Parkinson Disease, Late-Onset

A number sign (#) is used with this entry because of evidence that late-onset or sporadic Parkinson disease (PD) can have more than one genetic and/or environmental cause.

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 loci for autosomal dominant Parkinson disease have been identified, including PARK1 (168601) and PARK4, caused by mutation in or triplication of the alpha-synuclein gene (SNCA; 163890), respectively, on 4q22; PARK5 (191342), caused by mutation in the UCHL1 gene on 4p13; PARK8 (607060), caused by mutation in the LRRK2 gene (609007) on 12q12; PARK11 (607688), caused by mutation in the GIGYF2 gene (612003) on 2q37; PARK13 (610297), caused by mutation in the HTRA2 gene (606441) on 2p13; PARK17 (614203), caused by mutation in the VPS35 gene (601501) on 16q11; and PARK18 (614251), caused by mutation in the EIF4G1 gene (600495) on 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 6q26; 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; PARK19A (615528) and PARK19B (see 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. See also PARK21 (616361). 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 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.

In a retrospective analysis, Paleacu et al. (2005) found that 76 (32%) of 234 PD patients reported hallucinations. All experienced visual hallucinations, most commonly of human images, and 6 also reported mood congruent auditory hallucinations. The presence of hallucinations was correlated with family history of dementia and lower scores on the Mini-Mental State Examination (MMSE). Neither the dose nor duration of L-DOPA treatment was a significant variable for hallucinations.

Using PET scan, Ballanger et al. (2010) showed that 7 PD patients with visual hallucinations had increased binding to serotonin 2A receptors (HTR2A; 182135) in the ventral visual pathway compared to 7 PD patients without visual hallucinations. Areas of the ventral visual pathway that showed increased HTR2A binding included the bilateral inferooccipital gyrus, the right fusiform gyrus, and the inferotemporal cortex. The findings suggested that abnormalities in serotonin 2A receptor neurotransmission may be involved in the pathogenesis of visual hallucinations in PD.

Using single-photon emission CT with a radiolabeled ligand for several beta-2 (CHRNB2; 118507)-containing nicotinic acetylcholine receptors (nAChR), Fujita et al. (2006) showed that 10 nondemented PD patients had a widespread significant global decrease in nAChRs compared to 15 controls. The most significant decrease was in the thalamus.

Some studies have observed an increased risk of Parkinson disease among individuals with melanoma (155600) (see, e.g., Constantinescu et al., 2007 and Ferreira et al., 2007), suggesting that pigmentation metabolism may be involved in the pathogenesis of PD. From 2 existing study cohorts of 38,641 men and 93,661 women who were free of PD at baseline, Gao et al. (2009) found an association between decreasing darkness of natural hair color in early adulthood and increased PD risk. The pooled relative risks (RR) for PD were 1.0 (reference risk), 1.40, 1.61, and 1.93 for black, brown, blond, and red hair, respectively. These results were significant after adjusting for age, smoking, ethnicity, and other covariates. The associations between hair color and PD were particularly strong for onset before age 70 years. In a case-control study of 272 PD cases and 1,185 controls, there was an association between the cys151 SNP of the MC1R gene (R151C; 155555.0004), which confers red hair, and increased risk of PD relative to the arg151 SNP (relative risk of 3.15 for the cys/cys genotype). Noting that melanin, like dopamine, is synthesized from tyrosine, and that PD is characterized by the loss of neuromelanin-containing neurons in the substantia nigra, Gao et al. (2009) postulated a link between pigmentation and development of PD. Hernandez (2009) independently noted the association. Dong et al. (2014) did not find a significant association between the R151C MC1R variant and Parkinson disease in 2 large datasets of 808 PD patients and 1,623 controls and 5,333 PD patients and 12,019 controls. All the participants were non-Hispanic whites. Tell-Marti et al. (2015) did not find a significant association between the R151C MC1R variant and Parkinson disease among 870 Spanish PD patients and 736 controls.

In a study of 157,036 individuals, who did not have PD at baseline, over a 14 to 20-year follow-up period, Gao et al. (2009) identified 616 incident PD cases. A family history of melanoma in a first-degree relative was associated with a higher risk of PD (RR, 1.85; p = 0.004) after adjusting for smoking, ethnicity, caffeine intake, and other covariates. There was no association between a family history of colorectal, lung, prostate, or breast cancer and PD risk. The findings supported the notion that melanoma and Parkinson disease share common genetic components.

