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Supplementary table 1. Estimates of LRRK2 p.G2019S age-associated cumulative incidence

|Ethnicity |Sample |Statistical Analysis |Age range (penetrance) |Reference |

|Norwegian, American (United |13 LRRK2 families |Proportion of affected/total carriers |50-70 (17-85%) |[pic][1] |

|States), Irish and Polish |22 familial affected carriers | | | |

|French and North African |2 LRRK2 families |Not reported |55-76 (33-100%) |[pic][2] |

|families |6 familial affected carriers | | | |

|Ashkenazi Jews | 2975 familial relatives of 459 |Kin-cohort [3] |60-80 (12-24%) |[pic][4] |

| |probands |Relatives were not genotyped for mutation: | | |

| | |probability of carrying mutation was | | |

| | |estimated | | |

|Ashkenazi Jews |22 affected carriers |Penetrance calculated from odds ratio |Lifetime risk = 35% |[5] |

|Italian (UK Parkinson’s Disease |36 familial affected carriers |Kaplan Meier [6] |60-80 (15-32%) |[pic][7] |

|Brain Bank) | | | | |

|World-wide (mostly European) |133 LRRK2 families |Kaplan Meier [6] |59-79 (28-74%) |[8] |

| |327 affected members | | | |

|International Multi-site |22 familial affected carriers |Product limit survival estimate [6] |60-80 (30-55%) |[pic][9] |

|Arab-Berber |72 affected carriers |Kaplan Meier [6] |60-80 (50-100%) |[10] |

|European countries, mainly Italy|154 first degree relatives and |Kin-cohort [3] |1st degree |[pic][11] |

| |190 second degree relatives of 10|*No relatives were genotyped for mutation: |60-80 (12-33%) | |

| |p.G2019S carrier probands |probability of carrying mutation was | | |

| | |estimated |2nd degree | |

| | | |60-80 (10-30%) | |

|Northern Spain (Cantabria) |32 carriers |Kaplan Meier [6] |60-80 (12-47%) |[pic][12] |

Carriers refers to unrelated patients with LRRK2 p.G2019S (unless otherwise specified)

Supplementary table 2. Parkinsonism in LRRK2 p.G2019S carriers by gender

|  |LRRK2 |iPD |

|  |Female |Male |Female |

|Cognitive impairment |0.28 (0.67) |0.33 (0.74) |0.66 |

|Hallucinations and psychosis |0.14 (0.45) |0.23 (0.57) |0.35 |

|Depressed mood |1.28 (1.00) |1.40 (1.03) |0.08 |

|Anxious mood |1.06 (1.11) |1.02 (1.07) |0.32 |

|Apathy |1.22 (1.03) |1.19 (1.01) |0.53 |

|Features of dopamine dysregulation syndrome |0.05 (0.25) |0.06 (0.35) |0.95 |

Quantitative scales are from 0-4: 0 (normal) - 4 (most severe). Mean values (standard deviation) are given. 

Supplementary table 3b. UPDRS Part IB Mentation, Behaviour and Mood

| |LRRK2 |iPD |p-value |

|Sleep problems |0.96 (1.15) |0.87 (1.17) |0.30 |

|Daytime sleepiness |0.96 (0.96) |0.85 (0.92) |0.14 |

|Pain and other sensations |1.53 (1.21) |1.45 (1.12) |0.75 |

|Urinary problems |1.20 (1.27) |1.19 (1.20) |0.68 |

|Constipation problems |1.15 (1.21) |1.20 (1.14) |0.95 |

|Light headedness on standing |0.92 (1.10) |1.01 (1.06) |0.11 |

|Fatigue |1.86 (1.09) |1.74 (0.97) |0.57 |

Quantitative scales are from 0-4: 0 (normal) - 4 (most severe). Mean values (standard deviation) are given.

