Articulo 6. Priones

Journal of Geriatric
Psychiatry and Neurology

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The Prion Diseases

Khalilah Brown and James A. Mastrianni
J Geriatr Psychiatry Neurol 2010 23: 277 originally published online 11 October 2010
DOI: 10.1177/0891988710383576
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Journal of Geriatric Psychiatry

and Neurology
23(4) 277-298
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DOI: 10.1177/0891988710383576
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The Prion Diseases

Khalilah Brown, MD1 and James A. Mastrianni, MD, PhD1
Abstract
The prion diseases are a family of rare neurodegenerative disorders that result from the accumulation of a misfolded isoform of
the prion protein (PrP), a normal constituent of the neuronal membrane. Five subtypes constitute the known human prion
diseases; kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome (GSS), fatal insomnia (FI), and variant
CJD (vCJD). These subtypes are distinguished, in part, by their clinical phenotype, but primarily by their associated brain histopathology. Evidence suggests these phenotypes are defined by differences in the pathogenic conformation of misfolded PrP.
Although the vast majority of cases are sporadic, 10% to15% result from an autosomal dominant mutation of the PrP gene (PRNP).
General phenotype-genotype correlations can be made for the major subtypes of CJD, GSS, and FI. This paper will review some of
the general background related to prion biology and detail the clinical and pathologic features of the major prion diseases, with a
particular focus on the genetic aspects that result in prion disease or modification of its risk or phenotype.
Keywords
genetics, neurodegeneration, prion diseases, CJD, GSS, FI
Introduction
The human prion disorders include kuru, sporadic CreutzfeldtJakob disease (sCJD), familial CJD (fCJD), iatrogenic CJD
(iCJD), Gerstmann-Straussler-Scheinker disease (GSS), fatal
insomnia (FI), and new variant CJD (vCJD). As a group, they
are unique among neurodegenerative diseases in that they not
only have a sporadic and genetic occurrence, but they are horizontally transmissible. Additionally, prion diseases affect animals, some of which include scrapie of sheep, chronic wasting
disease of deer and elk (CWD), and bovine spongiform encephalopathy (BSE). The transmissible nature of these diseases
was first demonstrated experimentally in 1936 by Cuille and
Chelle through intraocular administration of scrapie-infected
spinal cord to a goat.1 Thirty years later, kuru, a disease of the
Fore people of New Guinea related to the practice of cannibalism, was transmitted to chimpanzees by Gajdusek,2 and 2 years
later, Gibbs followed suit with transmission of CJD.3 Initially
proposed to be a slow virus,4,5 the etiologic agent of these
diseases is now recognized as the prion, a misfolded isoform
of the prion protein (PrP).6-8 PrP exists in 2 major conformational isoforms: the nonpathogenic, predominantly a-helical,
protease-sensitive, cellular isoform (PrPC) and the pathogenic,
protease-resistant scrapie-inducing isoform (PrPSc) that is high
in b-pleated sheet structure9 (Figure 1). The initial conversion
of PrPC to PrPSc may be spontaneous or mutation-induced; however, once an infectious unit has been generated, propagation
of PrPSc occurs via protein-protein interaction, such that PrPSc
acts as a template to transfer its conformation onto PrPC, thereby
generating new PrPSc. Thus, PrP knockout mice (Prnp / ) do not

develop prion disease when challenged with scrapie.10-12
In humans, a single exon on the short arm of chromosome
20 encodes the 253 amino acid PrP.13 Differential splicing does
not occur. A 22-amino acid signal peptide is cleaved from the
amino terminus during synthesis in the endoplasmic reticulum
and a 23-residue signal sequence on the carboxy terminus is
cleaved upon addition of a glycoinositol phospholipid (GPI)
anchor,14 through which PrP attaches to the outer leaflet of the
plasma membrane. Two asparagine-linked glycosylation sites
lie within a loop region of the protein created by a disulfide
bond (Figure 2). PrP is regulated during development and constitutively expressed in the adult. An increase in mRNA levels
has not been detected during disease development in animals.8,15 The highest levels of expression are within neurons,16
but lower levels are detected in other peripheral tissues including lung, heart, kidney, pancreas, testis, white blood cells,17
and platelets.18 Peripheral and central anterograde neuronal
transport of PrPC has also been reported.15,19
Center for Comprehensive Care and Research on Memory Disorders,

Department of Neurology, University of Chicago, Chicago, IL, USA
Corresponding Author:
James A. Mastrianni, MD, Center for Comprehensive Care and Research on
Memory Disorders, Department of Neurology, University of Chicago,
Chicago IL, 60637, USA
Email: jmastria@uchicago.edu
277
278
Journal of Geriatric Psychiatry and Neurology 23(4)
Figure 1. Comparison of protease-sensitive, cellular isoform (PrPC) and protease-resistant scrapie-related isoform (PrPSc). Protease-resistant
scrapie-related isoform carries greater b-sheet structure (flat ribbons), with loss of the a-helical structure (curly ribbons), and displays the
properties of infectivity, insolubility, and protease-resistance. The western blot demonstrates the protease-sensitive nature of PrPC and the
protease-resistant core of PrPSc that migrates faster in the gel because it is partially cleaved at the amino-terminal. The primary difference
between PrPSc and PrPC is the proteinase-K resistance.
The normal function of PrPC is not known, although several

lines of evidence have led to a variety of proposed functions,
including the formation, function, and maintenance of
synapses20-23; signaling,24-26 neuritogenesis and neuroprotection27,28; copper binding and cellular delivery29-31; antioxidant
activity32; cellular adhesion33; and a possible role in immune
modulation (see ref 34 for review). Interestingly, in PrP
knockout mice, no obvious developmental or behavioral
abnormalities were noted,10 suggesting redundancy of function, although an alteration in synaptic function within the hippocampus of these animals has been reported by some20 but not
others.35 Recent work also suggests that adult mice lacking PrP
display some hippocampal-dependent spatial memory deficits36 and have impaired peripheral myelin maintenance.37
Some PrP knockout mouse lines also displayed disrupted circadian rhythm,38 and ataxia, the latter found to be related to upregulation of Prnd, a downstream gene that encodes a truncated
homolog of PrP known as Doppel, as a result of gene

splicing that occurred during the deletion of Prnp.39 An intriguing line of work has recently suggested a link between PrP
and Alzheimer disease, although the balance of its effect
has not been determined. For instance, 1 study suggests PrPC
normally inhibits b-secretase,40 a key enzyme involved in the
cleavage of amyloid precursor protein (APP) that generates
b-amyloid, thereby functioning in a protective role. In contrast,
other reports suggest PrPC might function as a receptor to
b-amyloid oligomers41 or to foster the generation of amyloid
plaques of Alzheimer disease,42 thereby functioning to promote
Alzheimer disease.
Molecular Genetics of Prion Disease

The worldwide incidence of prion disease is roughly 1 per 106
population per year for sporadic disease and 1 per 107 per year
278
Brown and Mastrianni
279
Figure 2. General organization of human prion protein (PrP) and related mutations and polymorphisms. The 762 base pair (bp) open-reading
frame of PRNP encodes the 253 amino acid protease-sensitive, cellular isoform (PrPC). Nuclear magnetic resonance (NMR) studies predict
3 a-helices (H1, H2, and H3), and 2 b strands (S1 and S2). Asn-linked glycosylation sites (CHO) occur at residues 181 and 197. The
octapeptide repeat segment extends between residues 51 and 91. Pathogenic mutations and polymorphisms of the PRNP gene are represented
below and above the schematic, respectively. A single octapeptide repeat deletion and a small number of single bp changes are considered
nonpathogenic polymorphisms, some of which act as phenotypic modifiers, most notably, residue 129. Octapeptide repeat insertions (OPRI)
of 1 to 9, excluding 3, are pathogenic, as are *30 bp changes. Letters preceding the numbers indicate the normal amino acid residue for
the position and letters following the numbers designate the new residue due to the mutation. Bold mutations are associated with GerstmannStraussler-Scheinker syndrome (GSS), the remainder cause Creutzfeldt-Jakob disease (CJD). * D178N is associated with either CJD or familial
fatal insomnia (FFI), depending on the allelic codon 129 sequence (Met FFI; Val CJD). H187R displays variable pathology in the limited
cases reported. Amino acid letter designations are as follows: A indicates alanine, D aspartate, E glutamate, F phenylalanine, H
histidine, I isoleucine, K lysine, L leucine, P proline, Q glutamine, R arginine, S serine, T threonine, V valine, Y tyrosine,
(-) stop signal.
for familial disease. There is no obvious gender bias.43 The

peak age for the sporadic form of disease is *67 years,
although patients aged 17 to 90 years have been reported.
Sporadic forms of the disease tend to occur in the seventh
decade and eighth and have a rapidly progressive course of
under a year (avg. 4 to 6 months), whereas inherited forms usually manifest at a younger age and have a more protracted
course (Table 1). True autosomal dominant forms of prion disease occur in about 10% to 15% of reported cases, although this
estimate may be spuriously low because of the variable and
often late age of disease onset in some forms of inherited prion
disease.44 No obvious environmental risk to disease has been
recognized, with the possible exception of vCJD that is linked
to BSE exposure and iCJD resulting from prion-contaiminated
biologicals or surgical instruments.
A single base pair (bp) change within codon 102 of the