There has been much controversy regarding the genetics of Parkinson disease, as no specific pattern of inheritance is readily apparent, and reports of Parkinson disease and parkinsonism may not necessarily refer to the same disease entity (Nussbaum and Polymeropoulos, 1997). However, a familial component to Parkinson disease and parkinsonism has long been recognized.

Gowers (1900) is believed to have been the first to observe that patients with PD often had an affected relative, and he suggested that hereditary factors may be important. Bell and Clark (1926) reviewed published pedigrees of 'paralysis agitans' and reported an additional one. Allan (1937) described impressive pedigrees from North Carolina.

Twin Studies

Kissel and Andre (1976) described a pair of female MZ twins, both of whom had a combination of parkinsonism and anosmia. Olfactory impairment is frequent in PD (Ward et al., 1983). Both twins reported onset of symptoms at age 36 years, which is unusually early, particularly for women (Kessler, 1978). Kissel and Andre (1976) noted that 2 families with the same association had previously been reported and they suggested a causative role for a genetically determined anomaly of dopamine metabolism.

Duvoisin et al. (1981) found zero concordance for Parkinson disease in the first 12 monozygotic twin pairs examined in an on-going twin study. There was evidence of premorbid personality differences between probands and cotwins dating back to late adolescence or early adult years. Among 43 monozygotic and 19 dizygotic twin pairs, Ward et al. (1983) found that only 1 monozygotic twin pair was definitely concordant for PD. Ward et al. (1983) noted that concordance for PD is no more frequent in twins than would be expected from the incidence of the disease, and concluded that major factors in the etiology of PD must be nongenetic.

Mendelian Inheritance

Spellman (1962) described a family in which multiple members in 4 generations had parkinsonism beginning in their thirties and progressing rapidly to death in 2 to 12 years. Tune et al. (1982) described Parkinson disease in 4 persons in 3 generations. Several of these also had manic-depressive illness.

Barbeau and Pourcher (1982, 1983) suggested that mendelian inheritance obtains in some cases, particularly in those whose illness started before the age of 40. In this early-onset group, there was a 46% incidence of familial cases. They divided Parkinson disease into 4 etiologic categories: postencephalitic, idiopathic, genetic, and symptomatic. They proposed the existence of 2 genetic subtypes: an akineto-rigid subtype transmitted as an autosomal recessive and a subtype with prominent tremor, dominant inheritance, and a high prevalence of family members with essential tremor.

Lazzarini et al. (1994) found that the cumulative risk of PD among sibs of probands with affected parents was increased significantly over that for sibs of probands without affected parents, suggesting significant familial aggregation in a subset of randomly ascertained families. Furthermore, in 80 multicase families, age-adjusted ratios approaching 0.5 and similar proportions of affected parents and sibs, as well as the distribution of ancestral secondary cases, were compatible with an autosomal dominant mode of inheritance with reduced penetrance in a subset of PD. Payami et al. (1995) studied age of onset of 137 patients with idiopathic Parkinson disease. The 21 probands with an affected parent, aunt, or uncle were younger at onset of PD (47.7 +/- 8.8 years) than were the 11 probands with an affected sib only (60.3 +/- 12.9 years) and the 105 probands with no affected relatives (59.2 +/- 11.4 years). Age of onset of affected family members differed significantly between generations (p = 0.0001) and was earlier, by an average of 17 years, in the proband generation than in the parental generation. The data were consistent with genetic anticipation and suggested the involvement of an unstable trinucleotide repeat. Markopoulou et al. (1995) studied a Greek-American kindred with 98 individuals in 6 generations. Sixteen individuals in 3 generations developed parkinsonism, which appeared to be transmitted in an autosomal dominant manner with evidence of anticipation. No pathologic data were presented.

Plante-Bordeneuve et al. (1995) studied 14 families in which the proband and at least one relative were affected by clinically typical Parkinson disease, based on Parkinson Disease Society brain bank diagnostic criteria (Hughes et al., 1992). No clinical differences were found between 31 individuals with familial Parkinson disease and 31 age-matched sporadic Parkinson disease controls. In the 14 families, genetic transmission was compatible with autosomal dominant transmission with several cases of male-to-male transmission. Although the total segregation ratio was 0.25, this was age-dependent, with a penetrance of zero below age 30 and a penetrance of 0.43 over the age of 70. Age at onset was identical within a generation but it was 26 +/- 4.6 years earlier in children than parents of the 8 multigenerational kindreds studied, suggesting an anticipation phenomenon.

