Supplementary table 1. Parkin mutations indentified in this study

Gene / pt. / Allele 1 / Allele 2
PARK 2 / 1 / exon 3-4 del / exon 4 del
2 / exon 3 del / exon 4 del
3 / exon 2-3-4 del / c.850G>C, p.Gly284Arg
4 / exon 3-4 del / exon 6 dup
Homozygous / 5 / exon 2 del / exon 2 del
6 / exon 4 del / c.597dup, p.His200ThrfsX6
7 / exon 2-3 del / exon 5 del
8 / exon 3 del / exon 4 del
9 / exon 2 del / exon 3-4 del
10 / exon 3 del / exon 4 del
11 / exon 4 del / exon 6 del
12 / exon 2-3-4 del, unknown zygosity
13 / exon 2 del / exon 4 del
14 / exon 3-4 del / exon 3 del
15 / exon 3-4 del / normal
16 / exon 3-4 del / normal
17 / c.814C>A,p.Leu272Ile / normal
18 / c.814C>A,p.Leu272Ile / c.1192G>A, p.Ala398Thr
19 / exon 2-3-4 dup / exon 5 del
20 / exon 2 dup / normal
21 / exon 3-4 del / normal
22 / exon 3-4 del / normal
23 / exon 2-3-4 del / normal
PINK 1 / 24 / c.835C>T, p.Arg279Cys / normal

Patients 11, 12, and 20 were not included in this study which compares the phenotype according to parkin genotype

Supplementary table 2.Demographics of patients with AAO below 35 years with and without parkin mutations

Total patients / Patients without mutations / Patients with a single mutation / Patients with two mutations
No. of patients / 42 / 24 / 4 / 14
Gender, M/F (male %) / 20/22 (47.6) / 11/13 (45.8) / 3/1 (75.0) / 6/8 (42.9)
Age at examination, years / 41.5±8.8 / 40.0±7.7 / 42.0 ± 10.1 / 43.9 ± 10.4
Age at onset, years* / 29.4±5.7 / 31.3±4.0 / 27.0 ± 4.6 / 26.9 ± 7.4
0-20 years, n (%) / 4 (9.5) / 1 (4.2) / 0 (0) / 3 (21.4)
21-30 years, n (%) / 14 (33.3) / 5 (20.8) / 3 (75.0) / 6 (42.9)
31-35 years, n (%) / 24 (57.1) / 18 (75.0) / 1 (25.0) / 5 (35.7)
Family History, n (%)† / 10 (23.8) / 3(12.5) / 2 (50.0) / 5 (35.7)
1st degree / 9 (21.4) / 2 (8.3) / 2 (50.0) / 5 (35.7)
2nd degree / 1 (2.4) / 1 (4.2) / 0 (0) / 0 (0)
Disease duration* / 12.0±7.8 / 8.8±6.2 / 13.8 ± 6.7 / 16.9 ± 8.1

AAO, age at onset; No., numbers; M, male; F, female.

Data are shown as mean±standard deviation unless otherwise indicated.

*p<0.05 for comparison between patients with and without parkin mutationsby t-test

†p=0.05 for comparison between patients with and without parkin mutationsby χ2 test

Supplementary table 3.Motor symptoms and signs of patients with AAO below 35 years with and without parkin mutations