Supplementary table 3c. UPDRS Part II Activities of Daily Living

| |LRRK2 |iPD |p-value |

|Speech |1.01 (0.98) |1.00 (0.96) |0.34 |

|Saliva and drooling |0.97 (1.13) |1.19 (1.24) |0.02 |

|Chewing |0.72 (0.90) |0.70 (0.87) |0.95 |

|Eating tasks |1.18 (0.89) |1.04 (0.82) |0.24 |

|Dressing |1.60 (1.08) |1.48 (1.05) |0.79 |

|Hygiene |1.71 (1.13) |1.59 (1.14) |0.34 |

|Handwriting |1.54 (1.19) |1.53 (1.17) |0.76 |

|Doing hobbies and other activities |1.86 (1.30) |1.71 (1.11) |0.99 |

|Turning in bed |1.56 (1.17) |1.44 (1.10) |0.80 |

|Tremor |2.00 (1.00) |1.98 (1.00) |0.74 |

|Getting out of bed, a car, or a deep chair |1.67 (1.15) |1.32 (1.05) |0.01 |

|Walking and balance |1.66 (1.04) |1.37 (0.98) |0.10 |

|Freezing |0.85 (1.13) |0.72 (1.08) |0.92 |

Quantitative scales are from 0-4: 0 (normal) - 4 (most severe). Mean values (standard deviation) are given.

Supplementary table 3d. UPDRS Part III

| |LRRK2 |iPD |P-value |

|Mean (SD) | | | |

|Part III. Total Rigidity Subscale |1.59 (0.71) |1.53 (0.76) |0.83 |

|Part III. Total Bradykinesia Subscale |1.65 (0.96) |1.49 (0.98) |0.63 |

|Part III. Total Tremor Subscale |0.76 (0.60) |0.65 (0.60) |0.31 |

|Part III. Total Postural Instability and Gait Disorder |1.33 (0.79) |1.27 (0.85) |0.40 |

|Subscale | | | |

Quantitative scales are from 0-4: 0 (normal) - 4 (most severe). Mean values (standard deviation) are given.

Supplementary table 3e. UPDRS Part IV Complications of Therapy

| |LRRK2 |iPD |p-value |

|Time spent with dyskinesias |0.47 (1.00) |0.30 (0.75) |0.83 |

|Functional impact of dyskinesias |0.46 (1.02) |0.27 (0.80) |0.52 |

|Time spent in the off state |1.34 (1.18) |1.14 (1.03) |0.34 |

|Functional impact of fluctuations |1.51 (1.50) |1.34 (1.36) |0.62 |

|Complexity of motor fluctuation |0.95 (0.97) |0.88 (0.91) |0.21 |

|Painful off-state dystonia |0.30 (0.75) |0.23 (0.60) |0.42 |

Quantitative scales are from 0-4: 0 (normal) - 4 (most severe). Mean values (standard deviation) are given.

Supplementary table 4. Autonomic dysfunction (SCOPA-Aut) individual scores

| |Control subjects |iPD |p-value |

| | | | |

|Gastrointestinal (SD) |0.64 (0.51) |0.74 (0.52) |0.04 |

|Urinary (SD) |0.80 (0.80) |0.87 (0.83) |0.10 |

|Cardiovascular (SD) |0.50 (0.59) |0.54 (0.54) |0.35 |

|Thermoregulatory (SD) |0.89 (0.76) |0.87 (0.73) |0.92 |

SCOPA-Aut subdomain scores were compared between patients. Quantitative scales are from from 0-4: 0 (normal) - 4 (most severe). SD: Standard deviation

Supplementary table 6. Summary of cognitive assessment compared between iPD, LRRK2 parkinsonism and control subjects

|Total |Control subjects |iPD |p-value |

|Epworth total score | | | |

| On state (SD) |5.35 (4.67) |5.25 (4.90) |0.98 |

| Off state (SD) |4.75 (4.48) |4.88 (5.19) | |

|Restless legs | | | |

| On state (%) |9/75 (12%) |15/118 (13%) |0.75 |

| Off state (%) |6/81 (7.4%) |11/113 (9.7%) | |

|REM sleep disorder | | | |

| On state (%) |12/75 (16%) |34/118 (29%) |0.001 |

| Off state (%) |14/81 (17%) |40/113 (35%) | |

|Sleep apnea | | | |

| On state (%) |7/75 (9.3%) |10/118 (8.5%) |0.65 |

| Off state (%) |9/81 (11%) |15/113 (13%) | |

Only a subset of patients had levodopa state recorded (see table 1c).

Supplementary table 8. Schwab & England ‘activities of daily living’

| |iPD |Control subjects |p-value |

|Epworth Total Score (SD) |5.03 (4.83) |2.06 (3.3) | ................
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