Bonifati et al. (1995) used epidemiologic methods to determine the frequency of clinical features of familial Parkinson disease. By studying 100 consecutive Parkinson disease cases presenting to their clinic, family history for Parkinson disease was positive in 24% of Parkinson disease cases and in only 6% of spouse controls. In a larger study of 22 nonconsecutive Parkinson disease families with at least 2 living and personally examined cases, the crude segregation ratios were similar for parents and sibs, with lifetime cumulative risks approaching 0.4. These data supported autosomal dominant inheritance with a strong age factor in penetrance.

Nussbaum and Polymeropoulos (1997) reviewed the genetics of Parkinson disease. They stated that for the previous 40 years, research into Parkinson disease had predominantly been the province of epidemiologists interested in pursuing the connection between the disorder and environmental factors such as viral infection or neurotoxins. Hereditary influences were discounted because of a high discordance rate among monozygotic twins found in studies that were later shown to be inadequate and inconclusive. On the other hand, a positive family history was recognized as a major risk factor for the disease and it became increasingly apparent from neuropathologic studies that the common, idiopathic form of Parkinson disease had a specific pathologic correlate in the form of Lewy bodies, an eosinophilic cytoplasmic inclusion body, distributed diffusely throughout the substantia nigra, hypothalamus, hippocampus, autonomic ganglia, and olfactory tracts. They referred to the 'particularly prescient paper' of Sommer and Rocca (1996), in which the authors suggested that autosomal dominant PD may be caused by a missense mutation in a cellular protein that changes its physical-chemical properties, leading to accumulation of the abnormal protein and neuronal death. This hypothesis has received substantial support.

Maher et al. (2002) collected information involving the nuclear families of 948 consecutively ascertained Parkinson disease index cases from 3 U.S. medical centers. They performed segregation analysis to assess evidence for the presence of a mendelian pattern of familial transmission. The proportion of male (60.4%) and female (39.6%) cases, the mean age of onset (57.7 years), and the proportion of affected fathers (4.7%), mothers (6.6%), brothers (2.9%), and sisters (3.2%) were similar across the 3 institutions. They concluded that the analyses supported the presence of a rare major mendelian gene for PD in both the age-of-onset and susceptibility model. The age-of-onset model provided evidence for a gene that influences age-dependent penetrance of PD, influencing age of onset rather than susceptibility. Maher et al. (2002) also found evidence for a mendelian gene influencing susceptibility to the disease. It was not evident whether these 2 analyses were modeling the same gene or different genes with different effects on PD. Genes influencing penetrance may interact with environmental factors or other genes to increase the risk of PD. Such gene-environment interactions, involving reduced penetrance in PD, may explain the low concordance rates among monozygotic twins for this disorder.

In a comparison of 221 PD patients with age at onset of 50 years or younger, 266 PD patients with age at onset of 50 years or greater, and 409 unaffected controls, Marder et al. (2003) found a similar relative risk (RR) of PD among first-degree relatives of both the early- and late-onset groups (RR = 2.9 and 2.7, respectively) compared to those of controls. There was also an increased risk of PD in sibs of affected patients (RR = 7.9 for early-onset and 3.6 for late-onset) compared to those of controls. Parents of the early-onset group were not at a significantly increased risk compared to those of controls (RR = 1.7), and parents of the late-onset group were at a higher increased risk compared to those of controls (RR = 2.5). Marder et al. (2003) concluded that the pattern was consistent with an autosomal recessive contribution to the inheritance of early- but not late-onset PD, but also noted that genetic factors are important in both groups.

'Familial Component'

Zareparsi et al. (1998) performed complex segregation analyses using kindreds of 136 Parkinson disease patients randomly ascertained from a clinic population. They rejected the hypotheses of a nontransmissible environmental factor, a major gene or type (sporadic), and all mendelian inheritance (dominant, recessive, additive, decreasing). They concluded that familial clustering of PD in this dataset was best explained by a 'rare familial factor' which is transmitted in a nonmendelian fashion and influences the age at onset of PD.