PRNP gene, resulting in an amino acid change from proline
to leucine (P102L) was first linked to the typical clinical presentation of GSS in 1989.45 Since then, multiple-point mutations, insertions, and deletions of the gene have been
identified (Figure 2, Tables 2 and 3). A handful of mutations
introduce an early stop signal at different positions within the
coding segment resulting in truncated forms of PrP, in 1 case
(Y145X) generating a protein roughly half the normal length.
Of the currently identified mutations, only 4 (P102L, D178N,
E200K, and a 144-bp insert) have been observed with high
enough frequency to generate significant logarithm of the odds
(LOD) scores for linkage. Several polymorphic sites of the
PRNP gene are known, the most common and best studied is
codon 129 that acts as a predisposing factor to sporadic,
279
280
Table 1. Clinical Phenotypes of Prion Disease

Disease
Primary features
Age at Onset (Range)
Duration
Pathology
Kuru
sCJD
Ataxia, then dementia

Dementia, ataxia, myoclonus
40 years (29-60)
61 years (17-83) rare <40
3 months1 year
<1 year
fCJD
Dementia, ataxia, myoclonus
Typically <55 years (20s to 80s)a
15 years
GSS
FFI
Ataxia, then dementia

Insomnia, dysautonomia,
ataxia, dementia
Behavioral changes,
later dementia
Typically <55 years (20s to 60s)a

45 + 10
26 years
*1 year
Teens/young adults
*1.5 years
Kuru plaques
Generalized grey matter vacuolation
and gliosis
Generalized grey matter vacuolation
and gliosis
PrP-plaques, gliosis, less vacuolation
Focal thalamic and olivary gliosis,
neuronal dropout
Florid plaques and diffuse spongiosis
vCJD
Abbreviations: fCJD, familial Creutzfeldt-Jakob disease; FFI, familial fatal insomnia; GSS, Gerstmann-Straussler-Scheinker syndrome; sCJD, Creutzfeldt-Jakob
disease; vCJD, variant Creutzfeldt-Jakob disease.
a
Large variability in some mutations versus others results in a broad range in disease onset.
iatrogenic, and vCJD, in addition to a phenotypic modifier of

sporadic and familial prion disease (discussed later).
As mutations of PRNP have been discovered, genotypephenotype correlations have been made, many of which
generally hold true, especially with regard to the general
pathology associated with each mutation. However, as more
patients with similar mutations are described, it has become
increasingly evident that the clinical features associated with
specific mutations may vary, sometimes considerably and
even within the same pedigree. Whether this feature represents subtle alterations in the conformational subtype
of PrPSc (see below), or an influence of other modifying
genes, is not clear.
A general classification scheme for the major phenotypes of
prion disease is based primarily on the pathologic features of
disease, which appear to be more consistently linked to a specific set of mutations. Using this parameter, excluding kuru,
4 major prion disease subtypes in humans are known; CJD,
GSS, FI, and vCJD. The pathognomonic feature of diffuse
spongiosis with few or no PrP-amyloid plaques is characteristic
of CJD, while extensive PrP-amyloid deposits with minimal
spongiform change denotes GSS (Figure 3). Focal thalamic
gliosis with minimal or absent spongiosis is seen in FI, and the
presence of dense core PrP-amyloid plaques surrounded by a
halo of vacuolar change, designated florid plaques, are seen
in vCJD. In addition to PrP immunoreactive plaques in GSS,
neurofibrillary tangles have been detected with at least 4 mutations (P105L, Y145Stop, F198S, and Q217R).102-105
Although it is not understood how PrPSc induces such a
broad range of pathological phenotypes, the distinct association
of the major subtypes with specific mutations and characteristic
pattern of protease-resistant PrPSc on Western blot (an indirect
measure of PrPSc conformation) argues that the conformational
subtype of PrPSc is ultimately responsible for the observed phenotypes (Figure 4). This was confirmed by the recognition that
sporadic FI is a phenocopy of familial FI that lacks the mutation associated with the latter but displays a similar PrPSc by
Western blot and all other histopathologic and transmissible
characteristics of familial FI.106
These findings in human disease have their origin in the study

of animal strains of prion disease. The first evidence for this
came from studies of hamsters infected with 2 phenotypically
different strains of transmissible mink encephalopathy (TME),
known as HYPER and DROWSY, which were found to be
linked to 2 distinct PrPSc conformations.107,108 Passage of these
2 PrPSc strains to new hamster hosts resulted in the stable transmission of clinical and pathologic phenotypes. This property of
prions was instrumental in determining that vCJD resulted from
exposure to BSE, since passage of BSE to a variety of animal
hosts including mice, macaques, and hamsters resulted in a characteristic migration pattern and glycosylation profile, by Western blot, that was similar to that found in PrPSc isolated from
brains of participants with vCJD.109-113 Evidence suggests that
both host PrPC and prion strain (ie, conformation of PrPSc) are
important contributors to the observed phenotype,114 although
the mechanisms that underlie the targeting of PrPSc to specific
cell populations, which leads to the phenotype, is still obscure.
Major Subtypes of Prion Disease

Creutzfeldt-Jakob disease
The majority of patients with CJD present with confusion and
memory loss that progress to severe cortical dementia, generally
in combination with ataxia and myoclonus. The electroencephalogram (EEG) typically shows bilateral periodic discharges with
a frequency of 0.5 to 2 per second and, when seen in combination with the above presentation, predicts the diagnosis with
about 90% certainty.115-117 In addition to these defining features,
a host of neurologic signs and symptoms have been reported,
including weakness, rigidity, bradykinesia, tremor, chorea, alien
hand syndrome, and sensory disturbances, among others. Vague
complaints of fatigue, headache, sleep disturbance, vertigo, and
behavioral changes may precede the development of frank progressive dementia in many cases.116 As many as 25% begin with
ataxia118 while a smaller percentage begins with cortical blindness, designated as the Heidenhain variant. Familial CJD has
been associated with point mutations at codons 178, 180, 183,
280
281
Table 2. Single Base Pair Changes of PRNP

Codon
Sequence Change
Amino Acid Changea
Codon 129
Pathologic Phenotype
Reference
102
102
105
105
105
114
117
129
131
133
145
148
160
163
171
178
178
180
183
187
188
196
198
200
202
203
208
210
211
212
217
219
226
227
232
238
CCG ! CTG
CTG
CCA ! CTA
ACA
TCA
GGT ! GTT
GCA ! GTG
ATG or GTG
GGA ! GTA
GCA ! GTG
TAT ! TAG
CGT ! CAT
Pro (P) ! Leu (L)

