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. Author manuscript; available in PMC: 2020 May 8.
Published in final edited form as: Am J Med Genet B Neuropsychiatr Genet. 2017 Jan;174(1):36–69. doi: 10.1002/ajmg.b.32505

Table 3.

Missense mutations in PRNP in literature & UCSF cohort*

PRNP
Mutation		 Codon
129
polymorphism		 # of
cases
in
literature
or
UCSF
cohort
# 		Clinical
phenotypes		 Age at
onset
(range)^
Y		 Disease
Duration
(M or Y)		 Pos
FHx## 		CSF marker
Sensitivity		 EEG
PSWC		 MRI
c/w
JCD§ 		Neuropath Neuropathl
Pheno-
type		 References
14-3-3 Total tau^^
P84S MV 1

  • Cog (1 Y)→ paranoia & RPD

 (60) (14) M 0% (0/1) N/A 0% (0/1) 0% (0/1) Multic
PrP-Plqs w/o
NFT
No V		 GSS [Jones et al., 2014]
S97N Cis M 1

  • AD

 (72) N/A 0% (0/1) N/A N/A 0% (0/1) N/A N/A [Zheng et al., 2008]
P102L MM/MV (most cis M) ~221

  • Early Cb w/late D

  • Some are RPD

  • LE areflexia common

 (27–66) (7–132) M 84–100% (15–20% ) 20% 0–35% 25–30% Multic PrP-Plqs GSS [Webb et al., 2008; Higuma et al., 2013; Krasnianski et al., 2015]
P102L UCSF Cis M 13 44±12 (24–57) 44±13 M (28–60) FHx Score
0 (n=1)
1 (n=2)
2 (n=6)		 0 % (0/3) 0% 0% (0/3) 33.3% (1/3)
P105L MV 13

  • D w/spastic paraparesis

  • Cb Atx

  • Pscyh Sxs sometimes

 Mean 44±10 (2nd to 7th decades) Mean 111±82 M 37% 0% 0% 0% 14% PrP-Pl, diff PrP (deep CLs) GSS [Higuma et al., 2013]
P105L UCSF N/A 1 (10) N/A FHx Score
0 (n=1)		 N/A N/A 0% (0/1) 0% (0/1)
P105T Cis M 13

  • Usually RPD;

  • Cb Atx freq

 (13–41) (2–5) Y 100% (2/2) 0% N/A 0% (0/3) 25% (1/4) V, PrP-S (all CLs) Unicentric PrP-Plqs (deep CLs) JCD [Rogaeva et al., 2006; Polymenidou et al., 2011]
P105S MV (Cis V) 1

  • Aphasia, frontal-type behavchanges, D, late Park

 (30) (10)Y 0% (0/1) N/A N/A 0% (0/1) 100% (1/1) Multic PrP-Plqs (HP), punctate aggregates (Cb), V (Pu) Atypic GSS [Tunnell et al., 2008]
G114V (MM/MV) 1

  • RPD.

  • Onset: Psych Sxs, D, Park, Pyr signs, myoclonus

  • GTCs in some

  • Absent or mild Cb signs

 (18–75) (1–4)Y 75% (3 in 4 probands)§§ 0% 0% (0/8) 42.9% (3/7) predom BG Mod V, G, NL. PrP-S, Type 1 PrPSc (predom monoglycos) JCD [Rodriguez et al., 2005; Ye et al., 2008; Liu et al., 2010; Beck et al., 2010]
A117V Cis V 33

  • Variable

  • Progressive D w/o Atx

  • LMN SYN w/D & Atx

 (20–64) (1–11 Y) 100% (4/4) N/A N/A N/A 0% (0/2) Ab PrP-Plqs, F V, NL, G GSS [Hsiao et al., 1991; Mastrianni et al., 1995; Kong et al., 2004]
A117V UCSF Cis V 6 34±14 (14–49) 46±21 M (27–78) FHx Score
0 (n=1)
2 (n=2)		 0 % 0 % 0% (0/3) 0% (0/5)
G131V MM/MV (cis M) 3

  • D w/behav changes & late Atx

  • Park

 (36–42) (9–16) Y 50% (1/2) N/A N/A 0% (0/1) 0% (0/1) PrP-Plqs, NFT (AH, ERC), No V GSS [Panegyres et al., 2001; Jansen et al., 2012]
S132I MM 2

  • RPD

 (62) (18) M 100% (1/1) N/A N/A N/A N/A diff unicentric & multic PrP-PLs (neocortex, BG, Cb)
Min V		 GSS [Hilton et al., 2009]
A133V MM 2