Montgomery et al. (1999) used a previously reported PD test battery to check for mild signs of motor slowing, impaired sense of smell, and depressed mood in first-degree relatives of patients with Parkinson disease, most of whom were considered sporadic cases. Abnormalities on the test battery were found in 22.5% of first-degree relatives, all of whom were judged normal on standard neurologic examination, but in only 9% of age-matched controls. The authors interpreted this familial clustering of minimal parkinsonian tendencies as an indication of genetic predisposition to Parkinson disease even in sporadic cases.

Sveinbjornsdottir et al. (2000) reviewed the medical records and confirmed the diagnosis of Parkinson disease in 772 living and deceased patients in whom the diagnosis had been made in Iceland during the previous 50 years. With the use of an extensive computerized database containing genealogic information on 610,920 people in Iceland over the past 11 centuries, they conducted several analyses to determine whether the patients were more related to each other than random members of the population. They found that there was a genetic component to Parkinson disease, including a subgroup of 560 patients with late-onset disease (onset after 50 years of age): patients with Parkinson disease were significantly more related to each other than were subjects in matched groups of controls, and this relatedness extended beyond the nuclear family. There was no highly penetrant mendelian pattern of inheritance, and both early and late-onset forms often skipped generations. The risk ratio for Parkinson disease was 6.7 for sibs, 3.2 for offspring, and 2.7 for nephews and nieces of patients with late-onset Parkinson disease.

Racette et al. (2002) described a very large Amish pedigree with classic idiopathic Parkinson disease in multiple members. They examined 113 members and classified 67 as having no evidence of PD, 17 as clinically definite PD, 6 as clinically probable PD, and 23 as clinically possible PD. The mean age at onset of the clinically definite subjects was 56.7 years. The mean kinship coefficient in the subjects with PD and those with PD by history was higher (p = 0.007) than in a group of age-matched normal Amish control subjects, providing evidence that PD is inherited in this family. Sequence analysis did not reveal any mutations in known PD genes. No single haplotype cosegregated with the disease in any of the chromosomal regions previously found to be linked to PD.

Environmental Factors

Some findings suggest that environmental factors may be more important than genetic factors in familial aggregation of Parkinson disease. Calne et al. (1987) reported 6 families in which onset of symptoms tended to occur at approximately the same time regardless of the age of the patient. In a hospital-based survey, Teravainen et al. (1986) concluded that there is a trend toward lower age of onset of Parkinson disease.

Calne and Langston (1983) advanced the view that in most cases the cause is an environmental factor, possibly toxic, superimposed on a background of slow, sustained neuronal loss due to advancing age. Finding parkinsonism in 1-methyl-4-phenyl-1,2,3,6-tetrahydropteridine (meperidine; MPTP) drug users (Langston et al., 1983) revived interest in reexamining environmental factors. Barbeau et al. (1985) also postulated that Parkinson disease is the result of environmental factors acting on genetically susceptible persons against a background of 'normal' aging.

Nathans (2005) noted the remarkable coincidence that the abbreviation MPTP, for the drug that causes Parkinson disease by selectively damaging dopaminergic neurons, is coincidentally the code for the first 4 amino acids of human, mouse, and rat tyrosine hydroxylase, the enzyme which marks all dopaminergic neurons.

In a case-control study of 418 Chinese PD patients and 468 controls, Tan et al. (2007) found a significant association between caffeine intake and decreased risk of PD (p = 2.01 x 10(-5)). The odds ratio was 0.48 for moderate and high caffeine intake and 0.71 for low intake. No difference was observed with genotyping for a common SNP in the CYP1A2 gene (124060), which influences the level of caffeine metabolism. The findings suggested that caffeine and its main metabolite paraxanthine are both neuroprotective.

Multifactorial Inheritance

Analysis of the experience at the Mayo Clinic led Kondo et al. (1973) to conclude that irregular dominant transmission is untenable and that multifactorial inheritance with heritability of about 80% is more likely. Young et al. (1977) favored multifactorial inheritance but could not exclude autosomal dominance with reduced penetrance, especially for some families. Affected relatives were bilaterally distributed more often than would be expected for autosomal dominance.

Vaughan et al. (2001) reviewed the genetics of parkinsonism. They suggested that nigral degeneration with Lewy body formation and the resulting clinical picture of Parkinson disease may represent a final common pathway of a multifactorial disease process in which both environmental and genetic factors have a role.

