19 376 unrelated patients with PD were genotyped for LRRK2 mutations. LRRK2 6055G→A, the mutation that causes LRRK2 Gly2019Ser, was found in 201 families and in 179 patients with apparently sporadic PD. summarises the frequency of LRRK2 Gly2019Ser in 24 populations; there were insufficient data to estimate the population frequencies of mutations other than LRRK2 Gly2019Ser; therefore, clinical data are reported as all mutations in LRRK2, the combination of mutations in LRRK2 other than LRRK2 6055G→A, and LRRK2 6055G→A (LRRK2 Gly2019Ser) only.
Frequency of LRRK2 Gly2019Ser in patients with PD and controls across 24 world populations
The worldwide frequency of LRRK2 Gly2019Ser was 1% of patients with sporadic PD and 4% of patients with hereditary PD (). The highest frequency of LRRK2 Gly2019Ser was seen in north African Arabs (hereditary 36%, sporadic 39%) and Ashkenazi Jews (hereditary 28%, sporadic 10%). The frequency was higher in southern European countries than in northern European countries. LRRK2 Gly2019Ser was rarely seen in Asians (Chinese, Japanese, Korean, and Indian); it was found in only four of 4172 patients (<0·1%). Completed pro formas were available for 356 patients with PD (hereditary or sporadic) who had any mutation in LRRK2, 313 of whom had LRRK2 Gly2019Ser. The mean disease duration was shorter for patients with any mutation in LRRK2 than for patients with idiopathic PD (10·9 years [SD 7·8 years] vs 15·1 years [SD 7·1 years], mean difference 4·2 years, 95% CI 3·2–5·2; p<0·0001).
The mean age of PD onset for all LRRK2 mutation carriers was 58·1 years (14·0 years). This did not differ significantly by sex, and was similar in patients with LRRK2 Gly2019Ser (57·5 years [13·9 years] and carriers of all LRRK2 non-Gly2019Ser mutations (59·9 years [13·8 years]). Patients in the QSBB series developed PD at a slightly older age than LRRK2 mutation carriers (61·0 years [10·9 years], mean difference 2·9 years, 95% CI 1·3–4·5; p<0·0001). 15 patients (3%) with LRRK2 Gly2019Ser developed PD after the age of 80 years, including five patients who developed PD after 90 years.
Mutations in PARK2
(parkin) are the second most common genetic cause of parkinsonism after mutations in LRRK2
Across the consortium, we identified 184 homozygous carriers of PARK2
mutations who had a mean age of PD onset of 29·2 years (10·4 years). shows the age of onset versus the cumulative percent of patients with mutations in LRRK2, PARK2
, or in the QSBB series. LRRK2
-associated PD develops at a younger age than the age of onset in the QSBB group; however, although the onset of LRRK2
-associated PD occurs at a slightly younger age than idiopathic PD does, it is of little clinical relevance. More clinically useful is the difference in the age of PD onset between the patients with LRRK2
mutations and those in the QSBB series, and patients who are homozygous for mutations in PARK2
. Only 29 LRRK2
mutation carriers (8%) or 25 patients with idiopathic PD (4%) developed symptoms of PD before the age of 40 years; by contrast, 155 (84%) of the patients who were homozygous for PARK2
mutations had presented with symptoms of PD by the age of 40 years.
Age of PD onset plotted against the cumulative percentage of patients in the PARK2, LRRK2, or QSBB series
The patients with mutations in LRRK2 had a mean duration from the onset of PD to Hoehn and Yahr scale stage 2 (bilateral symptoms, no difficulty walking) of 7·2 years (SD 4·1 years) and a similar duration was seen between LRRK2 Gly2019Ser and LRRK2 non-Gly2019Ser carriers; however, the numbers in the latter group were small and did not include many different mutations. There was no difference when adjusted for age or sex. The rate of disease progression in LRRK2 mutation carriers measured by the time to progression through each point on the Hoehn and Yahr scale and the percentage of those patients at each stage of the Hoehn and Yahr scale that had symptoms of PD for more than 10 years are summarised in .
Rate of disease progression in patients with all LRRK2 mutations and LRRK2 Gly2019Ser
For clinicians, the occurrence of falls is a more practical measure of the severity of disease than disease rating scales. The mean time to first fall in patients with a mutation in LRRK2 was longer than in the QSBB series (12·6 years [SD 7·9 years] vs 9·3 years [SD 5·9 years]; difference 3·3 years, 95% CI 2 ·4–4·2 years; p<0·0001).