Leu (L)
Pro (P) ! Leu (L)
Thr (T)
Ser (S)
Gly (G) ! Val (V)
Ala (A) ! Val (V)
Met (M) or Val (V)
Gly (G) ! Val (V)
Ala (A) ! Val (V)
Tyr (Y) ! Stop (-)
Arg (R) ! His (H)
Gln (Q) ! Stop (-)
Tyr (Y) ! Stop (-)
Asn (N) ! Ser (S)
Asp (D) ! Asn (N)
Asn (N)
Val (V) ! Ile (I)
Thr (T) ! Ala (A)
His (H) ! Arg (R)
Thr (T) ! Lys (K)
Glu (E) ! Lys (K)
Phe (F) ! Ser (S)
Glu (E) ! Lys (K)
Asp (D) ! Asn (N)
Val (V) ! Ile (I)
Arg (R) ! His (H)
Val (V) ! Ile (I)
Glu (E) ! Gln (Q)
Gln (Q) ! Pro (P)
Gln (Q) ! Arg (R)
Glu (E) ! Lys (K)
Tyr (Y) ! Stop (-)
Gln (Q) ! Stop (-)
Met (M) ! Arg (R)
Pro (P) ! Ser (S)
Met
Val
Val
Val
Val
Met
Val
GSS
GSS
GSS
GSS
Atypical GSS
CJD
GSS
46
47
48
49
50
51
52-54
45, 55
56
57
58
59
60
61
62
63
64
65
66
67, 68
60
69
70
71, 72
73
69
74
75-77
69
73
78
79
80
80
65, 81
82
AAC ! AGC
GAC ! AAC
AAC
GTC ! ATC
ACA ! ACG
CAC ! CGC
ACG ! AAG
GAG ! AAG
TTC ! TCC
GAG ! AAG
GAC ! AAC
GTT ! ATT
CGC ! CAC
GTT ! ATT
GAG ! CAG
CAG ! CCG
CAG ! CGG
GAG ! AAG
TAC ! TAA
CAG ! TAG
ATG ! AGG
CCA ! TCA
Met
Met
Met
Met
Met
Atypical GSS
Atypical GSS
GSS w/NFTs (PrP-CAA)
CJD
GSS
GSS
Val
Val
Met
Met
Met
Val
?
Met
Val
Met/Val
Val
Met
Met
Met
Met
Val
Val
Met
Val
Val
Met
Met
CJD
FFI
CJD
CJD
Atypicalc
CJD
CJD
GSS w/NFTs
CJD
GSS
CJD
CJD
CJD
CJD
GSS
GSS w/NFTs
b
PrP-CAA
GSS
CJD
CJD
Abbreviations: CJD, Creutzfeldt-Jakob disease; CAA, cerebral amyloid angiopathy; GSS, Gerstmann-Straussler-Scheinker syndrome; NFTs, neurofibrillary tangles;
PrP, prion protein.
a
Letters in parentheses indicate letter codes for amino acids.
b
Polymorphismsmay modify disease phenotype.
c
Either early psychiatric symptoms with or without dementia preceding ataxia with curly PrP deposits.
196, 200, 203, 208, 210, 211, 232, and insertions of 1, 2, 4, 5, 6,

7, and 9 octarepeat segments.
The defining pathology for this prion disease is the presence of
spongiform degeneration, or vacuolation, of cortical grey matter (Figure 3). The vacuoles observed by light microscopy represent focal swellings of axonal and dendritic neuronal processes,
associated with the loss of synaptic organelles and accumulation
of abnormal membranes by electron microscopy.119-121 They
may be distributed throughout the gray and white matter but are
generally most prominent in the gray matter neuropil. They
typically range in size from 5 to 25 mm,122 but in advanced
cases, they may be as large as 100 mm. When large vacuoles
are seen in the presence of severe astrogliosis and neuronal
loss, the constellation is termed status spongiosis. The distribution of vacuolation is typically within the cerebral
neocortex, subiculum of the hippocampus, caudate, putamen,

thalamus, and the molecular layer of the cerebellar cortex.122
A reactive gliosis is also consistently present, while an inflammatory response is conspicuously absent. Protease-resistant
PrP is easily detected in brain tissue from the majority of
patients with CJD. Transmission of CJD to nonhuman primates is relatively efficient (85%)123 and highly efficient
(approaching 100%) to Tg mice that express human PrP.124,125
In recent years, the bank vole has also been shown to be an
efficient host for human prion transmission.126
Iatrogenic CJD
Prior to the introduction of recombinant human growth hormone (hGH) in 1985, more than 80 individuals developed CJD
281
282
Table 3. Coding Alterations in Octarepeat Segmenta

Coding Change
Extra inserts
None
24-bp deletion
24-bp insertion
48-bp insertion
96-bp insertion
96-bp insertion
96-bp insertion
120-bp insertion
120-bp insertion
144-bp insertion
1
2
4
4
4
5
5
6
Sequence
Codon 129
R1,R2,R2,R3,R4
R3-R4 or R2 or R2-R3
R1,R2,R2,R2,R3,R4
R1,R2,R2, R3,R2a,R2a,R4
R2,R3,R2,R3
R1,R2(6),R3,R4
R1,R2,R2,R3,R2,R2,R2,R3,R4
R1,R2(2),R3,R2,R3g,R2(2),R3,R4
R1,R2(2),R3,R2,R2,R2,R2,R3,R4
R1,R2(3),R3,R2,R3g,R2(2),R3,R4
Met / Val
Met
Met
Met
Met
Met
Val
Met
Met
Met
144-bp
144-bp
144-bp
168-bp
168-bp
insertion
insertion
insertion
insertion
insertion
6
6
6
7
7
R1,R2(2),R3g,R2(2),R3g,R2(2),R3,R4
R1,R2,R2,R3,R2,R3g,R2,R3g,R2,R3,R4
R1,R2,R2,R2(6),R3,R4
R1,R2,R2c,R3,R2,R3,R2,R3,R2,R3g,R3,R4
Met
Met
Met
Met
Met
192-bp
192-bp
216-bp
216-bp
insertion
insertion
insertion
insertion
8
8
9
9
R1,R2,R2,R3,R2(7),R2a,R4
R1,R2,R2,R3g,R3,R2(6),R3,R4
R1,R2,R2,R3,R2,R3g,R2a,R2,R2,R2,R3g,R2,R3,R4
R1,R2,R2,R3,R2,R3,R3g,R2,R2a,R2,R3,R2,R3,R4
Val
Val
Met
Met
Pathologic Phenotype
Reference
N/A
Spongiosis (CJD-like)
83
84
85
86
87
84
86
88
89-91
CJD (spongiosis)
N/A
CJD (spongiosis)
CJD (spongiosis)
Variable, usu. spongiosis,
one pt. with PrP plaques
CJD (spongiosis)
CJD (spongiosis-variable)
CJD (spongiosis- variable)
CJD (spongiosis)
gliosis, no spongiosis
+ PrP deposits
GSS (PrP plaques)
GSS (PrP plaques)
GSS (PrP plaques)
N/A
92
93
94
95
96
86, 97
98
99, 100
101
Abbreviations: R, an octarepeat unit (Pro-(His/Gln)-Gly-Gly-Gly-(-/Gly)-Trp-Gly-Gln); N/A, pathology not available.

a
Small case letters indicate repeat units which contain a single base pair alteration, although the amino acid coding is unchanged.
Figure 3. Pathologic features of prion disease. A, Hemotoxylin and Eosin staining demonstrates typical spongiform degeneration (vacuolation)
of the grey matter neuropil characteristic of Creutzfeldt-Jakob disease (CJD). This feature is less obvious in fatal insomnia (FI) and GerstmannStraussler-Scheinker syndrome (GSS). B, PrP-positive multicentric plaques are pathognomonic for GSS. These are mostly present within the
molecular layer of the cerebellum but may be diffusely present throughout the cerebrum. C, Glial fibrillary astrocytic protein (GFAP)
antibodies demonstrate hypertrophy and proliferation of astrocytes. This feature is present in all prion subtypes. In FI, this is often found focally
within the anterior nucleus and dorsomedial nucleus of the thalamus and brainstem, in combination with neuronal dropout. In GSS it may
parallel PrP plaque pathology. D, The florid plaques of variant CJD (vCJD) consist of dense core PrP amyloid deposits surrounded by vacuoles.
through exposure to cadaver-derived human growth hormone

