Parkinson Disease 8, Autosomal Dominant

A number sign (#) is used with this entry because autosomal dominant Parkinson disease-8 (PARK8) is caused by heterozygous mutation in the LRRK2 gene (609007), which encodes dardarin, on chromosome 12q12.

For a phenotypic description and a discussion of genetic heterogeneity of Parkinson disease, see PD (168600).

Some patients with mutations in the LRRK2 gene may be classified as having Lewy body disease or Lewy body dementia (127750) or various forms of frontotemporal dementia (FTD; 600274).

Dachsel and Farrer (2010) provided a review of the LRRK2 gene and its role in Parkinson disease.

Clinical Features

Hasegawa and Kowa (1997) reported a large Japanese family with autosomal dominant parkinsonism characterized by laterality of parkinsonism at onset, mean age of onset at 51 +/- 6 years, and favorable response to dopaminergic medication. Neuropathologic examination showed pure nigral degeneration without Lewy bodies or neurofibrillary tangles.

Wszolek et al. (1995) reported a large family from western Nebraska in which 18 members spanning 6 generations had slowly progressive parkinsonism inherited in an autosomal dominant pattern. The family's ancestors probably immigrated to the United States from England. Clinical features included bradykinesia, rigidity, resting tremor, postural instability, and favorable response to levodopa. Postmortem examination of 1 affected individual showed neuronal and pigmentary loss, gliosis, and Lewy bodies in the substantia nigra. In a follow-up report of the same family, Wszolek et al. (2004) reported 4 additional affected members. Mean age at onset for all patients was 65 years. Pathologic examination of 4 patients showed neuronal loss and gliosis in the substantia nigra in all, but variable findings, including Lewy bodies in only 2 of 4 patients and tau (MAPT; 157140) pathology in 1 of 4, were also seen. Using PET scan to evaluate presynaptic dopaminergic integrity of the putamen in members of the family originally reported by Wszolek et al. (1995), Nandhagopal et al. (2008) found that 2 asymptomatic LRRK2 mutation carriers had progressive dopaminergic dysfunction affecting transport and uptake compared to 2 family members without the mutation over a 2- to 3-year span. One of the asymptomatic mutation carriers developed subtle clinical manifestations of PD by the time of the second scan. The findings suggested that PET abnormalities are present in asymptomatic carriers early in the illness.

Paisan-Ruiz et al. (2004) reported 4 families from the Basque region of Spain and 1 family from the United Kingdom with autosomal dominant Parkinson disease. Mean age at onset was 65 years, followed by a benign course with excellent response to low doses of L-DOPA. The majority of patients presented with unilateral leg or hand tremor. No cognitive decline was noted in any of the patients even after long disease duration. Paisan-Ruiz et al. (2005) reported that PET scan of 1 of the Basque patients showed nigrostriatal dysfunction with a typical pattern of idiopathic presynaptic Parkinson disease.

Pathologic Findings

The neuropathologic findings in patients with LRRK2 mutations are pleomorphic. The most common findings include classic alpha-synuclein (SNCA; 163890)- positive Lewy bodies and Lewy neurites, but these are not always present. Other less common findings include tau (MAPT; 157140)- and ubiquitin (UBB; 191339)-immunoreactive inclusions (Zimprich et al., 2004; Giasson et al., 2006; Ross et al., 2006).

Giasson et al. (2006) reported detailed neuropathologic findings of 3 patients with PARK8 who carried the common LRRK2 G2019S mutation (609007.0006). All showed extensive loss of pigmented neurons in the substantia nigra and locus ceruleus. Classic Lewy bodies were identified in 2 patients, 1 of whom also showed senile plaques and neurofibrillary tangles consistent with Alzheimer disease (104300), which may be have been part of normal aging. The third patient, who did not show Lewy bodies, uniquely demonstrated dystrophic neurons in the substantia nigra that stained intensely for LRRK2. Similar LRRK2 inclusions were not observed in analysis of more than 40 other brains with diverse neurodegenerative diseases.

