PRKN Clinical Characteristics And Pathogenic Mutation Evidence

Total, 197 LoF+D.miss carriers exist in AMP-PD cohort

(Lesage, 2020 #1751)

• From 1500 cases, they found 199 Parkin mutant-PD
  • 199 cases carried either homozygous (n = 92) or compound heterozygous (n = 59) PRKN mutations

Table 2. Demographic And Clinical Characteristics

TABLE 2. Demographic and Clinical Characteristics of Patients with Parkinson’s Disease with Pathogenic PRKN Variants (PRKN-PD) and of Patients without Pathogenic Variants (PD-NM)

Characteristics	PD-NM n=1181	PRKN-PD n=228	p Value	Coefficient or odds ratio (OR) (SE)	Cohen's f2	p Value
Baseline
Sex (% male)	727/1,181 (61.6%)	118/228 (51.8%)	0.016
Mean age at examination (SD), y	50.5 (13.2)	45.4 (12.9)	<0.0001
Mean disease duration (SD), y	8.8 (7.8)	14.1 (10.4)	<0.0001
Mean age at onset (SD), y	41.6 (12.0)	31.2 (10.7)	<0.0001
L-DOPA-treated	791/1,181 (67%)	148/228 (64.9%)	0.69
Levodopa responsiveness	659/738 (89.3%)	142/149 (95.3%)	0.045	1.9 (0.82)	0.007	0.15
Motor symptoms and signs
Dystonia at onset	164/990 (16.6%)	37/201 (18.4%)	0.69	0.84 (0.18)	0.001	0.46
Akinesia at onset	590/946 (61.3%)	99/206 (48.1%)	0.0010	0.51 (0.09)	0.015	0.0003
Tremor at onset	570/960 (59.4%)	142/205 (69.3%)	0.021	1.7 (0.29)	0.007	0.0076
Micrographia	308/927 (33.2%)	42/204 (20.6%)	0.0013	0.58 (0.11)	0.007	0.010
Asymmetry	1,001/1,035 (96.7%)	181/198 (91.4%)	0.0049	0.26 (0.09)	0.010	0.0005
Bradykinesia	1,033/1,069 (96.6%)	201/208 (96.6%)	1.0000	1.4 (0.63)	0.002	0.46
Rigidity	1,008/1,066 (94.6%)	194/204 (95.1%)	0.90	1.1 (0.42)	<0.001	0.77
Tremor	796/1,056 (75.4%)	168/205 (82%)	0.057	1.5 (0.32)	0.002	0.072
Mean UPDRS III "ON" state (/108) (SD)	19.6 (13.8)	15.9 (11.9)	0.0049	-3.3 (1.2)	0.008	0.014
Mean Hoehn & Yahr "ON" state (/5) (SD)	2 (0.91)	2.00 (0.93)	0.74	-0.14 (0.09)	0.003	0.16
Dyskinesia	457/667 (68.5%)	97/178 (54.5%)	0.0025	0.44 (0.09)	0.020	0.0005
Motor fluctuations	485/663 (73.2%)	82/177 (46.3%)	<0.0001	0.32 (0.07)	0.041	<0.0001
Non-motor symptoms and signs
Dysautonomia	254/470 (54.0%)	36/192 (18.8%)	<0.0001	0.19 (0.05)	0.095	<0.0001
Dementia	67/667 (10.0%)	6/153 (3.9%)	0.037	0.34 (0.16)	0.009	0.014

Data are expressed as mean (standard deviation) for continuous variables, and as counts (percentages) for categorical variables. We used t-tests to compare the two groups for continuous variables and Fisher’s exact tests for binary variables. Coefficients for continuous clinical features and odds ratios (ORs) for binary clinical features and standard error (SE), Cohen’s f2 and p-values were calculated from GLMs with mutation status, sex, age at onset, disease duration, L-DOPA group and age at onset vs disease duration for all 15 variables except for onset variables for which only mutation status, sex and age at onset were added. Linear models were used for continuous variables; GLMs with logit links and Bernoulli distributions were used for binary variables; UPDRS III, the motor subsection of the Unified Parkinson’s Disease Rating Scale.

Levodopa responsiveness was defined as a >30% improvement in subjective perceived motor symptoms.

PRKN Exon / Domain Variant Map

[Uncertain]ski, 2012 #692

the authors did two analysis at the same time

• UK Cohort 136명의 EOPD (이중 29 가 familial cases) 뒤져서 각각 다른 5개의 아래의 pathogenic Parkin mutation발견함 (모두 compound heteroz임, 그래서 아래에 mutation 1 & 2보임). (js: mean age: 52),

TABLE 2. Pathogenic mutations identified with descriptive clinical

	A	B	C	D	E
Gene Mutation 1	PARK2 42P	PARK2 c.154delA frameshift	PARK2 Del X2-3	PARK2 c.438del40 frameshift	PARK2 Dup X3
Mutation 2	Dup. X3	R275W	Del. X2	Del. X2	Dup X7
Age	49	58	49	53	50
AAO	37	35	8	20	20
Ethnicity	Welsh	Welsh	Welsh	British	British
Sex	Male	Male	Male	Female	Male
Family history	None	None	1 Sibling	None	None
Onset symptom	Lower limb stiffness/rigidity	Symmetrical resting tremor	Lower limb stiffness/rigidity	Lower limb dystonia	Lower limb stiffness/rigidity

*Parents unaffected. AAO, age at onset

More detailed clinical descriptions can be found in the supplementary material.

Systematic Review / ROPAD Notes

• Systematic review, 43 studies with 3952 (EOPD 일것) patients
  • 이중 8.6%가 Parkin mutation (아래기술 보면 이들이 모두 biallelic) (95% CI, 6.0%-12.4%; Fig.1, Table S3).
• 44.1% homozygous, 55.9% compound heterozygous
• Proportion (the author says this is ‘pathogenic parkin mutation’)
  • 15.5% in Familial EOPD vs 4.3% in sporadic EOPD

ROPAD

Skrahina, 2021 #1926): 10/1288 were biallelic prkn mutation. So this gives ~54,000 patients WW.

#682: only missense mutations!

I can’t find the mean age of the subjects in the paper.

PRKN Variant Annotation Table, Partial

Index	Databases	Parkin Variant	Annotation with clinical evidence	Functional group	Annotation with clinical and functional evidence
	Disease and population	p.R42P	Pathogenic	1	Pathogenic
	Disease and population	p.V56E	Pathogenic	1	Pathogenic
	Disease and population	p.K211N	Pathogenic	2	Pathogenic
	Disease and population	p.C212Y	Pathogenic	1	Pathogenic
	Disease and population	p.C238W	Pathogenic	1	Pathogenic
	Disease	p.C253Y	Pathogenic	1	Pathogenic
	Disease and population	p.G284R	Pathogenic	2	Pathogenic
	Disease and population	p.T415N	Pathogenic	2	Pathogenic
	Disease	p.C431F	Pathogenic	2	Pathogenic
	Disease and population	p.C441R	Pathogenic	1	Pathogenic
	Disease	p.T240R	Likely Pathogenic	2	Pathogenic

Uncertain Spans

• The citation prefix before “ski, 2012 #692” is cropped off at the left edge.
• Superscript footnote letters in Table 2 are not consistently legible; numeric values are retained without superscript letters where uncertain.
• Dense mutation labels inside the PRKN exon/domain map are preserved as an image rather than fully retyped because several labels are too small for lossless text reconstruction.
• The PRKN variant annotation table continues below the crop; only visible rows are transcribed here.