  • PSP-like, RPD

 (62) (4) M 0% (0/1) 0% 0% (0/1) 0% (0/1) diff V, G, NL multic PrP-Plqs in the (Mol), PrP-S (Th) Atypic GSS [Rowe et al., 2007]
R148H (MV/MM) 3

  • JCD

 (62–82) (6–18) M 0% (0 in 2)§§ 50% (1/2) 100% (1/1) 50% (1/2) 100% (1/1) predom BG 129MM – Similar to sJCDMM1. V, G, NL (deeper lCLs). PrP-S PrPSc Type 1 129MV - Similar to sJCDMV2 V predom in CLs V & VI, Kuru plaques in Cb & WM, PrP-S PrPSc type 2 (predom monoglycos) JCD [Krebs et al., 2005; Pastore et al., 2005]
R148H UCSF MM 1 (53) (2) M FHx Score
0 (n=1)		 N/A N/A N/A 100% (1/1)
D167G MM 1

  • JCD

 N/A N/A N/A N/A N/A N/A N/A sJCD PrP type 1 JCD [Bishop et al., 2009]
D167N MM 1

  • RPD w/Park & Pyram signs

 (33) (2) Y 0% (0/1)§§ N/A N/A 0% (0/1) 0% (0/1) N/A N/A [Beck et al., 2010]
V176G VV 1

  • RPD w/behavioral changes, Cb Atx, Pyram signs & myoclonus

 (61) (7) M 0% (0/1) 100% (1/1) 100% (1/1) 0% (0/1) 0% (0/1) Multic PrP-Plqs w/prominent tau GSS [Simpson et al., 2013]
D178N-129V MV/V V (Cis V) 209**

  • Progressive Cog decline, Cb Sxs, myoclonus, EP Sxs

 Mean 46 (26–56) Mean 23 M (7–60) 100% (12/12) N/A N/A N/A N/A Similar to sJCD VV1 JCD [Brown et al., 1992; Goldfarb et al., 1992; Kong et al., 2004]
D178N-129V UCSF Cis V 8 45±6 (37–52) (18–21) M FHx Score
2 (n=4)		 50% (1/2) 0% (0/1) 0% (0/2) 100% (2/2)
V180I Cis M 225

  • JCD phenotype, but w/slower prog

 Mean 77 Mean 25 M 0.7–6% 70%; 78.5% 11% 99% V PrP-S JCD [Kong et al., 2004;Higuma et al., 2013]
V180I UCSF Cis M 2 (84) (21) M FHx Score
1 (n=1)
2 (n=1)		 0% (0/1 0% (0/1) 100% (1/1)
T183A Cis M 3

  • bvFTD, AD

 45±4 (42–49) 4±2 Y (2–9) 100% (2/2) N/A N/A 0% (0/7) 0% (0/2) V & NL (CLs IV, V, VI), PrP (Cb, Pu) Small Plq-like PrP, Predom monoglycos PrPSC JCD [Nitrini et al., 1997; Grasbon-Frodl et al., 2004]
H187R MM/MV/VV 7

  • Early Cog & behavioral Sxs w/late Cb Atx

  • early Cb Atx & D after a few years

  • Case w/Pscyh Sxs in adolescence

 (20–53) (3–19) Y 100% (4/4) 0% (0/2) 0% (0/4) 0% (0/4) G multic-PrP-Plqs in some cases. Curly PrP-G GSS [Cervenakova et al., 1999; Butefisch et al., 2000;Hall et al., 2005; Colucci et al., 2006]
H187R UCSF Cis M 4 (30–41) (12–13) Y FHx Score
2 (n=1)		 0% (0/1) 0% (0/1) 0% (0/1) 0% (0/1)
T188R MV/VVV (Cis V) 12

  • JCD

 (55–66) (14–16) M 0% (0/1)§§ 50% (1/2 100% (1/1) 50% (1/2) 50% (1/2) V, NL, A PrP-S & plaque-like PrP, Type 1 PrPSc JCD [Tartaglia et al., 2010; Roeber et al., 2008]
T188K MM/MV (Cis M) 3

  • JCD

 Median 58 (39–76) (2–13) M 8–37%§§ 69% 12% 69% SE PrP-S JCD [Roeber et al., 2008; Chen et al., 2013; Shi et al., 2015]
T188A MM 1

  • JCD

 (82) (4) M 0% (0/1) 100% (1/1) 100% (1/1) 100% (1/1) 0% (0/1) Sev G, V, Mod NL (predom in OLs) PrP-Neg JCD [Collins et al., 2000]
T193I MM

  • JCD

 (70) (10) M 0% (0/1) 100% (1/1) 100% (1/1) 100% (1/1) 0% (0/1) N/A N/A [Kotta et al., 2006]
E196K N/A 13

  • JCD

 (64–69) (10–13) M 100% (1/1) N/A N/A 0% (0/1) N/A N/A N/A [Peoc’h et al., 2000]
F198S MV/VV 5

  • Cb Atx & D

  • freqPark.

