Parkin-PD Prevalence And GE/GMS Biomarker Cohort Proposal

Prevalence Of Parkin Mutations

Prevalence of Parkin mutations

left label / group	familial	sporadic
juvenile Parkinson's (JP): 21 y
Young onset (YOPD) (21-40) js: recent consensus seems <50 4-10% of total PD (Camargos, 2009 #689),	20% of YOPD patients have at least one first- or second-degree relative with PD either in the same or antecedent generation. (Klepac, 2013 #690) Parkin mutation: PARKIN pathogenic mutation has been found in 50% cases of familial PD and up to 15% of early onset sporadic cases in one cohort (Lücking, 2000 #693) although a recent meta-analysis (Kilarski, 2012 #692) concluded that the figure is around 15.5% of familial and 4.3% of sporadic cases. 아래로 정리 20200924 tDIB: Kilarski 2012: 136 명의 EOPD cases 중 29 가 familial cases, so 21% Kilarski 2012, 100 x 10% x 21% x 15.5% (the prevalence of PARK2 mutations in patients, p1525 에 3952 patients 중에서의 prevalence 라고 명시했고, patient 니까 homoz 혹은 compound heteroz 이겠지) = 0.33% of total PD = in the us, 3,255 cases	Majority cases of YOPD (80% 집으면), 다른 reference? - PARK2 mutation: 15% of YOPD (<45)). Then, 100 x 10% x 80% x 15% = 1.2% of total PD But according to Kilarski 2012, 100 x 10% (early onset) x 79% x 4.3% (the prevalence of PARK2 mutations in patients, p1525 에 3952 patients 중에서의 prevalence 라고 명시함, patient 니까 homoz 혹은 compound heteroz 이겠지) = 0.34% of total PD = in the us, 3,397 cases (Chaudhary, 2006 #928) YOPD (N=173)중 2 명만이 HOMOz or compound hetero 아래로 정리 20200924 tDIB: - 79% of YOPD cases are sporadic - 4.3% of sporadic YOPD have PARK2 mutations => 0.34% of total PD (~3,000 cases in the US)

Young-Onset Combined Estimate

Young onset Parkin-PD (Bi allelic) is 0.67% (0.33 + 0.34) in total PD. So 0.67% of total PD cases worldwide (6 million) is 402,000 cases.

(Alcalay, 2010 #691) 16.6% of YOPD patients (without regard to family history of PD.) have mutations (including (6.7%) PRKN, (3.6%) LRRK2, (6.7%) GBA, and (0.2%) DJ1 -> then Parkin-mutant PD is 3.6% of YOPD without regard to family history of PD. (ie 0.36% of total PD cases)

Late-Onset Estimate

left label / group	familial	sporadic
Late onset (>50)	(Payami, 2002 #927) LOPD (N=343) 의 6%가 familial PD 이라는 것 같음 (FIG, 80 세 기준) (Oliveira, 2003 #917, n=363) park-PD is 2% of LO familial PD 100 x 90% x 6% x 2% = 0.1% of total PD = in the us, 1,080 cases (Chaudhary, 2006 #928) YOPD (N=173) 아래로 정리 20200924 tDIB: - 6% of LOPD cases are familial - 2% of familial LOPD have PARK2 mutations => 0.1% of total PD (~1,000 cases in the US)	86% of total (Camargos, 2009 #689, 2nd, the rest include drug-induced parkinsonism). (Chaudhary, 2006 #928) LOPD (N=51), No homoz or compound heteroz PARK2 mutation

Targeting And Rare-Disease Note

Parkin-mutant PD 가
- sporadic일 수도 있고, hereditary ('AR' ie 친척중에 Parkin-mutant PD가질수도) 일수도 있다.
대략 1% of total PD (1 million in US, 6 million worldwide) 잡으면 10,000 PATIENTS IN US, so this is a rare disease (In the United States, a rare disease is defined as a condition that affects fewer than 200,000 people in the US.) -> but, js, should we only target EOPD with pathogenic Parkin variants (regardless whether they are familial or sporadic)? -> according to Kilarski 2012, it is 0.65% of total PD (= 0.31 + 0.34), and this is 'pathogenic' parkin mutation according to the author.
- (Vollstedt, 2019 #822): 1,500 pathogenic variants in Parkin WWW reported

Variant Types, Protein Level, And Mitophagy Evidence

row	Single base-pair substitutions	(small & big) deletions	Multiplication (duplication)	Splice site mutation
Parkin mRNA		(Zanellati, 2015 #712) in fibroblast: 3 명이 deletion, dupliction 혼재했는데, parkin m RNA level ~35% control
Parkin Protein level	Yi 2019 보면됨 (↓ d/t protein destabilization)	(Zilocchi, 2020 #901) in fibroblast: 5 명이 deletion, dupliction 혼재했는데, parkin protein level ~0% control (Zanellati, 2015 #712) in fibroblast: 3 명이 deletion, dupliction 혼재했는데, parkin protein level <10% control (Pacelli, 2011 #725) n=2, compound heteroz deletional mutation, complete absence of parkin protein (WB)
mitophagy	Yi 2019 보면됨	Can't find evidence

Comp Bio / Candidate Pool Notes

Comp Bio

UK Biobank
- 6 subjects with 1 potentially pathogenic pLoF in PRKN with G20 diagnosis
- Likely pathogenic missense variants have not been assessed
 