Also see review of Parkinson disease by Nussbaum and Ellis (2003).

Mitochondrial Inheritance

Another theory of parkinsonism suggests that genetic predisposition may be transmitted through mitochondrial inheritance (Di Monte, 1991); see 556500. Schapira (1995) reviewed nuclear and mitochondrial genetics in Parkinson disease. He stated that Gowers (1900) had noted the occurrence of PD in relatives and suggested that hereditary factors are important.

From a study of Parkinson disease in twins, Tanner et al. (1999) concluded that 'no genetic component was evident when the disease begins after age 50 years.' Parker et al. (1999) and Simon (1999) pointed out that whereas this may be true as far as mendelian (nuclear) genetic mechanisms are concerned, this may not be true for mitochondrial factors in Parkinson disease. Since MZ and DZ twins each receive all of their mitochondrial DNA from their mother, differences in concordance rates between MZ and DZ twins cannot be used to address the potential influence of mitochondrial genetic factors.

To test the hypothesis that mitochondrial variation contributes to Parkinson disease expression, van der Walt et al. (2003) genotyped 10 single-nucleotide polymorphisms that define the European mitochondrial DNA haplogroups in 609 white patients with Parkinson disease and 340 unaffected white control subjects. Overall, individuals classified as haplogroup J (odds ratio = 0.55; 95% CI 0.34-0.91; p = 0.02) or K (odds ratio = 0.52; 95% CI 0.30-0.90; p = 0.02) demonstrated a significant decrease in risk of Parkinson disease versus individuals carrying the most common haplogroup H. Furthermore, a specific SNP that defines these 2 haplogroups, 10398G (516002.0002), is strongly associated with this protective effect (odds ratio = 0.53; 95% CI 0.39-0.73; p = 0.0001). The 10398G SNP causes a nonconservative amino acid change from threonine to alanine within the ND3 (516002) of complex I. After stratification by sex, this decrease in risk appeared stronger in women than in men. In addition, the 9055A SNP of ATP6 (516060) demonstrated a protective effect for women. Van der Walt et al. (2003) concluded that ND3 is an important factor in Parkinson disease susceptibility among white individuals and could help explain the role of complex I in Parkinson disease expression.

Gill et al. (2003) delivered glial cell line-derived neurotrophic factor (GDNF; 600837) directly into the putamen of 5 Parkinson patients in a phase 1 safety trial. One catheter needed to be repositioned and there were changes in the MRIs that disappeared after lowering the concentration of GDNF. After 1 year, there were no serious clinical side effects, a 39% improvement in the off-medication motor subscore of the Unified Parkinson Disease Rating Scale (UPDRS), and a 61% improvement in the activities of daily living subscore. Medication-induced dyskinesias were reduced by 64% and were not observed off medication during chronic GDNF delivery. Positron emission tomography (PET) scans of [18F]dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, suggesting a direct effect of GDNF on dopamine function.

Voon et al. (2007) evaluated 21 patients with Parkinson disease who developed pathologic gambling (606349) after receiving pharmacologic treatment with dopaminergic agonists. Compared to 42 PD patients without compulsive behaviors, those who developed pathologic gambling had a younger age at PD onset, higher novelty seeking (601696), tended to have medication-induced hypomania or mania, impaired planning, and a personal or family history of alcohol use disorders (103780).

L-DOPA is predominantly metabolized to the inactive 3-O-methyldopa by COMT (116790). Entacapone is a COMT inhibitor that acts to prolong the half-life of L-DOPA and yields prolonged therapeutic benefits. A val158-to-met (V158M) polymorphism in the COMT gene (rs4680; 116790.0001) confers increased (val) or decreased (met) COMT activity. In a randomized control trial of 33 PD patients, Corvol et al. (2011) found that those homozygous for the high-activity val158 allele had significantly increased COMT inhibition by entacapone and significantly better bioavailability of and clinical response to L-DOPA compared to patients homozygous for the low-activity met158 allele. The findings indicated that homozygosity for the val158 allele in PD patients enhances the effect of entacapone on the pharmacodynamics and pharmacokinetics of levodopa. The response to entacapone in heterozygous patients was not studied.