 (40–71) Y Mean 5 Y (2–12) 100% (3/3) N/A N/A N/A 0% (0/1) Uni- & multic PrP-Plqs GSS [Farlow et al., 1989; Dlouhy et al., 1992; Ghetti et al., 1995; Kong et al., 2004]
F198S UCSF Cis V 5 55±8 (46–66) 67±23 M (34–84) FHx Score
1 (n=2)
2 (n=1)		 33.3% 100% (1/1) 0% (0/4) 0% (0/3)
F198V MM 1

  • D w/visual hallucination s, myoclonus & Park

  • Clinical dx of early onset AD

 (56) (4) Y N/A N/A N/A 0% (0/1) 0% (0/1) N/A N/A [Zheng et al., 2008]
E200K MM/MV/VV 571

  • Similar to sJCD

  • Peripheral neuropathy & supranuclear gaze palsy in some

 Mean 60 (33–84) (1–18) M 50% 85–100% (80–100%) 42–85% 50–88% Usually sJCD MM1 PrPSc types 1 & 2 JCD [Spudich et al., 1995; Meiner et al., 1997; Kovacs et al., 2005; Kovacs et al., 2011; Krasnianski et al., 2015]
E200K UCSF Cis M (n=16) & Cis V (n=1) 34 60±13 (36–84) 11 ±17 (1–78) FHx Score
0 (n=2)
1 (n=10)
2 (n=12)		 57.1 % (4/7) 37.5% (3/8) 88.9% (16/18)
E200G MV (Cis V) 1

  • RPD, Cb Atx, Park ↓sensation in LEs

 (57) (30) M 0% (0/1) 0% (0/1) 100% (1/1) 0% (0/1) 100% (1/1) SE w/type 2 PrPSc JCD [Kim et al., 2013]
D202G MV (cis V) 1

  • Slowly progressive D w/Cb Atx Later Pyram & EP signs

 (55) (16) Y 100% (1/1) 100% (1/1) 0% (0/1) 0% (0/1) 0% (0/1) N/A N/A [Heinemann et al., 2008]
D202N VV 1

  • D (AD) w/Cb Atx

 (73) (6) Y N/A N/A N/A N/A N/A PrP-Plqs, NFT GSS [Piccardo et al., 1998]
V203I N/A 17

  • JCD

 (69) (1) M 0% (0/1) N/A N/A 100% (1/1) N/A N/A N/A [Peoc’h, 2000 #12035]
R208H MM/VV 15

  • D w/behav changes

  • Park & Pyram signs freq

  • Report of a PSP-like phenotype

 (58–63) (3–16) M 20% (1/5) 50% (4/8) 57.1% (4/7) 25% (2/8) SE, PrP-S (perineuronal perivacuolar) Type 1 PrP JCD [Roeber et al., 2005; Capellari et al., 2005; Matej et al., 2012 Vita et al., 2013; Shi et al., 2015]
V210I Cis M 247

  • JCD

 Mean 59 (39–82) Median 5 (2–20) M 12–31% 90–100% 100% 44–80% 15–33% Similar to sJCD MM1 JCD [Kovacs et al., 2005; Kong et al., 2004; Breithaupt et al., 2013 Krasnianski et al., 2015]
V210I UCSF Cis M 3 57±15 (47–74) (1) M FHx Score
0 (n=2)
2 (n=1)		 100% (1/1) 33.3% (1/3) 100% (2/2)
E211Q MM 11

  • JCD

 (42–81) (6–32) M 100% (2/2) N/A N/A 100% (4/4) N/A V, G Mi PrP-S types 1 & 2 PrPSc JCD [Peoc’h et al., 2000; Ladogana et al., 2001; Peoc’h K et al. 2012]
E211D VV 1

  • Cb Atx, & late D

 (53–68) (3–13) Y 50% (1/2) N/A N/A 0% (0/2) 0% (0/2) Multic PrP-Plqs, Dystrophic neurites & NFT GSS [Peoc’h et al., 2000; Peoc’h et al., 2012]
Q212P MM 2

  • Cb Atx w/o D

  • Dx of olivoponto Cb degeneration

 (60) (8) Y N/A N/A N/A N/A N/A Mod PrP Mi, PrP-Plqs GSS [Piccardo et al., 1998]
I215V MM 1

