Pathogenic LRRK2 mutations are relatively common and present in diverse geographic populations. The following studies describe individuals with parkinsonism that is clinically indistinguishable from PD. In all studies, the individuals with LRRK2-associated parkinsonism had variable age of disease onset, even among kindreds. A slower disease progression compared with idiopathic PD has been reported (Nichols et al., 2005). Incomplete age-dependent penetrance was also documented (Di Fonzo et al., 2005; Kachergus et al., 2005; Nichols et al., 2005).
Zimprich et al. (2004a) identified 4 (9%) of 44 PD families each with a different LRRK2 mutation. These families originated from Austria, Germany, and the United States. Subsequently, Kachergus et al. (2005) identified the commonest known LRRK2 mutation, 6055G > A (G2019S), by sequencing multiplex families with autosomal dominant parkinsonism linked to PARK8. They reported that 7 (2.8%) of 248 affected individuals with familial PD had a G2019S LRRK2 substitution. These individuals were derived from families with ancestral roots in the United States, Norway, Ireland, and Poland. Di Fonzo et al. (2005) reported that 4 (6.6%)
of 61 individuals from geographically diverse PD families, including some asymptomatic carriers. The frequency of a LRRK2 G2019S mutation in familial parkinsonism was examined by Nichols et al. (2005). Thirty-five (5%) of 767 affected individuals from 358 multiplex families tested positive for LRRK2 6055G > A (G2019S) mutation.
The LRRK2 6055G > A (G2019S) substitution has been reported in individuals with apparent idiopathic PD. Six individuals were observed to have the G2019S substitution among a cohort of 806 European descendants with idiopathic PD (Kachergus et al., 2005). Three of the 6 did not have a family history of PD. Gilks et al. (2005) estimated that the mutation may be responsible for idiopathic PD in a clinic-based study where 8 (1.6%) of 482 individuals tested positive for the 6055G > A (G2019S) mutation. Three of these individuals had autopsies performed (Table 1).
Short clinical and pathologic descriptions of an affected individual from one of our families (Family 111) with the LRRK2 6055G > A (G2019S) mutation are presented in Fig. 1 and Table 1. The index case from this family developed restless legs syndrome during the course of his illness, suggesting that restless legs syndrome may be part of the phenotype in G2019S substitution carriers.
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