(hGH) from at least 3 separate sources in the United Kingdom,
France, and the United States.127-131 In contrast to sCJD,
patients with iCJD more often display cerebellar ataxia rather

than cognitive problems, and the EEG shows a diffusely slow
wave pattern instead of periodic sharp waves complexes.132,133
282
283
Figure 4. Western blot comparing the major isoforms observed in the 4 principal subtypes of prion disease. To the left of the blot displays the
prion protein (PrP) segment that is represented in the adjacent blot. The highest molecular weight of PrP is the diglycosylated fraction of PrP,
whereas the monoglycosylated and unglycosylated fractions run faster in the gel, because of their lower molecular weight. In CJD, FI, and vCJD,
proteinase-K cleaves the first *67 amino acids of protease-resistant scrapie-related isoform (PrPSc), leaving the PK-resistant core, PrP90-231.
In most cases of Gerstmann-Straussler-Scheinker syndrome (GSS), a second C-terminal cleavage that removes the glycosylated segment
occurs endogenously, leaving a nonglycosylated central segment.
This disease has also been linked to dura mater obtained

primarily from a single manufacturer in Germany whose
preparative procedures were inadequate to decontaminate
prions.132,134-139 Throughout the world, more than 100 cases
of iCJD related to contaminated dura exposure between 1979
and 1996 have been reported.138,140 Other iatrogenic forms of
prion disease include a single corneal transplant,141 2 patients
exposed to improperly decontaminated depth electrodes used
for seizure focus localization,142 and at least 5 cases of CJD
in women after receiving human pituitary gonadotropin.143-145
Variant CJD
To date, since 1995, vCJD has been reported in more than 200
patients throughout the world, with the greatest number of
cases in the United Kingdom (170) and France (25), but
also reported in the Republic of Ireland, Italy, the United States
(3 emigrants from the United Kingdom and Saudi Arabia),
Canada, Japan, The Netherlands, Portugal, and Spain.146-151
Compared with sCJD, vCJD more often presents with psychiatric features, particularly apathy and depression, in addition to painful distal sensations, it occurs in younger
individuals (ages 17 to 42 years), and has a slightly protracted

course of greater than 1 year. The pathognomonic feature in
the brain is the presence of dense core PrP plaques surrounded
by a halo of spongiform change, also known as florid plaques (Figure 3). The protease-resistant fraction of PrPSc in
the brain of these patients has a faster migration rate on Western blot than typical sCJD, and the diglycosylated PrP (the
highest of the 3 bands of PrP) is more prominent, in contrast
to sCJD, in which PrPSc is predominantly monoglycosylated.152
As mentioned above, this predominance of the diglycosylated
form was a key feature used in transmission studies to support
the hypothesis that vCJD resulted from exposure to BSEtainted beef. All but 1 case of vCJD resulting from primary
infection with BSE have been homozygous for Met at codon
129 (see below), further supporting this as a risk factor to prion
disease. Secondary infection was first reported in an asymptomatic codon 129 heterozygote (129MV) who died of unrelated
causes 5 years after receiving a transfusion of blood derived
from a patient who developed signs of vCJD 18 months following blood donation.153 Since then, 4 additional cases of potential
transfusion-related vCJD have been reported, one of which was a
hemophiliac who received blood products rather than whole
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blood.154-156 These findings have raised concerns about the

prevalence of asymptomatic carriers of vCJD in the United
Kingdom and the safety of the blood supply and has led to
major changes in the handling of blood products in the United
Kingdom and the United States.
Gerstmann-Straussler-Scheinker Syndrome
This subtype of prion disease is always familial and has been
found associated with point mutations at codons 102, 105,
117, 131, 145, 160, 198, 202, 212, 217, and in some cases of
octapeptide repeat insertions (OPRI), especially those with a
higher number of inserts. In its classic form, as originally
described by Gerstmann,157,158 ataxia of gait and/or dysarthria
are presenting features followed by variable degrees of pyramidal and extrapyramidal symptoms and often late development
of dementia. There are, however, several variants of this disease in which ataxia is not a prominent feature. Reports of
impaired memory, spastic paraparesis, movement disorder, or
behavioral features, with a presentation suggestive of frontotemporal dementia or Alzheimer disease have been reported.
The EEG commonly lacks periodic discharges but may show
slow waves. Duration of disease typically ranges from 2 to 7,
but up to 10 or more years. Aspiration pneumonia is a significant risk because of impaired coordination of swallowing.
The presence of plaque deposits immunoreactive to anti-PrP
antibodies is the defining hallmark of GSS. Vacuolation may
be minimal. PrP amyloid is PAS positive and shows birefringence under polarized light after Congo Red staining in most
cases. The most characteristic is the multicentric plaque,
defined as a dense central core surrounded by smaller satellites122 (Figure 3), although other morphologies, from punctate
to diffuse, have been recognized. Various-sized plaques, often
termed primitive because they lack the characteristic green
birefringence with Congo red staining, are seen in many of the
GSS cases, suggesting there are variations in the maturity of
amyloid formed among the different mutations. Plaque deposits isolated from at least 4 of the GSS-associated mutations
(P102L, A117V, F198S, Q217R) appear to be composed of
peptide fragments of 7 and/or 11-14 kDa, which have been
amino- and carboxy-terminally clipped and span residues of
58-150 and 81-150 of the mutant alleles.159
Fatal insomnia
Originally reported and defined as a familial form of prion disease, this is now known to occur on a familial (FFI) and sporadic (sFI) basis.64,160-162 The characteristic clinical profile
includes intractable insomnia, which may be observed for several months prior to the obvious onset of disease that may
include dysautonomia, ataxia, variable pyramidal and extrapyramidal signs and symptoms, and relatively spared cognitive
function until late in the course. Diffuse slowing rather than
periodic discharges is observed on the EEG.161 Magnetic resonance imaging (MRI) is unhelpful, but functional imaging
(PET or SPECT) shows a reduction in metabolic activity or
blood flow to the thalamus early in the disease.163 Age at

disease onset ranges from 25 to 61 years (avg. 48 years), and
time to death is generally 1 to 2 years (range of 7 to 33
months).161 Not all cases are clear-cut. A sleep study may be
required in less clinically obvious cases to recognize a shortening of total sleep time. A family with phenotypic heterogeneity
from Australia was reported with the FFI haplotype
(D178N,129M),164 and while some members were found to have
clinically apparent insomnia early or late in the presentation, others did not exhibit it, suggesting even this disease may have a
variable presentation.164
The neuropathologic features of FI include neuronal loss
and astrogliosis within the thalamus and inferior olives, and
to a lesser degree, the cerebellum. Vacuolation is minimal to
absent in typical cases. Protease-resistant PrP is detectable in
the brains of affected patients but is usually present only in
small amounts and is often restricted to specific regions such
as the thalamus and temporal lobe.165
Polymorphisms and Mutations of PRNP

Several polymorphisms have been identified in the PRNP gene.
The most common and important ones are highlighted.
Codon 129
This codon may be either ATG, which codes for Met, or GTG,
which codes for Val. The allelic frequency of Val in the general
Caucasian population is 0.34 while that of Met is 0.66.55 The
genotype distribution in this population is 37% Met/Met,
51% Met/Val, and 12% Val/Val. Homozygosity at this position
predominates in sCJD. In 1 series of 45 patients with sCJD
from the United Kingdom, 89% were homozygous (Met/Met
or Val/Val) at codon 129,166 compared with only 49% of 106
normal participants.55 Similar findings were reported in France
and Italy. The frequency of Met homozygosity was found to be
between 41% and 45% in unaffected control participants and
between 71% and 81% in 41 definite and/or probable sCJD
patients.167,168 Homozygosity at codon 129 is also overrepresented in iCJD, but most dramatically in vCJD, where all but
1 patient with confirmed vCJD, resulting from primary exposure to BSE, carried the 129MM genotype.169 The importance
of homozygosity in prion susceptibility is further supported by
studies in transgenic (Tg) mice that demonstrate more efficient
transmission of prions when the recipient Tg mouse expresses
human PrPC carrying the same amino acid at position 129 of
the human PrPSc inoculum.170-172 These epidemiologic and
Tg animal studies support the concept that sequence homology
between PrPSc and PrPC facilitates their interaction and subsequent generation of more PrPSc, which have also recently been
demonstrated using FRET to assess the specific interaction of
homologous and heterologous PrP molecules.171 It should be
noted that the allelic frequencies in Japan are 0.96 for Met and
0.04 for Val, masking a relative risk of homozygosity.173
The codon 129 genotype also modifies the phenotype of
sCJD. A cognitive onset with rapid progression is associated
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with the 129MM genotype, while slower progression and an