  • JCD

 (55–76) (12–15) M 0% (0/2) (1/3) 100% (2/2) 50% (1/2) NL, G, V, PrP-Neg JCD
Q217R VV/MV (Cis V) 3

  • D w/Cb Atx

  • Cog decline, stereotypical behav

  • Late Park & apraxia. Clinical dx of bvFTD & CBS

 (45–66) (5–13) Y 100% (3/3) N/A N/A 0% (0/1) 0% (0/1) Uni- & multic PrP-Plqs, NFT (neocortex) GSS [Hsiao et al., 1992; Woulfe et al., 2005; Piccardo et al., 1998; Munoz-Nieto et al., 2013]
Y218N VV 1

  • Atypic D w/AD & bvFTD features

  • Early language & executive impairment

  • No Atx

 (54–61) (6) Y 100% (1/1) N/A N/A 0% (0/2) 0% (0/2) Uni & multic PrP-Plqs, NFT w/hyperP tau. GSS [Alzualde et al., 2010]
A224V VV (Cis V) 1

  • RPD

 (48) (32) M 0% (0/1)§§ 100% (1/1) N/A 100% (1/1) Diff V w/PrPSc type 1 JCD [Watts et al., 2015]
M232 R MM 63

  • Similar to sJCD, some w/slower prog

 Mean 64 (15–81) Mean 8 (0–32) M ~0% 55–75% 55–93% 20–100% 85% sJCD MM1 JCD [Shiga et al., 2007; Zheng et al., 2008; Nozaki et al., 2010; Higuma et al., 2013]
M232 T MV

  • Cb Atx, spastic paraparesis & D

 N/A (6) Y 0% (0/1) N/A N/A N/A N/A Multic PrP-Plqs GSS [Bratosiewicz et al., 2000]
P238S N/A

  • JCD

 N/A N/A N/A N/A N/A N/A N/A N/A N/A [Windl et al., 1999]
*

If UCSF cohort differs from the literature, this information is provided in the table.

**

Including D178N-129V & D178N-129M.

#

By nine PrD surveillance centers, according to Minikel et al., 2016.

##

Positive family history of dementia w/similar clinical features (as of the proband) or PrD. For UCSF family history FHx (family history) Score scale: 0 when there was no positive FMH suspicious for or known PrD; 1 when there was at least one first-degree relative w/dementia, encephalopathy or movement disorder; or 2 in patients who were part of families w/known PRNP mutations, or had positive history for clinical or path-proven PrDs.

§

According to most commonly used European 2009 and UCSF 2011 criteria [Zerr et al., 2009; Vitali et al., 2011].

§§

there is evidence of incomplete penetrance, as asymptomatic older carriers also were identified.

^

Data on age at onset & duration of disease are shown as mean±SD (range), unless otherwise indicated.

^^

positive if > total tau 1200 pg/mL

Abbreviations: Ab = abundant; AD = Alzheimer-type dementia; AH = Ammon horn; atypic = atypical; Atx = ataxia; BG = basal ganglia; bvFTD = behavioral variant Frontotemporal Dementia; c/w = consistent with; Cb = cerebellum; CBS = corticobasal syndrome; CLs = cortical layers; Cog = cognitive; D = dementia; diff = diffuse; dx = diagnosis; ERC = entorhinal cortex; EP = extrapyramidal; FHx = family history; F = focal; freq = frequent; G = gliosis ; GTC = generalized tonic clonic seizures; HP = hippocampus; HyperP = hyperphosphorylated; LE = lower extremities; LMN = lower motor neuron; M = months; Mi = mild; Min = minimal; Mod = moderate; Mol = molecular layer of the cerebellum; monoglycos = monoglycosylated; multic = multicentric; N/A = not available; Neuropath = Neuropathology; NFT = neurofibrillary tangles; NL = neuronal loss; OLs = occipital lobes; Park = parkinsonism; Pos = positive, prog = progression; predom = predominant; PrP-G = granular PrP deposits; PrP-Neg = negative PrP staining; PrP-Plqs = PrP-amyloid plaques; PrP-S = synaptic PrP deposits; PSP=progressive supranuclear palsy; PSWC = periodic sharp wave complexes; Pu = putamen; Pyram = pyramidal; SE = spongiform (vacuolated) encephalopathy; Sev = severe; SYN = syndrome; Th = thalamus; WM = white matter.; Psych = psychiatric; Sxs = symptoms; V = vacuolation; w/ = with; w/o = without; Y = years