Using unbiased phenotypic screens as an alternative to target-based approaches, Tardiff et al. (2013) discovered an N-aryl benzimidazole (NAB) that strongly and selectively protected diverse cell types from alpha-synuclein (163890) toxicity. Three chemical genetic screens in wildtype yeast cells established that NAB promoted endosomal transport events dependent on the E3 ubiquitin ligase Rsp5 (NEDD4; 602278). These same steps were perturbed by alpha-synuclein itself. Tardiff et al. (2013) concluded that NAB identifies a druggable node in the biology of alpha-synuclein that can correct multiple aspects of its underlying pathology, including dysfunctional endosomal and endoplasmic reticulum-to-Golgi-vesicle trafficking.

Chung et al. (2013) exploited mutation correction of iPS cells and conserved proteotoxic mechanisms from yeast to humans to discover and reverse phenotypic responses to alpha-synuclein, a key protein involved in Parkinson disease. Chung et al. (2013) generated cortical neurons from iPS cells of patients harboring alpha-synuclein mutations (A53T; 163890.0001), who are at high risk of developing PD dementia. Genetic modifiers from unbiased screens in a yeast model of alpha-synuclein toxicity led to identification of early pathogenic phenotypes in patient neurons, including nitrosative stress, accumulation of endoplasmic reticulum-associated degradation substrates, and ER stress. A small molecule, NAB2, identified in a yeast screen, and NEDD4, the ubiquitin ligase that it affects, reversed pathologic phenotypes in these neurons.

Evidence for Genetic Heterogeneity

Polymeropoulos et al. (1996) demonstrated genetic linkage between an autosomal dominant form of PD and genetic markers on 4q21-q23. The locus was designated PARK1 (168601). In 94 Caucasian families, Scott et al. (1997) could not demonstrate linkage to 4q21-q23. They also found no linkage even when the 22 families from their study with at least 1 case of early-onset PD were examined separately. Gasser et al. (1997) excluded linkage in 13 multigenerational families with Parkinson disease, with the exception of 1 family for which they achieved a maximum multipoint lod score of 1.5 for genetic markers in the 4q21-q23 region.

Scott et al. (2001) described a genetic linkage study conducted in 1995-2000 in which a complete genomic screen was performed in 174 families with multiple individuals diagnosed as having idiopathic PD, identified through probands in 13 clinic populations in the continental United States and Australia. Significant evidence for linkage was found in 5 distinct chromosomal regions: chromosome 6 in the parkin gene (PARK2; 602544) in families with at least 1 individual with PD onset at younger than 40 years (lod = 5.47); chromosomes 17q (lod = 2.62), 8p (lod = 2.22), and 5q (lod = 1.50) overall and in families with late-onset PD; and 9q (lod = 2.59) in families with both levodopa-responsive and levodopa-nonresponsive patients. The data suggested that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic, late-onset PD.

Pankratz et al. (2002) studied 160 multiplex families with PD in which there was no evidence of mutations in the parkin gene, and used multipoint nonparametric linkage analysis to identify PD susceptibility genes. For those individuals with a more stringent diagnosis of verified PD, the highest lod scores were observed on the X chromosome and on chromosome 2 (lod scores equal to 2.1 and 1.9, respectively). Analyses performed with all available sib pairs, i.e., all examined individuals treated as affected regardless of their final diagnostic classification, yielded even greater evidence of linkage to the X chromosome and to chromosome 2 (lod scores equal to 2.7 and 2.5, respectively). Evidence of linkage was also found to chromosomes 4, 5, and 13 (lod scores greater than 1.5). Pankratz et al. (2002) considered their findings consistent with those of other linkage studies that had reported linkage to chromosomes X and 5.

Pankratz et al. (2003) studied 754 affected individuals, comprising 425 sib pairs, to identify PD susceptibility genes. Genomewide, nonparametric linkage analyses revealed potential loci on chromosomes 2, X, 10, and 14. The authors hypothesized that gene-by-gene interactions are important in PD susceptibility.

Associations Pending Confirmation

Maraganore et al. (2005) performed a 2-tiered, genomewide association study of PD including 443 sib pairs discordant for PD and 332 case-unrelated control pairs. A SNP (rs7702187) within the semaphorin-5A gene (SEMA5A; 609297) on chromosome 5p had the lowest combined p value (p = 7.62 x 10(-6)). The protein encoded by this gene plays an important role in neurogenesis and in neuronal apoptosis, which was consistent with hypotheses regarding PD pathogenesis.