ataxic onset is more common with the 129MV or 129VV genotype.174 The conformation of PrPSc, which is approximated by
limited protease digestion and gel electrophoresis, differs
between 129MM patients (Type 1 PrPSc migrates *21 kDa)
and 129VV (Type 2 PrPSc migrates *19kDa).174,175 These
findings imply an important function of the amino acid residue
at position 129 in protein-protein interaction and PrPSc conformation determination.171
In familial prion disease, the polymorphic codon 129 also
plays a modifying role. This is most striking with the D178N
mutation; when D178N is coupled to 129M, the clinicopathologic phenotype of FFI results in a protease-resistant PrPSc
fragment of *19 kDa, whereas coupling of D178N with
129V results in the fCJD phenotype and a PrPSc fragment of
*21 kDa.176 Coupling of the F198S and 144-bp insert mutations with homozygosity at 129 also appears to lower the age
at onset and decrease the duration of disease.
Other Polymorphisms:
a. 24-base pair (bp) deletion:This results in the loss of a
stretch of 8 amino acids within the octapeptide repeat
segment of PrP. Codons 51 through 91 encode a series of
5 repeating elements of Pro-(His/Gln)-Gly-Gly-Gly(-/Gly)-Trp-Gly-Gln, the first of which includes 27
nucleotides encoding 9 amino acid residues, while the
4 subsequent ones are 24 bp in length encoding 8 residues
each. A deletion of 1 of the repeat elements was initially
detected in 3 healthy members of a Moroccan family177
and then incidentally in a cosmid library construct derived
from the HeLa human cell line.178 It is generally considered to be a nonpathogenic polymorphism occurring in
about 3% of the normal population.83,177,179
b. N171S: This rare polymorphism was incidentally noted in
a 69-year-old healthy control participant.62 A family with
psychiatric disease was reported with this polymorphism,
and although it was suggested that it may be linked to schizophrenia, 1 healthy member carried the polymorphism180
and another study found no evidence for the N171S polymorphism in a schizophrenia population.181
c. E219K polymorphism: Codon 219 normally encodes glutamate (E) in the Caucasian population, although lysine
(K) coding is found in about 6% of the Japanese population.79 This polymorphism was also reported on the same
allele as the P102L mutation in a Japanese family in which
dementia rather than ataxia was prominent and cerebellar
plaque pathology was less prominent compared with
cases of the P102L mutation alone.182 However, variability in presentation of GSS was also observed in an Italian
family in the absence of the E219K polymorphism.
Recent transmission studies in transgenic knock-in mice
suggest a heterozygous state at codon 219 confers
reduced susceptibility to prion transmission.183
d. G127V polymorphism: This rare polymorphism was
recently reported in the population within New Guinea, in
the area where kuru was endemic. Sampling the population

suggests that this polymorphism is protective against
prion infection.184 Studies are in progress to determine this
experimentally.
Selected PRNP Mutations That Cause CJD

D178N, 129V
A transition of G to A at the first nucleotide of codon 178 of the
PRNP gene was initially reported in a Finnish family63 and
then shortly thereafter in 2 American families, one of Dutch
and the other of Hungarian origin,185 and in a French family
from Brittany 186. The clinical phenotype displays a younger
mean age at onset (46 vs 62 years), a more prolonged disease
duration (avg 2 years, range 9 to 51 months), and slowing of the
EEG rather than periodic triphasic waves, compared with
typical sCJD.185,187,188 Memory disturbance is the presenting
feature in the vast majority of carriers, followed typically by
cerebellar ataxia and myoclonus, in addition to varying degrees
of visual disturbance, reduced speech output, extrapyramidal,
and pyramidal tract features. Less than 10% develop seizures.
Brain pathology shows diffuse spongiform degeneration, gliosis, and neuronal loss within the frontotemporal cerebral cortex, caudate, and basal ganglia, with relative sparing of deep
thalamic nuclei and the cerebellum.161,185,189
V180I
This point mutation (GTC to ATC) was initially reported in
2 unrelated individuals with no obvious family history and a
presentation similar to fCJD associated with the D178N mutation.65 Since then, only a handful of cases have been detailed,
although a recent genetic survey in Japan identified the mutation in 84 cases of prion disease over the past 10 years.190 Most
reported cases appear to lack a clear family history. The mutation has been consistently found allelic with 129M. A presentation of subacute dementia, often with aphasia, and subsequent
myoclonus, but no periodic discharges on EEG, is most common. Neuropathological findings include typical CJD changes
of diffuse vacuolation, neuronal loss, and gliosis of the cortex.
Western analysis shows protease-resistant PrP that lacks the
higher molecular weight diglycosylated fraction of PrPSc,
although expression of PrPV180I in cell culture appears normally glycosylated, suggesting selective conversion of monoand unglycosylated PrPV180I.50,191
T183A
This was first described in a Brazilian family with 9 affected
members who developed a progressive dementia with clinical
features suggesting a frontotemporal neurodegenerative process.66 Behavioral features, including aggressiveness, hyperorality, and verbal stereotypes, were prominent early in the disease
course with all patients. Disease begins in the fourth or fifth
decade (average 45 years, range 37 to 49 years) and has a somewhat protracted course of 2 to 9 years (average 4.2 years).
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Spongiform change was prominent in frontotemporal regions.

Another report in a 40-year-old with more typical CJD and relatively prolonged course of 4 years, with similar pathology, was
also reported.192 This mutation was allelic with 129M.
E200K
This is the most common mutation of PRNP worldwide. A
change in coding from GAG to AAG at codon 200 of the gene
was first detected in an unusual cluster of CJD cases in rural
Slovakia72 where the annual mortality rate was about 100 per
million population and almost simultaneously in a Libyan Jewish family.193 It is linked to CJD with a LOD score of 4.85.194
Carriers of this mutation have been identified from more than
10 different countries71,195-197 and were initially thought to
have a common ancestral origin of a Sephardic Jew whose descendents emigrated from Spain and Portugal during the Inquisition. This was further supported by the consistent association
of the E200K mutation with the 129M. A report of this mutation in a Japanese family with no evidence of racial intermixing198 and the detection of the mutation in association with
Val coding at codon 12972 indicates at least 2 additional founders and supports the more likely possibility that the mutation
arose spontaneously in several populations from the deamination
of a methylated CpG in a germline PRNP gene. Clusters of this
mutation are seen in populations from Israel, Chile, and Eastern
Europe. Surveillance studies from France and England have
detected the E200K mutation in patients without a clear family
history, supporting the variable onset of CJD(E200K).167,199
The phenotype associated with this mutation is quite variable but is generally comparable to sCJD.200 Forgetfulness and
confusion are typically early manifestations, followed by ataxia
and myoclonus and the appearance of periodic discharges on
EEG.201 The average age at disease onset is *61 and time to
death is typically under 1 year (*4.5 months), similar characteristics to that of sCJD. Pathology is also similar to sCJD, with
widespread spongiform degeneration and no PrP plaque pathology. However, the fCJD(E200k,129V) case included PrP plaque deposits within the cerebellum.72 Chapman et al,202
compared clinical data from 14 patients with fCJD(E200K) and
noted a wide variability in age at onset (34 to 65 years) and in
disease duration (2 to 66 months), along with a host of varied
clinical features that included cerebral, basal ganglia, brainstem, cerebellar, and spinal cord dysfunction. A large kindred
of German ancestry was reported in which 5 of 9 members with
CJD, for whom neuro-ophthalmologic data were available, had
supranuclear palsy as an early feature, while myoclonus and
periodic EEG were uncommon.196 Demyelinating peripheral
neuropathy, which could not be attributed to a coexisting disease process, was reported in 2 patients who developed CJD
related to the E200K mutation,203 while three others have been
described with motor axonal neuropathy.202 Severe insomnia
was prominent, but not the presenting feature of disease in a
single E200K carrier.204
The variable age at onset with this disease suggests reduced
penetrance; however, using life-table analyses, the risk to
disease development for fCJD(E200K) is age-dependent and

penetrance is nearly complete by the ninth decade of life.44,205
The situation in which a child develops the disease yet one of
the parents either is a healthy carrier or died from other causes
prior to developing disease is therefore a potential feature to
consider when ruling out familial disease by history alone.
Transmission of this familial form of prion disease to experimental animals was initially demonstrated in nonhuman primates,206 and later in Tg transgenic mice.125
R208H
A transition at the second nucleotide of codon 208 from G to A
resulting in a missense coding for histidine rather than arginine
was reported in a 60-year-old who presented with confusion
and memory problems and later developed paranoia, ataxia,
myoclonus, and a positive EEG, over a 7-month course.74
Neuropathology was typical of CJD (diffuse spongiosis, neuronal loss, and gliosis) and protease-resistant PrP was present
throughout the brain. A family history was not evident, possibly related to the premature deaths of the patients father,
from an unrelated condition. Additional reports of R208H
linked to 129M, include a clinicopathologic phenotype characteristic of sCJD,207 another with tau pathology in the
entorhinal cortex, ballooned neurons, and an extra 17 kDa
PK-resistant PrPSc fragment,208 and a unique case, allelic with
129V, was reported with a rapidly progressive syndrome of
behavioral changes, cerebellar ataxia, and kuru type cerebellar plaques.209
V210I
This was initially reported in Italy75 and France76,77 without
evidence of a family history but has now been reported in several countries, including the United States.77,210,211 As with the
E200K mutation, the presentation is somewhat variable and
includes a cerebellar syndrome, bilateral myoclonic jerks,
dysarthria, stroke-like features such as hemisensory loss and
hemiparesis, sudden onset of visual disturbances, or the onset
of behavioral changes, all beginning between 50 and 70 years
of age. The EEG displays periodic discharges. Disease duration is typically less than 6 months. Protease-resistant PrP is
similar to that of typical sCJD. Spongiform degeneration is
diffusely present in the brain. Because healthy carriers of the
V210I mutation aged 67 to 82 years76 have been detected and
some patients lack a clear family history, this mutation also
appears to display variable penetrance compared with other
PRNP mutations.
M232R
Clear evidence for an autosomal dominant effect of this
mutation is lacking, but it has been reported in several cases,
primarily in the Japanese population. It too presents as sCJD,
with a typically rapid disease course and an absent family
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287
history.65,82,212,213 In addition, this sequence alteration was

