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 ... 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.
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 ... 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.
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 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).
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 ... 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.