Table 29.1.
PRNP missense mutations
| PRNP mutation | Codon 129 polymorphism | # of cases in literatureb | Clinical phenotypes | Age at onset (range)f (years) | Disease duration (months or years) | Positive family historyc | CSF marker
sensitivity |
EEG PSWC | MRI c/w JCDd | Neuropathology | Neuropathology phenotype | References | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 14-3-3 | Total taug | ||||||||||||
| P84S | MV | 1 | Cog (1 year) → paranoia and RPD | (60) | (14) months | 0% (0/1) | N/A | 0% (0/1) | 0% (0/1) | Multicentric 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) months | 84–100% | (15–20% ) | 20% | 0–35% | 25–30% | Multicentric PrP-Plqs |
GSS | Webb et al. (2008); Higuma et al. (2013); Krasnianski et al. (2016) |
| P102La | Cis M | 13 | 44 ± 12 (24–57) | 44 ± 13 months (28–60) | FHx score 0 (n = 1) 1 (n = 2) 2 (n = 6) |
0% (0/3) | 0% | 0% (0/3) | 33.3% (1/3) | Takada et al. (2017)) | |||
| P105L | MV | 13 | D w/ spastic paraparesis Cb Atx Pscyh Sxs sometimes |
Mean 44 ± 10 (2nd to 7th decades) | 111 ± 82 months | 37% | 0% | 0% | 0% | 14% | PrP-Plqs diff PrP (deep CLs) |
GSS | Higuma et al. (2013) |
| P105La | N/A | 1 | (9) | N/A | FHx Score 0 (n = 1) |
N/A | N/A | 0% (0/1) | 0% (0/1) | N/A | Takada et al. (2017) | ||
| P105T | Cis M | 13 | Usually RPD; Cb Atx freq |
(13–41) | (2-5) years | 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 behavioral changes, D, late Park | (30) | (10) years | 0% (0/1) | N/A | N/A | 0% (0/1) | 100% (1/1) | Multicentric PrP-Plqs (HP), punctate aggregates (Cb), V (Pu) | Atypic GSS | Tunnell et al. (2008) |
| G114V | (MM/MV) | 1 | RPD Onset: Psych Sxs, D, Park, Pyram signs, myoclonus GTCs in some Absent or mild Cb signs |
(18–75) | (1–4) years | 75% (3 in 4 probands) e | 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); Beck et al., (2010);Liu et al. (2010) | |
| A117V | Cis V | 33 | Variable Progressive D w/o Atx LMN SYN w/ D and Atx |
(20–64) | (1–11 years) | 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* | Cis V | 6 | 34 ± 14 (14–49) | 46 ± 21
months (27–78) |
FHx score 0 (n = 1) 2 (n = 2) |
0% | 0% | 0% (0/3) | 0% (0/5) | Takada et al. (2017) | |||
| G131V | MM/MV (cis M) | 3 | D w/ behavioral changes and late
Atx Park |
(36–42) | (9–16) years | 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) months | 100% (1/1) | N/A | N/A | N/A | N/A | Diff unicentric and multicentric
PrP-PLs (neocortex, BG, Cb) Min V |
GSS | Hilton et al. (2009) |
| A133V | MM | 2 | PSP-like, RPD | (62) | (4) months | 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) months | 0% (0 in 2)e |
50% (1/2) | 100% (1/1) | 50% (1/2) | 100% (1/1) predom BG |
129MM - similar to sJCDMM1. V, G, NL (deeper
CLs). PrP-S PrPSc type 1 129MV - similar to sJCDMV2 V predom in CLs V and VI, Kuru plaques in Cb and WM, PrP-S PrPSc type 2 (predom monoglycos) |
JCD | Krebs et al. (2005); Pastore et al.(2005) |
| R148H* | MM | 1 | (53) | (2) months | FHx score 0 (n = 1) | N/A | N/A | N/A | 100% (1/1) | Takada et al. (2017) | |||
| 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 and Pyram signs | (33) | (2) years | 0% (0/1)e | 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 and myoclonus | (61) | (7) months | 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/VV (cis V) | 209a | Progressive Cog decline, Cb Sxs, myoclonus, EP Sxs | Mean 46 (26–56) | Mean 23 months (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-129Va | Cis V | 8 | 45 ± 6 (37–52) | (18–21) months | FHx score 2 (n = 4) | 50% (1/2) | 0% (0/1) | 0% (0/2) | 100% (2/2) | Takada et al. (2017) | |||
| D178N-129M | Cis M | 106 | Insomnia Sympathetic overactivity | Mean 52 (~20–76) | Median 12.6 (4–40) months | 60–88% | 14.4% | 8% | 2.1% | 16.5% | Deg of Th (md and av nu) and inf olivary nu, little to no Vor PrPSc dep | FFI | Reder et al. (1995); Collins et al. (2001); Kovacs et al. (2005); Zarranz et al. (2005); Sano et al. (2013); Krasnianski et al. (2016) |