reported in a V180I carrier on the normal allele.
144-bp insertion
This 6 octapeptide repeat insertion (OPRI) was described in a
large kindred in the United Kingdom. It is linked to an interesting disease phenotype in which behavioral symptoms and personality disorders of long-standing duration are observed prior
to the onset of a slowly progressive dementia.89,90,91,214-216 A
variation in the degree of cerebellar ataxia, dysarthria, and pyramidal and extrapyramidal signs are observed among affected
individuals, as is myoclonus. The pathology is also quite variable, ranging from severe spongiosis to no obvious signs of
pathology, generally without plaques, although in 1 patient,
cerebellar plaques were observed.90,216 Since the initial report
of a family with this insertion, additional families from the
United Kingdom,93 Japan,92 the United States,88 and Basque94
have been described. All have similar variations in disease phenotype and all have the mutation on the Met 129 allele. Curiously, there are slight variations in the sequence of the insert
(Table 3), although their role in phenotype modification is not
apparent.
Additional OPRI Mutations

Although there is significant variability in the presentation
and pathologic features of prion disease related to the repeat
expansions, they are discussed here as a group for ease of presentation. Between codons 51 and 91 of PRNP, 9 different
insertions of the gene have been described, none of which disrupt the overall sequence of the remainder of the protein
beyond residue 91. Most are coupled to Met coding at codon
129. The largest family reported is the British family with
6-OPRI described above (144-bp insert). Octapeptide repeat
insertions of 1 to 9 additional repeats have been described
(Table 3). Genotype-phenotype correlations have been difficult
to make, based on the small number of affected patients within
most families and because variability of presentation is common with these mutations. There is no obvious anticipation and
the length of the insert appears stable during meiosis.217 In general, the length of the insert correlates inversely with the age at
onset of disease. In patients with 7 to 9 extra repeats, disease
presents in the 30s, while in those with 1 to 4 extra repeats, disease may be delayed until the sixth to seventh decade.94,218 The
duration of illness, however, appears to be proportional to the
length of insert, ranging from 5 to 120 months, with an increase
in insert number from 1 to 7.218 A Huntington disease-like phenotype (HDL-1) was reported in a family with an 8-OPRI.219
Interestingly, another individual was reported with the HDL1 phenotype but later found to be a member of the 6-OPRI
kindred described above, further supporting the variable phenotype observed with OPRI mutations, in addition to the
importance of genetic testing in neurodegenerative disease.220
A minority of patients has the typical clinicopathologic features of sCJD; rather, the majority has a more chronic course
often including atypical features such as aphasia, apraxia, and

a personality disorder associated with memory loss. The personality disorder may appear as a primary or early feature in
as many as half of the carriers of these mutations. Dementia
eventually occurs in all and may be precipitous after a long
prodrome of mild cognitive problems or behavioral features.
Cerebellar ataxia and extrapyramidal features are also somewhat common in their course. Myoclonus may occur in less
than one half of carriers, while periodic discharges on EEG are
even less frequent (<30% of cases). Neuropathologic variability occurs within and among families and may show no pathology, focal, or diffuse spongiform change in the cortex and
Congophilic or nonCongophilic PrP-plaques.86,98,99
The basis for the variation in pathology, onset of disease,
duration, and clinical features with these repeat diseases is not
well understood. Perhaps the insert imparts increased flexibility of the protein, and in doing so may have variable effects
on more conformationally important downstream regions of the
protein. Distant effects of mutations are predicted based on the
3-dimensional conformation of PrP,221 and a large protein segment insert might induce several potential changes in conformation. A Tg mouse that expresses PrP with a 6-OPRI was
shown to display a neurological disease, with histopathological
findings that did not appear to be classical spongiform degeneration, and a low level of insoluble PrPSc-like protein that was
not transmissible to mice.222
Selected PRNP Mutations That Cause GSS:

GSS(P102L)
The substitution of thymine for cytosine at codon 102 results in
the coding of leucine (L) instead of the normal proline (P). It presumably results from the deamination of a methylated cytosine
50 to guanine (CpG) in the germ cells of multiple founders. Identified in multiple families from Europe, the United States, and
Japan, this was the first mutation of PRNP linked to prion disease.46 It is the most common GSS-related mutation, now recognized in multiple families from 9 different countries,52,223-226
including the original Austrian family described by Gerstmann.227 An LOD score exceeding 4.5 has been calculated for
this mutation.46,228 Penetrance appears to be complete. The typical phenotype is that described for classic GSS, with an ataxic
onset and late-developing dementia occurring over a 1- to 7year course. It is often accompanied by pyramidal and extrapyramidal features, as are many forms of prion diseases. The EEG is
slow but not periodic. Classic GSS pathology is observed, with
multicentric, primitive, and/or dense core PrP plaques deposited
throughout the cerebrum and most prominently in the molecular
layer of the cerebellum. The progressive cerebellar syndrome
associated with this mutation may be easily confused with some
forms of spinocerebellar ataxia (SCA). Variation of this presentation among and within families has been reported.223,226,229
The majority of P102L mutations are in chromosomal phase
with 129M coding, although some cases allelic with 129V are
known. The E219K polymorphism was also found allelic with
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288
the P102L mutation in a Japanese family that showed variability in presentation and weak Congo Red staining of plaques
compared with typical GSS plaques associated with the
P102L mutation alone,182 suggesting that polymorphisms other
than codon 129 (ie, codon 219) might influence the phenotype
of dominant mutations.
The clinical and pathologic features of GSS, including obvious ataxia and PrP plaque deposits, were duplicated in a mouse
constructed with a transgene harboring the equivalent P102L
human mutation.230 These mice, which overexpress the mouse
equivalent (PrP-P101L) of human PrP-P102L, develop spontaneous ataxia at about 150 days. Transmission of GSS(P102L)
has been reported in nonhuman primates and mice, although
the rates of transmission (*40%) is much less than sporadic
and familial CJD (*85%).231
P105L
A cytosine (C) to thymine (T) transition at the second nucleotide of codon 105 (CCA to CTA) results in the substitution of
leucine for proline in the protein, and in all cases, is coupled
to 129V. This mutation, recognized primarily in Japan, is
classically associated with the development of spastic paraparesis, manifest as weakness with hyperreflexia and extensor
plantar responses, prior to, or along with, the development of
dementia, progressing eventually to tetraparesis with a pseudobulbar affect over a 7- to 12-year course.48,232,233 Although
cerebellar symptoms were uncommon and neither periodic discharges on the EEG nor myoclonus were present in most
patients reported with this mutation, subsequent reports suggested some members of this pedigree did develop more typical signs of GSS. Age at onset ranged from 38 to 48 years.
Pathologic findings were confined to the telencephalon where
diffuse-type PrP immunoreactive plaques were present
throughout the gray matter of the cortex, particularly within
frontal motor cortex and temporal lobes and deep gray nuclei
of the basal ganglia and thalamus. Severe neuronal loss and
gliosis were also present within those same areas, although
spongiform change was absent.
In addition to the leucine mutation at codon 105, a threonine substitution (ie, P105T) was identified in a Canadian
family49 and a serine substitution (P105S) in an American
family.50 P105T appears to have a generally typical GSS
clinical phenotype, with the exception of an unusual onset
of psychiatric symptoms found in a 13-year-old family
member, whereas the P105S mutation was detected in a
31-year-old woman who developed a clinical presentation
characteristic of frontotemporal lobar dementia without
ataxia or spastic paraplegia, and a combination of intense
focal vacuolation of the basal ganglia and dramatic plaque
pathology in the cerebellum and hippocampus. These findings provide support to the concept that the substitution
itself, rather than the loss of the normal amino acid, is the
determinant of phenotype, presumably by inducing different
PrPSc conformations.
A117V
This mutation was initially identified in a French family with
8 affected members spanning 4 generations52 and later in 2
American families of German descent.53,54 In all cases, the
dominant mutation is carried on the 129V allele. In the
French family, the presentation was consistent with a primary
dementing syndrome with variable degrees of pyramidal,
extrapyramidal, and cerebellar features. The affected members of one American family (designated GCSA) presented
with presenile dementia followed by pyramidal and extrapyramidal features without obvious cerebellar involvement.53,234
The disease was originally considered to be familial Alzheimer disease, based on this clinical presentation and the neuropathologic finding of multiple amyloid plaques scattered
throughout the cerebral but not the cerebellar cortex.234 The
plaques, however, did not immunoreact with anti-Ab antibody but did with anti-PrP antibody,235 confirming it to be
a prion disease. In contrast to this telencephalic presentation, the second US family with the A117V mutation displayed the classic GSS phenotype of ataxia with pyramidal
and extrapyramidal features and late-developing dementia.54
The proband of that family had widespread deposition of
PrP-plaques throughout both the cerebral and cerebellar cortex. Follow-up reports of some members from subsequent
generations of the French family also suggested a cerebellar
onset with progressive gait difficulties, dysarthria, and dysphagia, leading eventually to mental deterioration and
dementia,236 and plaque deposition in some was widespread.237 These findings suggest a clear correlation of plaque pathology with clinical phenotype and variability of
clinical phenotype due to the same point mutation. Common
features include the absence of periodic discharges on EEG,
an early onset (third to fifth decade), moderately prolonged
duration (average 3 years), and the presence of GSS plaque
pathology. In some cases, protease-resistant PrP is difficult
to detect, whereas in most, a low level of a 14 kDa fragment
is observed. Several attempts to transmit this disease to
rodents have been unsuccessful.236 A Tg mouse that
expresses the mouse-equivalent PrP-A116V mutation allelic
with 129V and develops severe progressive ataxia beginning
at *120 days until their death *30 days later, has been generated.238 The brains demonstrate PrP amyloid deposits in the
cerebellum and hippocampus and a *13 to 14 kDa proteaseresistant PrP fragment. In humans with GSS(A117V), PrP
displayed a significantly higher level of a transmembrane
form of PrP, suggesting that this mutation affects the translocation of PrP.239 Whether this can fully explain the pathogenic properties of the molecule and the reduced
transmissibility seen with this particular prion disease variant
remains to be determined.
F198S
This mutation, which is coupled to Val at codon 129, was
identified in a very large kindred in Indiana.240 Of the
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1200-member family spanning 6 generations, 67 individuals