Ross et al. (2006) reported neuropathologic findings of 8 patients with PD or Lewy body disease who carried the LRRK2 G2019S mutation. All had classic Lewy bodies with a range of distribution from the brainstem to diffuse regions of the brain, but there was no apparent correlation between Lewy body pathology and disease progression. Three patients had a family history of PD. Four patients had autonomic dysfunction, 2 had dementia with Lewy bodies, and 1 had dementia with Alzheimer disease. One healthy control individual with the G2019S mutation who died at age 68 years had no significant neuropathologic findings, consistent with reduced penetrance; another control with the G2019S mutation had concomitant Alzheimer disease.

By postmortem examination of a man with PD who carried the G2019S mutation, Rajput et al. (2006) found a medial temporal tauopathy and Alzheimer-type pathology with cortical amyloid deposits and neurofibrillary deposits in multiple deep brain regions. Lewy bodies were not observed, and there was not significant neuronal loss outside of the substantia nigra. Coimmunoprecipitation studies showed no evidence of a direct interaction between LRRK2 and MAPT.

Using antibodies to LRRK2 epitopes located outside the folded domains of the protein, Zhu et al. (2006) found LRRK2 immunoreactivity within Lewy bodies of patients with sporadic PD. The findings suggested that LRRK2 is a component of Lewy bodies. However, Covy et al. (2006) concluded that LRRK2 is not present in Lewy bodies, based on their studies of various LRRK2 antibodies. Covy et al. (2006) suggested that cross-reactivity with other proteins may occur.

Clinical Variability

In a series of 434 cases of various neurodegenerative disorders, Chen-Plotkin et al. (2008) identified 2 unrelated patients with a clinical diagnosis of corticobasal degeneration and primary progressive aphasia, respectively, who were found to have heterozygous mutations in the LRRK2 gene. These diagnoses fall within the broad clinical category of frontotemporal dementia (FTD; 600274). The first patient, who carried the common G2019S mutation, developed difficulties in planning, organization, and memory at age 52 years. The disorder was progressive, and she later developed apraxia and extrapyramidal features including increased tone and shuffling gait. She never developed tremor. The second patient, who had a preexisting seizure disorder, presented at age 66 years with progressive speech difficulties that developed into expressive aphasia, and cognitive impairment. She had intention tremor and mild flattening of the right nasolabial fold. Brain MRI showed cortical atrophy of the left temporal lobe. Chen-Plotkin et al. (2008) concluded that the LRRK2-associated neurodegenerative phenotype may be more heterogeneous than previously assumed.

Pathogenesis

Gehrke et al. (2010) found that LRRK2 interacted with the microRNA (miRNA) pathway to regulate protein synthesis. They showed that mRNAs for Drosophila E2f1 (189971) and Dp (TFDP1; 189902), which had previously been implicated in cell cycle and survival control (Girling et al., 1993), were translationally repressed by the miRNAs Let7 (MIRLET7A1; 605386) and miR184* (613146), respectively. Pathogenic human LRRK2 antagonized Let7 and miR184*, leading to overproduction of E2f1 and Dp, which was critical for LRRK2 pathogenesis. In Drosophila, genetic deletion of Let7, antagomir-mediated blockage of Let7 and miR184* action, transgenic expression of Dp target protector, or replacement of endogenous Dp with a Dp transgene nonresponsive to Let7 each had toxic effects similar to those of pathogenic LRRK2. Conversely, increasing the level of Let7 or miR184* attenuated pathogenic LRRK2 effects. Human LRRK2 associated with Drosophila Argonaute-1 (EIF2C1, or AGO1; 606228) or human Argonaute-2 (EIF2C2, or AGO2; 606229) of the RNA-induced silencing complex (RISC). In aged fly brain, Ago1 protein level was negatively regulated by human LRRK2. Furthermore, pathogenic LRRK2 promoted the association of phosphorylated 4EBP1 (EIF4EPB1; 602223) with human AGO2. Gehrke et al. (2010) concluded that deregulated synthesis of E2F1 and DP caused by miRNA pathway impairment is a key event in LRRK2 pathogenesis, suggesting that novel miRNA-based therapeutic strategies may be useful for Parkinson disease.