| V180I | Cis M | 225 | JCD phenotype, but w/ slower prog | Mean 77 | Mean 25 months | 0.7–6% | 70%; | 78.5% | 11% | 99% | V PrP-S | JCD | Kong et al. (2004); Higuma et al. (2013) |
| V180I* | Cis M | 2 | (84) | (21) months | FHx score 1 (n = 1) 2 (n = 1) |
0% (0/1) | 0% (0/1) | 100% (1/1) | Takada et al. (2017) | ||||
| T183A | Cis M | 3 | bvFTD, AD | 45 ± 4 (42–49) | 4 ± 2 years (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 and behavioral Sxs w/late Cb Atx Early Cb Atx and D after a few years Case w/ Pscyh Sxs in adolescence |
(20–53) | (3–19) years | 100% (4/4) | 0% (0/2) | 0% (0/4) | 0% (0/4) | G multicentric 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* | Cis M | 4 | (30–41) | (12–13) years | FHx score 2 (n = 1) | 0% (0/1) | 0% (0/1) | 0% (0/1) | 0% (0/1) | Takada et al. (2017) | |||
| T188R | MV/VVV (cis V) | 12 | JCD | (55–66) | (14–16) months | 0% (0/1)e | 50% (1/2) | 100% (1/1) | 50% (1/2) | 50% (1/2) | V, NL, A PrP-S and plaque-like PrP, type 1 PrPSc | JCD | Roeber et al. (2008); Tartaglia et al.(2010) |
| T188K | MM/MV (cis M) | 3 | JCD | Median 58 (39–76) | (2–13) months | 8–37%e | 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) months | 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. (2001) |
| T193I | MM | JCD | (70) | (10) months | 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) months | 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 and D freq Park | (40–71) years | Mean 5 years (2–12) | 100% (3/3) | N/A | N/A | N/A | 0% (0/1) | Uni- and multicentric PrP-Plqs | GSS | Farlow et al. (1989); Dlouhy et al. (1992); Ghetti et al. (1995); Kong et al. (2004) |
| F198S* | Cis V | 5 | 55 ± 8 (46–66) | 67 ± 23
months (34–84) |
FHx score 1 (n = 2) 2 (n = 1) |
33.3% (1/3) | 100% (1/1) | 0% (0/4) | 0% (0/3) | Takada et al. (2017) | |||
| F198V | MM | 1 | D w/ visual hallucinations, myoclonus and Park Clinical dx of early-onset AD |
(56) | (4) years | 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 and supranuclear gaze palsy in some |
Mean 60 (33–84) | (1–18) months | 50% | 85–100% | 80–100% | 42–85% | 50–88% | Usually sJCD MM1 PrPSc types 1 and 2 | JCD | Spudich et al. (1995); Meiner et al. (1997); Kovacs et al., (2005, 2011); Krasnianski et al. (2016) |
| E200K* | Cis M (n = 16) and cis V (n = 1) | 34 | 60 ± 13 (36–84) | 11 ± 17 (1–78) |
FHx score 0 (n = 2) 1 (n = 10) 3 (n = 12) |
57.1% (4/7) | 37.5% (3/8) | 88.9% (16/18) | Takada et al. (2017) | ||||
| E200G | MV (cis V) | 1 | RPD, Cb Atx, Park ↓sensation in LEs | (57) | (30) months | 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 and EP signs | (55) | (16) years | 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) years | 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) month | 0% (0/1) | N/A | N/A | 100% (1/1) | N/A | N/A | N/A | Peoc’h (2000) |
| R208H | MM/VV | 15 | D w/ behav changes Park and Pyram signs freq Report of a PSP-like phenotype |
(58–63) | (3–16) months | 20% (1/5) | 50% (4/8) | 57.1% (4/7) | 25% (2/8) | SE, PrP-S (perineuronal perivacuolar) type 1 PrP | JCD | Capellari et al. (2005); Roeber 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) months | 12–31% | 90–100% | 100% | 44–80% | 15–33% | Similar to sJCD MM1 | JCD | Kong et al. (2004);Kovacs et al. (2005);Breithaupt et al. (2013);Krasnianski et al. (2016) |
| V210I* | Cis M | 3 | 57 ± 15 (47–74) | (1) month | FHx score 0 (n = 2) 2 (n = 1) |
100% (1/1) | 33.3% (1/3) | 100% (2/2) | Takada et al. (2017) | ||||
| E211Q | MM | 11 | JCD | (42–81) | (6–32) months | 100% (2/2) | N/A | N/A | 100% (4/4) | N/A | V, G Mi PrP-S types 1 and 2 PrPSc |