At some point during the course of the disease, tremor, bradykinesia, and rigidity were seen in 93% (331) of patients with mutations in LRRK2 and 94% (510) of patients in the QSBB series. Tremor was the most common presenting symptom in both groups (63%  of patients with mutations in LRRK2 and 52%  in the QSBB series), then bradykinesia (27%  and 36% , respectively), and rigidity (10%  and 12% , respectively). The higher incidence of tremor in the patients with mutations in LRRK2 than the QSBB was significant (odds ratio [OR] 1·49, 95% CI 1·1–2·0; p<0·003). Of the 271 patients (76%) with mutations in LRRK2 who had descriptive accounts of their tremor, the tremors were characterised as ‘rest’ tremor in 73%, and ‘leg’ tremor—described by four independent centres as an abduction–adduction leg movement—was a first symptom in 9% of patients, compared with only three of 193 patients (2%) in the QSBB series who had descriptive accounts of their tremor.
Any form of dystonia was seen in 126 of 301 patients (42%) with mutations in LRRK2 compared with 121 of 487 patients (25%) with idiopathic PD; in most patients this was a painful “off period” foot dystonia. Dystonia occurred during the first 2 years of the disease in 22 of 126 patients (18%) with mutations in LRRK2 compared with 5 of 21 (4%) of patients with idiopathic PD (OR 4·5, 95% CI 2·4–8·4; p<0·0001). Only one patient with a mutation in LRRK2 had dystonia before dopamine-replacement treatment. Atypical examples of dystonia that affected the arm (n=2), neck (n=2), tongue (n=1), and that caused blepharospasm (n=4) were also reported in patients with mutations in LRRK2.
Dopamine-replacement regimens varied across centres, but the clinical assessment of the responses were good or excellent in 88% (313 of 356) of patients, modest in 9% (32), and poor in 3% (10). The clinical responses were similar to those in patients with idiopathic PD (good or excellent in 83% [450 of 543], modest in 12% , and poor in 5% ). Patients with idiopathic PD needed treatment earlier than patients with mutations in LRRK2: the mean time from the onset of PD to the start of dopamine-replacement treatment was 4·01 years (SD 2·50 years) for patients with mutations in LRRK2 and 3·03 years (2·90 years) for patients with idiopathic PD (difference 0·98 years, 95% CI 0·61–1·35 years; p<0·0001). 66 (19%) patients with mutations in LRRK2 compared with 38 (7%) patients with idiopathic PD (p=0·003) were not on dopamine-replacement treatment 5 years after disease onset.
Drug-induced, interdose dyskinesia was reported by 206 (58%) patients with mutations in LRRK2 and by 293 (54%) patients in the QSBB group. Although the incidence of dyskinesia was similar in both groups, the time to onset was longer in patients with mutations in LRRK2 than in patients with idiopathic PD (8·4 years [SD 4·6 years] vs 5·6 years [SD 3·7 years], difference 2·8 years, 95% CI 2·3–3·3 years; p<0·0001). Only 39 (11%) patients with mutations in LRRK2 were dyskinetic after 5 years of treatment, and only 114 (32%) were dyskinetic after 10 years of treatment. By comparison, 136 (25%) patients with idiopathic PD were dyskinetic after 5 years of treatment and 223 (41%) patients were dyskinetic after 10 years of treatment.
Stereotactic functional neurosurgery was done on 22 patients with mutations in LRRK2: 18 had unilateral or bilateral subthalamic nucleus stimulation, three had pallidotomy, and one had thalamotomy. The mean time from PD onset to surgery was 11·4 years (SD 6·2), and the indications were usually either motor fluctuation or dyskinesia. Of the 12 patients who had detailed measurements of clinical outcome, eight were good or excellent, two moderate, and two poor.