Other Features

Silveira-Moriyama et al. (2008) found that 19 patients with PARK8 and the common G2019S mutation (609007.0006) scored lower on a test of smell, indicating decreased olfactory function and hyposmia, compared to controls or to 2 asymptomatic G2019S carriers. Postmortem examination of the rhinencephalon in 4 PARK8 patients, only 1 of whom had been clinically tested and had hyposmia, showed alpha-synuclein accumulation in olfactory pathways. The authors commented that hyposmia has been reported in up to 80% of patients with Parkinson disease.

Saunders-Pullman et al. (2011) examined olfaction in 31 individuals with G2019S-related PD, 30 with non-LRRK2 PD, 28 nonmanifesting G2019S carriers, and 46 controls. The mean score of all those with PD reflected impaired olfaction compared to controls, although G2019S-related PD patients had less severe impairment compared to non-LRRK2 PD patients. Nonmanifesting LRRK2 mutation carriers had subtle olfactory impairment that was less severe than that in manifesting mutation carriers. However, the study could not determine if the subtle olfactory deficit in nonmanifesting disease carriers could predict future development of motor symptoms, and the authors suggested that longitudinal studies were warranted.

Marras et al. (2011) examined the clinical features of 112 individuals from 15 families with the G2019S mutation, including 25 PD-manifesting mutation carriers and 29 nonmanifesting mutation carriers (54 mutation carriers total). Among the manifesting carriers, tremor was the most commonly recognized initial symptom, and tremor, postural instability, and gait disorders were most common even in early disease. Olfaction was abnormal only in 2 of 7 with short disease duration, but was abnormal in 8 of 10 with long disease duration. Eleven of 19 manifesting patients tested showed impaired color discrimination. Compared to 84 individuals with idiopathic PD, G2019S PD patients had better olfactory sense, worse depression scores, worse color discrimination, more common tremor at presentation and gait dysfunction, and slightly better motor scores earlier in disease duration. However, the phenotypes were largely overlapping. Nonmanifesting mutation carriers had an increased frequency of tremor (31%) compared to noncarriers (12%) and to unrelated controls (13%). Nonmanifesting mutation carriers had increased constipation (12%) compared to controls (2%), as well as worse color discrimination compared to controls.

Aasly et al. (2012) studied 26 patients with LRRK2 mutations, including 18 asymptomatic carriers and 8 patients at an early stage of PD. Symptomatic patients had reduced CSF levels of beta-amyloid-42 (APP; 104760), total tau (MAPT; 157140), and phosphorylated tau compared to asymptomatic mutation carriers. PET scan for 3 markers of dopaminergic function in the striatum showed significantly reduced values for all 3 markers in all symptomatic mutation carriers, whereas only 4 asymptomatic mutations carriers had reduction of all 3 tracers studied. There was a trend towards a correlation between decreased striatal dopaminergic function and reduced CSF beta-amyloid-42 and tau levels, with significant values only for beta-amyloid-42 and fluorodopa uptake. When cases were restricted to those with the G2019S mutation, significant correlations were also observed for tau. The findings suggested a link between beta-amyloid and tau deposition and the pathogenesis of LRRK2-related PD. However, Aasly et al. (2012) noted that this was an exploratory study, that the data should be interpreted with caution, and that the results need to be replicated.

In a cross-sectional study of 490 Jewish patients with PD, Inzelberg et al. (2012) found that 79 (16.1%) carried the common G2019S mutation. Eighteen (23%) G2019S mutation carriers had a non-skin cancer compared to 49 (12%) nonmutation carriers (odds ratio = 2.18). A significant ethnicity effect was noted for those of Ashkenazi Jewish ancestry: the age-adjusted odds ratio for the development of non-skin cancer among Ashkenazi Jewish carriers of the G2019S mutation was 3.38. The most common cancer was breast, which accounted for 15% of the cancer types. The LRRK2 G2019S causes a gain of function for the kinase, which could potentially play a role in tumorigenesis. However, Bandmann and Cookson (2012) noted that the study showed an association between G2019S and non-skin cancer, but did not prove causation.