were affected at the time of the report in 1989. Linkage of the
mutation was demonstrated with a LOD score of 6.37.240 The
presentation is generally one of progressive gait ataxia, dysarthria, and impaired short-term memory, often associated with
extrapyramidal symptoms of bradykinesia and rigidity, and less
often with pyramidal tract signs. The dementia is slowly
progressive, occurring at a mean age of 52 (range 30s to 60s)
and lasting on average 6 years (range 2 to 12).241 Disease may
present 10 years earlier in patients homozygous for Val at codon
129.240 Ocular signs, including supranuclear gaze palsy, jerky
pursuits, and gaze-evoked nystagmus in all directions, were
noted in the early phase of the disease. Myoclonus is present
in some but not all patients. The EEG may show slowing, but
it does not exhibit periodic discharges, consistent with other GSS
diseases. Histopathology includes diffusely distributed PrP plaques throughout the cerebrum and cerebellum with minimal
spongiform change.242 In addition, tau-positive neurofibrillary
tangles are found primarily in frontal, parahippocampal cortex,
cingulate gyrus, and insular cortex.243,244
Q217R
An A to G transition at the second nucleotide of codon 217
(CAG to CGG) results in the missense coding of arginine
instead of glutamine. A small number of individuals in a single
American family of Swedish origin have been described, each
of whom developed a progressive dementia at least 4 years
before they developed progressive gait ataxia, dysphagia, and
parkinsonism several months prior to their deaths at the ages
of 67 and 71 years.78 Disease duration was 5 and 6 years. EEG
results were not reported. The primary neuropathologic feature
was diffusely deposited PrP plaques throughout the neocortex.
The plaques were shown to be derived from the mutant PrP and
composed of amino and carboxy-terminal clipped fragments
extending from residues 81 or 82 to 145 or 146.245 In addition,
neurofibrillary tangles were diffusely present throughout the
neocortex and several subcortical grey structures that denote
the similarity of pathologic phenotype with that of GSS(F198S)
and GSS(Y145Stop). Experimental transmission of this prion
disease has not been demonstrated.
Truncation Mutations of GSS

A stop sequence (TAG) at codon 145 was initially described on
the 129M allele in a Japanese patient with a clinical diagnosis
of Alzheimer disease, with plaque deposits of truncated
PrP.58,104 The patient developed a 20-year course of disturbance in memory, eventually progressing to severe dementia
and death at 59 years of age. Periodic discharges were not evident on EEG. Neuronal loss and gliosis was severe, but spongiform change was absent. PrP deposits were found in and around
small- and medium-sized blood vessels and neurofibrillary tangles (NFTs) were evident throughout the cerebral cortex,104
labeling this as a vascular variant of GSS and a cerebral
amyloid angiopathy (PrP-CAA) 159.
Since that case, 4 additional truncation mutations have been

described; Q160X,60 Y163X,61 Y226X, and Q227X.80 The
Q160X case does show GSS type pathology, but it has not yet
been fully described (personal communication). The Y163X
case also displayed PrP-CAA, whereas the Y226X and
Q227X mutations, although differing by only 1 residue, were
found in 2 Dutch patients with 2 distinct disease subtypes. The
Y226X mutation was found in a 55-year-old woman who
developed cognitive problems, aphasia, and hallucinations. In
contrast to typical GSS, the CSF 14-3-3 was positive and the
EEG displayed PSWCs. The disease ran a course of 27 months
and the histopathology revealed PrP-CAA in the absence of
neurofibrillary tangles. The Western blot was not described.
The Q227X mutation was found in a 44-year-old woman with
a 72-month slowly progressive course of hypokinetic rigid gait
with cognitive and behavioral changes, and parkinsonian features, suggesting frontotemporal dementia (FTD). The histopathology displayed multicentric amyloid plaques throughout
the cerebrum and severe neurofibrillary lesions without PrPCAA, and Western blot revealed a 7 kDa unglycosylated PrPSc
fragment truncated at both the N- and C-terminal ends.
The consistent demonstration that PrP amyloid deposits are
linked to truncation mutations validates the finding in Tg
mice that express PrP lacking the GPI anchor, and develop
extensive PrP amyloid plaque deposits.246 Thus, the absence
of the GPI anchor results in PrP secretion to the extracellular
space, leading to amyloid formation. Why specific point
mutations result in this presumed secretion of PrP is currently
undetermined.
Diagnostic Considerations
A rapidly progressive dementia associated with ataxia, myoclonus, and periodic discharges on the EEG, in an afebrile 65year-old individual provides a straightforward diagnosis of
CJD. However, this constellation of features may be observed
in less than 60% of cases. It should be clear from the above
descriptions of the presentations of prion disease that the range
of clinical phenotypes now is quite broad. As such, the diagnosis of prion disease should be considered as part of the differential in all cases presenting with dementia, an atypical
movement disorder, or late onset psychiatric disease, especially
if the rate of disease progression is rapid or if it is accompanied
or preceded by other neurological signs or symptoms and/or a
family history of a similar disease. Other diseases with overlapping symptoms include Alzheimer disease, cortical basal
degeneration (CBD), dementia with Lewy bodies (DLB), Huntington disease (HD), Spinocerebellar ataxias (SCAs), and the
frontotemporal lobar dementias (FTLD), including the behavioral variant of FTD, semantic dementia, and progressive nonfluent aphasia, among other conditions. Central nervous system
(CNS) vasculitis may be entertained in some rapidly progressive forms of prion disease, although a normal MRI usually
argues against it. Angiogram may be considered in some cases.
The inherited metabolic disorder of ceroid lipofuscinosis (Kufs
disease in the adult) can also present with dementia and
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myoclonus. Metabolic causes of a prion-like presentation