Total
patients
(N = 42) / Patients without mutations
(N=24) / Patients with two mutations
(N=14) / p-valuea / p-valueb
Symptoms at onset
Tremor, n (%) / 27 (64.3) / 17 (70.8) / 8 (57.1) / 0.391 / 0.519c
Bradykinesia, n (%) / 11 (26.2) / 6 (25.0) / 4 (28.6) / 1.000 / 0.908c
Rigidity, n (%) / 6 (14.3) / 4 (16.7) / 1 (7.1) / 0.633 / 0.416c
Gait disturbance, n (%) / 7 (16.7) / 3 (12.5) / 4 (28.6) / 0.387 / 0.118c
Dystonia, n (%) / 3 (7.1) / 2 (8.3) / 1 (7.1) / 1.000 / 0.517c
Sensory symptoms, n (%) / 4 (9.5) / 2 (11.1) / 2 (14.3) / 0.616 / 0.846c
Poor balance, n (%) / 3 (7.1) / 2 (8.3) / 1 (7.1) / 1.000 / 0.524c
Micrographia, n (%) / 0 (0) / 0 (0) / 0 (0)
Symmetry, n (%) / 4 (9.5) / 1 (4.2) / 2 (14.3) / 0.542 / 0.677c
Symptoms at examination
Tremor, n (%) / 38 (90.5) / 21 (87.5) / 13 (92.9) / 1.000 / 0.873
Bradykinesia, n (%) / 35 (83.3) / 20 (83.3) / 11 (78.6) / 1.000 / 0.360
Rigidity, n (%) / 36 (85.7) / 19 (79.2) / 13 (92.9) / 0.383 / 0.439
Off dystonia, n (%) / 14 (33.3) / 7 (29.2) / 5 (35.7) / 0.675 / 0.489
Hyperreflexia, n (%) / 4 (9.5) / 4 (16.7) / 0 (0) / 0.276 / 0.999
Poor balance, n (%) / 25 (59.5) / 11 (45.8) / 11 (78.6) / 0.088 / 0.984
Freezing, n (%) / 20 (47.6) / 9 (37.5) / 8 (57.1) / 0.240 / 0.230
Sleep benefit, n (%) / 20 (47.6) / 11 (45.8) / 7 (50.0) / 0.804 / 0.907
Hoehn & Yahr stage, mean / 2.8 ± 1.0 / 2.7 ± 1.1 / 2.8 ± 0.8 / 0.799 / 0.363
Dyskinesia, n (%) / 22 (52.4) / 9 (37.5) / 9 (64.3) / 0.111 / 0.370
Motor fluctuations, n (%) / 23 (54.8) / 10 (41.7) / 9 (64.3) / 0.179 / 0.341
Latency of dyskinesia, years / 9.7±6.1 / 7.4±3.1 / 8.3 ± 2.8 / 0.094 / 0.952
Latency of motor fluctuation, years / 7.6±7.8 / 4.1±3.4 / 8.4 ± 2.8 / 0.022 / 0.351
LEDD*, mg/day / 590.0±470.7 / 505.6±456.1 / 516.8 ± 286.4 / 0.926 / 0.350
Taking levodopa, n (%) / 26 (61.9) / 12 (50.0) / 10 (71.4) / 0.309 / 0.819
Dose of levodopa, mg/day / 428.5±468.0 / 357.3±448.9 / 336.4 ± 320.2 / 0.880 / 0.200

AAO, age at onset; LEDD, levodopa equivalent daily dose.

Data are shown as mean±standard deviation unless otherwise indicated.

a, p values for comparison between patients with two mutations and without mutations by t-test for continuous variables and by χ2 test or Fisher’s exact test for categorical variables

b, p values adjusted for age at onset and disease duration

c, p values adjusted only for age at onset

*, LEDD was calculated as follows; 100 mg of standard levodopa = 140 mg of controlled-release levodopa = 10 mg of bromocriptine = 1 mg of pergolide = 1 mg of pramipexole=4 mg of ropinirole.
Supplementary table 4.Nonmotor symptoms and signs of patients with AAO below 35 years with and without parkin mutations.