Mapping

Funayama et al. (2002) performed a genomewide linkage analysis in the family reported by Hasegawa and Kowa (1997). Allele typing was performed for 31 individuals from 4 generations. Parametric 2-point linkage analysis yielded a maximum lod score of 4.32 at D12S345 (12p11.2). Parametric multipoint linkage analysis of the 13.6-cM interval around this marker yielded lod scores greater than 4.0 at D12S85 (12q12). Haplotype analysis showed 2 recombination events which further defined the candidate region. The haplotype was shared by 15 affected individuals and by 8 unaffected individuals, which raised the possibility of incomplete penetrance. Nonparametric linkage analysis also supported mapping of the parkinsonism locus to 12p11.2-q13.1.

In 21 Caucasian families with Parkinson disease and an inheritance pattern compatible with autosomal dominant transmission, Zimprich et al. (2004) tested for linkage to the PARK8 region. Two families, one a German Canadian family and the other a family from western Nebraska (Wszolek et al., 1995), reached significant linkage on their own, with a combined maximum multipoint lod score of 3.33.

In a genomewide association study and 2 replication studies in a total of 2,011 cases and 18,381 controls from Japan, Satake et al. (2009) found strong association with the LRRK2 gene (609007) on 12q12 (p = 2.72 x 10(-8)), implicated in PARK8. Tan et al. (2010) specifically analyzed 3 SNPs at the PARK8 locus in 433 PD patients and 916 controls, all of Chinese ethnicity, and independently confirmed a significant association with PARK8.

Molecular Genetics

In affected members of 4 Basque families and 1 English family with autosomal dominant PD, Paisan-Ruiz et al. (2004) identified 2 different heterozygous mutations in the LRRK2 gene (609007.0001 and 609007.0002, respectively). The disease showed 100% penetrance.

In affected members of a Nebraskan kindred with autosomal dominant PD originally reported by Wszolek et al. (1995), Zimprich et al. (2004) identified a heterozygous mutation in the LRRK2 gene (609007.0003).

In affected members of 4 of 61 (6.6%) families with autosomal dominant PD, Di Fonzo et al. (2005) identified a heterozygous gly2019-to-ser (G2019S; 609007.0006) mutation in the LRRK2 gene. Two families were from Italy, and 1 each were from Portugal and Brazil. Gilks et al. (2005) identified the G2019S mutation in 8 of 482 (1.6%) unrelated patients with Parkinson disease. Five of the patients had no family history of the disorder, suggesting either a de novo occurrence or reduced penetrance. Nichols et al. (2005) identified the G2019S mutation in 20 of 358 (6%) families with PD. In 1 family, 1 sib was heterozygous for the mutation and another was homozygous; the homozygous individual did not differ in clinical presentation from the sib and did not have early disease onset or more rapid progression. Nichols et al. (2005) suggested genetic screening for the G2019S mutation in patients with familial PD.

In all 19 affected members of the original Japanese family with PARK8 (Hasegawa and Kowa, 1997), Funayama et al. (2005) identified a heterozygous mutation in the LRRK2 gene (609007.0007).

Farrer et al. (2005) identified pathogenic mutations in the LRRK2 gene in 5 (0.6%) of 786 probands with idiopathic Parkinson disease. Four probands carried the common G2019S mutation.

Paisan-Ruiz et al. (2005) identified 2 different LRRK2 mutations in 3 of 23 unrelated probands with autosomal dominant Parkinson disease. Two probands had the common G2019S mutation. In a case-control study of 121 unrelated Parkinson disease patients and 250 controls, Paisan-Ruiz et al. (2005) found no association between PD and any of 4 LRRK2 polymorphisms examined.