include bismuth or lithium toxicity. Hashimotos encephalopathy is an important treatable condition to rule out. It can produce intermittent episodes of confusion, cerebellar ataxia,
and may even demonstrate periodic discharges. Antithyroperoxidase antibody (anti-TPO) and antithyroglobulin will be considerably elevated. Corticosteroid therapy may completely
reverse the symptoms.
Key diagnostic studies include MRI, EEG, cerebrospinal
fluid (CSF) analysis, and sometimes PET scan. EEG findings
of periodic sharp wave complexes (PSWCs) consisting of
triphasic or sharp wave bursts every 0.5 to 2.0 seconds support
the diagnosis of prion disease. Although PSWCs are observed
in a small percentage of individuals with genetic prion
disease, their presence seems to be highly dependent on the
associated causal mutation and resultant clinical phenotype;
those mutations that produce a CJD-like clinical phenotype
and spongiform degeneration pathology seem more likely to
have a positive EEG.
Hyperintensity on diffusion weighted magnetic resonance
imaging (DWI), especially within the basal ganglia or involving the cortical ribbon, appears to be highly predictive of CJD,
although the studies with familial CJD are limited, as are those
with GSS. A PET scan is typically uninformative for CJD or
GSS, but it may show focal hypometabolism of the thalamus
in sporadic and familial forms of FI. In addition, a clear pattern
of Alzheimer disease (hypometabolism of temporoparietal
lobes) or frontal lobar dementia (focal frontal and temporal
lobe hypometabolism) may be useful to rule out prion disease,
but this may not be 100% certain.
Cerebrospinal fluid often shows a mild, *10%, elevation of
total protein without a cytological response. Significant elevations in 14-3-3, total tau, or neuron-specific enolase have been
shown to be highly predictive of prion disease, more specifically sCJD.247-250 An elevation in the level of these proteins
represents rapid neuronal death with leakage of the cell contents into the spinal fluid. Thus, these appear to be more predictive of faster-progressing, nonfamilial forms of prion disease.
False negatives are known in some reports over 40% of the
time.250 False positives have been reported with herpes encephalitis, hypoxic brain damage, acute stroke, and other conditions that induce neuronal damage. Genetic analysis of the
PRNP gene may be helpful whether a family history of disease
is present, as the late and often variable age at onset of the prion
diseases may obscure a positive family history.
A definitive diagnosis of prion disease can only be made by
pathologic confirmation following biopsy (no longer a common practice because of the preparation and cleanup required
for the operating room) or autopsy. Transmission of disease
to a proper host animal is considered the ultimate diagnostic
test for the presence of prions; however, these studies are
expensive and time consuming, in some cases requiring more
than 2 years to complete. Newer technologies, using in vitro
methods such as the protein misfolding cyclic amplification
(PMCA) process may prove more useful. In this process, a
small amount of prion-affected sample is mixed with a large
excess of normal brain homogenate and subjected to a series

of incubations and sonications to break up PrP fibrils and create new PrPSc seeds resulting in the amplification of PrPSc
several fold.251 This technique has been shown to detect
prions in blood and, as such, might eventually be used in diagnostic testing of peripherally infected individuals, such as in
vCJD.252
Therapy
There are currently no therapeutic agents designed to slow the
progression or reverse the effects of prion disease. Thus, therapy
is aimed at controlling symptoms. If present, seizures may be
treated with general antiepileptic agents such as phenytoin or carbamazepine. Myoclonus often responds to low doses of clonazepam. Issues related to dysphagia are often difficult to resolve and
the decision to place a feeding tube should be weighed against the
confidence of the diagnosis of these terminal diseases. Severe
psychiatric symptoms that may include hallucinations and/or
delusions are best managed by small doses of atypical antipsychotics, such as quetiapine. Evaluation by a social worker is mandatory to assist the family in management planning.
The most extensive clinical trials for prion therapy focused
on quinacrine, an antimalarial that showed promise in curing
infectious PrPSc from cultured neuroblastoma cells chronically
infected with scrapie.253 The results of studies from the United
States and the United Kingdom did not support a clinical benefit of quinacrine for CJD. Other agents, particularly polysulfated compounds such as pentosan polysulfate, suramin, and
heparan sulfate,254,255 prolong the incubation period of experimental scrapie in animals, although they must be administered
prior to, or simultaneous with, the inoculation of the animal
with prions, making these impractical for the symptomatic
patient who presented for medical attention.256 Pentosan polysulfate was administered intracerebrally to a single patient with
vCJD, with unclear clinical benefit although his course
appeared to be prolonged.257 The mechanism by which these
drugs exert their effects is unclear, but some consider that the
highly charged molecules sequester prions away from other
interacting proteins. In addition to these agents, anti-PrP antibody therapy, designed to block the interaction of PrPSc with
PrPC,258-260 is under investigation, as is the attractive approach
of siRNA therapy, which will act to knock down PrPC expression, leading to less substrate for conversion to PrPSc.261
Although such treatments are in dire need, better methods of
detection and early diagnosis will need to be developed, to
afford the best chance for successfully inhibiting disease progression. Genetic detection of familial forms paired with developing strategies of brain imaging and PMCA of body fluids
may assist in that goal.
Declaration of Conflicting Interests
The author(s) declared a potential conflict of interest (e.g. a financial
relationship with the commercial organizations or products discussed
in this article) as follows: Dr. Mastrianni is a consultant to the FDA
TSE Advisory Committee.
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291
Funding
The author(s) disclosed receipt of the following financial support for
the research and/or authorship of this article: Dr. Mastrianni receives
funding from the NIH for prion disease research.
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Journal of Geriatric

Psychiatry and Neurology

The Prion Diseases

>> Version of Record - Nov 2, 2010

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Journal of Geriatric Psychiatry

The Prion Diseases

generating new PrPSc. Thus, PrP knockout mice (Prnp / ) do not

Center for Comprehensive Care and Research on Memory Disorders,

Journal of Geriatric Psychiatry and Neurology 23(4)

The normal function of PrPC is not known, although several

homolog of PrP known as Doppel, as a result of gene

Molecular Genetics of Prion Disease

Brown and Mastrianni

for familial disease. There is no obvious gender bias.43 The

A single base pair (bp) change within codon 102 of the

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Journal of Geriatric Psychiatry and Neurology 23(4)

Table 1. Clinical Phenotypes of Prion Disease

Age at Onset (Range)

Ataxia, then dementia

Dementia, ataxia, myoclonus

Typically <55 years (20s to 80s)a

Ataxia, then dementia

Typically <55 years (20s to 60s)a

iatrogenic, and vCJD, in addition to a phenotypic modifier of

These findings in human disease have their origin in the study

Major Subtypes of Prion Disease

Brown and Mastrianni

Table 2. Single Base Pair Changes of PRNP

Amino Acid Changea

Pro (P) ! Leu (L)

196, 200, 203, 208, 210, 211, 232, and insertions of 1, 2, 4, 5, 6,

neocortex, subiculum of the hippocampus, caudate, putamen,

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Journal of Geriatric Psychiatry and Neurology 23(4)

Table 3. Coding Alterations in Octarepeat Segmenta

Abbreviations: R, an octarepeat unit (Pro-(His/Gln)-Gly-Gly-Gly-(-/Gly)-Trp-Gly-Gln); N/A, pathology not available.

through exposure to cadaver-derived human growth hormone

patients with iCJD more often display cerebellar ataxia rather

Brown and Mastrianni

This disease has also been linked to dura mater obtained

individuals (ages 17 to 42 years), and has a slightly protracted

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Journal of Geriatric Psychiatry and Neurology 23(4)

blood.154-156 These findings have raised concerns about the

blood flow to the thalamus early in the disease.163 Age at

Polymorphisms and Mutations of PRNP

Brown and Mastrianni

with the 129MM genotype, while slower progression and an

the area where kuru was endemic. Sampling the population

Selected PRNP Mutations That Cause CJD

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Journal of Geriatric Psychiatry and Neurology 23(4)

Spongiform change was prominent in frontotemporal regions.

disease development for fCJD(E200K) is age-dependent and

Brown and Mastrianni

history.65,82,212,213 In addition, this sequence alteration was

Additional OPRI Mutations

often including atypical features such as aphasia, apraxia, and

Selected PRNP Mutations That Cause GSS:

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Journal of Geriatric Psychiatry and Neurology 23(4)

Brown and Mastrianni