Total patients
(N = 42) / Patients without mutations
(N = 24) / Patients with two mutations
(N = 14) / p-valuea / p-valueb
Sensory symptoms, n (%) / 15 (35.7) / 8 (33.3) / 6 (42.9) / 0.557 / 0.463
Hyposmia, n (%) / 7 (16.7) / 4 (16.7) / 2 (14.3) / 1.000 / 0.878
Dysautonomia*, n (%) / 24 (57.1) / 13 (54.2) / 9 (64.3) / 0.542 / 0.569
Urinary impairment, n (%) / 11 (26.2) / 6 (25.0) / 4 (28.6) / 1.000 / 0.408
Gastointestinal impairment, n (%) / 8 (19.0) / 6 (25.0) / 1 (7.1) / 0.227 / 0.406
Impotencyd, n (%/male) / 3 (15.0) / 2(18.2) / 1 (16.7) / 1.000 / 904
Cardiovascular dysfunction, n (%) / 21 (50.0) / 10 (41.7) / 9 (64.3) / 0.179 / 0.126
Excessive sweating, n (%) / 3 (7.1) / 1 (4.2) / 2 (14.3) / 0.542 / 0.434
Sleep Problems†, n (%) / 29 (69.0) / 16 (66.7) / 10 (71.4) / 1.000 / 0.435
EDS / 1 (2.4) / 1 (4.2) / 0 (0) / 1.000 / 1.000
Insomnia / 17 (40.5) / 10 (41.7) / 5 (35.7) / 0.717 / 0.331
RBD / 16 (38.1) / 8 (33.3) / 7 (50.0) / 0.311 / 0.805
RLS / 4 (9.5) / 3 (12.5) / 1 (7.1) / 1.000 / 0.572
Behavioral and psychiatric disturbances‡, n (%) / 21 (50.0) / 12 (50.0) / 8 (57.1) / 0.671 / 0.691
Agitation /aggression/anxiety behaviors / 7 (16.7) / 4 (16.7) / 3 (21.4) / 1.000 / 0.980
Depression/disphoria / 19 (45.2) / 11(45.8) / 7 (50.0) / 0.804 / 0.876
Delusions/hallucinations / 4 (9.5) / 1 (4.2) / 3 (21.4) / 0.132 / 0.099
ICRBs§, n (%) / 8 (19.0) / 2 (8.3) / 6 (42.9) / 0.034 / 0.171c
Excessive shopping / 5 (11.9) / 2 (8.3) / 3 (21.4) / 0.337 / 0.916c
Excessive eating / 2 (4.8) / 1 (4.2) / 1 (7.1) / 1.000 / 0.949c
Hypersexuality / 2 (4.8) / 2 (8.3) / 0 (0) / 0.522 / 0.999c
Pathologic gambling / 2 (4.8) / 0 (0) / 2 (14.3) / 0.129 / 0.999c
Punding / 8 (19.0) / 2 (8.3) / 3 (21.4) / 0.337 / 0.549c
K-MMSEe / 28.6± 1.5 / 28.9± 1.6 / 28.4 ± 1.7 / 0.429 / 0.446
BDIf / 11.5±10.9 / 10.0±8.9 / 13.6 ± 11.9 / 0.461 / 0.629
Depression, n (%) (BDI≥10) / 15 (39.5) / 7 (33.3) / 6 (42.9) / 0.568 / 0.948
Depression¥, n (%) (BDI≥19) / 10 (26.3) / 5 (23.8) / 4 (28.6) / 1.000 / 0.786

AAO, age at onset;EDS, excessive daytime sleepiness; RBD, rapid-eye-movement sleep behavior disorder; RLS, restless legs syndrome; ICRBs, impulse control and repetitive behavior disorders; K-MMSE, Korean version of the Mini-Mental State Examination; BDI, Beck Depression Inventory.

Data are shown as mean±standard deviation unless otherwise indicated.

a,p values for comparison between patients with two mutations and without mutationsby t-test for continuous variables and by χ2 test or Fisher’s exact testfor categorical variables

b,p values adjusted for age at onset and disease duration

c,pvalues adjusted for age at onset, disease duration and LEDD

d,Information available from 6malepatients with two mutationsand 11 male patients without mutations

e,Information available from 14patients with two mutationsand 22 patients without mutations

f,Information available from 14patients with two mutationsand 21 patients without mutations

*, Dysautonomia included urinary dysfunction, gastrointestinal impairment, impotency, cardiovascular dysfunction, and excessive sweating.

†, Sleep problems were assessed by PD nonmotor symptoms questionnaire.

‡, Behavioral and psychiatric disturbances were assessed bythe Neuropsychiatric Inventory-Questionaire.

§, ICRBs were assessed by modified version of the Minnesota Impulsive Disorders Interview.

¥,BDI≥19 indicates moderate to severe depression.