Ishihara et al. (2006) found no observable phenotypic differences between 26 patients with Parkinson disease who were homozygous for the G2019S mutation, including 20 patients of Tunisian origin, and reports of patients who were heterozygous for the mutation. In addition, 3 clinically unaffected Tunisian individuals were homozygous for the mutation at ages 42, 45, and 70 years. The findings did not support a gene dosage effect.

Alcalay et al. (2010) identified the G2019S mutation in 35 (3.6%) of 953 patients with early-onset PD before age 51, including 77 and 139 individuals of Hispanic and Jewish ancestry, respectively. Four of the 35 patients had the G2019S mutation and another mutation in the PRKN (PARK2; 602544) or GBA genes (606463).

Genotype/Phenotype Correlations

Alcalay et al. (2009) found that 34 (3.7%) of 925 patients with early-onset PD, defined as age at onset before age 51 years, carried the G2019S mutation. Compared to noncarriers, carriers of the G2019S mutation were more likely to be of Ashkenazi Jewish descent (55.9% vs 11.9%), to have a lower tremor score (p = 0.03), and to have a higher score of postural instability and gait difficulty (PIGD; 92.3% vs 58.9%, p = 0.003). The PIGD phenotype in general is associated with a more severe phenotype and a faster rate of cognitive decline compared to the tremor dominant phenotype, so the findings of this study suggested implications for disease course in G2019S mutation carriers.

Mutations in the LRRK2 gene 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 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 57.5 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.

Population Genetics

Orr-Urtreger et al. (2007) identified a heterozygous G2019S mutation in 12.3% of 472 Jewish PD patients, and in 14.8% of the 344 patients in this group who were specifically of Ashkenazi Jewish origin. The mutation was also detected in 2.4% of Ashkenazi Jewish controls. A common shared haplotype identified by Lesage et al. (2005) was found in 97% of mutation carriers. None of 42 Jewish patients from Iraq or Morocco carried the G2019S mutation.

Skipper et al. (2005) identified a subset of tagging-SNPs (tSNP) that captured the majority of common variation within the LRRK2. Both single tSNP and tSNP haplotype analyses, using a large epidemiologically-matched sporadic case-control series comprising 932 Chinese individuals, yielded significant evidence for association with Parkinson disease. The authors identified a haplotype that dramatically increased disease risk when present in 2 copies (odds ratio = 5.5; P = 0.0001).

Choi et al. (2008) did not identify the G2019S mutation in 72 unrelated Korean patients with onset of PD before age 50, suggesting that it is not a common cause of PD in this population.

Lesage et al. (2008) identified the G2019S mutation in 7 (41%) of 17 North African patients with familial PD and 40 (34%) of 119 North African patients with sporadic PD. All were heterozygous for the mutation except 3 patients, who were homozygous. One (1.5%) of 66 Algerian controls was homozygous for the mutation, but showed no evidence of disease at age 41 years, which is younger than the average age of disease onset.

Lesage et al. (2009) found 8 potentially or proven pathogenic mutations, including 4 novel mutations, in the LRRK2 gene in 22 (9.7%) of 226 probands with autosomal dominant Parkinson disease, including 182 from France and 14 from North Africa. The common G2019S mutation was identified in 13 (5.8%) probands, including 6 (43%) from North Africa. Heterozygous mutations R1441H (609007.0008) and I1371V were found in 2 probands each. Most of the mutations were located in the functional domains of the LRRK2 protein. Some of the patients had been previously reported.

Animal Model

Liu et al. (2008) found that Drosophila expressing the human LRRK2 G2019S mutation in neuronal cells showed adult-onset loss of dopaminergic neurons, locomotor dysfunction, and early mortality. Overexpression of LRRK2 resulted in a less severe form of parkinsonism. Treatment of mutant flies with L-DOPA improved locomotor impairment but did not prevent loss of dopaminergic cells. Expression of mutant protein in photoreceptor cells resulted in retinal degeneration. The findings provided a gain-of-function animal model for human LRRK2-linked PD.

Lee et al. (2010) presented evidence demonstrating that pharmacologic inhibitors of LRRK2 kinase activity are protective in both in vitro and in vivo mouse models of LRRK2-induced neurodegeneration.