JCD | Peoc’h et al. (2000, 2012); Ladogana et al. (2001) |
| E211D | VV | 1 | Cb Atx, and late D | (53–68) | (3 –13) years | 50% (1/2) | N/A | N/A | 0% (0/2) | 0% (0/2) | Multicentric PrP-Plqs Dystrophic neurites and NFT |
GSS | Peoc’h et al. (2000, 2012) |
| Q212P | MM | 2 | Cb Atx w/o D Dx of olivoponto Cb degeneration | (60) | (8) years | 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) months | 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 and apraxia. Clinical dx of bvFTD and CBS | (45–66) | (5–13) years | 100% (3/3) | N/A | N/A | 0% (0/1) | 0% (0/1) | Uni- and multicentric PrP-Plqs, NFT (neocortex) | GSS | Hsiao et al. (1992); Piccardo et al. (1998); Woulfe et al. (2005); Munoz-Nieto et al. (2013) |
| Y218N | VV | 1 | Atypic D w/AD and (54–61) bvFTD features Early language and executive impairment No Atx | (6) years | 100% (1/1) | N/A | N/A | 0% (0/2) | 0% (0/2) | Uni- and multicentric PrP-Plqs, NFT w/ hyperP tau | GSS | Alzualde et al. (2010) | |
| A224V | VV (cis V) | 1 | RPD | (48) | (32) months | 0% (0/1) e | 100% (1/1) | N/A | 100% (1/1) | Diff V w/ PrPSc type 1 | JCD | Watts et al. (2015) | |
| M232R | MM | 63 | Similar to sJCD, some w/ slower prog | Mean 64 (15–81) | Mean 8 (0–32) months | ~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) |
| M232T | MV | Cb Atx, spastic paraparesis and D | N/A | (6) years | 0% (0/1) | N/A | N/A | N/A | N/A | Multicentric 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) | |
Including D178N-129V and D178N-129M.
By nine prion disease (PrD) surveillance centers, according to Minikel et al. (2016).
Positive family history of dementia with similar clinical features (as of the proband) or PrD. For UCSF FHx (family history) score scale: 0 when there was no positive family medical history suspicious for or known PrD; 1 when there was at least one first-degree relative with dementia, encephalopathy, or movement disorder; or 2 in patients who were part of families with 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 and duration of disease are shown as mean ± sd (range), unless otherwise indicated.
positive if > total tau 1200 pg/mL.
If there are differences between data published in the literature from the more recently published University of California, San Francisco (UCSF) cohort, this information is provided in the table separately for that mutation.
Ab, abundant; AD, Alzheimer-type dementia; AH, Ammon horn; atypic, atypical; Atx, ataxia; av, anteroventral; BG, basal ganglia; bvFTD, behavioral variant frontotemporal dementia; Cb, cerebellum; CBS, corticobasal syndrome; CLs, cortical layers; Cog, cognitive; CSF, cerebrospinal fluid; c/w, consistent with; D, dementia; deg, degeneration; dep, deposition; diff, diffuse; dx, diagnosis; EEG, electroencephalogram; EP, extrapyramidal; ERC, entorhinal cortex; FFI, fatal familial insomnia; FHx, family history; F, focal; freq, frequent; G, gliosis; GSS, Gerstmann–Sträussler–Scheinker; GTC, generalized tonic-clonic seizures; HP, hippocampus; HyperP, hyperphosphorylated; inf, inferior; JCD, Jakob–Creutzfeldt disease; LE, lower-extremities; LMN, lower motor neuron; md, mediodorsal; Mi, mild; Min, minimal; Mod, moderate; Mol, molecular layer of the cerebellum; monoglycos, monoglycosylated; MRI, magnetic resonance imaging; N/A, not available; NFT, neurofibrillary tangles; NL, neuronal loss; nu, nuclei; OLs, occipital lobes; Park, parkinsonism; predom, predominant; prog, progression; 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; Psych, psychiatric; RPD, rapidly progressive dementia; SE, spongiform (vacuolated) encephalopathy; Sev, severe; sJCD, sporadic Jakob–Creutzfeldt disease; SYN, syndrome; Th, thalamus; Sxs, symptoms; V, vacuolation; w/, with; WM, white matter; w/o, without.