The sample sizes for each non-motor symptom were reduced owing to missing data or not using validated or self-reported diagnostic scales in routine practice. Formal mini-mental state examination data on cognition were obtained on 162 patients with mutations in LRRK2. These results and those for other neuropsychiatric symptoms are shown in . 37 patients (23%) with mutations in LRRK2 had evidence of cognitive impairment (mini-mental state examination score ≤24) compared with 340 patients (70%) with idiopathic PD. The mean disease duration of patients with cognitive impairment was 15·2 years (SD 5·9 years) for those with mutations in LRRK2 and 14·4 years (SD 5·9 years) for those with idiopathic PD. However, this must be considered in light of a mean 4·2 years (3·2–5·2 years) longer duration for the entire QSBB series. A more comparable measure is the proportion of patients who develop cognitive impairment within 2 years of symptom onset: 6 patients (3·4%) with mutations in LRRK2 compared with 48 patients (9·8%) with idiopathic PD (p=0·0016).
Point prevalence of neuropsychiatric symptoms in patients with mutations in LRRK2 after various durations of the symptoms of PD
The response rate for olfaction was low (n=43) because only UPSIT data were accepted. Abnormal olfaction was found in 22 patients (51%) with LRRK2 Gly2019Ser after a mean disease duration of 5·6 years (SD 4·3).
Urinary symptoms affected 58 of 204 (28%) of the patients with LRRK2 Gly2019Ser, but these did not vary significantly when stratified by disease duration or by mutation. The most common symptoms were frequency and urge incontinence. 48% (93 of 194) of patients had constipation. 11% of men with LRRK2 Gly2019Ser reported erectile dysfunction, all of whom were older than 60 years.
69% (186 of 268) of patients with LRRK2 Gly2019Ser had sleep disturbances; however, there was no significant difference from the controls when this symptom was stratified by disease duration or by mutation. Insomnia and sleep fragmentation were the most common symptoms. Formal sleep studies identified 13 patients with rapid eye movement (REM) sleep behaviour disorder and five patients with restless legs syndrome. However we do not have accurate frequency estimates for these two symptoms because most patients did not have formal sleep studies.
9% (30 of 342) of patients with LRRK2-associated PD had diabetes mellitus, which was unexpectedly high and might be due to the effect of multiple-comparison testing. The mean age of these diabetic patients was 54 years (range 42–66 years) but we could not establish the age of diabetes onset. The prevalences of other common medical conditions were similar to those reported for the general population.
There were no apparent differences between the patients with mutations in LRRK2 and those with idiopathic PD groups with respect to employment history, exposure to toxins, or educational status; however, with the exception of smoking history (n=306), these sections of the pro forma were poorly completed. Smoking (past or present) was seen in 28% of patients with LRRK2 Gly2019Ser compared with 39% of the QSBB series. There was no correlation between smoking history and age of symptom onset.
In this study, six mutations in LRRK2 met the consortium's criteria for being ‘proven pathogenic’: Gly2019Ser (n=391), Arg1441Gly (n=33), Arg1441Cys (n=9), Arg1441His (n=5), Ile2020Thr (n=5), and Tyr1699Cys (n=2), where n is the number of unrelated individuals or families that carry the mutation. Conclusions made about mutations of low frequency are likely to be less robust than those drawn from mutations of higher frequency.
Penetrance estimates were calculated for LRRK2 Gly2019Ser on the basis of results from 1045 patients in 133 families. These comprised 327 affected patients (index and non-index cases) and 718 unaffected participants, with a mean of 8 individuals per family (range 3–45). Sporadic (singleton) cases were included when there were data on age and affection status from at least both parents (n=67). Similar calculations were made for all mutations in LRRK2 combined, on the basis of results for 1387 patients in 152 families and 94 singletons.
Survival analysis was done on a subset of carriers after exclusion of all index cases (152). Kaplan-Meier analysis estimated the cumulative risk of PD as 36% at 59 years, 59% at 69 years, and 80% at 79 years. In the maximum-likelihood estimation, there were no significant differences in displacement by sex or ethnic group; however, there were significant displacements for patients with LRRK2 Gly2019Ser (mean displacement 1·66, SE 0·06; p< 0·02) and patients with the other mutations in LRRK2 combined (mean displacement 2·00, SE 0·13; p<0·01). When this difference was taken into account, the cumulative risk for carriers of LRRK2 Gly2019Ser was 28% at 59 years, 51% at 69 years, and 74% at 79 years; the cumulative risk for carriers of LRRK2 non-Gly2019Ser mutations combined was 40% at 59 years, 64% at 69 years, and 84% at 79 years. shows the penetrance estimates calculated with the Kaplan-Meier and the maximum-likelihood methods.