PRKN Heterozygous Carrier Frequency, EOPD Risk, And Neuropathology

Heterozygous PRKN Carrier Notes

Table2) pathogenic SNV & CNV heterozygous carrier 가, 약 2000 명 이상의 PD 환자중 1.2%,
약 2000 명 이상의 control 에서 1.8% 로 차이부 (오히려 PD 에서 적음, JS: This tells us that
heteroz PRKN mutation is not a risk factor for LOPD 왜냐면 LOPD 환자가 majority
였으니까,)
 
Pathogenic SNV & CNS is 14% of total (SNV & CNV) (1.52/10.7)
 
Pathogenic Parkin variant should mean the variants that show reduction of either parkin
function or parkin expression (applied in 2019 Yi). Target? Controversial, so is there any
means to address this?

CNS in the visible note may be an OCR/typing issue for CNV; it is left as visible/uncertain text rather than silently corrected.

EOPD-Only Carrier Analysis

Note:

[EOPD only]
Is it a risk factor for EOPD? -> (table S5) no association (p>0.05), but trend (OR=~1.5)
Pathogenic SNV & CNS is ~20% of total (SNV & CNV)

Table transcription:

analysis in participants below 50	Carriers in patients, No. (%)	Carriers in controls, No. (%)	SKAT-O
SNV	50 (12.5)	276 (9.38)	0.507
CNV	7 (1.75)	29 (0.982)	0.594
SNV & CNV	55 (13.7)	293 (9.9)	0.584
Patho SNV	5 (1.25)	23 (0.778)	0.814
Patho SNV & CNV	12 (2.99)	52 (1.76)	0.765
No Benign SNV	34 (8.48)	186 (6.3)	0.507
No Benign SNV & CNV	40 (9.97)	203 (6.87)	0.589

Additional visible row notes:

Early vs late not specified
 
Comp Bio 보자!
PD=1,272
Prodromal=57
HC=676
 
{Huttenlocher, 2015 #1924}
1415 PD patients and 40 474 controls ≥65 y
OR=1.67. 4.55% in total 인듯 (ie PD+ non PD), Arg275rp 가 mocst common.

Population Estimates And Penetrance

Source label:

Takeda internal

Group (age ≥ 18)	Biallelic PRKN mutations in general population	Biallelic PRKN mutations with symptomatic PD	Monoallelic PRKN mutations with symptomatic PD
United States and Europe	23,000-70,000	1,622-13,000	33,000-45,000
United States	10,000-30,000	930-7,400	19,000-26,000
Europe (EU + UK)	13,000-40,000	692-5,500	14,000-19,000
Japan	40-107	NA	NA
China	420-1,100	NA	NA

Penetrance note:

Penetrance of Heterozygus parkn mutation
 
{Castelo Rueda, 2021 #1923}
Mean age: 45
Penetrance is (2.44-) 7.5% (table s1,
PDS11, ie PD medication)

Neuropathology Notes

[Poulopoulos et al 2012]. The most prominent and most common feature was the finding of neuronal loss in pigmented nuclei of the brain stem. Unlike Parkinson
disease of other etiologies, the neuronal loss was greater in SNpc than in LC (see Parkinson Disease Overview). Typical alpha-syn-containing Lewy bodies were identified
in only two affected individuals, whereas one affected individual had basophilic Lewy body-like pathology of the pedunculopontine nucleus. Tau-containing
neurofibrillary tangles were observed in two affected individuals. In summary, the spectrum of postmortem findings is broad and thus reminiscent of the situation in
LRRK2 Parkinson disease [Kasten et al 2018].
 
{Doherty, 2013 #778}: review논문 아니지만, 다른 postmortem study 결과 많이 게재함.

LB/a-syn

however, there is a distinct lack of LB formation
 
No juvenile-onset cases have ever been reported with LBs postmortem.22,23 Movement Disorders, Vol. 28, No. 6, 2013
 
In a relatively large series of patients with PRKN-related PD and a review of the literature, together with autopsy reports of 13 patients with PRKN-related PD, only 3 out of 13 had
any LBs. (Aasly, 2020 #781)
 
{Seike, 2021 #1271} 3 out of 8 patients show LB (한명: brain-stem predominant, 두번째환자: limbic subtypes, 세번째환자: lc, DORSOVAGAL NUCLEUS, BUT NOT IN snPC)

Neuronal Loss

{Doherty, 2013 #778}:
 
of course SN,
 
Mild neuronal loss in the locus coeruleus and dorsal motor nucleus of the vagus (in the medulla) (mild in 2 of 3 cases examined) and
the cerebellum (js: cerebrum 아님!) (examined at the level of the dentate nucleus and the superior cerebellar peduncle), which showed
mild Purkinje cell loss with empty baskets,
 
but not in the nucleus basalis of Meynert, raphe nucleus, or other brain regions
 
{Seike, 2021 #1271} variable degree of neuronal loss in SN & LC

Gliosis

Mild to moderate gliosis accompanied the neuronal loss previously described,
 
also evidence of gliosis (in the absence of detectable neuronal loss) in the raphe nucleus, NBM, striatum, globus pallidus, dentate nucleus,
amygdala, hippocampus, and cerebral cortices (Figure 2B).
 
{Seike, 2021 #1271} mild to moderate gliosis in SN & LC

Regional Neuronal Loss And Gliosis Figure

Figure/caption text:

Figure 2. Regional neuronal loss (A) and gliosis (B) in parkin, Parkinson
disease (PD), and control cases. A, The severity of neuronal loss in various
brain regions in the 5 parkin, 5 PD, and 4 control cases (not all structures
were available for examination in all cases [eg, the raphe was only available
for examination in 3 parkin, 2 PD, and 3 control cases]). B, The severity of
gliosis in various brain regions in the parkin, PD, and control cases.
GP indicates globus pallidus; DMV, dorsal motor nucleus of the vagus;
LC, locus coeruleus; NBM, nucleus basalis of Meynert; SN, substantia nigra.

Note below the caption:

neuronal dropout (의미 못 찾겠음) and gliosis are the neuropathologic findings Movement Disorders, Vol. 28, No. 6, 2013

Schneider 2017 PARKIN Autopsy Reports

Note:

Good postmortem review on (Schneider, 2017 #1056)

Table title:

TABLE 5. Summary of PARKIN autopsy reports

Header and first row. The table continues beyond the bottom of this photo.

Report	Number of autopsies	Genotype	Phenotype	Pattern of neuronal loss	LB, LN pathology	LB distribution - Braak stage	Tau pathology - NFT stage	Other inclusions
Takahashi et al 1994	2	No details reported	JPD	LC>SNpc	-	-	n.d.	-

Uncertain Spans

• Page 98 of 104 is from the visible Word statusbar and conflicts with earlier synthesized pages that used a different denominator.
• CNS in Pathogenic SNV & CNS appears in OCR/visible text but probably refers to CNV; it is not normalized here.
• OR=1.67. 4.55% in total 인듯 has ambiguous punctuation; it may represent separate values rather than one sentence.
• Arg275rp 가 mocst common is left close to the visible text. It may intend Arg275Trp and most common.
• Heterozygus parkn mutation, PDS11, and table s1 are visible/OCR-derived spellings and should be verified.
• {Seike, 2021 #1271} LB distribution note uses lc/LC and snPC/snpc inconsistently in the visible source text.
• The regional neuronal loss/gliosis figure is preserved as an image asset; individual bar heights are not transcribed.
• Schneider 2017 TABLE 5 is only partially visible; only the header and first row are captured here.