% of elderly and 6.35% of young controls. The proportion of severe GBA mutation carriers among patients was 29% compared to 7% among young controls. Severe and mild GBA mutations increased the risk of developing PD by 13.6- and 2.2-fold, and were associated with decreased age at PD onset. Gan-Or et al. (2008) concluded that genetic variance in the GBA gene is a risk factor for PD. Gutti et al. (2008) identified the GBA L444P mutation in 4 (2.2%) of 184 Taiwanese patients with PD. Six other GBA variants were identified in 1 patient each, yielding a total of 7 different mutations in 10 patients (5.4%). Gutti et al. (2008) suggested that sequencing the entire GBA gene would reveal additional variants that may contribute to PD. Mata et al. (2008) identified heterozygosity for either the GBA L444P or N370S mutation in 21 (2.9%) of 721 PD patients, 2 (3.5%) of 57 patients with Lewy body dementia, and 2 (0.4%) of 554 control subjects individuals, all of European origin. Mata et al. (2008) estimated that the population-attributable risk for GBA mutations in Lewy body disorders was only about 3% in patients of European ancestry. In a 16-center worldwide study comprising 5,691 PD patients (including 780 Ashkenazi Jewish patients) and 4,898 controls (387 Ashkenazis), Sidransky et al. (2009) demonstrated a strong association between GBA mutations and Parkinson disease. Direct sequencing for only the L444P or N370S mutations identified either mutation in 15% of Ashkenazi patients and 3% of Ashkenazi controls. Among non-Ashkenazi individuals, either mutation was found in 3% of patients and less than 1% of controls. However, full gene sequencing identified GBA mutations in 7% of non-Ashkenazi patients. The odds ratio for any GBA mutation in patients compared to controls was 5.43 across all centers. Compared to PD patients without GBA mutations, patients with GBA mutations presented earlier with the disease, were more likely to have affected relatives, and were more more likely to have atypical manifestations, including cognitive defects. Sidransky et al. (2009) concluded that while GBA mutations are not likely a mendelian cause of PD, they do represent a susceptibility factor for development of the disorder. Neumann et al. (2009) identified 14 different heterozygous mutations in the GBA gene, in 33 (4.18%) of 790 British patients with Parkinson disease and in 3 (1.17%) of 257 controls. Three novel mutations (see, e.g., D443N; 606463.0048) were identified, and most common mutations were L444P (in 11 patients), N370S (in 8 patients), and R463C (in 3 patients; 606463.0008). Four (12%) patients had a family history of the disorder, whereas 29 (88%) had sporadic disease. The mean age at onset was 52.7 years, and 12 (39%) patients had onset before age 50. Fifteen (about 50%) patients with GBA mutations developed cognitive decline, including visual hallucinations. The male to female ratio of GBA carriers within the PD group was 5:2, which was significantly higher than that of the whole study group. Most patients responded initially to L-dopa treatment. Neuropathologic examination of 17 GBA mutation carriers showed typical PD changes, with widespread and abundant alpha-synuclein pathology, and most also had neocortical Lewy body pathology. The prevalence of GBA mutations in British patients with sporadic PD was 3.7%, indicating that mutations in the GBA gene may be the most common risk factor for development of PD in this population. In an accompanying letter, Gan-Or et al. (2009) found that the data presented by Neumann et al. (2009) indicated that patients with mild GBA mutations had a later age at onset (62.9 years vs 49.8 years) and lower frequency of cognitive symptoms (25% vs 55.6%) compared to patients with severe GBA mutations. Alcalay et al. (2010) identified mutations in the GBA gene in 64 (6.7%) of 953 patients with early-onset PD before age 51, including 77 and 139 individuals of Hispanic and Jewish ancestry, respectively. There were 18 heterozygous L444P carriers, 38 heterozygous N370S carriers, and 2 homozygous N370S carriers. Six of the 64 patients had a GBA mutation and another mutation in the LRRK2 or PRKN (PARK2; 602544) genes. - Modifier Genes Plaitakis et al. (2010) identified a 1492T-G polymorphism in the GLUD2 gene (S445A; 300144.0001) that was associated with earlier age of onset in 2 cohorts of patients with Parkinson disease. Among 584 Greek patients, 1492G hemizygous males developed PD 8 to 13 years earlier than did patients with the T (p = 0.003), the G/T (p less than 0.001), or the T/T (p = 0.01) genotype. Among 224 North American patients, 1492G hemizygotes also developed PD earlier than those with other genotypes, but the mean age differences reached statistical significance only when G hemizygotes were compared to G/T heterozygotes (mean age difference: 13.1 years, p less than 0.05). The substitution was demonstrated to confer a gain of function, which Plaitakis et al. (2010) postulated may increase glutamate oxidation and the production of reactive oxygen species in the brain.
Trenkwalder et al. (1995) used a door-to-door survey to investigate the prevalence of parkinsonism in a rural Bavarian population of individuals older than 65 years. In this population, the prevalence of Parkinson disease was 0.71%; drug-induced parkinsonism, 0.41%; ... Trenkwalder et al. (1995) used a door-to-door survey to investigate the prevalence of parkinsonism in a rural Bavarian population of individuals older than 65 years. In this population, the prevalence of Parkinson disease was 0.71%; drug-induced parkinsonism, 0.41%; vascular parkinsonism, 0.20%; multiple systems atrophy, 0.31%; Fahr disease, 0.10%; and normal pressure hydrocephalus, 0.41%. Fifty percent of these cases were newly diagnosed. In a community-based survey of Singaporeans (9,000 Chinese, 3,000 Malays, and 3,000 Indians) aged 50 years and older, Tan et al. (2004) found that the prevalence rate of PD was approximately 0.30%, which is comparable to that of Western countries. In a study of over 14,000 twin pairs in the Swedish Twin Registry, Wirdefeldt et al. (2004) found that only 2 twin pairs were concordant for PD, suggesting that environmental factors were more important in the development of the disease in this population.