GENOMics England
- 6 subjects with tier 1 and tier 2 mutations in PRKN with the diagnosis of 'Early onset and familial PD'
  - 2 Homozygous, 4 compound heterozygous, 0 single heterozygous
  - The 6 subjects are likely to be able to be contacted for blood samples.
    - Questions

GE / GMS Cohort Framing Notes

My summary -> GE; feasibility & realistic timeframe to recruit -> james will let us know NHS Genomic Medicine Service (GMS) Research Collaborative
We need plasma, so not interested in RNA blood samples (two)
How best to frame it
Set up prospective cohort, : no application form but email) summary (n, group, plasma, benefit
Access review committee
  - Form
    - Best possible outcome (our understanding of the disease, stratification, informed drug discovery, clinical trial)
 
Late onset sPD (from clinical data set, GE team, bioinformatics team) and control (Unaffected family members)
Us shipment experienced
very clear justification and rationale as to which specific samples you would seek to acquire from either the treating clinician or directly from the participants by recalling them into clinic.
Anticoagulant: EDTA (preferred than heparin)
Tube? (no specific requirement at Takeda side)
How the blood sample was collected (e.g. which tube was used to collect samples)?
how those are stored,
whether we can process them, or should be processed by GE vendor?
If we want to detect some markers in these samples, do we have to work with GE's designated vendors or could blood samples be shipped to us?
Financial contribution?

Access Route Comparison

item	My summary	GE Access Review Committee.	NHS Genomic Medicine Service (GMS) Research Collaborative
URL / contact		https://www.genomicsengland.co.uk/library-and-resources/	https://www.england.nhs.uk/genomics/genomic-research/nhs-genomic-medicine-service-research-collaborative/ secretariat on: ENGLAND.genomics@nhs.net.
review interval		every 3 month	every 3 month
Research proposal submission form		Not found	found
Turnaround time		2w

Draft Email To James

Hi James,
 
Hello, sorry for not getting back to you earlier. The discussion with you at the call was extremely useful in understanding what GE does with 100,000 Genomes Project and the process involving Access review committee and then GMS Research Collaborative. As promised, please find below the summary of our current proposal so you can better look into how feasible to set up cohorts (prospective/retrospective) and how to frame it. If you need anything further that you think is helpful moving forward please let us know.

Observational Cross-Sectional Study Proposal

form field	visible content
Study title	A observational cross-sectional study for mitochondrial biomarker discovery in PD
Rationale	Parkinson's disease (PD) is a mechanistically heterogenous condition and a subset of late-onset sporadic PD (sPD) should have mitochondrial dysfunction as a pathogenic driver. Currently there are no biomarkers that can effectively reflect mitochondrial function in the patients with PD and can be used to monitor treatment response. Also it is largely unknown how many patients with sPD have mitochondrial dysfunction. Parkin-PD are caused by loss-of-function mutation in Parkin gene. Parkin-PD patients have established mitochondrial dysfunction causing PD pathology and may provide benchmark for exploring candidate mitochondrial biomarkers for sPD. For the future purpose of screening/selecting sPD patients, the changes of the biomarkers in blood will be a major focus of the current study.
Research overview: aims and objectives	The primary objective of this study is to assess mitochondrial biomarkers in the blood in cohorts of i) Parkin-PD, ii) sPD, and iii) healthy controls with the goal of addressing the aims below. - To determine what mitochondrial biomarkers are altered in Parkin-PD - What Biomarkers can be used to select/identify sPD patients in future clinical trials in PD who are likely to respond to mitochondrial treatment?
Research Plan: [Subjects]	Parkin-PD group will comprise of eleven known subjects established in GE (Participants id: 285, 990, 137, 583, 506, 880, 176, 044, 347, 000, 806). These patients will be prospectively recontacted for blood sampling as there is no plasma sample available from the patients stored at GE. The plasma will also be collected from twenty sPD patients and twenty healthy controls. sPD patients are describd as the PD patients with onset age >50 and without known causative mutations of PD. Healthy controls are the subjects with age >50 who do not present major neurological disorders and do not carry known causative mutations of PD. We are interested in the possibility that sPD subjects and healthy controls may be identified from the existing database at GE and the plasma samples are already available.
Research Plan: [Assessment]	The samples will be shipped to Takeda Neuroscience Drug Discovery Unit in Japan and analysed for the following mitochondrial biomarkers using relevant assays including immunoassays and PCR. The total amount of required plasma for the analysis will be 500 μL per subjects. Literatures suggest that these candidate markers may be altered in Parkin-PD and a subset of sPD patient, as a consequence of primary mitochondrial deficit. Ps65-ub (a marker of mitochondrial clearance), Parkin, TOM40/20 (Markers of mitochondrial abundance), Mitochondrial DNA damage, Mitochondrial DNA copy number, ATP (a marker of mitochondrial respiratory function)
Intended impact of the research on patients and the research in the field	Identifying biomarkers of mitochondrial dysfunction in PD would be extremely valuable in monitoring treatment response as well as identifying patients with a high degree of mitochondrial dysfunction for clinical trials of drugs in PD designed to enhance mitochondrial function.
Collaborators [150 words max] and explain the role of key collaborators involved in the research. Collaboration with other stakeholders such as Clinical Trials Units should also be described.
Patient and Public Involvement [150 max]

Uncertain Spans

location	text/status	reason
rare-disease note	0.65% of total PD (= 0.31 + 0.34)	This differs from the visible 0.33 + 0.34 combined estimate; source note may contain a typo or older calculation.