Gao et al. (2009) conducted a genomewide linkage screen of 5,824 SNPs in 278 families of European non-Hispanic descent to localize regions that harbor susceptibility loci for Parkinson disease. These 278 families included 158 families included in a previous screen (Scott et al., 2001) and 120 families not previously screened. In the overall screen of all 278 families, the highest multipoint MLOD scores were obtained under a dominant model of inheritance in an 11-cM interval on chromosome 3q25 (MLOD = 2.0) and a 9-cM interval on chromosome 18q11 (MLOD = 1.8). Since the combined screen did not detect linkage overall in regions previously implicated, Gao et al. (2009) suspected that clinical and locus heterogeneity might exist. They stratified the dataset into previously screened and unscreened families. In the 120 families not previously screened, Gao et al. (2009) achieved significant evidence for linkage on chromosome 18q11 (maximum lod score = 4.1) and suggestive evidence on chromosome 3q25 (maximum lod score = 2.5). There was little evidence for linkage to these regions overall in the original 158 families. Simulation studies suggested that these findings were likely due to locus heterogeneity rather than random statistical error. See also PARK18 (614251), which is caused by mutation in the EIF4G1 gene (600495) on 3q27.

To identify susceptibility variants for Parkinson disease, Satake et al. (2009) performed a genomewide association study and 2 replication studies in a total of 2,011 cases and 18,381 controls from Japan. They identified a novel susceptibility locus on chromosome 4p15. Four SNPs (rs11931532, rs12645693, rs4698412, and rs4538475) reached p less than 5 x 10(-7) in the combined analysis. The 4 SNPs were located 4.1 kb downstream of intron 8 of the BST1 gene (600387). Satake et al. (2009) also identified a locus on chromosome 1q32 (PARK16; 613164), replicated by Simon-Sanchez et al. (2009), and replicated associations on 4q22 (see PARK1, 168601) and 12q12 (see PARK8, 607060). Tan et al. (2010) confirmed associations at the PARK16, PARK1, and PARK8 loci in 433 PD patients and 916 controls, all of Chinese ethnicity. However, they did not identify a significant association at the BST1 locus.

By a genomewide association study of 2,000 individuals with late-onset PD and 1,986 unaffected controls, all of European ancestry from the NeuroGenetics Research Consortium (NGRC), Hamza et al. (2010) found an association between PD and rs11248051 in the GAK gene (602052) on chromosome 4p (p = 3.1 x 10(-4); odds ratio (OR) of 1.32). When combined with data from a previous study (Pankratz et al., 2009), metaanalysis of the combined dataset of 2,843 patients yielded a significant association (p = 3.2 x 10(-9); OR, 1.46). Hamza et al. (2010) designated this possible locus PARK17, but that symbol has been used for a confirmed PD locus on chromosome 16q13 (see 614203). They also found a significant association between PD and rs3129882 in intron 1 of the HLA-DRA (142860) gene on chromosome 6p21.3 (p = 2.9 x 10(-8)). The authors designated this possible locus PARK18, but that symbol has been used for a confirmed PD locus on chromosome 3q27 (see 614251). The association was significant even after adjusting for age, sex, and genetic substructure among Americans of European descent (as defined by Jewish ancestry and country of origin). The findings were replicated in 2 datasets comprising 1,447 patients, and metaanalysis of the 3 populations showed a combined p value of 1.9 x 10(-10) and odds ratio of 1.26. The HLA association was uniform across all genetic and environmental risk strata, and was strong in both sporadic (p = 5.5 x 10(-10)) and late-onset (p = 2.4 x (10-8)) disease. A data repository of expression QTL indicated that rs3129882 is a cis-acting regulatory variant that correlated significantly with expression levels of HLA-DRA, HLA-DQA2 (613503), and HLA-DRB5 (604776). Hamza et al. (2010) suggested that their findings supported the involvement of the immune system in the pathogenesis of Parkinson disease. However, Mata et al. (2011) failed to replicate the associations between Parkinson disease and the loci at chromosome 4p and 6p21 in a study of 1,445 PD patients and 1,161 controls from northern Spain. The SNPs studied included rs11248051 in the GAK gene and rs3129882 in the HLA-DRA gene. Mata et al. (2011) concluded that the loci designated PARK17 and PARK18 by Hamza et al. (2010) required further validation.

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